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Largest-ever analysis of its kind finds Cushing’s syndrome triples risk of death

Heart disease and infections rank as top causes of death among those with rare disorder

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Introduction

Case report, statement of ethics, disclosure statement, a case report of cushing’s disease presenting as hair loss.

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Emily G. Lefkowitz , Jack P. Cossman , John B. Fournier; A Case Report of Cushing’s Disease Presenting as Hair Loss. Case Rep Dermatol 28 April 2017; 9 (1): 45–50. https://doi.org/10.1159/000457898

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Cushing’s syndrome is a rare endocrine disorder that comprises a large group of signs and symptoms resulting from chronic exposure to excess corticosteroids. Most cases of Cushing’s syndrome are due to increased adrenocorticotropic hormone production from a pituitary adenoma, which is referred to as Cushing’s disease. Most of the signs and symptoms are nonspecific and common in the general population, making a diagnosis often challenging. However, several dermatological manifestations, such as fragile skin, easy bruising, and reddish purple striae, are more discriminatory. Because uncontrolled Cushing’s syndrome of any etiology is associated with substantial morbidity, including increased cardiovascular disease and mortality, it is important to make an early diagnosis. Unfortunately, median delays of 2 years to diagnosis have been reported. We report a case of a woman who had multiple dermatological findings, including facial plethora, easy bruising, violaceous striae, hirsutism, and acne, the latter 2 signs reflecting androgen excess. Of interest, our patient presented with a chief complaint of hair loss, a common complaint in the general population that occurs with a greater frequency in patients with Cushing’s disease and is attributed to androgenetic alopecia, but it is rarely the presenting symptom.

Cushing’s syndrome is characterized by signs and symptoms that result from prolonged exposure to excessive plasma corticosteroids. While the most common cause is iatrogenic from medically prescribed corticosteroids, endogenous Cushing’s syndrome is a relatively rare disease. A recent US-based study estimated the incidence of endogenous Cushing’s syndrome at 8 per million people [ 1 ]. Pituitary-secreting tumors, first described by Harvey Cushing in 1912 and now referred to as Cushing’s disease, account for approximately 70% of cases, while ectopic adrenocorticotropic hormone (ACTH)-secreting tumors and adrenal tumors account for 10 and 20% of cases, respectively [ 2 ].

Although the diagnosis of Cushing’s syndrome can be straightforward, when several clinical findings are present, it is often challenging to make the diagnosis. None of the symptoms or signs are pathognomonic of the syndrome, and many symptoms (such as obesity, hypertension, glucose intolerance, weight gain, fatigue, weakness, menstrual abnormalities, and depression) are found in the general population. In contrast, the dermatological manifestations of Cushing’s syndrome that include skin atrophy, alopecia, easy bruisability, and striae are less commonly observed in other individuals [ 3 ]. We report an unusual case of a woman who presented with a chief complaint of hair loss and who was found to have Cushing’s disease.

A 33-year-old female with a history of gastritis, depression, and obesity presented to the dermatology clinic with a chief complaint of hair loss. She reported that the hair on her head began to thin rapidly 6 months prior to presentation, although she had been experiencing progressive thinning for about 1 year. There was minimal improvement with daily minoxidil 5% foam after 3 months.

The patient had a pituitary microadenoma that was known to exist for at least a decade, but a recent magnetic resonance imaging had shown the microadenoma to be stable in size. Serum prolactin, follicle-stimulating hormone, and luteinizing hormone levels were normal.

Physical examination showed a middle-aged female in no acute distress with facial plethora and prominent truncal, facial, and nuchal adiposity. Examination of the skin revealed diffuse nonscarring alopecia on the frontal scalp and vertex of the scalp (Fig.  1 ), and miniaturized hairs were seen on dermoscopy. To a lesser extent, the density of temporal and occipital hair was also decreased. There were erythematous inflammatory papules and pustules on her face and mid to lower back, violaceous striae on the abdomen and axillae, and ecchymoses on the abdomen and extremities. Facial hirsutism and patches of coarse hypertrichosis on her back were also noted (Fig.  2 ).

Diffuse hair loss on the frontal scalp and vertex of the scalp with decreased thickness of temporal and occipital hair.

Coarse patches of hypertrichosis and erythematous inflammatory papules and pustules on the mid to lower back and violaceous striae on the flanks bilaterally.

Serum ferritin, iron, thyroid-stimulating hormone, antinuclear antibody, albumin, total protein, and vitamin B 12 were all negative or within normal limits. Punch biopsy from the scalp showed a normal number of follicles without fibrosis or follicular dropout but a striking increase in the ratio of catagen and telogen hairs to anagen hairs and a sparse peribulbar lymphocytic infiltrate.

Subsequent tests were ordered: 24-h urine cortisol: 384 µg (range 3.5–45 µg/24 h), dehydroepiandrosterone sulfate: 380 µg/dL (range 45–270 µg/dL), and ACTH: 76 pg/mL (range 9–52 pg/mL). The results were consistent with a diagnosis of Cushing’s disease. The patient was referred to an endocrinologist and subsequently underwent a transsphenoidal resection of the pituitary microadenoma.

Dermatologists may encounter skin findings that reflect an underlying endocrine disorder. While many of the signs and symptoms of Cushing’s syndrome are nonspecific, those features that best distinguish Cushing’s syndrome are proximal muscle weakness, facial plethora, easy bruising, and purple (violaceous) striae [ 3 ]; the latter 3 dermatological findings were seen in our patient on physical examination.

The often prominent skin findings reflect the hypercatabolic effects of hypercortisolism – inhibition of epidermal cell division and collagen synthesis, resulting in thinning of the stratum corneum and loss of subcutaneous fat [ 4 ]. Skin atrophy may be prominent, and the loss of subcutaneous connective tissue results in easy bruising after minimal injury. The atrophy and disruption of collagenous subcutaneous fibers lead to the development of broad, purple striae because the increasingly thin skin does not hide the color of venous blood in the underlying dermis. Another skin finding is hyperpigmentation due to excess ACTH, which is most commonly seen in ectopic ACTH syndrome, less commonly in Cushing’s disease (i.e., pituitary-secreting ACTH tumor), and never in adrenal Cushing’s syndrome; the hyperpigmentation is a result of ACTH binding to melanocyte-stimulating hormone receptors.

In contrast to the aforementioned skin changes, female baldness or female hair loss has been variably reported and is rarely the chief complaint of a patient presenting with Cushing’s syndrome [ 2 ]. In a review of Cushing’s syndrome that included 7 case series of 33–100 patients, 4 case series did not report female baldness, whereas it was reported in 3 of the case series with an incidence ranging from 13 to 51% [ 5 ]. More recently, the European Registry on Cushing’s Syndrome reported “hair loss” in 110 of 351 (31%) patients with Cushing’s syndrome and in 76 of 224 (34%) patients in the subset with Cushing’s disease [ 6 ]. In a recent matched case-control study using a commercial health-care insurance claims database that included 1,875 patients with Cushing’s syndrome, female balding was found to be 5 times more common than in the matched controls; the combination of weakness/fatigue and female baldness was 10 times more common [ 7 ].

Female balding in Cushing’s syndrome results from androgen hypersecretion that occurs in ACTH-dependent forms (i.e., pituitary or ectopic ACTH tumors) or with adrenocortical cancers but never with adrenal adenomas. Androgenetic alopecia, often referred to as female-pattern hair loss (FPHL), is a nonscarring form of hair loss in which the growth (anagen) phase of hair follicles is shortened resulting in follicular miniaturization [ 8 ]. The frontal scalp and vertex of the scalp are the primary sites of involvement, and the occipital scalp is usually relatively spared. The exact pattern of hair loss varies among women but typically presents with a diffuse central thinning pattern or with prominent frontal scalp thinning referred to as a “Christmas tree” pattern.

FPHL is a common condition with a reported prevalence of 19% in 1 series of 1,006 Caucasian women in the United States [ 9 ]. While most women show no signs of androgen excess, a careful workup is warranted. In a series of 109 women referred for the evaluation of moderate to severe FPHL, laboratory evidence for hyperandrogenism was present in 39%, with the most common diagnosis being polycystic ovarian syndrome [ 10 ]. Our patient was noted to have an elevated dehydroepiandrosterone sulfate level, a metabolic intermediate in the biosynthesis of androgens. Women who present with FPHL should be evaluated for associated signs or symptoms of androgen excess, such as hirsutism, moderate to severe acne, and irregular menses or amenorrhea. As expected, our patient who presented with alopecia had associated findings of hirsutism and acne. It should be noted, however, that in Cushing’s syndrome the amenorrhea is likely due to cortisol-mediated inhibition of gonadotrophin release rather than to hyperandrogenism.

In a review of Cushing’s syndrome, Findling and Raff [ 11 ] noted that the diagnosis of Cushing’s syndrome “is the most challenging problem in clinical endocrinology.” Patients with Cushing’s syndrome and persistent hypercortisolism have a 4–5 times excess mortality compared to the general population, highlighting the urgency of diagnosis [ 12 ]. In the European Registry on Cushing’s Syndrome, the median delay to diagnosis was a remarkable 2 years [ 6 ]. They found that general practitioners were consulted 76% of the time, endocrinologists 25%, gynecologists 24%, psychiatrists/psychologists 12%, rheumatologists 11%, and dermatologists 8% of the time.

As noted above, the majority of clinical signs and symptoms of Cushing’s syndrome are relatively nonspecific, whereas dermatological manifestations, such as fragile skin, easy bruising, and purple striae, are more discriminatory [ 3 ]. Broder et al. [ 7 ] noted hirsutism to be 61 times more common in Cushing’s syndrome than in the general population. In contrast, FPHL is commonly seen in the general population, although with a 5 times greater frequency in patients with Cushing’s syndrome.

Our patient presented with a history of a pituitary adenoma and findings of central obesity, easy bruising, purple striae, hypertrichosis, and female balding, and a diagnosis was rapidly made. Of interest, the case was unusual in that it was the hair loss that caused the patient to seek medical attention.

The authors have no ethical conflicts to disclose. The patient has given her informed consent, including the use of the photographs.

The authors have no conflicts of interest to disclose. No funding support was obtained for this work.

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Diagnostic dilemma in Cushing’s syndrome: discrepancy between patient-reported and physician-assessed manifestations

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• Open access
• Published: 25 June 2024

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• Yuma Motomura 1   na1 ,
• Shin Urai 1   na1 ,
• Hironori Bando 2 ,
• Masaaki Yamamoto 1 ,
• Masaki Suzuki 1 ,
• Naoki Yamamoto 1 ,
• Genzo Iguchi 1 , 3 , 4 ,
• Wataru Ogawa 1 &
• Hidenori Fukuoka   ORCID: orcid.org/0000-0001-9255-653X 2  

Early diagnosis and immediate treatment of Cushing’s syndrome (CS) are critical for a better prognosis but remain a challenge. However, few comprehensive reports have focused on this issue or investigated whether patient-reported manifestations are consistent with physician-assessed symptoms of CS. This study aimed to clarify the differences in patient-reported and physician-assessed manifestations of signs and symptoms of CS that prevent early diagnosis.

This single-center retrospective study included 52 patients with CS (16 with Cushing’s disease and 36 with adrenal CS). Upon clinical diagnosis, medical records were used to independently review the patient-reported and physician-assessed manifestations of typical (such as purple striae and proximal myopathy) and nonspecific features (such as hirsutism and hypertension). The correlations and differences between the patient-reported and physician-assessed manifestations were then analyzed.

We observed a positive correlation between the total number of manifestations of nonspecific features reported by patients and those assessed by physicians, but not for typical features. Moreover, manifestations reported by the patients were less frequent than those assessed by physicians for typical features, leading to discrepancies between the two groups. In contrast, there were no differences in most nonspecific features between the patient-reported and physician-assessed manifestations. Notably, the concordance between patient-reported and physician-assessed manifestations of typical features was not associated with urinary free cortisol levels.

Regardless of disease severity, patients often do not complain of the typical features of CS that are crucial for formulating a diagnosis.

Avoid common mistakes on your manuscript.

Introduction

Endogenous Cushing’s syndrome (CS) is caused by chronic and excessive glucocorticoid exposure. This occurs primarily due to adrenocorticotropic hormone (ACTH)-producing pituitary tumors (Cushing’s disease; CD) or cortisol-producing adrenal tumors (adrenal Cushing’s syndrome; ACS) [ 1 ]—and has a high mortality rate owing to cardiovascular disease, severe infection, and suicide, even when diagnosed and treated appropriately [ 1 , 2 ]. Moreover, the prognosis is poor if the disease is not adequately treated or remains undiagnosed [ 2 ]. Therefore, early diagnosis and immediate intervention are important, as remission of CS due to surgical and pharmacological treatment can reduce the risk of mortality [ 3 , 4 ].

CS is a rare disease with a prevalence of 57 per million individuals and an annual incidence of 3.2 per million, and its epidemiology is consistent across various regions worldwide [ 5 , 6 ]. Most symptoms and signs of CS are common in general metabolic disorders, including obesity, hypertension, osteoporosis, and diabetes mellitus [ 7 ]. However, CS should be suspected if these symptoms appear as unusual features for their age [ 1 , 8 ]. Consequently, the identification of CS is challenging and labor-intensive [ 1 , 9 , 10 ]. In fact, recent research revealed that a definitive diagnosis of CD (the most common form of CS), took an average of 3.8 ± 4.8 years from the onset of symptoms, and patients typically consulted 4.6 ± 3.8 medical professionals before this disease was identified [ 11 ]. Typical features of CS include symptoms of moon face, central obesity, or buffalo hump [ 12 ], which are similar to other symptoms such as primary obesity and therefore can lead to misdiagnosis. Furthermore, although purple striae or thin skin with an increased propensity for bruising are other typical features of CS [ 12 ], these attributes are not commonly acknowledged by the general population [ 1 , 9 ].

Attempts have been made to diagnose CS early, including the development of scoring systems to estimate the pre-test probability of CS and facial image analysis software to diagnose the specific facial features of CS [ 13 , 14 , 15 ]; however, these have not yet been used widespread or fully and the early diagnosis of CS remains dependent on the experience-based medical skills of the clinical staffs [ 16 ].

Additionally, although it is difficult for patients to recognize complex and nonspecific symptoms [ 17 , 18 ], the significance of patients recognizing their illness has recently been reported for various diseases such as heart failure and malignant carcinoma [ 19 , 20 , 21 ]. It is widely acknowledged that patients’ self-recognition can result in early detection of the disease, reduce its severity and recurrence, and enhance their quality of life [ 19 ]. In patients with endocrine diseases, there is increasing focus on issues surrounding self-recognition [ 22 , 23 , 24 ]. For example, a previous study focusing on acromegaly reported a discrepancy between patient-reported and physician-reported manifestations and indicated that resolving this discrepancy could shorten the time to diagnosis [ 25 ].

Identifying CS may be challenging for primary care physicians who are yet to specialize. Therefore, endocrinologists with extensive experience in CS have often noticed that patients and these physicians struggle to identify the symptoms of CS; however, few comprehensive reports have focused on this issue or investigated whether patient-reported manifestations are consistent with physician-assessed symptoms of CS.

Therefore, this study aimed to investigate the unreported manifestations of CS among individuals referred to non-specialist healthcare providers, including primary care physicians, and to recognize potential challenges with the current diagnosis of CS with the goal of facilitating early detection.

Materials and methods

Patients, study design, and data collection.

This single-center retrospective study was conducted to identify the discrepancies between patient-reported and physician-assessed symptoms and investigate the factors causing these differences.

From September 2004 to December 2022, 199 patients were referred to our department at a tertiary medical institution upon suspicion, evaluation, or follow-up for hypercortisolism. Of these patients, 92 were newly diagnosed with CS (36 with CD, 51 with ACS, and 5 with ectopic ACTH syndrome) based on the diagnostic guidelines [ 3 , 8 , 12 ], with a diagnosis confirmed by pathological evaluation after surgical resection [ 26 ]. However, 35 patients were excluded due to a lack of detailed clinical data on the manifestations at diagnosis. Similarly, we excluded individuals diagnosed with ectopic ACTH syndrome because of the lack of comprehensive information on symptoms reported by the patients and primary care physicians due to the rapid progression and severity of this disease. Therefore, 52 patients (16 with CD and 36 with ACS) were enrolled in this study.

Upon clinical diagnosis, the manifestations included in the comprehensive standardized interview at the time of diagnosis and those assessed by the physician through collaborative assessment with multiple board-certified endocrinologists as routine practice were independently reviewed from the medical records. We categorized these manifestations reviewed from the medical records into the following two categories based on the diagnostic guidelines including those of the Japan Endocrine Society: typical features, including moon face, central obesity or buffalo hump, purple striae of ≥1 cm, thin skin and easy bruising, and proximal myopathy; and nonspecific features (shown as atypical in Japan Endocrine Society’s guideline), including hypertension, menstrual abnormalities, acne, hirsutism, peripheral edema, glucose metabolism impairment, osteoporosis, pigmentation (which is not expected in patients with ACS), and mental abnormalities [ 1 , 8 , 12 ]. Central obesity or buffalo hump can also be observed in pseudo CS. However, in this study, features were classified as the same typical feature according to clinical guidelines [ 12 , 27 ]. We also reviewed the biochemical findings, comorbidities, duration from the initial recognition of CS-related symptoms to diagnosis, and number of medical institutions visited before diagnosis.

The present retrospective study was performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Kobe University Hospital (Approval No. 1351). The patients had the option of an opt-out process, and all procedures were part of routine medical care.

Definition of patient-reported and physician-assessed manifestations

In the context of routine clinical care, physicians asked the patients about the presence or absence of manifestations and comorbidities (e.g., hypertension, menstrual abnormalities, glucose metabolism impairment, osteoporosis, and mental abnormalities), which were documented in the medical records. These reports in the medical records were defined as patient-reported manifestations in this study. In contrast, the manifestations and comorbidities of CS were assessed within several weeks after the patient was referred to our department for suspected CS. Additional diagnostic information on comorbidities is provided in the subsequent section. Physician-assessed manifestations were subsequently defined based on these findings.

Comorbidities of Cushing’s syndrome

All comorbidities were diagnosed according to the appropriate guidelines [ 28 , 29 , 30 ]. For example, hypertension was diagnosed if patients were taking oral antihypertensive medication or had more than grade 1 hypertension (≥140/90 mmHg) in a treatment-naïve state [ 28 ]. Moreover, glucose metabolism impairment—including diabetes mellitus, impaired glucose tolerance, and impaired fasting glucose—was diagnosed based on the results of blood glucose levels during fasting and after a 75-g oral glucose tolerance test, as well as hemoglobin A1c (HbA1c) levels [ 29 ]. Patients taking medications for diabetes mellitus at the time of CS diagnosis were also categorized as having diabetes.

Other comorbidities included mental abnormalities, menstrual abnormalities, and the presence of osteoporosis. Mental abnormalities were defined as the use of anxiolytic medications, sleeping pills, or antidepressants prescribed by experienced psychologists, and menstrual abnormalities were defined as women with irregular menstrual cycles. Furthermore, the presence of osteoporosis was defined as bone mineral density (BMD) of <–2.5 standard deviations (SD) of the T-score of the lumbar vertebrae (L2–L4), femoral neck, or distal radius measured using dual-energy x-ray absorptiometry (DXA; Horizon A DXA System), and/or an experience of a fragility fracture [ 30 ]. As per the specifications of the measurement system employed, L1 was not included in the assessment. The Z-score was also employed as a diagnostic reference among young adults. Patients also diagnosed with osteoporosis who were receiving medications for this disease.

Hormone assay

In this study, blood samples were collected after an overnight fast. Subsequently, serum cortisol levels were measured using a chemiluminescent enzyme immunoassay [CLEIA] (TOSOH, Tokyo, Japan, RRID:AB_3099658) or enzyme immunoassay [EIA] (TOSOH, Tokyo, Japan, RRID:AB_3076600). Similarly, plasma ACTH levels were measured using a CLEIA (TOSOH, Tokyo, Japan, RRID:AB_3099657, or Siemens, Tokyo, Japan, RRID:AB_2909441) and EIA (TOSOH, Tokyo, Japan, RRID:AB_2783633). In both methods, the measurements showed good correlation and no conversion was required [ 31 , 32 ].

Urinary free cortisol (UFC) levels were also measured using radioimmunoassays (RIA; TFB, Tokyo, Japan, RRID:AB_2894408) or chemiluminescent immunoassays (CLIA; Siemens, Tokyo, Japan, RRID:AB_2893154). Using the following formula, the UFC levels measured by RIA were then corrected to the value measured by CLIA: Y = 0.832X − 4.23 (Y = UFC levels using CLIA, X = UFC levels using RIA) [ 33 ].

Statistical analysis

All statistical analyses were performed using SPSS ver. 28.0 software (IBM Corp., Armonk, NY, USA). All continuous variables were analyzed using the Shapiro–Wilk normality test to confirm a normal distribution, whereas Fisher’s exact test was used to analyze categorical data. Between the two groups, differences in normally or non-normally distributed data were compared using the unpaired Student’s t -test or the Mann–Whitney U test, respectively.

Cohen’s kappa coefficient was used to describe the concordance between the patient-reported and physician-assessed manifestations. As previously reported [ 19 , 20 , 34 ], the concordance based on the value of Cohen’s kappa coefficient was rated as follows: 0.00–0.20 for “Slight,” 0.21–0.40 for “Fair,” 0.41–0.60 for “Moderate,” 0.61–0.80 for “Substantial,” and 0.81–1.00 for “Almost Perfect.” For correlation analysis between two variables of non-normally distributed data, we used Spearman’s rank correlation coefficient. Multivariate logistic regression analyses were then performed to investigate variables associated with the discrepancies between patient-reported and physician-assessed manifestations.

The results are presented as mean ± SD for normally distributed data and median [interquartile range] for non-normally distributed data, and differences were considered statistically significant when the P value was <0.05.

Clinical characteristics of the patients

We included 52 patients diagnosed with CS in this study. Their clinical characteristics are presented in Table 1 . Notably, this group consisted of 5 males and 47 females, with a mean age of 49.4 ± 15.8 years, median body mass index (BMI) of 23.0 [21.3–28.0] kg/m 2 , and median UFC level of 272.1 [126.0–435.0] µg/day. Of the CS patients, 16 had CD and 36 had ACS, which is consistent with epidemiological data on CS observed in Asians (including Japanese individuals); however, this differed from epidemiological data from Western countries [ 35 , 36 ]. Regarding comorbidities, 43 patients were diagnosed with hypertension—of which 34 were prescribed antihypertensive medications—with a mean systolic blood pressure (BP) of 136.4 ± 21.5 mmHg and diastolic BP of 83.5 ± 15.0 mmHg. In addition, 44 patients were diagnosed with glucose metabolism impairment—of which, 20 were prescribed oral hypoglycemic agents and/or insulin—with a median fasting serum glucose level of 99.5 [87.3–116.5] mg/dL and median HbA1c level of 6.3% [5.7–7.4]. Moreover, 29 patients were diagnosed with osteoporosis, of which 4 were prescribed antiosteoporosis medication, with BMD T-score SDs of -1.54 ± 1.39, -1.76 ± 1.12, and -0.50 [-1.53–0.50] for the lumber spine, femoral neck, and distal radius, respectively. Notably, the UFC levels were higher in patients with CD than in those with ACS (412.6 [243.2–1,100.3] vs . 215.3 [114.0–387.8] µg/day); however, there were no significant differences attributed to sex, age, BMI, or the proportion of patients with respect to comorbidities, including hypertension and glucose metabolism impairment, between patients with CD and ACS.

The median duration from the patients’ initial recognition of CS-related manifestations to diagnosis was 44.0 [13.3–125.3] months, and it took more than 3 years to diagnose CS in 30 patients (58%). Furthermore, the median number of medical facilities visited by patients before diagnosis was 3.0 [2.0–5.0]; however, there were no significant differences in the duration or number of medical institutions between patients with CD and those with ACS.

Frequency and concordance between patient-reported and physician-assessed CS-related manifestations

Each manifestation reported by a patient or assessed by a physician is shown vertically for individual cases in Fig. 1 . Compared with nonspecific features, typical features appeared to not be reported by the patients but were only assessed by the physicians. In addition, compared to nonspecific features, there were fewer cases in which the manifestations reported by the patients were consistent with those assessed by physicians for typical features.

Consistency between patient-reported and physician-assessed manifestations for each individual case. The consistencies or discrepancies between patient-reported and physician-assessed manifestations are shown. Vertical lines represent manifestations in individual patients. CD Cushing’s disease, ACS adrenal Cushing’s syndrome

Consistent with the impact of these visually distinctive presentations shown in Fig. 1 , no correlation was observed in the number of typical features between patient-reported and physician-assessed manifestations ( r  = –0.20, P  = 0.16) (Fig. 2A ), whereas a positive correlation was found for nonspecific features ( r  = 0.62, P  < 0.01) (Fig. 2B ). Moreover, the total number of patient-reported manifestations of typical features was lower than that of physician-assessed manifestations (1.0 [0.0–2.0] vs . 3.5 [3.0–4.0], P  < 0.01), and four of the five typical features were reported less frequently by patients than by physicians, except for proximal myopathy (Table 2A ). According to Cohen’s kappa coefficient, the concordance between patient-reported and physician-assessed manifestations was marked as “Fair” to “Slight,” indicating a discrepancy for all typical features. Similarly, the total number of patient-reported manifestations of nonspecific features was also lower than that in physicians (2.5 [2.0–3.0] vs . 4.0 [3.0–5.0], P  < 0.01). However, except for glucose metabolism impairment or osteoporosis, there were no differences in the frequencies of nonspecific features between patient-reported and physician-assessed manifestations, and the concordance of the nonspecific features between the patient-reported and physician-assessed manifestations was “Almost perfect” for menstrual abnormality and “Substantial” for mental abnormality and hypertension, whereas that for glucose metabolism impairment and osteoporosis was “Fair.” This suggests that the discrepancy between patient-reported and physician-assessed manifestations was more significant for typical than for nonspecific features. However, no differences in these discrepancies were observed between patients with CD and those with ACS (Table 2B, C ).

Correlation between the total number of patient-reported and physician-assessed manifestations. Correlations between the total number of patient-reported and physician-assessed manifestations are shown for typical ( A ) and nonspecific features ( B ). CD is plotted by ×, and ACS is plotted by ○. The Spearman’s rank correlation coefficients and P value are presented. CI confidence interval, CD Cushing’s disease, ACS adrenal Cushing’s syndrome

We performed logistic regression analyses using UFC to investigate whether excess cortisol levels influenced the discrepancy between patient-reported and physician-assessed manifestations. Notably, we observed no association between UFC levels and discrepancies between patient-reported and physician-assessed manifestations in the univariate or multivariate logistic regression analyses adjusted for sex and age (Table 3A ). In addition, no association was observed after adjusting for other variables such as BMI and disease duration. Similarly, we found that the serum cortisol levels after the low-dose dexamethasone suppression test (LDDST) were not associated with discrepancies between patient-reported and physician-assessed manifestations (Table 3B ). Thus, these disparities were shown to be insignificant when directly related to the severity of CS.

In the present study, we highlight the challenges associated with the diagnosis of CS—a condition resulting from excessive glucocorticoid exposure—and elucidate the divergence between patient-reported and physician-assessed manifestations. Thus, this study may aid in the early detection of CS by identifying symptoms that patients are unable to recognize based on the disparities between patient-reported and physician-assessed manifestations of CS.

In this study, the number of patient-reported manifestations of both typical and nonspecific features was lower than that of physician-assessed manifestations, suggesting that CS symptoms may have been overlooked by relying solely on patient reports. Additionally, analysis of the concordance between patient-reported and physician-assessed manifestations revealed a tendency for these manifestations to be inconsistent for both typical and nonspecific features, with a tendency to be more significant for typical features. Furthermore, the UFC and serum cortisol levels after the LDDST, which represent the severity of CS, were not associated with the concordance of manifestations between patients and physicians, suggesting that even in cases of severe CS, patients may not recognize their symptoms. These findings imply that typical features, which are essential for diagnosing CS, may be difficult for patients to recognize and poorly identified or conveyed to patients by non-specialist physicians, who are typically the first to interact with individuals with CS. The importance of educating healthcare providers such as primary care physicians, family physicians and gynecologists for early diagnosis of CS should be highlighted.

According to a previous report on the diagnostic history of 176 patients with CD, 83% of the patients visited their family physician for manifestations such as weight gain and hypertension, while 46% visited a gynecologist for menstrual abnormalities before the diagnosis of CD [ 11 ]. Thus, the typical features of CS were not recognized. The examination may reveal nonspecific features. However, individuals who are non-specialists may not recognize these features as indications of CS. Therefore, patients are often unaware of the potential complications associated with CS. This is consistent with the results of our study, in which patient-reported and physician-assessed manifestations were more consistent for hypertension and menstrual abnormalities than for other manifestations such as typical features, glucose metabolism impairment, and osteoporosis. This makes diagnosis challenging as non-specialist physicians and, more prominently, patients may not recognize the full range of symptoms associated with CS, especially the typical features with high diagnostic value. In addition, older patients diagnosed with CS present with a lower BMI and waist circumference than younger patients [ 37 ], and they typically do not exhibit symptoms commonly associated with CS such as skin alterations, depression, hair loss, hirsutism, and reduced libido. These findings may further complicate the diagnosis of CS in elderly patients.

By evaluating only the patient-reported manifestations, it appears that manifestations such as peripheral edema and proximal myopathy were more common. Possibly, these symptoms were not considered features of CS by physicians, in comparison to the degree of symptoms experienced by the patients. However, this may not necessarily imply diminishing the significance of the patient’s signs and symptoms, as these manifestations can be considered as the unidentified complaints and may result in a postponement of the diagnosis of CS. Patients may be experiencing symptoms that physicians do not perceive, indicating the importance of interview and physical examination. Further investigation is needed to elucidate underlying factors.

Considering the rarity of CS, it is crucial to suspect and diagnose the condition based on clinical symptoms and perform the appropriate screening tests without over- or under-screening [ 7 ]. Although CS screening in patients with diabetes mellitus and hypertension has been reported to lead to a diagnosis in only 0–0.7% and 0.1–0.5% of these patients, respectively [ 38 , 39 , 40 , 41 ], it is ineffective in terms of false positives and cost [ 9 ]. Therefore, patients with typical features that are highly specific for CS, such as purple striae, easy bruising, and proximal myopathy [ 1 , 8 , 12 ], as well as those with obesity, diabetes mellitus, or hypertension in combination with these features, should be screened for CS [ 7 , 27 ]. However, our results suggest that these symptoms are unlikely to be self-recognized. Therefore, the appropriate screening measures must be implemented to establish an early and effective diagnosis of CS.

In these situations, it is crucial for physicians to utilize their knowledge and experience to suspect CS based on symptoms such as typical features [ 10 ]. It has been reported that years of clinical experience in endocrine practice can contribute to the estimation of the pre-test probability of CS [ 16 ]. In contrast, non-specialists are less likely to encounter patients with CS in their lifetime, which can make it difficult to properly suspect CS [ 9 ]. From this perspective, it is of utmost importance that family physicians and general internists are knowledgeable regarding the manifestations that require screening for CS, as early diagnosis of this uncommon and severe condition is crucial [ 11 ]. Therefore, it is important for physicians who routinely treat patients presenting with common symptoms such as obesity, diabetes mellitus, and hypertension to meticulously interview and observe for any indicators of CS, even if the patient does not recognize them. Failure to adopt an appropriate tone in these situations may cause the disease to become undetectable.

In rare disorders such as CS, in addition to enhancing public recognition of the disease, the appropriate sharing of information and provision of specialized care in clinical practice remain important issues [ 42 ]. Early identification of such rare diseases can be achieved by promoting an understanding of the disease and its symptoms among family, friends, and patients who may be the first to recognize the signs and symptoms in an individual. In fact, in a questionnaire survey of 340 patients with CS across 30 countries, the diagnosis of CS was made in 5.6% of cases by the patients themselves and in 0.9% by their family or friends [ 43 ]. In the present study, we found that it took more than 3 years to diagnose CS in 58% of the cases. If CS and its symptoms are popularized among the public, the typical features of CS could be more readily reported to physicians and the time to diagnosis might be shorter. Furthermore, a primary care physician who is well-educated and knowledgeable is crucial in ensuring that the concerns of such individuals are not overlooked.

This study has some limitations. First, this single-center retrospective study included a relatively small sample size with few male patients. Second, CD and ACS have different pathologies; therefore, the frequencies of several CS-related manifestations will differ depending on their subtypes [ 3 , 44 ]. However, in this study, there was no difference in the discrepancies between patient-reported and physician-assessed manifestations in patients with CD or ACS. Nonetheless, it is crucial that comprehensive research is conducted in larger patient populations with a focus on employing methods that accurately reflect the pathophysiology of CD and ACS. Third, patient reports may be inaccurate in terms of onset and duration because they depend on the patient’s memory. Fourth, the endocrinologists who examined the patients differed, which may have affected the presence or absence of physician-assessed manifestations. Finally, this study investigated the differences between the manifestations reported by patients and those assessed by endocrinologists, although the evaluations conducted by primary care physicians, which are crucial for the early detection of CS, were not available. Future research is needed to investigate the differences in recognizing manifestations between non-specialist physicians and endocrinologists with extensive experience in CS and to examine the changes before and after education for these non-specialists to determine if they can lead to earlier diagnosis of CS.

In conclusion, endocrinologists have been shown to be aware of CS-related symptoms, especially typical features, whereas patients do not recognize these manifestations, even when the disease is severe. Therefore, the key to the early diagnosis and treatment of CS is a more proactive approach of questioning and examining patients suspected of having the disease.

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Acknowledgements

We thank all the physicians and medical assistants who were involved in this study. We are grateful to all the laboratory members for their excellent discussions and fruitful suggestions. We also thank Editage ( www.editage.jp ) for English language editing.

This work was partially supported by the Japan Society for the Promotion of Science (KAKENHI, grant numbers 22K08654 (HF) and 21K08555 (GI)) and the Hyogo Science and Technology Association (HF). Open Access funding provided by Kobe University.

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Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, 650-0017, Japan

Yuma Motomura, Shin Urai, Masaaki Yamamoto, Masaki Suzuki, Naoki Yamamoto, Genzo Iguchi & Wataru Ogawa

Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Hospital, Kobe, Hyogo, 650-0017, Japan

Hironori Bando & Hidenori Fukuoka

Medical Center for Student Health, Kobe University, Kobe, Hyogo, 657-8501, Japan

Genzo Iguchi

Department of Biosignal Pathophysiology, Kobe University Graduate School of Medicine, Kobe, Hyogo, 657-8501, Japan

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Conceptualization and methodology: Y.M., S.U., G.I., and H.F.; Data curation and investigation: Y.M. and S.U.; Resources: Y.M., S.U., M.Y., M.S., N.Y., and H.F.; Formal analysis: Y.M. and S.U.; Writing - original draft preparation and visualization: Y.M. and S.U.; Writing - review and editing: H.B., M.Y., M.S., N.Y., G.I., W.O., and H.F.; Project administration and supervision: H.F. All the authors contributed to the discussion and approved the final version of the manuscript.

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Correspondence to Hidenori Fukuoka .

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Motomura, Y., Urai, S., Bando, H. et al. Diagnostic dilemma in Cushing’s syndrome: discrepancy between patient-reported and physician-assessed manifestations. Endocrine (2024). https://doi.org/10.1007/s12020-024-03935-9

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Cushing’s syndrome during pregnancy - two case reports

Laurence Katznelson, Stanford University, United States

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The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Cushing’s syndrome (CS) during pregnancy is a rare endocrine disorder characterized by hypercortisolism, which is significantly associated with maternal-fetal complications. Despite its rarity, CS during pregnancy may be related to a high risk of complications for both the mother and fetus.The aim of the present case study is to update the diagnostic approach to CS during pregnancy and the therapeutic strategies for this medical condition to minimize maternal-fetal complications.

Here, we present two cases of CS in pregnant women, one of whom had twins. Typical clinical symptoms and signs of hypercortisolism developed at the beginning of pregnancy. The plasma cortisol diurnal rhythm of the pregnant patient was absent. CS was confirmed by cortisol and adrenocorticotropic hormone (ACTH) assessment, as well as imaging examination. We investigated the changes in the hypothalamic-pituitary-adrenal axis during normal pregnancy and the etiology, diagnosis and treatment of CS during pregnancy.

Due to the associated risks of laparoscopic adrenalectomy,it is uncertain whether this treatment significantly decreases overall maternal mortality. Additional observational research and validation through randomized controlled trials (RCTs) are required. We advise that CS in pregnant women be diagnosed and treated by experienced teams in relevant departments and medical centers.

1. Introduction

Cushing’s syndrome (CS) is an endocrine disorder characterized by hypercortisolism with various causes. CS during pregnancy is rare but troublesome. There are fewer than 200 reported cases of this syndrome during pregnancy in the literature ( 1 ). Gonadotropin synthesis could be inhibited by excessive glucocorticoid secretion in female patients with CS during pregnancy, resulting in disorders in ovarian and endometrial functions. They are prone to oligomenorrhea, irregular menstruation and amenorrhea, and trouble getting pregnany. Additionally, expectant individuals with Cushing’s syndrome face a notably elevated risk of experiencing severe complications throughout pregnancy. Long-term exposure to hypercortisolism may cause maternal hypertension, hypokalemia, centripetal obesity, abnormal glucose metabolism, heart failure, pulmonary edema, opportunistic infections, pathological osteoporosis, bone fracture, and even death.The primary cause of CS in pregnant women is adrenal adenoma, followed by Cushing’s disease and ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS). Adrenal adenoma occurs in 15% of nonpregnant women with CS and approximately 50% of pregnant women ( 2 – 4 ). The diagnosis of CS during pregnancy is challenging. Misdiagnosis of CS is also common because it can easily be confused with preeclampsia or gestational diabetes mellitus (GDM). CS during pregnancy may result in maternal-fetal complications. Not only its manifestations, including hypertension and hyperglycemia but also the underlying causes of CS require effective treatment in pregnant women.

Here, we present two cases of Cushing’s syndrome (CS) during pregnancy. One of the pregnant women with CS was expecting twins. The other pregnant woman was diagnosed with ACTH-independent CS and underwent a successful unilateral laparoscopic adrenalectomy. The objective of this study is to describe therapeutic strategies for managing CS during pregnancy to minimize both maternal and fetal complications.

2. Case report

2.1. case one.

A28-year-old woman presented with abdominal striae and abnormal glycemic metabolism at 31 weeks of pregnancy. She was admitted to the West China Hospital of Sichuan University for gestational diabetes mellitus (GDM) and suspected Cushing’s syndrome (CS) during pregnancy. During the physical examination, her blood pressure was measured at 132/80 mmHg. She exhibited physical characteristics such as a moon face, buffalo hump, central obesity with a body mass index (BMI) of 28.9 kg/m², abdominal purple striations over 1 cm wide, and mild lower extremity edema. Given these signs, CS was suspected, leading to a referral for laboratory and functional tests related to CS. Hormonal analyses revealed serum cortisol concentrations of 892.26 nmol/L, 759.01 nmol/L, and 929.39 nmol/L at 8:00, 16:00, and 24:00, respectively (normal reference range: 118 ~ 618 nmol/L). Morning serum ACTH was <0.1 ng/L (normal range: 5 ~ 78 ng/L). Midnight saliva cortisol concentrations on three different dates were 66.89 nmol/L, 43.12 nmol/L, and 59.95 nmol/L (normal reference range: 0-10.4 nmol/L). Additionally, 24-hour urinary free cortisol (UFC) concentrations were 723.1 ug/24h and 591.2 ug/24h on two separate occasions (reference range: 20.26-127.55 ug/24h) (see Table 1 ). A 2 mg low-dose dexamethasone suppression test (LDDST) resulted in a serum cortisol concentration of 68.5 nmol/L, and an 8 mg high-dose dexamethasone suppression test (HDDST) showed a concentration of 48.7 nmol/L.Her liver and renal functions and electrolytes were normal. The patient was diagnosed with ACTH-independent CS, and the primary diagnosis was confirmed by magnetic resonance imaging (MRI), which showed a 2.6×2.5 cm adenoma in her leftadrenal gland ( Figure 1 ). There were no abnormalities on fetal ultrasound imaging.

Table 1

Laboratory findings and HPA of the pregnant patient with CS on admission.

MRI of the adrenal adenoma in a woman with CS during pregnancy.

The female patient successfully underwent a unilateral laparoscopic adrenalectomy at 32 weeks of gestation. Adrenalectomy was performed under general anesthesia; during the operation, she was placed in the right lateral decubitus position. No complications developed during surgery. The pathological examination of the removed adenoma revealed adrenal cortical adenoma. This was consistent with the diagnosis of ACTH-independent CS. Three days after surgery, her morning serum cortisol concentration at 8:00 was 185 nmol/L, and she also had fatigue and anorexia. She was administered 30 mg of hydrocortisone (20 mg at 8:00 a.m. and 10 mg at 4:00 p.m.) supplementation due to relative adrenal insufficiency. She was discharged 10 days after laparoscopic adrenalectomy. Her serum cortisol concentration was 200.6 nmol/L, and her cortisol level was 46.5nmol/L after a 1mg dexamethasone suppression test (DST). Her replacement therapy was therefore stopped. A follow-up visit performed 8 weeks after discharge showed normal results. Subsequently, she delivered a healthy baby at 39 weeks gestation through normal delivery, with a birth weight of 3.6 kg. Nine months post-delivery, a 1mg DST indicated cortisol concentrations of 105 nmol/L and ACTH 1.40 ng/L (normal range: 5-78 ng/L), signifying continuous remission.

2.2. Case two

A 34-year-old G2P1 female patient visited the West China Hospital of Sichuan University, reporting abnormal blood glucose levels for the past 4 years. She had experienced a weight gain of 10 kg in the last year, along with muscle weakness and elevated blood pressure over the past 4 weeks. Four years prior, she had been diagnosed with gestational diabetes mellitus (GDM) during her first pregnancy at a local hospital. Postpartum, she maintained near-normoglycemia through dietary changes, exercise, and other lifestyle interventions. One year ago, the patient developed centripetal obesity, and her attempts at weight control through diet and exercise proved ineffective. An oral glucose tolerance test (OGTT) revealed a 1-hour blood glucose concentration of 5.37 mmol/L and a 2-hour blood glucose concentration of 10.76 mmol/L after a 75g glucose load. Subsequently, she was found to be pregnant again and received treatment for GDM.

During pregnancy, the patient gradually suffered from facial and back acne, abdominal purple lines, increased body hair, and decreased hairline. Laboratory findings and HPA on admission was shown in Table 1 . Due to safety concerns, the pregnant woman declined further MRI examination. It is crucial to conduct diagnostic analyses for Cushing’s syndrome (CS) early in pregnancy. In the absence of sufficient evaluation and examination for CS, the patient underwent a cesarean section at 33 weeks of gestation, delivering two male infants who required intensive care for10 days and at-home feeding after 1 month. During a subsequent visit, a 1mg dexamethasone suppression test (DST) was conducted, revealing non-inhibition of cortisol. Enhanced abdominal computed tomography (CT) displayed a 22 mm occupation of the left adrenal branch. An MRI of the sellar regionrevealed no abnormalities in the pituitary glands.

Two weeks after delivery, her blood pressure measured 160/100 mmHg, and oral antihypertensive medications proved ineffective. Consequently, she was admitted to the Department of Endocrinology and Metabolism at West China Hospital. A physical examination revealed a blood pressure of 164/110 mmHg, along with symptoms such as moon face, decreased hairline, abdominal obesity, evident neck and back acne, and abdominal purple stripes. Her serum potassium level was 2.32 mmol/L. Results from the oral glucose tolerance test (OGTT) showed blood glucose levels of 5.18 mmol/L at 0 hours and 11.94 mmol/L at 2 hours after meals. Aldosterone in the decubitus position was measured at 11.65 ng/dL (normal range: 4.5-17.5 ng/dL). The supine aldosterone/decubitus renin activity ratio (ARR) was 3.34, within the normal. ACTH<1.00 ng/L (normal range: 5-78 ng/L), cortisol circadian was absent. The 24-hour urinary free cortisol (UFC) levels were 585.9 ug/24h and 738.6 ug/24h, respectively (normal range: 20.26-127.55 ug/24h).

Bone mineral density (BMD) examination showed that the average Z values of the femoral neck and total hip were -1.7 and -1.7, respectively, and the average Z value of L1-L4 was -2.8. Adrenal contrast-enhanced CT revealed a 2.7x2.5 cm soft tissue density nodule of the left adrenal gland, indicating the possibility of a left adrenal adenoma.

The patient was subsequently transferred to the Department of Urology and underwent laparoscopic adrenalectomy on May 11, 2016. The operation was conducted successfully, and the postoperative pathological examination indicated a left adrenal cortical adenoma. Two days after the surgery, she was transferred back to the Department of Endocrinology and Metabolism.

To address adrenal insufficiency following the surgery, glucocorticoid supplementation therapy (prednisone 10 mg in the morning and 5 mg in the afternoon) was initiated. One week later, she was discharged from the hospital with a blood pressure reading of 140/94 mmHg. Her blood potassium level was 3.6 mmol/L, and her ACTH was 1.05 ng/L, with cortisol concentrations within the normal range.

After discharge, the hormone dose was adjusted and gradually reduced during outpatient follow-ups. Two months post-surgery, a re-examination revealed an ACTH level of 18.46 ng/L. Two years later, the ACTH level increased to 45.84 ng/L, and the 24-hour urinary free cortisol (UFC) was measured at 100.9 ug/24h. Additionally, an oral glucose tolerance test (OGTT) displayed fasting blood glucose at 4.62 mmol/L, 2-hour blood glucose at 10.70 mmol/L, HbA1c at 4.9%, and blood potassium at 3.67 mmol/L.The twin brothers are currently thriving and well-developed.

3. Discussion

Pregnancy brings about several physiological alterations, one of which involves the activation of the maternal hypothalamic-pituitary-adrenal axis. This study explores uncommon situations and results in expectant women dealing with Cushing’s syndrome (CS). CS is a collection of syndromes arising from prolonged, excessive cortisol secretion or exogenous intake, influenced by various causes.

The initial documentation of Cushing’s syndrome (CS) during pregnancy was presented in 1953 by Hunt and his colleagues ( 5 ). In the initial case series, the fetal mortality rate was noted to be 43%. Recent reports have consistently affirmed that complications affecting both the mother and the fetus are prevalent in Cushing’s syndrome (CS) during pregnancy ( 6 ). As pregnancy progresses and the pituitary glands undergo growth, there is a natural physiological increase in pituitary-adrenal axis activity with advancing gestational weeks. This results in elevated levels of ACTH, hepatic corticosteroid binding globulin (CBG), increased serum, salivary, and urinary free cortisol, as well as a lack of suppression of cortisol concentration after dexamethasone administration and placental production of ACTH ( 7 ). Hence, the elevated cortisol levels induced by pregnancy pose a challenge in diagnosing Cushing’s syndrome (CS). It is frequently misdiagnosed during pregnancy due to its resemblance to gestational diabetes mellitus (GDM).

In our current study, the presence of a typical Cushing’s phenotype, elevated cortisol levels coupled with low ACTH concentrations, and the identification of adrenal adenoma images on abdominal CT collectively resulted in the diagnosis of ACTH-independent Cushing’s syndrome. This case was determined to be Cushing’s syndrome caused by adrenal cortical adenoma, the most prevalent cause of CS in pregnancy. The mechanism behind pregnancy-induced Cushing’s syndrome may involve luteinizing hormone (LH) and human chorionic gonadotropin (HCG) in pregnant women inducing the overexpression of relevant receptors (such as the chorionic gonadotropin receptor), which exerts a similar effect on the ACTH receptor, leading to adrenal hyperplasia and excessive cortisol production ( 8 ).

Our patients exhibited typical symptoms and signs of Cushing’s syndrome (CS). The typical clinical manifestations of pregnancy complicated with CS resemble those in nonpregnant patients, including Cushing’s appearance such as moon face and buffalo back, weight gain centripetal obesity, water and sodium retention, and so forth. CS has repercussions for both the mother and the fetus.In fetuses, a recent review indicated a noteworthy rise in fetal mortality and complications among individuals with Cushing’s syndrome (CS). These complications encompass stillbirth, premature birth, spontaneous abortion, neonatal death, fetal intrauterine growth restriction, fetal malformation, and adrenal insufficiency ( 1 ). The placenta utilizes 11β-hydroxysteroid dehydrogenase type 2 (11-β-HSD2) enzymes to enhance the metabolism of cortisol, safeguarding the fetus from excessive cortisol levels ( 9 ).

In addition to the typical Cushing’s face, the second patient presented not only abnormal glucose tolerance during pregnancy, hypertension, and osteoporosis but also hypokalemia. A review of the literature revealed that there are limited reported cases of pregnancy complicated by Cushing’s syndrome and persistent hypokalemia in China ( 10 ). The occurrence of hypokalemia might also be linked to deficiencies in 11-β-HSD2 enzymes in individuals with Cushing’s syndrome. These deficiencies result in decreased conversion of cortisol to inactive corticosteroids and an augmented binding of cortisol to corticosteroid receptors, consequently elevating potassium excretion ( 11 ). In this instance, hypokalemia was a recurring issue before surgery, and the Aldosterone-to-Renin Ratio (ARR) was employed to rule out primary aldosteronism. Blood potassium levels normalized within a week after surgery, suggesting a connection between hypokalemia and Cushing’s syndrome induced by adrenal adenoma. Given the infrequency of pregnancy complicated by Cushing’s syndrome, the existing diagnostic criteria are based on empirical observations.

In this case, ACTH was lower than the lower limit of the reference value, indicating that hypercortisolism may still play a major role in the feedback inhibition of the HPA axis. The 24-hour UFC was more than 3 times higher than normal, and the circadian rhythm disappeared, which was in line with the characteristics of typical CS. Currently, there is no established diagnostic standard for pregnancy complicated by Cushing’s syndrome. Typically, a combination of endocrine laboratory tests and imaging examinations is employed to diagnose suspected cases, aiming to confirm Cushing’s syndrome and provide further clarification on its etiology. Following the International Endocrine Society guidelines for diagnosing Cushing’s syndrome, recommended diagnostic measures for pregnant women suspected of having this syndrome include the measurement of midnight serum or salivary cortisol concentrations (at least twice), 24-hour urinary free cortisol (UFC), and the 2 mg low-dose dexamethasone suppression test (LDDST) ( 12 ). Plasma ACTH concentration was used for the differential diagnosis of ACTH-dependent and ACTH-independent CS. The preferred method for screening adrenal cortical adenomas is now renal ultrasound examination. In the case of pregnant individuals with suspected pituitary tumors, the safety of using nonenhanced MRI on the fetus has not been fully established ( 13 ). There are reports indicating that individuals with suspected Cushing’s syndrome in the early stages of pregnancy received a definitive diagnosis of Cushing’s disease through the use of high-resolution MRI and bilateral inferior petrosal sinus sampling (BIPSS) ( 14 ).

The management of Cushing’s syndrome during pregnancy involves both surgical and medicinal approaches. It is advisable for individuals experiencing pregnancy complicated by Cushing’s syndrome to opt for surgical intervention following the early termination of the pregnancy. Typically, laparoscopic adrenalectomy is the preferred initial treatment for those with cortisol-secreting adrenal adenomas. Medication may be considered when the lesion cannot be identified or surgery is contraindicated. Due to the potential risk of spontaneous abortion in early pregnancy post-surgery and the susceptibility of the fetus to various drugs, medication treatment becomes a consideration. Additionally, anesthesia during surgery could potentially lead to premature birth in late pregnancy. Although there have been successful reports of adrenalectomy, it is noted that the laparoscopic approach is deemed safe ( 6 ). For pregnant women diagnosed with Cushing’s syndrome in the final weeks of the third trimester, medical treatment administration and the postponement of surgery until after delivery are often recommended.

As indicated in a recent account, a pregnancy case involving Cushing’s syndrome caused by adrenal cortical adenoma was effectively managed through a combination of metyrapone at 0.5 g three times a day and ketoconazole at 0.4 g twice a day ( 15 ). The patient declined surgery and opted for oral medication throughout the pregnancy, demonstrating good drug tolerance and no medication-related complications. Eventually, she successfully delivered a healthy baby boy via cesarean section with an Apgar score of 8. No drug-induced teratogenic effects were observed in the neonate. Following delivery, the adenoma was surgically resected. After a five-year follow-up, the prognosis was favorable. In our observational report, the pregnant patient persisted in preserving the fetus and declined surgical intervention for Cushing’s syndrome until a successful delivery. Two years postoperative, both the mother and baby remained in good health.

4. Conclusion

In conclusion, the timely diagnosis and treatment of Cushing’s syndrome (CS) are crucial. Both surgery and medication are viable treatment options for CS during pregnancy. Our findings indicate that pregnancy should not be considered an absolute contraindication for laparoscopic adrenalectomy; rather, this procedure can be regarded as a safe and effective treatment for pregnant women with adrenal CS. However, due to the associated risks of laparoscopic adrenalectomy, it remains unclear whether the treatment significantly reduces overall maternal mortality. Further observational studies and confirmation through randomized controlled trials (RCTs) are necessary. We recommend that CS in pregnant women be diagnosed and treated by experienced teams in relevant departments and medical centers.

Data availability statement

Ethics statement.

The studies involving humans were approved by the Ethics Committee of West China Hospital of Sichuan University (approval number 2022-840). The studies were conducted in accordance with the local legislation and institutional requirements. The patient(s)/participant(s) provided written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author contributions

SC: Data curation, Formal analysis, Investigation, Resources, Visualization, Writing – original draft. YL: Investigation, Writing – original draft. HT: Conceptualization, Funding acquisition, Supervision, Validation, Writing – review & editing.

Acknowledgments

We would like to thank our patient and her mother for their help and enthusiasm. We also acknowledge our clinical colleagues in the Division of Endocrinology and Metabolism of West China Hospital for their help in organizing various investigations. We are grateful to Prof. Hoffman (Andrew R. Hoffman, Division of Endocrinology, Gerontology and Metabolism, Stanford University School of Medicine) for his support and advice regarding the submission and revision of this paper.

Funding Statement

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the 1·3·5 project for disciplines of excellence–Clinical Research Incubation Project, West China Hospital, Sichuan University (No.2020HXFH034) and Sichuan Province Health Commission Project (No.20PJ046).

Abbreviations

ACTH, Adrenocorticotropic hormone; ARR, aldosterone renin-activity ratio; BMI, Body mass index; BMD, Bone mineral density; BIPSS, bilateral inferior petrosal sinus sampling; CS, Cushing’s syndrome; CT, Computed tomography; CBG, Corticosteroid binding globulin; DST, dexamethasone suppression test; EAS, ectopic ACTH syndrome; HPA, Hypothalamic-pituitary-adrenal; HbA1c, Glycosylated hemoglobin A1c; HCG, Human chorionic gonadotropin; HSD2, Hydroxysteroid dehydrogenase type 2; HDDST, High-dose dexamethasone suppression test; IGT, Impaired glucose tolerance; LH, Luteinizing hormone; LDDST, Low-dose dexamethasone suppression test; MRI, magnetic resonance imaging; OGTT, oral glucose tolerance test; GDM, gestational diabetes mellitus; UFC, urinary free cortisol.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

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CASE REPORT article

Case report: comprehensive follow-up of a colombian family carrying a novel men1 variant linked to a rare acth-producing pancreatic neuroendocrine carcinoma.

• 1 Department of Pathology and Molecular Oncology, Instituto Nacional de Cancerología, Bogotá, Colombia
• 2 Faculty of Medicine, Universidad Cooperativa de Colombia, Villavicencio, Colombia
• 3 Department of Bioethics, Universidad El Bosque, Bogotá, Colombia
• 4 Department of Physiological Sciences, Faculty of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia
• 5 Endocrine Oncology Unit, Instituto Nacional de Cancerología, Bogotá, Colombia

Background: Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disorder marked by pathogenic variants in the MEN1 tumor suppressor gene, leading to tumors in the parathyroid glands, pancreas, and pituitary. The occurrence of ACTH-producing pancreatic neuroendocrine carcinoma is exceedingly rare in MEN1.

Case presentation: This report details a Colombian family harboring a novel MEN1 variant identified through genetic screening initiated by the index case. Affected family members exhibited primary hyperparathyroidism (PHPT) symptoms from their 20s to 50s. Uniquely, the index case developed an ACTH-secreting pancreatic neuroendocrine carcinoma, a rarity in MEN1 syndromes. Proactive screening enabled the early detection of pituitary neuroendocrine tumors (PitNETs) as microadenomas in two carriers, with subsequent surgical or pharmacological intervention based on the clinical presentation.

Conclusion: Our findings underscore the significance of cascade screening in facilitating the early diagnosis and individualized treatment of MEN1, contributing to better patient outcomes. Additionally, this study brings to light a novel presentation of ACTH-producing pancreatic neuroendocrine carcinoma within the MEN1 spectrum, expanding our understanding of the disease’s manifestations.

Introduction

Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disorder with a global prevalence ranging from 1 to 10 cases per 100,000 individuals, showing no preference for gender. Its penetrance increases significantly with age, being reported at 50% by age 20, exceeding 95% by age 40, and nearing 100% beyond age 70 ( 1 ). The condition primarily results from loss-of-function variants in the MEN1 gene on chromosome 11q13. This gene encodes Menin, a 610-amino acid scaffold protein that plays a crucial role in various cellular processes. Menin interacts with several intracellular molecules, such as JunD, NFκB, and Smad3, implicating it in transcriptional regulation, maintaining genome stability, and controlling cell division and proliferation ( 2 ).

MEN1 is characterized by the development of primary hyperparathyroidism (PHPT) in 95% of cases, pituitary neuroendocrine neoplasms (PitNENs) in 30–40%, and duodenal-pancreatic neuroendocrine tumors (DP-NETs) in 40–70% of patients ( 3 ). Additionally, the presence of carcinoids, adrenocortical tumors, and facial angiofibromas highlight the syndrome’s clinical variability.

The diagnosis of MEN1 is complex, dependent on either the identification of two or more MEN1-associated tumors, finding a MEN1 tumor in a patient with a first-degree relative who has a MEN1 pathogenic variant, or uncovering an asymptomatic carrier via genetic cascade screening. Given MEN1 protracted natural progression, early-stage diagnosis presents significant challenges. This difficulty is compounded by clinical variability and the interplay of genetic and environmental factors, highlighting the crucial role of genetic testing. Such testing is instrumental in not only confirming MEN1 diagnoses but also in identifying individuals at risk, ensuring timely intervention and management ( 4 ).

Here, we present a comprehensive 14-year follow-up of a Colombian family affected by a novel pathogenic variant MEN1: c.698dup, p.Met233IlefsTer4. This genetic variant impacted five family members across three generations, discovered through cascade genetic screening (CGS) initiated after identifying the index case. Notably, the index case manifested with an adrenocorticotropic hormone (ACTH)-producing pancreatic neuroendocrine carcinoma, leading to ectopic Cushing’s syndrome—a presentation not previously reported in MEN1.

Materials and methods

Genetic test and analysis.

Molecular analysis of the MEN1 gene was conducted at the Instituto Nacional de Cancerología, Bogotá D.C., Colombia, utilizing Sanger sequencing to analyze genomic DNA from peripheral lymphocytes of the index case and consenting asymptomatic family members. We targeted the entire coding sequence and exon-intron junctions of the MEN1 gene, amplifying nine exons with eight primer pairs. The amplified products were sequenced using the BigDye Terminator Cycle Sequencing Kit v3.1 on an Applied Biosystems/HITACHI 3500 Genetic Analyzer, USA, according to standard protocols.

Electropherograms were analyzed against reference sequences NG_008929.1 and NM_130799.2 using SeqA v6.0 and SeqScape v3.0 software from Applied Biosystems, USA, ensuring precise variant identification. Variant analysis followed the American College of Medical Genetics and Genomics (ACMG) guidelines ( 5 ).

Additionally, in silico analyses predicted the impact of frameshift indels using the SIFT Indel tool ( 6 ). The potential for nonsense-mediated decay (NMD) induced by the variant was assessed with the ‘masonmd’ R package by Hu, Yau, and Ahmed ( 7 ). For structural analysis and visualization, the PyMOL Molecular Graphics System by DeLano Scientific, San Carlos, CA, USA, was used.

Index and carries clinical follow-up

Our protocol for monitoring asymptomatic MEN1 variant carriers adheres to the Endocrine Society’s guidelines ( 8 ), incorporating biochemical and radiological tests specified for different tumor types from certain ages, as outlined in Tables 1 and 2 . For parathyroid tumors, annual screenings of calcium and PTH start at age eight, bypassing imaging. DP-NET screenings—gastrinomas from age 20 with gastrin and gastric pH tests, insulinomas from age 5 with fasting glucose and insulin levels, and other NETs from age 10 with Chromogranin-A and additional markers—are supported by yearly imaging (MRI, CT, or EUS). Pituitary tumors are screened from age 5 using prolactin and IGF-I levels, plus triennial MRI scans. Adrenal screenings, initiating at age 10, involve yearly MRI or CT scans, triggered by specific symptoms or when detecting tumors exceeding 1 cm.

Table 1 Clinical and biochemical findings in family members with MEN1 during the follow-up.

Table 2 Biochemical findings in patients with functional DP-NETs.

Patients and results

Index case iii-2.

The index patient, III-2, a 24-year-old female, exhibited symptoms of hyperinsulinemic hypoglycemia for a year before being diagnosed in March 2009. Symptoms included asthenia, adynamia, syncopal episodes, and a seizure a month prior to diagnosis. An endoscopic ultrasound identified a focal hypoechoic lesion with regular edges, measuring 18 mm, located at the pancreas’s head and body junction.

In April 2009, a partial pancreatectomy and splenectomy were performed, revealing a multifocal, well-differentiated grade 1 NET according to the WHO 2000 criteria. Reclassification under the WHO 2022 criteria would correspond to a Grade 1 neuroendocrine tumor (well-differentiated, 0 mitoses per 2 mm², and a Ki67 proliferation index of 1%).

The immunohistochemistry (IHC) studies performed showed the tumor was positive for CKA1AE3, chromogranin, synaptophysin, and focal positivity for insulin. The mitotic rate was 0 per 2 mm², and the Ki67 index was 1%, indicative of an insulinoma. Examination confirmed no necrosis, vascular invasion, or extrapancreatic extension. The pancreatic section edge, spleen, and a peripancreatic lymph node were all tumor-free. Examination confirmed no necrosis, vascular invasion, or extrapancreatic extension. The pancreatic section edge, spleen, and a peripancreatic lymph node were all tumor-free.

After eight months free of hypoglycemic symptoms, the patient developed tonic-clonic seizures and hyperinsulinemic hypoglycemia again. New abdominal imaging showed another lesion in the pancreatic head. An octreotide scintigraphy (99mTc-OCTREOTIDE HYNIC) did not show any hypercaptating lesions expressing somatostatin receptors in the gastroenteropancreatic region or other organs (no image available).

This led to further surgery at the Instituto Nacional de Cancerología, Bogotá D.C., Colombia, including a residual pancreatectomy, duodenal resection, and peripancreatic soft tissue resection in May 2010. Pathology confirmed a well-differentiated, grade 1 NET (WHO 2010 criteria), with two lymph nodes involved, one positive for gastrin and ACTH ( Table 2 ).

The subsequent development of PHPT was surgically addressed with subtotal parathyroidectomy and reimplantation. After this intervention, the patient required insulin therapy for the management of post-surgical diabetes mellitus.

The identification of multiple DP-NETs and parathyroid adenomas prompted the suspicion of MEN1, resulting in a referral for genetic testing in July 2010. Sanger sequencing identified a novel heterozygous variant in the MEN1 gene: c.698dup, p.Met233IlefsTer4. This finding initiated CGS within the family ( Figure 1A ).

Figure 1 MEN1 variant analysis and menin protein structure in a colombian family. (A) Family pedigree across four generations highlighting the index patient (arrow). (B) Forward Sanger sequencing results for the proband (III-2), the proband’s father (II-4), and the proband’s daughter (IV-1), indicating the presence of the MEN1: c.698dup frameshift variant. (C) Three-dimensional crystal structure of human Menin (PDB ID: 3U84), frontal and back views. Domains are color-coded: N-terminus (light pink), Thumb (light violet), Palm (pale yellow), with regions affected by MEN1: c.698dup, p.Met233IlefsTer4 highlighted in gray. The critical Met233-to-isoleucine mutation within the compromised domains is marked in red, affecting the Palm and complete Finger domain, and illustrating the disruption’s impact on MIPs interaction regions. MIPs, Menin interaction proteins. Created with BioRender.com .

The patient lost contact in 2011 due to pregnancy but returned in 2013 with hyperglycemia and severe hypokalemia, leading to a diagnosis of ACTH-dependent ectopic Cushing’s syndrome (EAS). Imaging (abdominal and pelvic MRI) showed focal hepatic lesions and pelvic bone involvement but no pancreatic or thoracic lesions. An octreotide scintigraphy (99mTc-OCTREOTIDE HYNIC) performed in June 2013 before the surgical intervention did not show any lesions expressing somatostatin receptors.

Treatment with ketoconazole partially controlled hypercortisolism, and a left hemihepatectomy with periportal lymph node resection was performed in June 2013 to address liver compromise. Pathology revealed liver and periportal lymph node metastases from a poorly differentiated small cell neuroendocrine carcinoma (WHO 2010 criteria). Reclassification under the WHO 2022 criteria would correspond to a small cell neuroendocrine carcinoma (25 mitoses per 2 mm² and a Ki67 index of 50%), with focal ACTH positivity in both the liver lesion and metastatic nodes.

Other causes of ACTH-producing tumors were excluded by performing comprehensive imaging studies, including brain MRI, chest CT, and abdominal-pelvic MRI. Additionally, an octreotide scintigraphy (HYNIC TOC) was conducted, revealing no other tumor lesions apart from those in the liver and a bone lesion in the pelvis. A PET 68-Ga-Dota scan was not performed due to unavailability, but a HYNIC TOC scintigraphy was done prior to the left hemi-hepatectomy, and the liver lesion did not express somatostatin receptors, confirming the cause of EAS as ACTH-producing tumors.

Despite external radiotherapy and chemotherapy with etoposide/cisplatin, the disease progressed to involve the liver, bones, and lungs, leading to the patient’s death five years post-diagnosis.

Variant analysis and curation

The novel 698-base pair (T) duplication in the MEN1 gene was identified via Sanger sequencing ( Figure 1B ), resulting in a significant frameshift variant designated as MEN1 (NM_000244): c.698dup, p.Met233IlefsTer4 ( Figure 1B ). This frameshift variant affects transcript NM_000244.3 (NCBI) and an alternative transcript, ENST00000377316.6 (Ensembl). It remains unreported in ClinVar, the French MEN1 database ( http://www.umd.be/MEN1/ ), and other genomic variation databases (1000Genomes, ExAC, dbSNP, and HGMD).

Protein modeling, as shown in Figure 1C , predicted a compromise in the Palm and Finger domain of the Menin protein (PDB ID: 3U84), which affects the Pocket region—a well-known interaction area with other significant oncogenic proteins. Given the variant’s class (insertion/duplication), we employed the SIFT Indel tool ( 6 ). Using sequence data based on GRCh37/hg19, we predicted that our variant is likely to be damaging, with a confidence score of 0.858. Additionally, this tool uses a basic criterion for predicting nonsense-mediated decay (NMD), suggesting that our variant could trigger NMD due to its location within the transcript.

Further analysis with the algorithm developed by Hu, Yau, and Ahmed ( 7 ), using ENTREZ ID: 4221, classified the variant as likely to elicit NMD. This classification takes into account criteria such as having more than two exons (our case 9 exons), the distance of the stop codon from the last exon-exon junction being greater than 50 bp (in our case, 1365 bp), and the premature termination codon (PTC) being located more than 200 bp downstream from the start codon (in our case, 856 bp), resulting in a mutated coding sequence length of 1850 nt. Our variant meets these criteria, further supporting its potential to initiate NMD.

Following the analysis, the variant was initially classified as “likely pathogenic” based on the phenotype of the index case, aligning with PVS1 and PM2 criteria. Subsequently, the detailed follow-up, which demonstrated the variant’s familial segregation (meeting the PP1 criterion) and the appearance of MEN1 symptoms in carriers (fulfilling the PP4 criterion), led to an upgrade in its classification to “pathogenic.” This revision highlights the significant correlation between the observed clinical features and a disease with a genetic foundation ( 9 ).

Cascade genetic screening

From 2010 to 2022, a cascade genetic screening, preceded by pretest genetic counseling, was conducted on eight family members spanning three generations ( Figure 1A ), utilizing Sanger sequencing. This screening uncovered four asymptomatic carriers of the pathogenic variant MEN1 : c.698dup, p.Met233IlefsTer4. The initial screening in 2010 focused on the daughters of the index case, leading to the identification of one carrier (IV-2). Further testing of her parents revealed that her mother was not a carrier, while her father (II-4) was found to be a carrier in 2013. In the same year, screenings were extended to the paternal aunts of the index case, all of whom tested negative. However, the fraternal sister of the index case was also identified as a carrier. After II-4’s remarriage and the birth of a son, the child, given the family’s medical history, was tested in 2021 and confirmed as a carrier of the MEN1 variant. Following the identification of this variant, clinical follow-up started after post-test genetic counseling was provided ( Figure 2 ).

Figure 2 Timeline of molecular and clinical manifestations of MEN1 in the colombian family with MEN1: c.698dup. *index case. Created with BioRender.com .

Follow-up MEN1 carriers

Patient II-4, the father of the index case, was identified as a MEN1 variant carrier on June 21, 2013 ( Figure 2 ), at 48 years old but remained asymptomatic until 2020, at age 55, when he began experiencing dyspepsia and self-limited diarrhea. This led to the discovery of hypergastrinemia. An upper digestive tract endoscopy uncovered a nodular lesion in the duodenum, and a biopsy confirmed well-differentiated, multifocal, grade I NETs. Abdominal MRI later revealed a lesion adjacent to the uncinate process and another near the third portion of the duodenum, both without compressive effects, along with an intramural lesion in the second portion of the duodenum. The disease was considered unresectable not only due to the duodenal mass but also because of conglomerated lymph nodes around the pancreas and duodenum. Given the inoperability, treatment was initiated with proton pump inhibitors and Lanreotide, stabilizing the disease for a year. However, in January 2022, disease progression was observed, leading to the administration of four cycles of lutetium-177 DOTATOC treatment, totaling a dose of 800 mCi by September 2022, which resulted in stable disease six months post-treatment.

Additionally, in early 2021, PHPT was diagnosed, leading to a left lower parathyroidectomy in March 2021. Histopathological examination confirmed a parathyroid adenoma, achieving biochemical control post-surgery. As of the last follow-up, there has been no documented pituitary involvement.

Patient III-3, the sister of the index case, was identified as a MEN1 variant carrier in June 2013 at 21 years old ( Figure 2 ). Three years after her identification, she was diagnosed with a prolactin-secreting pituitary microadenoma, prompting the initiation of cabergoline treatment. Concurrently, PHPT was diagnosed, leading to the surgical intervention of right lower parathyroidectomy. These treatments successfully controlled her prolactin and calcium levels.

In June 2020, a follow-up pituitary MRI revealed no visible lesion, leading to the discontinuation of cabergoline. However, six months later, she experienced a recurrence of symptomatic hyperprolactinemia, necessitating the resumption of cabergoline therapy. Now, at 31 years old, she remains under treatment, and as of the latest assessments, no duodenal-pancreatic neuroendocrine tumors (NETs) have been detected.

Patient III-4 was confirmed as a MEN1 variant carrier in March 2022 at 22 ( Figure 2 ). Following the discovery, the patient consulted with endocrinology and genetic services. Eight months after variant identification, screening unveiled a lobulated pituitary adenoma measuring 9 x 9 x 9 mm. Biochemical evaluations indicated excesses in growth hormone (GH) and prolactin. Consequently, a transsphenoidal surgical approach was employed to remove the pituitary lesion within the same year. Histology of the excised tissue revealed a pituitary microadenoma with a focal expression of prolactin and growth hormone and a Ki67 proliferation index of 3%. Following surgery, the patient developed central hypocortisolism, necessitating the initiation of hydrocortisone supplementation. Despite surgery, persistently elevated insulin-like growth factor 1 (IGF-1) and GH levels were observed, leading to the prescription of somatostatin analog treatment.

In parallel, PHPT was diagnosed with scintigraphy detecting a left lower parathyroid lesion. The patient is currently awaiting surgical intervention for this condition. As of the last evaluation, no duodenal-pancreatic NETs have been identified.

Patient IV-1 ( Figure 2 ), the daughter of the index case, was confirmed as a MEN1 variant carrier in December 2010 when she was only one year old. Now, at the age of 14, she continues to be asymptomatic, with no tumors detected through ongoing monitoring.

Here, we present clinical monitoring of a Colombian family where a novel frameshift variant in the MEN1 gene is present across three generations. The variant, MEN1: c.698dup, p.Met233IlefsTer4, was classified as pathogenic using ACMG criteria and in silico tests and observed clinical features within the family.

Although frameshift variants constitute the most prevalent alterations in MEN1, accounting for 42% of cases ( 10 ), the precise molecular mechanisms underlying their impact remain varied and undefined. Welch et al. ( 11 ) described a frameshift variant, c.674delG, located in exon 4 of MEN1, merely 8 codons proximal to our identified variant. This variant was identified in four family members diagnosed with PHPT and DP-NETs, with one member also presenting additional tumor types. Despite certain clinical resemblances with our case, the manifestations in our family exhibit greater variability, which might be attributed to variances in clinical follow-up protocols and the specific molecular mechanisms of the variant.

Welch et al. ( 11 ) attributed the clinical impacts of their variant to a loss of interaction (LOI) with proteins like FANCD2 and FOXN3. This mechanism could similarly apply to our variant (see Figure 1C ), as it compromises the palm domain, affecting the Pocket region—a well-known site associated with interaction with most of the menin interaction proteins (MIPs) involved in the oncogenic process in MEN1 ( 12 ). However, since truncating menin proteins are frequently undetectable in MEN1 patients, frameshift variants like ours are likely subject to nonsense-mediated decay (NMD), positioning NMD as the primary disease mechanism in this context. Supporting this theory, our in silico analyses strongly predict NMD for the c.698dup variant, rather than LOI. This underscores the molecular diversity of frameshift variants in MEN1 and helps elucidate the variability in clinical presentations observed in families affected by MEN1.

The family described herein exhibits classical MEN1 phenotypes, including PHPT in 4 out of 5 carriers, and various neoplasms such as DP-NETs in 2 out of 5 carriers, and PitNENs in 2 out of 5 carriers ( 3 ). However, notable variations in phenotype were observed. Regarding DP-NETs, we observed an unusual deviation from the typical non-functional tumor presentation, which usually occurs at a rate of 40% ( 13 ). Notably, we identified two instances of functional NETs within a single family. Specifically, Case II-4 was diagnosed with Zollinger-Ellison syndrome at age 48.

Moreover, the index case initially presented with an insulinoma at 24, experienced a relapse at 25, and exhibited metastatic spread to two lymph nodes, with one testing positive for gastrin and ACTH. This case evolved into Cushing’s syndrome due to ectopic ACTH secretion syndrome (EAS) provoked by liver metastasis originating from a pancreatic neuroendocrine carcinoma (NEC), an occurrence not previously documented in MEN1 literature for pancreatic NECs. Ectopic ACTH secretion syndrome (EAS) is typically associated with bronchial, lung, and thymus neuroendocrine neoplasms ( 14 ) and is rare about DP-NETs. Thus, our index case underscores the significance of this clinical manifestation within the context of MEN1, presenting, to our knowledge, the first reported case of MEN1 with this specific clinical presentation.

Neuroendocrine carcinomas (NECs), whether small-cell (SCNECs) or large-cell (LCNECs), exhibit aggressive clinical behavior and poor prognosis, characterized by high-grade nuclear features, high mitotic counts (often >20 per 2 mm²), and a Ki-67 index usually exceeding 55% ( 15 ). They are rarely associated with hormonal syndromes. However, the index case features a functional ACTH-producing pancreatic-SCNEC (P-SCNEC), a rarity in MEN1-associated NETs, suggesting potential tumor grade progression from a well-differentiated DP-NET. This observation underscores the dynamic evolution of MEN1-associated tumors and highlights the complexity and heterogeneity of pNETs, including variations in histopathological grade, hormone secretion, and genetic alterations ( 13 , 16 ). The phenomenon of grade progression, more common in metachronous than synchronous metastases, further emphasizes the evolving nature of these tumors ( 17 ). In our index case, this progression could be related to the rapid progression despite external radiotherapy and chemotherapy.

On the other hand, Pituitary Neuroendocrine Neoplasms (PitNENs) occur in 30% to 50% of individuals with MEN1 ( 18 ), typically emerging between the fourth and sixth decades ( 19 ). While PitNETs are usually macroadenomas (85%), our findings include two family members, III-3 and III-4, aged 23 and 25 respectively, with microadenomas, mainly as prolactinomas, and in one instance, with additional GH secretion, a rarity in only 5% of PitNETs ( 20 ). This finding of microadenomas, diverging from the typical macroadenoma presentation in MEN1, suggests the benefits of early detection through proactive screening. Early identification allows for more straightforward surgical management and minimizes neurological impacts, emphasizing the advantage of screening before the appearance of clinical symptoms for better management and outcomes.

This family report underscores the complexity and dynamic progression of MEN1, unveiling the identification of a functional ACTH-producing P-SCNEC as a novel entity within the spectrum of MEN1-associated DP-NETs. Additionally, we report the discovery of a pathogenic frameshift variant, c.698dup, in the MEN1 gene. This variant is subject to NMD, which may explain the varied clinical manifestations seen in this family.

While our findings emphasize the importance of cascade screening in facilitating early diagnosis and individualized treatment of MEN1, it is essential to note that our conclusions are based on a single-family cohort. Therefore, the significance of these findings should be considered with caution and in the context of broader studies. Nonetheless, proactive cascade genetic screening remains crucial for identifying asymptomatic carriers, optimizing patient care, and improving outcomes before the disease progresses to more critical stages.

Data availability statement

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.

Ethics statement

This study was approved by the Institutional Review Board of the Instituto Nacional de Cancerología. It was conducted in accordance with local legislation and institutional requirements. Written informed consent was obtained from the individuals for the publication of any potentially identifiable images or data included in this article.

Author contributions

JR: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. AG: Conceptualization, Formal analysis, Investigation, Supervision, Writing – original draft, Writing – review & editing. WT: Conceptualization, Data curation, Formal analysis, Supervision, Validation, Visualization, Writing – review & editing. VM: Methodology, Validation, Writing – review & editing. AR: Methodology, Validation, Writing – review & editing. IV: Data curation, Formal analysis, Investigation, Methodology, Writing – review & editing. JA: Data curation, Formal analysis, Investigation, Methodology, Writing – review & editing. JB: Data curation, Formal analysis, Investigation, Methodology, Writing – review & editing. JB: Data curation, Formal analysis, Investigation, Methodology, Writing – review & editing. OT: Data curation, Formal analysis, Investigation, Methodology, Writing – review & editing. LM: Data curation, Formal analysis, Investigation, Methodology, Supervision, Validation, Writing – review & editing.

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The Universidad Cooperativa de Colombia provided financial support for the publication of this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: multiple endocrine neoplasia type 1 (MEN1), cascade genetic screening, neuroendocrine tumors (NETs), frameshift variant, neuroendocrine - carcinoma

Citation: Riaño-Moreno JC, González-Clavijo AM, Torres J. WC, Medina B. VL, Romero-Rojas AE, Vieda-Celemin I, Avila-Moya JA, Baron-Cardona JA, Bravo-Patiño JP, Torres-Zambrano OS and Maya LFF (2024) Case report: Comprehensive follow-up of a Colombian family carrying a novel MEN1 variant linked to a rare ACTH-producing pancreatic neuroendocrine carcinoma. Front. Endocrinol. 15:1398436. doi: 10.3389/fendo.2024.1398436

Received: 09 March 2024; Accepted: 08 July 2024; Published: 22 July 2024.

Reviewed by:

Copyright © 2024 Riaño-Moreno, González-Clavijo, Torres J., Medina B., Romero-Rojas, Vieda-Celemin, Avila-Moya, Baron-Cardona, Bravo-Patiño, Torres-Zambrano and Maya. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Julián C. Riaño-Moreno, [email protected]

† These authors have contributed equally to this work

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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• Published: 17 July 2024

Hemodynamic responses to the cold pressor test in individuals with metabolic syndrome: a case-control study in a multiracial sample of adults

• Jon Stavres   ORCID: orcid.org/0000-0003-0564-7252 1 ,
• Anabelle Vallecillo-Bustos 1 ,
• Ta’Quoris A. Newsome 1 ,
• Ryan S. Aultman 1 ,
• Caleb F. Brandner   ORCID: orcid.org/0000-0002-6870-6291 2 &
• Austin J. Graybeal   ORCID: orcid.org/0000-0003-4520-9230 1  

Journal of Human Hypertension ( 2024 ) Cite this article

Metrics details

• Hypertension
• Metabolic diseases
• Risk factors

Previous research shows that exercise pressor and metaboreflex responses are significantly exaggerated in individuals with metabolic syndrome, but it is unclear if these exaggerated responses extend to the cold pressor test (CPT). This study tested the hypothesis that, contrary to previously reported exaggerated responses during exercise, CPT responses would not be significantly exaggerated in individuals with MetS compared to matched controls. Eleven individuals with MetS and eleven control participants matched by age, race, sex, and ethnicity completed a cardiometabolic prescreening and a CPT. Each CPT required participants to immerse their hand in ice water for two minutes while beat-by-beat blood pressure, heart rate (HR), and leg blood flow (LBF) were continuously measured. Leg vascular conductance (LVC) was calculated as LBF divided by mean arterial pressure (MAP). The precent changes in MAP, systolic blood pressure (SBP), diastolic blood pressure (DBP), HR, LBF, and LVC were compared across time (BL vs. Minutes 1 and 2 of CPT) and between groups (MetS vs. Control) using repeated measures analyses of variance. As expected, MAP ( f  = 32.11, p  < 0.001), SBP ( f  = 23.18, p  < 0.001), DBP ( f  = 40.39, p  < 0.001), and HR ( f  = 31.81, p  < 0.001) increased during the CPT, and LBF ( f  = 4.75, p  = 0.014) and LVC ( f  = 13.88, p  < 0.001) decreased. However, no significant main effects of group or group by time interactions were observed ( f  ≤ 0.391, p  ≥ 0.539). These findings indicate that the hemodynamic responses to the CPT are not significantly exaggerated in MetS, and therefore, previous reports of exaggerated exercise pressor and metaboreflex responses in MetS cannot be attributed to generalized sympathetic overexcitability.

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Data availability.

The raw data used in this study will be made available by authors upon reasonable request without undue delay and within the regulations of the University of Southern Mississippi.

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Acknowledgements

The authors would like to thank Kieron Cox, Diavion Stanfield, Alex Henderson, Havens L. Wise, Brandy Lowe, and Anne Speed for their technical support.

This study was supported by the Mississippi Center for Clinical and Translational Research, the National Institutes of Health, and the National Institute of General Medical Sciences (U54GM115428), as well as the University of Southern Mississippi (to J. Stavres and A.J. Graybeal).

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Jon Stavres, Anabelle Vallecillo-Bustos, Ta’Quoris A. Newsome, Ryan S. Aultman & Austin J. Graybeal

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Conceived and designed research: JS and AJG; Performed experiments: JS, RA, TN, AVB, CFB, AJG; Analyzed data: JS, RA, TN, AVB, CFB, AJG; Interpreted results of experiments: JS, RA, TN, AVB, CFB, AJG; Prepared figures: JS; Drafted manuscript: JS; Edited and revised manuscript: JS, RA, TN, AVB, CFB, AJG; Approved final version of manuscript: JS, RA, TN, AVB, CFB, AJG.

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Stavres, J., Vallecillo-Bustos, A., Newsome, T.A. et al. Hemodynamic responses to the cold pressor test in individuals with metabolic syndrome: a case-control study in a multiracial sample of adults. J Hum Hypertens (2024). https://doi.org/10.1038/s41371-024-00938-x

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• Published: 22 July 2024

Reducing the Gap in Knowledge and Expectations between Clinicians and People with Polycystic Ovary Syndrome or Adrenal Conditions: Simulation via Instant Messaging—Birmingham Advance: Patient and Public Involvement (SIMBA-PPI) Study

• Eka Melson 1 , 2   na1 ,
• Fatema Rezai 3   na1 ,
• Carina Pan 3   na1 ,
• Sung Yat Ng 3 ,
• Tamzin Ogiliev 4 ,
• Ella Blendis 3 ,
• Haaziq Sheikh 3 ,
• Harjeet Kaur 3 ,
• Catherine Cooper 5 , 6 ,
• Farah Abdelhameed 7 ,
• Francesca Pang 3 ,
• Shreya Bhatt 3 ,
• Dania Shabbir 8 ,
• Zahra Olateju 3 ,
• Eloise Radcliffe 3 ,
• Prashanthan Balendran 3 ,
• Abby Radcliffe 3 ,
• Gar Mun Lau 3 ,
• Meri Davitadze 9 , 10 ,
• Dengyi Zhou 3 , 11 ,
• Kashish Malhotra 10 , 12 ,
• Caroline Gillett 2 ,
• SIMBA and CoMICs team &
• Punith Kempegowda 10 , 13  

BMC Medical Education volume  24 , Article number:  784 ( 2024 ) Cite this article

Metrics details

To evaluate the efficacy of SIMBA as an educational intervention for both HCPs and people with either PCOS or adrenal conditions and to study the change in knowledge of people with PCOS or adrenal conditions about the conditions and expectations from the HCPs involved in their  care following SIMBA-PPI sessions.

Two SIMBA-PPI sessions (SIMBA-PPI Polycystic ovary syndrome (SIMBA-PCOS) and SIMBA-PPI Adrenal conditions (SIMBA-Adrenal conditions)) were conducted in September 2021 and March 2022. In both sessions, HCPs interacted with moderators on patient management through WhatsApp. Patients with respective conditions underwent workshop-style learning in the same cases. SIMBA-PCOS transcripts were also translated into Brazilian Portuguese and workshops were held in both Brazilian Portuguese and English. The two groups (HCPs and patients) were then brought together to discuss exploring gaps in knowledge and expectations. The Wilcoxon Signed-Rank test compared differences in pre- and post-SIMBA self-reported confidence levels in HCPs and patients. Qualitative data from the online recordings were transcribed and analysed with inductive thematic analysis to identify gaps in knowledge and expectations from managing the cases.

48 HCPs and 25 patients participated in our study. When compared to pre-SIMBA confidence levels, SIMBA-PPI sessions effectively improved clinicians’ confidence in managing PCOS (40.5%, p  < .001) and adrenal conditions (23.0%, p  < .001) post-SIMBA. Patient participants’ confidence in HCPs significantly increased in the PCOS session (SIMBA-PCOS: 6.25%, p  = 0.01).

Conclusions

Integration of PPI into SIMBA improved HCPs' confidence in managing PCOS and adrenal conditions. SIMBA-PPI also improved patients’ confidence in HCPs. Our findings suggest that participating in SIMBA-PPI sessions can reduce the gap in knowledge and expectations between patients and HCPs involved in their care.

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Introduction

Patient and public involvement (PPI) are essential for an equal partnership in clinical decisions and patient-centred care [ 1 ]. The General Medical Council, the regulatory body of doctors in the United Kingdom, first highlighted the importance of PPI in the standards for undergraduate education in “Tomorrow’s Doctors”, published in 2009 and later in the postgraduate ‘Standard for Deaneries’ calling for deaneries to ensure active and meaningful involvement of patients and the public in doctors’ training [ 2 , 3 ]. Until then, patients’ role in education was indirect or passive, with limited contribution to curriculum development and its delivery and student assessment [ 4 , 5 , 6 ]. Yet, amidst this recognition, robust models that effectively integrate established educational theories into PPI initiatives within healthcare settings are lacking. There is a paucity of such activities in doctors’ postgraduate medical education. There is a lack of ontological and epistemological aspects and evidence of reproducibility, scalability, and sustainability in the published PPI models in medical education [ 7 , 8 , 9 ].

Despite the richness of educational theories such as Experiential Learning and Participatory Action Research [ 10 ], their application in developing comprehensive frameworks for PPI within medical education is limited (a brief explanation of all educational theories and frameworks referenced is supplied in Supplementary 1). While theories like the Health Belief Model [ 11 ] and Theory of Planned Behaviour [ 12 ] offer valuable insights into patient behaviours and attitudes, their integration into educational models specifically tailored for fostering patient-provider collaboration is sparse. The potential of the Transtheoretical Model to cater to diverse patient readiness levels for engagement in healthcare decisions remains underexplored. Similarly, empowerment theory [ 13 ] and social cognitive theory [ 14 ], which hold promise in cultivating empowered, informed patient partnerships, have yet to find their place in structured curricula to train future healthcare professionals. This scarcity of models utilising these theories in the context of PPI represents a critical gap in healthcare education. The dearth of comprehensive frameworks that integrate these well-established educational theories stifles the development of healthcare professionals capable of effectively collaborating with, learning from, and empowering patients and communities.

Simulation via Instant Messaging—Birmingham Advance (SIMBA) is a virtual simulation platform that successfully improved participating clinicians’ confidence in managing various simulated cases with a reasonable acceptance rate and reproducibility [ 15 , 16 , 17 , 18 ]. SIMBA sessions have been limited to healthcare professionals (HCPs) who underwent simulation-based learning through text messages in WhatsApp, followed by interactive discussions on Zoom. We recently conducted two educational sessions through SIMBA involving HCPs and people affected by PCOS or adrenal conditions. We called these sessions Simulation via Instant Messaging-Birmingham Advance Public and Patient Involvement (SIMBA-PPI). The two SIMBA-PPI sessions were SIMBA-PPI Polycystic ovary syndrome (SIMBA-PCOS) and SIMBA-PPI Adrenal conditions (SIMBA-Adrenal conditions).

The SIMBA-PPI model is based on the simulation game and Kolb’s experiential learning theory [ 19 ]. A simulation game is characterised by the outcomes of choices enacted by participants, interconnected within a framework of rules and resource references mirroring real-life scenarios [ 19 ]. David Kolb’s experiential learning theory is a model of human learning with 4 distinct stages [ 20 ]:

Stage 1—concrete experience—is enacted by the simulation session whereby HCPs partake in case scenarios, and patients with PCOS and adrenal pathologies undergo the same cases in workshop-style learning

Stage 2—reflective observation—is depicted by the post-simulation discussion with experts via Zoom. The HCPs and patients joined the same discussion, allowing a dialogue regarding bridging the knowledge gap between the two groups.

Stage 3—abstract conceptualisation—was facilitated by the use of post-SIMBA surveys, which were distributed to all HCPs and patients partaking in SIMBA.

Stage 4—active experimenting—is when HCPs and patients can apply their knowledge from the SIMBA simulation sessions to their own lives [ 20 ].

The aims of this study were:

To evaluate the efficacy of SIMBA as an educational intervention for both HCPs and people with either PCOS or adrenal conditions

To study the change in knowledge of people with PCOS or adrenal conditions about the conditions and expectations from the HCPs involved in their care following SIMBA-PPI sessions.

The SIMBA-PCOS session was conducted on 21st September 2021, and the SIMBA-Adrenal conditions session was conducted on 8th March 2022. Both sessions were carried out based on integrating the six-step conceptual framework described by Kern et. al [ 21 ] and the Plan, Do, Study, Act (PDSA) cycle framework (Supplementary 2). This study has received ethics approval from the Science, Technology, Engineering and Mathematics Ethics Committee at the University of Birmingham (ERN_2023-0495). HCPs were recruited via advertisements on the SIMBA website and social media platforms (Facebook and Twitter). PPI participants were recruited through various support groups. Participation was entirely voluntary. Informed consent was taken from each participant.

SIMBA-PCOS six-step conceptual framework and PDSA cycle 1

Problem identification and general needs assessment.

PCOS commonly affects 10–20% of women worldwide [ 22 ]. Following the diagnosis, people with PCOS are often left with unmet information needs, which can further impact their mental health [ 23 , 24 ]. This is probably due to the diverse symptoms of PCOS and the lack of awareness among HCPs and patients regarding the international consensus guidelines for managing people with PCOS [ 25 ]. Current educational interventions towards improving knowledge, attitudes, and practices of PCOS amongst HCPs have limited patient and public involvement. Further, there is a deeply rooted mistrust of HCPs among people with PCOS [ 24 , 26 ]. The collaboration between patients and HCPs can effectively bridge the existing knowledge gap between these two groups. This collaborative approach may encourage greater patient engagement in their healthcare journey and potentially enhance educational initiatives to improve knowledge, attitudes, and practices related to PCOS among healthcare providers.

Targeted needs assessment

We recognised the need for a model to increase understanding of their condition among people with PCOS. Our objective centred on reducing the knowledge gap between HCPs and patients, primarily due to the varied nature of PCOS symptoms, allowing HCPs and affected patients to engage in a dialogue.

Goals and objectives

Promote patient and public involvement in clinical decisions and care to achieve an equal partnership between healthcare professionals and patients,

Involve people with PCOS in educational interventions to represent and support others,

Integrate PPI into medical education at both undergraduate and postgraduate levels. This involves active and meaningful participation of patients and the public in doctors' training.

Education strategies

The SIMBA-PPI model is based on the simulation game and Kolb’s experiential learning theory [ 19 ].

Implementation of the educational model and PDSA Cycle 1

Planning cycle 1.

This session was divided into two arms: one focused on HCPs with 29 participants and another component involving people with PCOS with 15 participants. The cases for SIMBA PCOS were designed based on PCOS clinical guidelines and a study on the learning needs of people with PCOS and HCPs [ 25 , 27 , 28 ]. These scenarios were converted into anonymised transcripts, with experts' inputs, which included information on past medical history, clinical examinations, laboratory investigations, and imaging results (an example transcript is provided for SIMBA PCOS and SIMBA Adrenal conditions as supplementary 4A-B).

Doing cycle 1

Moderators for the simulation were recruited through advertisements and trained in each simulated scenario. HCPs interacted with moderators on WhatsApp, taking relevant history and requesting appropriate investigations to make diagnoses and management/follow-up plans. The moderators provided the information requested by the HCPs from the pre-prepared transcripts. If the requested information was unavailable in transcripts, the moderator replied, 'Information requested is not available’. After completing all the simulated cases, participants attended a discussion about the cases with appropriate experts. We previously published a detailed description of the various steps involved in the SIMBA session, and a summary is included in Supplementary 5 [ 18 ].

In parallel, people with PCOS were invited to participate in workshop-style learning. Here, the transcripts of cases used in SIMBA PPI-HCP were presented to participants, sharing information on how people with PCOS were managed in real life. This was followed with a discussion of the instances concentrating on ‘what was done well’, ‘what could be done better’, and ‘what was not covered’ during the case management. A participant was invited to volunteer and summarise each case, which was presented to the other participants during the discussion.

Case discussion with Q&A

This session brought together HCPs and people with PCOS to discuss the cases in detail. Thirty minutes were allocated per case. In the first 5 min, experts presented the case to the group. This was followed by a discussion of the cases about evidence-based guidelines (5 min). In the following five minutes, HCPs who participated in the simulation asked their queries on the cases. The participant from the SIMBA PPI-PCOS group who summarised the discussions shared their findings on that case for five minutes. Each session was concluded with a 10-min discussion on the challenges of managing the cases to identify the gap in knowledge and expectations between people with PCOS and their HCPs. In total the case discussion lasted 2.5 h.

Evaluation and feedback

Studying cycle 1 and acting cycle 1.

We invited feedback from the SIMBA team and the expert chairs of the session. This was combined with the feedback from HCPs and PPI participants. The summary of the feedback is as follows which was implemented:

SIMBA team members suggested a serial instead of a parallel approach for HCP and PPI sessions to better distribute the workload.

Chairs recommended a pre-session meeting instead of just emails to understand the session better.

The main feedback from HCP participants was to conduct a session on various cases.

PPI participants recommended either breaking down the cases over multiple sessions or reducing the number of cases to allow for more in-depth exploration enabling equal participation from all attendees and ensure representation from a broader range of patient groups.

SIMBA-Adrenal conditions six-step conceptual framework and PDSA cycle 2

In contrast, compared to PCOS, most adrenal conditions are classified as rare diseases due to their low prevalence [ 29 , 30 ]. However, if they remain unrecognised, patients can develop adrenal crisis, which can be fatal. Therefore, HCPs must establish effective educational interventions to recognise adrenal conditions early on. Involving those with adrenal conditions can help HCPs improve their communication skills in the diagnosis and management of adrenal conditions. In this session, we considered all the suggestions from the SIMBA-PCOS session and worked to optimise the model to address better our aim of bridging the knowledge gap between patients and HCPs.

We identified the need for a model to accommodate better the HCPs and patients participating in the SIMBA PPI study. Instead of both HCP and PPI arms in parallel, people with adrenal conditions were invited on a separate day beforehand. This was implemented following feedback from the SIMBA team members, as detailed above. It also provided more options for PPI members, enabling them to arrange the session at a time of their convenience instead of a fixed slot. This also allowed the SIMBA team more time to summarise the discussions of each case beforehand.

Furthermore, we created an opportunity for input from Brazilian Portuguese-speaking communities. To facilitate this, the six case transcripts were translated into Brazilian Portuguese. A SIMBA team member fluent in English and Brazilian Portuguese held the workshop-style learning in Brazilian Portuguese. They transcribed and summarised the discussion from the workshop into English, which was presented at the discussion.

We aimed to develop a model that promoted PPI in clinical decisions and allowed an open dialogue between patients and HCPs, improving the clinical care of people with adrenal conditions.

As with SIMBA-PCOS, the SIMBA-Adrenal conditions model is based on the simulation game and Kolb’s experiential learning theory [ 19 ].

Implementation of the educational model and PDSA Cycle 2

Planning cycle 2.

For the session, the cases included Addison’s disease, adrenal incidentaloma, adrenocortical carcinoma, Cushing’s syndrome, mild autonomous cortical secretion, and primary aldosteronism. Instead of both HCP and PPI arms in parallel, people with adrenal conditions were invited on a particular day beforehand. This was implemented following feedback from the SIMBA team members, as detailed above. The rest of the planning was similar to the first cycle, where PCOS scenarios were simulated.

Doing cycle 2

27 HCPs underwent simulation-based learning focusing on six case scenarios of adrenal conditions as detailed in the SIMBA-PCOS session. PPI workshops were held a week before the SIMBA-Adrenal conditions session, and conducted similar to SIMBA-PCOS session.

We introduceds several changes to the case discussion compared to the first cycle. ItWe extendeds the total duration to 3.5 hours, compared to 2.5 hours in the first version, by increasing the time allocated per to ensure each case discussion lasted to 30 minutes. NotablyIn contrast to cycle one, each case discussionit beginsan with a 10-minute pre-recorded expert talk to avoid technical issues and save time, unlike the live 5-minute expert presentation in the first version. Additionally, a SIMBA PPI-Adrenal group member provides a 5-minute summary, and the session concludes with a longer, 15-minute open Q&A, involving all expert panel members, allowing for a more comprehensive discussion. These changes aim to streamline the process and enhance the depth of interaction between healthcare professionals and participants.

Studying cycle 2

We gathered feedback from SIMBA team members, chairs, experts involved in the discussion, and participants. The primary feedbacks were:

SIMBA team members felt the session was much better regarding organisation and delivery than the SIMBA-PPI PCOS session.

Chairs recommended a follow-up email following the pre-session meeting to summarise the plans for the session.

Participants recommended to continue organising similar sessions but aim for weekdays instead of weekends.

Acting cycle 2

We gathered all the feedback and analysed the data from both sessions to recommend future sessions, as detailed in the results and discussion sections below.

Data collection and statistical analyses

To answer our research questions, we used a mixed quantitative and qualitative research method. The analysis included data from participants who completed both pre- and post-SIMBA surveys.

HCP participants

Baseline characteristics, including location and level of training, were recorded. The differences in pre- and post-SIMBA questionnaire responses measured the changes in participants' self-reported confidence levels in managing cases included in the SIMBA-PPI session. The impact of participant’s responses to the six domains of medical education based on the core competencies of the Accreditation Council for Graduate Medical Education (ACGME) was also assessed [ 31 ]. Participants could select as many competencies as they found relevant to the session, including patient care, professionalism, knowledge of patient management, system-based practice, practice-based learning, and communication skills.

PPI participants

demographic information including age, ethnicity, location, and years since diagnosis were recorded. The efficacy of SIMBA in increasing knowledge of the respective conditions was explored through a series of questions and measured using a 5-point Likert scale. Pre- and post-SIMBA questionnaires were used to evaluate the efficacy (Supplementary 6A-D). These consisted of questions on knowledge regarding the conditions pre- and post-simulation. Unfortunately, due to the split between the workshop and the HCP simulation, many PPI participants did not attend the discussion session; hence, post-SIMBA questionnaires were not filled. The workshops and discussion sessions were recorded and transcribed via Zoom. The content of the transcripts was closely examined and analysed thematically by two independent study authors. Responses from the transcribed sessions were first read and familiarised, systematically identifying the text's main points and attaching labels/codes to capture the main ideas. Relevant and recurrent codes were then collated into themes inductively (data-driven themes) and reviewed.

Statistical analysis of quantitative data was performed using STATA (STATA/SE 17.0 for Mac). Confidence levels are reported in frequencies and percentages and are presented as bar charts (Fig.  3 ). The Wilcoxon Signed-Rank test was used to compare pre- and post-SIMBA self-reported confidence levels. Statistical significance was accepted at a 95% confidence level. In addition, improvement in participants' confidence levels of simulated cases compared to non-simulated cases, followed by all sessions combined, was included in the comparison and reported as above (Figs.  1 and 2 ).

SIMBA-PCOS A ) Illustration of changes in healthcare professionals’ confidence levels for managing simulated vs non-simulated cases. B Illustration of changes in confidence levels of women with PCOS for their confidence in HCPs to manage simulated vs non-simulated PCOS-related issues. C Illustration of changes in confidence levels of women with PCOS for their confidence in HCPs’ awareness of options available for managing simulated vs non-simulated PCOS-related issues

SIMBA-Adrenal conditions: An illustration of changes in healthcare professionals’ confidence levels for managing simulated vs non-simulated cases

Post-SIMBA questionnaires for HCP also included open-ended questions regarding the overall feedback of the session. We performed a thematic inductive analysis for these open-ended questions to identify common feedback themes.

Patient and public involvement statement

Various patient support groups and public were involved since the start of the project. Patients and public underwent workshop-style learning in parallel, using the same cases. HCPs, patients and public then came together to discuss the issues with the experts via Zoom. This promoted patient and public involvement in clinical decisions and care to achieve an equal partnership between healthcare professionals and patients alongside integrating PPI into medical education at both undergraduate and postgraduate levels. This model was codesigned by a PPI expert coordinator (CG).

HCP Results

Twenty-five out of 29 participants (86%) completed both pre- and post-SIMBA questionnaires. Characteristics of participants are described in Supplementary 7. Clinicians’ confidence in managing PCOS-related issues increased post-SIMBA for all eight domains of PCOS measured in this session (skin, weight, fertility, menstruation, menopause, diabetes, mental health, and endometrial cancer). Simulated cases and non-simulated cases showed a 41.0% ( p  < 0.001) and 40.0% ( p  < 0.001) increase in confidence, respectively, with all cases combined showing a 40.5% increase in confidence ( p  < 0.001) (Fig.  1 A). There was an improvement in patient care (64.0%), communication skills (40.0%), professionalism (28.0%), knowledge of patient management (72.0%), system-based practice (32.0%), and practice-based learning (60.0%) (Fig.  2 ). 88.0% of SIMBA-PCOS participants strongly agreed/agreed that simulated topics applied to their practice, and 100% would attend similar SIMBA sessions in the future. Content analysis of feedback from SIMBA-PCOS participants to open-ended questions showed a positive rating and constructive comments for future sessions. Suggestions focused on three themes: time considerations, Q&A discussion format, and session content. Participants reflected on requiring more time for cases and discussion to allow for more questions to be answered. There was a call for more focus on assessing and managing the cases during the Q&A discussion.

SIMBA-Adrenal conditions

Twenty-three out of 27 (85%) HCP participants completed both pre- and post-SIMBA questionnaires. Characteristics of participants are described in Supplementary 7. Self-reported confidence increased post-SIMBA-Adrenal conditions for all ten adrenal conditions measured in the session (Addison’s disease, adrenal incidentaloma, adrenocortical carcinoma, Cushing’s syndrome, minimal autonomous cortisol secretion, primary aldosteronism, bilateral adrenal hyperplasia, congenital adrenal hyperplasia, phaeochromocytoma, and virilisation). Simulated cases and non-simulated adrenal cases showed a 22.5% ( p  < 0.001) and 24.0% ( p  < 0.001) increase in confidence, respectively, with all cases showing a 23.0% increase in confidence ( p  < 0.001) (Fig.  2 ). Participants reported improvement in confidence in practice-based learning (69.6%), system-based practice (43.5%), knowledge of patient management (87.0%), professionalism (43.5%), communication skills (26.1%), and patient care (43.5%) (Fig.  3 ). 95.6% strongly agreed/agreed that the simulated cases applied to their practice, and 100% would attend similar SIMBA sessions. Content analysis of feedback from SIMBA-Adrenal conditions participants to open-ended questions showed positive and constructive themes. Suggestions for improvement focussed on session length and structure, with participants reflecting on having smaller groups between chairs and participants for Q&A and using fewer cases to allow for a more in-depth discussion.

HCP’s Self-reported increase in confidence across competencies post-SIMBA-PCOS and SIMBA-Adrenal conditions

Patient results

Fifteen women with PCOS attended the session. Twelve (80%) completed both pre- and post-session surveys. Supplementary 8 shows the demographics of women with PCOS who participated in the session. The median age of PCOS diagnosis ( n  = 10) was 20.5 (IQR 19–25) years. 83.3% ( n  = 10/12) of people were aware of the criteria for diagnosing PCOS, and no significant difference after the session was noted ( p  = 1.000). People with PCOS reported their confidence in HCPs increased by 6.25% post-session ( p  = 0.0141) (Fig.  1 B).

Similarly, people with PCOS’ confidence in HCPs’ awareness of options for managing PCOS-related issues increased by 17.7% ( p  = 0.0002) (Fig.  1 C). 90% strongly agreed/agreed that SIMBA-PCOS benefit people with PCOS to better understand their condition and clinicians’ perspectives on the diagnosis and management of PCOS. In addition, 100% of people with PCOS strongly agreed/agreed that SIMBA-PCOS benefits clinicians in understanding patients’ perspectives on diagnosing and managing PCOS. Content analysis on open-ended questions was performed on all 12 participants who completed the post-SIMBA survey. Table 1 summarises these findings. Participants found the session informative, with engaging discussion and organised structure. Suggestions for improvement for future sessions centred around the format of the session advising breaking down the cases over sessions or reducing the number of cases to allow for future exploration of cases, together with organising structured feedback for future session discussions, allowing the equal contribution of all participants and representation from a broader range of patient groups.

Ten people diagnosed with adrenal conditions attended SIMBA-Adrenal conditions, and all 10 (100%) completed post-SIMBA surveys. Adrenal conditions represented were Addison's disease ( n  = 5), adrenocortical carcinoma ( n  = 3), Cushing’s disease ( n  = 1), and primary aldosteronism ( n  = 1). The median age of diagnosis with an adrenal condition was 39 (IQR 33–53) years. After the session, 70% knew the criteria for diagnosing their adrenal condition. 90% strongly agreed/agreed that SIMBA-Adrenal conditions benefited people with various adrenal conditions to understand their conditions better. 80% thought the session helped them understand clinicians’ perspectives on diagnosing and managing relevant adrenal conditions. Additionally, 80% of participants strongly agreed/agreed that SIMBA-Adrenal conditions benefit clinicians in understanding patients’ perspectives on diagnosing and managing adrenal conditions.

Content analysis was performed on all 10 participants’ feedback to open-ended questions. People with adrenal conditions revealed positive comments, including well-presented cases, open information sharing and a shared experience between doctor and patient (Table  2 ). Suggestions for improvement included bringing more doctors to discussion sessions having an agenda for discussion sessions alongside acknowledging individual circumstances and levels of understanding.

SIMBA-PPI sessions effectively improved clinicians’ confidence in managing PCOS and adrenal conditions. There was a greater improvement in HCP confidence in managing PCOS compared to adrenal conditions. This is likely due to a lower baseline confidence in managing simulated PCOS compared to adrenal conditions. For both SIMBA-PCOS and SIMBA-Adrenal conditions, most HCPs agreed that the simulated topics were applicable to their practice, and all participants indicated they would attend similar SIMBA sessions in the future. We acted upon HCPs’ feedback from the first SIMBA-PPI session, including allocating more time for case discussions and focussing more on assessment and management during the longer Q&A sessions. Feedback from HCPs for SIMBA-Adrenal was favourable for these changes. We will incorporate the suggestions for smaller groups for Q&A sessions and use fewer cases for more in-depth discussion in future sessions.

People with PCOS and adrenal conditions agreed that SIMBA-PPI sessions helped them learn more about their needs and understand clinicians’ perspectives on diagnosis and management. Our findings suggest there is a gap in knowledge and expectations between patients and HCPs involved in their care, and this gap can be reduced by attending SIMBA sessions involving both affected people and HCPs.

Drawing from theories such as Experiential Learning [ 20 ] and Participatory Action Research [ 10 ], the SIMBA-PPI model places patients and the public at the forefront. By recognising the importance of community engagement and empowerment, Community-Based Participatory Research [ 32 ] (CBPR) principles are woven into the fabric of the SIMBA-PPI model, emphasising collaboration, relevance, and cultural responsiveness. This educational framework aligns with the Health Belief Model [ 11 ] and Theory of Planned Behaviour [ 12 , 13 ], acknowledging the significance of individual beliefs, attitudes, and readiness to engage in healthcare decisions. At its core, the SIMBA model harnesses the power of Empowerment Theory [ 13 ] and Social Cognitive Theory [ 14 ] to cultivate an educational environment that educates future healthcare providers and empowers patients and the public to participate in their care actively. It champions the development of a new generation of healthcare professionals who value partnership, empathetic communication, and collaboration with patients and communities.

To our knowledge, this is the first educational activity with PPI to identify the knowledge gap between HCPs and people with PCOS and adrenal conditions. The efficacy of SIMBA as an educational tool in improving clinicians’ confidence in managing simulated cases, with a high acceptance rate, is consistent with our previous SIMBA sessions on diabetes, endocrinology and acute medicine [ 16 , 18 , 33 , 34 ]. In SIMBA, participants completed three stages of Kolb’s experiential learning cycle before going into the fourth stage—active experimenting -, when they can apply the knowledge learnt from SIMBA into their real-life clinical practice. In SIMBA-PPI, the patients provided additional learning to the HCP participants at each of the three stages of the learning cycle. The experience shared by the patients enabled HCPs to reflectively observe and form a better conceptualisation of the content through lived experiences.

Several studies have highlighted the gap in knowledge, attitude, and perception of clinical care between HCPs and people with PCOS and adrenal conditions. Delays in diagnoses of PCOS and inadequate information given to people with PCOS upon diagnosis have been reported worldwide [ 23 , 24 , 35 ]. Poor experiences with diagnoses and management of PCOS have been associated with increased anxiety and depression, further negatively impacting self-management [ 36 , 37 , 38 ]. This has led to patients and their carers relying on mostly non-evidence-based information online, potentially containing inaccuracies and contradicting what patients have been advised by the HCPs [ 36 ]. Similarly, patients with adrenal conditions often receive late diagnoses [ 39 , 40 , 41 ]. Previous studies have also shown that patients were unaware of appropriately adjusting steroid doses during acute illness due to suboptimal and inconsistent education [ 40 , 41 ]. SIMBA-PPI helps to address this issue by bringing HCPs and patients together to share real-life experiences and provides a platform where both can teach and learn from each other [ 36 , 39 ]. Such educational events can also help patients understand evidence-based strategies and clinicians' limitations. This may potentially reduce any unrealistic expectations of the patients and the gap in knowledge and expectations between patients and HCPs.

The content analysis of feedback from open-ended questions identified several areas for improvement as part of the PDSA cycle. Further feedback from SIMBA-Adrenal conditions suggests future sessions should be more tailored to individual patient circumstances and different levels of understanding. Additional work is needed to determine whether our findings of increased self-reported confidence levels translate to a long-term improvement in clinical performance and patient-reported outcome measures.

The integrative SIMBA model envisions a curriculum where students learn from, with, and about patients and the public. Through immersive, experiential learning opportunities, students engage in authentic healthcare scenarios, fostering critical reflection, and applying insights gained from collaborative interactions. It promotes the creation of inclusive spaces where patients, healthcare professionals, educators, and researchers co-create knowledge and solutions, thereby bridging the gap between theory and practice. In essence, the SIMBA patient public involvement medical education model represents a transformative approach, transcending traditional pedagogical boundaries to nurture a healthcare ecosystem rooted in empathy, collaboration, and patient-centred care.

While the study has several strengths in the design and outcomes, we acknowledge that some factors may limit our findings' generalisability, one being that the results are from only two sessions. Our PPI participants were invited through various support groups and were interviewed for their interest in participating. This may be considered as a potential selection bias due to this convenience sampling method. However, the interview was necessary to ensure their engagement for the entire duration of our session. Another limitation was that for SIMBA-Adrenal conditions due to the split between the workshop and the HCP simulation, many PPI participants did not attend the discussion session; hence, post-SIMBA questionnaires were not filled. This can be mitigated in the future by reducing the time gap between the workshop and HCP simulation, ensuring clear communication, sending timely reminders and engaging participants actively in the process. In addition, our small sample size may also impact our results and may not be representative of the general patient population. However, applying a mixed-method approach helped consolidate the findings from the study. The study questionnaires were not validated, which could affect their reliability.

Follow-up studies based on the principles of Diffusion of Innovation Theory [ 42 ] and Transtheoretical Model [ 43 ] are needed to study long-term impact. Further studies will look into the differences in opinions, experiences, and expectations of HCPs trained in the UK versus abroad. Similarly, we want to incorporate a wider perspective of patients from different backgrounds. Following the successful implementation of SIMBA in undergraduate education, we are looking to introduce PPI. We also want to implement SIMBA-PPI as a continuing professional development activity for specialist trainees.

SIMBA-PPI is an effective learning tool for people with PCOS and adrenal conditions and their healthcare professionals to enhance their understanding of the condition. SIMBA is open access and cost-effective. The model also helped identify and reduce gaps in knowledge and expectations between HCPs and patients with PCOS and adrenal conditions. Future large-scale studies are needed to study the long-term impact on clinical practice and patient-reported outcome measures.

Availability of data and materials

Data available on request to the corresponding author.

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Acknowledgements

We thank the HCPs and patients who participated in this study. We thank PCOS and adrenal support groups—PCOS Verity, PCOS vitality, DAISy-PCOS, PCOS Club India, Abaddison Brasil, ACC Support UK, Addison’s Disease Self-Help Group, Alex-The Leukodystrophy Charity, The Association for Multiple Endocrine Neoplasia Disorders and Cushing's UK Facebook group—for their support for the study. We thank the University of Birmingham Medical School students who participated as moderators in this study. We also thank the Health Education West Midlands Specialist trainee committee, Institute of Metabolism and Systems Research, University of Birmingham, and Institute of Applied Health Research, University of Birmingham, for supporting this study. We thank Dr Helena Gleeson, Dr Konstantinos Manalopoulus, Dr Justin Chu, Dr Michael O’Reilly, and Professor Wiebke Arlt for their expert inputs during discussion.

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The study did not receive any funding.

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Eka Melson, Fatema Rezai and Carina Pan are joint first authors.

Authors and Affiliations

Institute of Clinical Sciences, Imperial College London, London, United Kingdom

Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom

Eka Melson & Caroline Gillett

College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

Fatema Rezai, Carina Pan, Sung Yat Ng, Ella Blendis, Haaziq Sheikh, Harjeet Kaur, Francesca Pang, Shreya Bhatt, Zahra Olateju, Eloise Radcliffe, Prashanthan Balendran, Abby Radcliffe, Gar Mun Lau & Dengyi Zhou

University of Lancaster, Lancaster, United Kingdom

Tamzin Ogiliev

Walsall Manor Hospital, Walsall, United Kingdom

Catherine Cooper

Queen Charlotte’s and Chelsea Hospital, London, United Kingdom

University of Warwick, Conventry, United Kingdom

Farah Abdelhameed

Jinnah Medical and Dental College, Karachi, Pakistan

Dania Shabbir

Clinic NeoLab, Tbilisi, Georgia

Meri Davitadze

Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom

Meri Davitadze, Kashish Malhotra & Punith Kempegowda

Northwick Park Hospital, London North West University Healthcare NHS Trust, London, United Kingdom

Dengyi Zhou

Rama Medical College Hospital, Hapur, Uttar Pradesh, India

Kashish Malhotra

Queen Elizabeth Hospital Birmingham, University Hospitals NHS Foundation Trust, Birmingham, Uttar Pradesh, United Kingdom

Punith Kempegowda

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Contributions.

All authors have contributed to the manuscript as per ICMJE criteria. EM, FR, and CP contributed equally to the study and are listed as joint first authors. SYN, TO, EB, JS, HK, CC, FA, FP, SB, DS, ZO, ER, PB, AR, GML, MD, DZ, and HG contributed to the study as moderators and interviewed SIMBA-PPI. KM, JC, MOR, WA, and CG contributed as experts to the conditions studied. PK conceptualised and supervised the delivery of all aspects of SIMBA and critically reviewed the manuscript. The final version has been reviewed and approved by all the named authors. The SIMBA team included members who contributed in all study phases and hence are included as collaborating authors. This includes Emily Warmington, Pavithra Sakthivel, Vina Soran, Anisah Ali, Harshin Pallathoor Balakrishnan, Maiar Elhariry, Sangamithra Ravi, Rachel Nirmal, Aditya Swaminathan, Shams Ali Baig, Isabel Allison, Tamzin Ogiliev, Dwi Delson, Soon Chee Yap, Vardhan Venkatesh, Fazna Rahman, Dr Helena Gleeson, Dr Konstantinos Manalopoulus, Dr Justin Chu, Dr Michael O’Reilly, and Professor Wiebke Arlt .

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Melson, E., Rezai, F., Pan, C. et al. Reducing the Gap in Knowledge and Expectations between Clinicians and People with Polycystic Ovary Syndrome or Adrenal Conditions: Simulation via Instant Messaging—Birmingham Advance: Patient and Public Involvement (SIMBA-PPI) Study. BMC Med Educ 24 , 784 (2024). https://doi.org/10.1186/s12909-024-05772-w

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Chromosomal instability in a patient with ring chromosome 14 syndrome: a case report

• Juan Pablo Meza-Espinoza 1 ,
• Juan Ramón González-García 2 ,
• Nayeli Nieto-Marín 3 ,
• Liliana Itzel Patrón-Baro 3 ,
• Rosa María González-Arreola 4 ,
• Eliakym Arámbula-Meraz 5 ,
• Julio Benítez-Pascual 6 ,
• Alberto Kousuke De la Herrán-Arita 7 ,
• Claudia Desireé Norzagaray-Valenzuela 8 ,
• Marco Antonio Valdez-Flores 7 ,
• Tomás Adrián Carrillo-Cázares 7 &
• Verónica Judith Picos-Cárdenas 7  

Molecular Cytogenetics volume  17 , Article number:  17 ( 2024 ) Cite this article

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Metrics details

Ring chromosome 14 syndrome is a rare disorder primarily marked by early-onset epilepsy, microcephaly, distinctive craniofacial features, hypotonia, intellectual disability, and delay in both development and language acquisition.

Case presentation

A 21-year-old woman with a history of epileptic seizures since the age of 1.5 years presented with distinctive craniofacial features, including a prominent and narrow forehead, sparse and short eyebrows, palpebral ptosis, horizontal palpebral fissures, a broad nasal bridge, a prominent nasal tip, a flat philtrum, hypertelorism, midfacial hypoplasia, horizontal labial fissures, a thin upper lip, crowded teeth, an ogival palate, retrognathia, and a wide neck. Additional physical abnormalities included kyphosis, lumbar scoliosis, pectus carinatum, cubitus valgus, thenar and hypothenar hypoplasia, bilateral hallux valgus, shortening of the Achilles tendon on the left foot, and hypoplasia of the labia minora. Chromosomal analysis identified a ring 14 chromosome with breakpoints in p11 and q32.33. An aCGH study revealed a ~ 1.7 Mb deletion on chromosome 14qter, encompassing 23 genes. Genomic instability was evidenced by the presence of micronuclei and aneuploidies involving the ring and other chromosomes.

The clinical features of our patient closely resembled those observed in other individuals with ring chromosome 14 syndrome. The most important point was that we were able to verify an instability of the r(14) chromosome, mainly involving anaphasic lags and its exclusion from the nucleus in the form of a micronucleus.

Human ring chromosomes are structural abnormalities resulting from two breaks in the DNA strand that fuse to form a circular DNA molecule, often leading to genetic material loss. These chromosomes can possess one or more centromeres or lack one entirely, affecting their segregation during anaphase. Ring chromosomes have been reported for all human chromosomes, with approximately half involving acrocentric chromosomes, including chromosome 14 [ 1 ]. Numerous cases of chromosome 14 rings have been documented, with the deleted region’s size ranging from 0.3 to 5 megabases (Mb) [ 2 ]. The severity of the phenotype, known as ring chromosome 14 syndrome [r(14) syndrome, Online Mendelian Inheritance in Man (OMIM) #616,606], varies among patients [ 3 ]. Key clinical features include early-onset epilepsy, microcephaly, hypotonia, intellectual disability, developmental and language delays, and distinctive craniofacial dysmorphisms such as hypertelorism, micrognathia, a thin upper lip, down-turned mouth corners, a high-arched palate, and large, low-set ears [ 4 ]. Additional features include motor skill issues, retinal abnormalities, feeding difficulties, and behavioral disorders [ 2 , 3 , 5 ]. The deletion of specific genes on 14q32.2-32.3 is believed to cause the primary clinical features of the syndrome [ 3 ], although other genes outside the deleted region might also influence the phenotype [ 6 ].

Ring chromosomes exhibit inherent instability due to the sister chromatid exchange process, which can create dicentric or interlocked ring chromosomes. During mitosis, these chromosomes can undergo anaphase lagging, nondisjunction, or fragmentation, leading to cells without the ring chromosome, cells with multiple ring chromosomes, binucleated cells, internuclear bridges, nuclear protrusions, and micronuclei (MN). This phenomenon is known as tissue-specific dynamic mosaicism [ 7 ]. Ring chromosomes show variable instability in vivo based on their size and genetic content [ 8 ], but there is no clear correlation between the size of a ring chromosome, the occurrence of dynamic mosaicism, and clinical severity [ 9 ].

In this report, we present the case of a female with a ring chromosome 14, who exhibited epileptic seizures, craniofacial dysmorphism, skeletal abnormalities, and genital alterations. Chromosomal instability was also observed through the presence of MN and aneuploidies.

A 21-year-old woman, the fifth child of healthy, unrelated parents, experienced epileptic seizures beginning at 1.5 years old, which were managed with valproic acid. She has been seizure-free since the age of 2 and has been off treatment since the age of 8. Currently, she has a height of 162 cm (50th percentile) and a head circumference of 53.5 cm (10th-25th percentile), along with a high anterior hairline. She exhibits craniofacial dysmorphism, including a prominent and narrow forehead, sparse and short eyebrows, palpebral ptosis, horizontal palpebral fissures, a broad nasal bridge, a prominent nasal tip, a flat philtrum, hypertelorism, midfacial hypoplasia, horizontal labial fissures, a thin upper lip, crowded teeth, an ogival palate, retrognathia, and a wide neck. Additional features include kyphosis, lumbar scoliosis, bilateral cubitus valgus, thenar and hypothenar hypoplasia, bilateral hallux valgus, shortening of the Achilles tendon on the left foot, and hypoplasia of the labia minora. Although clinical images are not provided due to lack of parental authorization, her clinical characteristics align with those typically reported for ring chromosome 14 syndrome (Table  1 ).

Conventional cytogenetic studies

Peripheral blood lymphocytes from the patient were cultured and harvested using standard methods for karyotype analysis. Chromosomal analysis of GTG-banded metaphases revealed the presence of a ring chromosome 14 (Fig.  1 A). Both parents had a normal karyotype. FISH (fluorescense in situ hybridization) analysis using the TCL1 break-apart and IGH/BCL2 probes indicated the breakpoint occurred distal to the TCL1 (q32.13) but proximal to the IGH (q32.33) genes (Fig.  1 B and D). Additionally, FISH with a nucleolus organizer region (NOR) specific probe showed no signal in the r(14) chromosome (Fig.  1 C). The frequencies of cells with TCL1 break-apart signals in interphase FISH were as follows: 198/243 cells (81.5%) had two signals, 30/243 cells (12.3%) had only one signal, suggesting the loss of the r(14) chromosome, and 15/243 cells (6.2%) had three signals, likely indicating a duplicated dicentric r(14) chromosome.

Cells from the patient cultured, harvested, and stained using standard methods for karyotype analysis. A GTG-banded metaphase showing the r(14) chromosome. B The same metaphase was sequentially analyzed by FISH with IGH/BCL2 probes, revealing that the r(14) chromosome lacks the IGH signal. C FISH with NORs probes showed that the r(14) chromosome lacks NORs signals. D FISH with the TCL1 probe indicated that the deleted region is distal to the TCL1 gene. Additionally, two abnormal cells were identified: one with three signals, likely indicating a dicentric r(14), and one with only one signal, suggesting a loss of the r(14) chromosome

Microarray study

To determine the extent of the genomic imbalance, array comparative genomic hybridization (aCGH) was performed using CytoScan™ Technology (Thermo Fisher Scientific Inc). The processes of digestion, ligation, Polymerase chain reaction (PCR), purification of PCR products, quantification, fragmentation, labeling, matrix hybridization, washing, staining, and scanning arrays were carried out following the supplier’s recommendations. Data analysis was conducted with ChAS 4.3 software. Results were interpreted using several databases, including the Database of Genomic Variants, Cytogenomics, Array Group CNV Database, Ensembl Resources, OMIM, UCSC Genome Browser, ClinGen, ClinVar, and CHD wiki. The analysis revealed a terminal deletion of approximately 1.7 Mb on chromosome 14, encompassing 23 genes: BRF1, BTBD6, PACS2, TEX22, MTA1, CRIP2, CRIP1, TEDC1, IGH, TMEM121, LOC105370697, MIR8071-1, MIR8071-2, ELK2, MIR4539, MIR4507, MIR4538, MIR4537, FAM30A, ADAM6, LINC00226, LINC00221 , and MIR5195 (Fig.  2 ).

Based on all the studies, the patient’s karyotype was concluded to be 46,XX, r(14).ish r(14)(p11q32.33) (NOR-,TCL1+,IGH-).arr[GRCh38] 14q32.33(105,194,385_106,876,229)x1 dn.

Analysis of aCGH. Left, image representing chromosome 14. Right, plot of weighted log2 ratio. The red arrows indicates the deleted region: arr[GRCh38] 14q32.33 (105,194,385_106,876,229)x1

Ring mitotic instability

Given the known mitotic instability of several ring chromosomes, we investigated this phenomenon in our patient. A new culture of the patient’s peripheral blood lymphocytes, stimulated with phytohaemagglutinin, was prepared. Unlike the standard culture used for karyotype analysis, this culture was directly fixed and washed in a cold solution of absolute methanol: glacial acetic acid (3:1) after 72 h of incubation, without exposure to colchicine or hypotonic shock. Cells suspended in fixative solution were dropped onto microscope slides and stained with Giemsa. Cells in metaphase, anaphase, telophase, or cytokinesis were analyzed for mitotic disturbances, and micronucleated cells were counted. Selected microscopic coordinates were recorded for subsequent FISH analyses using IGH and TCL1 break-apart probes. This method revealed various mitotic disturbances. Several cells failed to align at the classical metaphase plate, showing chromosome compaction and distribution similar to those in a classical colchicine block (Fig.  3 A-D). Additionally, some cells displayed chromosome laggards affecting chromosomes other than the r(14) (Fig.  3 E-H) or exhibited a multipolar mitosis-like chromosome organization (Fig.  3 I-L) (for comparison, see Barajas-Torres et al., 2016 [ 10 ]).

Giemsa-stained altered mitotic cells, sequentially studied by FISH using the TCL1 break-apart probe. These cells were harvested without colchicine block and KCl shock. A-D Two metaphase cells with chromosome compaction and distribution resembling those harvested with colchicine. E-H Metaphase cells displaying lagging chromosomes, excluding chromosome 14 and r(14). I-L Mitotic cells with multipolar-like configurations, also showing lagging chromosomes

Sequential FISH assays demonstrated that the segregation of the r(14) chromosome was preferentially affected (Fig.  4 : B-C, E-F, and H-I). As a result of this anomalous anaphase-telophase segregation, the r(14) chromosome would be excluded from the main nucleus in the daughter cells, likely forming a micronucleus. The analysis of mitotic figures revealed the following counts of abnormal cells: 33 out of 81 (41%) metaphase cells, 2 out of 10 (20%) anaphase cells, and 4 out of 28 (14%) telophase-cytokinesis cells.

Giemsa-stained mitotic cells serially studied by consecutive FISH with IGH and TCL1 break apart probes (these cells were harvested without both colchicine block and hypotonic shock). A-C Anaphase cell in which a dicentric (duplicated) r(14) is in the middle of the mitotic spindle due probably to the nullification of forces generated by the centromeric traction to opposite poles. D-F Anaphasic r(14) lagging probably caused by a merotelic union. G-I Telophasic cell with r(14) chromosome lagging in both daughter nuclei which, probably, will be a micronucleus in each daughter cell

Consistent with these findings, we observed MN in 27 out of 305 (9%) interphase cells. FISH analysis of 21 out of those 27 micronucleated cells confirmed the presence of the r(14) chromosome in all of them (Fig.  5 ).

Selected micronucleated cells studied by consecutive FISH with the IGH and TCL1 break apart probes. A, D, G, J Giemsa-stained micronucleated cells. B, E, H, K Here, micronucleated cells show only one signal of the IGH gene located in the normal chromosome 14. Whereas, in C, F, I, L these cells show two signals of the TCL1 gene; interestingly, one of these signals is in the micronucleus of each cell, thus demonstrating that the micronucleus contains the genetic material of the r(14) chromosome. Furthermore, it is noteworthy that MN in I and L show double TCL1 signal, suggesting the presence of a dicentric (duplicated) ring chromosome

Discussion and conclusions

Our patient exhibited typical clinical features of ring chromosome 14 syndrome, including epileptic seizures, craniofacial dysmorphism, and skeletal abnormalities. In 23 reported cases with pure genomic deletions ranging from 0.3 to 5 Mb, including ours (Table  1 ), a consistent phenotype was observed, particularly with epileptic seizures (23/23), intellectual disability (23/23), microcephaly (22/22), speech impairment (22/23), hypotonia (19/21), and facial dysmorphism (17/23). However, other clinical features such as scoliosis (10/18), ocular anomalies (11/20), and susceptibility to infections (10/19) were also present although at a lower frequency.

Chromosomal instability in our case led to chromosome 14 monosomy in some cells (12.3%) and duplication of r(14) sequences in others (6.2%) (Fig.  2 -D). This is similar to what has been observed in rings derived from chromosomes other than 14 [ 14 ]. The mechanism behind this co-occurrence involves anaphase segregation after a sister chromatid exchange in the r(14) chromosome [ 2 , 9 ]. However, other mechanisms such as loss of the ring chromosome due to dicentric chromosome formation or merotelic unions may also contribute to chromosome 14 monosomy.

Loss of the ring chromosome can also be caused by other mechanisms. When a dicentric duplicated r(14) chromosome is pulled towards opposite poles at anaphase, the traction forces will be nullified. The dicentric chromosome will remain in the middle of the equatorial plaque (as exemplified in Fig.  4 A-C) giving rise to two daughter cells with monosomy, one of which could retain the dicentric chromosome as a micronucleus (as observed in Fig.  5 G-L). Merotelic unions of the r(14) are other mechanisms of origin of monosomy 14; in Fig.  4 D-F an r(14) chromatid is lagged in the middle of the anaphase cell, probably due to a merotelic union, and then, that chromatid will be absent from the nucleus of the daughter cell. A potential third mechanism of r(14) loss could be a delayed alignment in the equatorial plane of the r(14) at metaphase, as suggested in the Fig.  4 G-I, where both r(14) chromatids are lagged during telophase despite an apparent kinetochore-microtubule amphitelic attachment; subsequently, both daughter cells would lose the r(14) chromosome, becoming monosomic. On the other hand, micronucleated cells were detected with a frequency of 9% (27/305). The most significant finding was that all MN from 21 micronucleated cells tested by FISH studies had r(14) chromosome sequences (Fig.  5 ).

We have not identified reports of micronucleated cells in patients with an r(14) chromosome. However, evidence from ring chromosomes of other chromosomes indicates a propensity for these rings to be excluded from the main nucleus as MN. Ledbetter et al. [ 15 ] observed in a case of r(15) that 5 out of 1,000 cells were micronucleated and exhibited one or two silver NOR signals, suggesting the presence of monocentric and dicentric r(15) chromosomes in these MN. Similarly, Los et al. [ 16 ] reported 18 chromosome-derived MN in a patient with r(18). Yip et al. [ 17 ] observed MN in 4% of interphase cells and 16% of cells treated with cytochalasin B in a patient with r(3). Using whole chromosome painting (WCP3), they demonstrated chromosome 3 sequences in all MN. Urban et al. [ 18 ] reported 2.8% of cells with MN in a patient with r(6), all of which contained chromosome 6 centromeric sequences. In a case of r(7), Mehraein et al. [ 19 ] observed 3.5% micronucleated cells and confirmed the presence of chromosome 7 material in these MN using FISH with WCP7 and D7Z1 probes. A comparable finding was reported in a case of r(13), with 1% of micronucleated cells and 40% of these MN containing sequences derived from chromosome 13 [ 20 ]. Petter et al. [ 21 ] also found MN in three cases of r(13); all exhibiting chromosome 13 signals, as confirmed by WCP13. These findings support the hypothesis that the structure of ring chromosomes inherently leads to their exclusion from the main nucleus as MN. This hypothesis is further supported by Rudd et al. [ 22 ], who demonstrated experimentally that small ring chromosomes from chromosomes 17 and X missegregate more than normal chromosomes.

Additionally, 33 out of 81 (41%) metaphase cells exhibited abnormalities such as disorganized chromosome alignment in the equatorial plane, characterized by lagging chromosomes other than r(14), chromatin over-compaction similar to colchicine blockade, and multipolar spindle configurations (Fig.  3 ). It is unlikely that these abnormalities are solely due to the haploinsufficiency of genes in the deleted region, given that TEDC1 (tubulin epsilon and delta complex 1, required for centriole stability; Breslow et al. [ 23 ]) is the only gene directly related to these findings.

A common feature of ring chromosomes, including r(14), is the absence or reduction of the canonical telomeric sequence TTAGGG. Studies on telomere dynamics in interphase lymphocytes show that telomeres are located near the central nuclear region, whereas during postmitotic assembly, they move to the nuclear periphery [ 24 , 25 ]. Interestingly, during the G2 phase, telomeres assemble into a disk structure [ 26 , 27 ]. The impact of this telomere positioning on mitosis has not been studied. If the telomeric disk observed in G2 persisted into mitosis, it could act as an anchor for microtubule-kinetochore attachment, ensuring proper chromosome orientation in the equatorial plane and preventing monotelic, syntelic, and merotelic attachments [ 28 ].

A delay in microtubule-kinetochore binding or chromosome misorientation due to the lack of telomeric sequences on ring chromosomes could activate the spindle attachment checkpoint (SAC) [ 29 , 30 , 31 ], arresting metaphase progression until the issue is resolved. It has been noted that a single unattached kinetochore can activate the SAC and inhibit mitotic progression [ 32 ]. A prolonged prometaphase arrest triggers cellular responses such as apoptosis, DNA damage repair activation [ 33 , 34 ], telomere instability [ 35 ], and affects daughter cell proliferation [ 36 ]. Thus, SAC activation could explain the observed instability in many ring chromosome cases, including our r(14) case (Fig.  3 ), characterized by misaligned chromosomes, over-compacted chromosomes, and multipolar spindle configurations, which disrupt centriole duplication independently of cell-cycle progression [ 37 , 38 , 39 ]. The coalescence of extra centrosomes might explain findings by Rivera and Dominguez [ 40 ], who observed hypodiploidy (34 to 45 chromosomes) and polyploidy (74 to 96 chromosomes) in a patient with a r(4) chromosome.

In conclusion, ring chromosome syndrome is a pathological entity with significant variability due to factors including the affected chromosome, gene loss, positional effects of genes near breakpoints, and unbalanced segregation following ring chromosome sister chromatid exchange. Although previous work has suggested instability associated with chromosome rings, the evidence has been inconclusive [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. Remarkably, we have demonstrated an instability of the r(14) chromosome, mainly involving anaphasic lags and its exclusion from the nucleus in the form of a micronucleus. Further research into the inherent instability of ring chromosomes is needed to clarify these observations in patients with ring chromosomes.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

Array comparative genomic hybridization

Fluorescense in situ hybridization

G-bands by trypsin using Giemsa

Micronuclei

Nucleolus organizer region

Online Mendelian inheritance in man

Polymerase chain reaction

Spindle attachment checkpoint

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Alberto Kousuke De la Herrán-Arita, Marco Antonio Valdez-Flores, Tomás Adrián Carrillo-Cázares & Verónica Judith Picos-Cárdenas

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Contributions

J.P.M.E. Data collection and article drafting. J.R.G.G. and R.M.G.A. Performing and interpreting the cytogenetic studies and providing intellectual input during the manuscript drafting. N.N.M., L.I.P.B., and E.A.M. Collection of samples, making, and interpretation microarrays studies. J.B.P., M.A.V.F., C.D.N.V., and T.A.C.C. Patient recruitment and clinical examination. A.K.D.A. Intellectual input during discussion and revision of the draft. V.J.P.C. Conception and design of the study, drafting, acquisition and interpretation of data. All the authors contributed to the critical review and approved the final version of the manuscript.

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Meza-Espinoza, J.P., González-García, J.R., Nieto-Marín, N. et al. Chromosomal instability in a patient with ring chromosome 14 syndrome: a case report. Mol Cytogenet 17 , 17 (2024). https://doi.org/10.1186/s13039-024-00686-0

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Received : 25 May 2024

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DOI : https://doi.org/10.1186/s13039-024-00686-0

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