Nonclassic Congenital Adrenal Hyperplasia Research Articles

Analysis of the CYP21A2 gene pathogenic variants in CAH patients from Surgut using next-generation sequencing (NGS)

Background21-hydroxylase deficiency is present in 90–95% of cases of congenital adrenal hyperplasia (CAH). Eleven major pathogenic variants account for 93% of all identified variants in the CYP21A2 gene in various clinical forms of the disease. Each population has its own range of significant pathogenic variants. We aimed to study the frequency of pathogenic variants in the CYP21A2 gene using NGS technology and real-time PCR in Surgut patients with different clinical forms of CAH. NGS was performed on 70 patients with salt-wasting and non-classical clinical forms of 21-hydroxylase deficiency, verified by direct Sanger sequencing and PCR–RFLP analysis.ResultsEleven different pathogenic variants were found in 68.57% (48/70) of patients. Among 92.86% (13/14) of patients with salt-wasting CAH, variants were found to be homozygous, with CYP21A2 gene deletion as the most frequent mutation (46.4% or 13/28 alleles). In the group with non-classical CAH, pathogenic variants were identified only in 60.71% (34/56) of patients. V282L was discovered to be the most common variant in heterozygous carriers (45.45%, 15/33). NGS method identified 2 variants that were not determined by the standard method for major mutations detection: p.C170* and p.W22X, accounting for 3% of all known pathogenic variants.ConclusionOur data make it possible to clarify the specific spectrum of CYP21A2 gene pathogenic variants in CAH patients from Surgut. The NGS method allows for the identification of rare pathogenic variants (3%) in the CYP21A2 gene that are not included in the conventional PCR–RFLP analysis.

Cardiovascular risk in women with nonclassical congenital adrenal hyperplasia.

The outcomes related to cardiovascular risk (CVR) in patients with nonclassical form of congenital adrenal hyperplasia (NCAH) are unknown, especially those related to therapeutic options, including low doses of glucocorticoids (GCs) or oral contraceptive pills. to analyze CVR by markers of atherosclerosis in females with nonclassical form according to therapeutic options. a cross-sectional study at a tertiary center. Forty-seven females with NCAH (33.4 ± 10 years) were subdivided into: G1 (n = 28) treated with dexamethasone (0.14 ± 0.05 mg/m2/day); G2 (n = 19) with oral contraceptive pills; and G3 (30 matched controls). CVR was analyzed through serum lipids, HOMA-IR, inflammatory cytokines levels and quantitative image evaluations (pulse wave velocity-PWV, endothelial function by flow mediated dilatation-FMD, carotid intima media thickness-CIMT and visceral fat-VAT by abdominal tomography. There were no statistically significant differences in BMI, HOMA-IR, HDL-cholesterol, or triglyceride levels among groups (p > 0.05). Serum interleukin-6 levels ​​were higher in G1 than in G2 (p = 0.048), and interleukin-8 levels were higher in G1 than in G2/3 (p = 0.008). There were no statistically significant differences in VAT, PWV, FMD or CIMT among groups (p > 0.05). In multivariable regression analysis, there was no statistically significant association between glucocorticoid dose and evaluated outcomes. Adult females with NCAH did not show increased CVR using methodologies for detection of precocious atherosclerosis. Although patients receiving dexamethasone therapy had increased IL-6 and 8 levels, these data were not associated with radiological markers of atherosclerosis. Our cohort was composed of young adults and should be reevaluated in a long-term follow-up.

Prevalence of endocrine disorders in 304 premenopausal women referred with oligomenorrhoea.

We aimed to evaluate 304 premenopausal women admitted to our clinic for oligomenorrhoea, and to screen for Cushing's syndrome (CS) in this population. The study included 304 premenopausal women referred to our clinic for oligomenorrhoea. Anthropometric measurements and Ferriman-Gallwey score were evaluated, and thyroid hormone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone, prolactin, dehydroepiandrosterone sulphate (DHEA-S), and 17-hydroxyprogesterone (17-OHP) levels were measured in all patients. If basal 17-OHP was > 2 ng/mL, we evaluated adrenocorticotropic hormone (ACTH)-stimulated 17-OHP levels. CS was screened by 1 mg-dexamethasone suppression test, and if the cortisol value was > 1.8 μg/dL, we performed additional confirmatory tests, and if necessary, pituitary magnetic resonance imaging (MRI) and inferior petrosal sinus sampling (IPSS) were performed. The most common cause of oligomenorrhoea was polycystic ovary syndrome (PCOS) that was detected in 81.57% of cases, followed by hyperprolactinemia at 7.23% and hypothalamic anovulation at 5.26%. The prevalence of premature ovarian failure (POF) was 1.6%, and non-classical congenital adrenal hyperplasia (NCAH) was 1.97%. CS was detected in 7 (2.30%) patients. All the patients with CS were found to have Cushing's disease (CD). Although 3 patients with CD had classical signs and symptoms, 4 had none. Patients with CD had similar total testosterone values to those in the PCOS and NCAH groups, but they had significantly higher DHEA-S compared to both groups (CD vs. PCOS, p = 0.001 and CD vs. NCAH, p = 0.030). We found higher prevalence of CS in patients with oligomenorrhoea even in the absence of clinical signs. Therefore, we suggest routine screening for CS during the evaluation of patients with oligomenorrhoea and/or PCOS. The likelihood of CS is greater in patients with high androgen, especially DHEA-S levels.

Steroid metabolites producing adenoma: a case report

Hyperandrogenism is the most prevalent cause of menstrual cycle abnormalities and infertility in women. Here, we present a case of a 32-year-old woman with a 7-year history of menstrual irregularity and infertility. Laboratory test results revealed elevated 17-hydroxyprogesterone, progesterone 21-deoxycortisol. Abdominal computed tomography found a 3,9х2,9х2,6 cm left adrenal tumor. Non-classic congenital adrenal hyperplasia was diagnosed initially, however, treatment with supraphysiological doses of dexamethasone proved ineffective and progesterone and 17-hydroxyprogesterone levels remained high. Genetic testing revealed no 21-hydroxylase deficiency. Laparoscopic adrenalectomy was performed with subsequent pathological report being compatible with an adrenal cortical adenoma. 17-hydroxyprogesterone, progesterone 21-deoxycortisol levels returned to the normal range postoperatively and the patient’s menstrual cycle normalized without additional medication. Steroid metabolites producing adenomas are also extremely rare with only a few cases found in patients without previous CAH diagnosis. When a patient with clinically and biochemically diagnosed NCCAH demonstrate no typical features and shows poor response to steroid therapy, the patient should receive multisteroid LC–MS/MS assay for glucocorticoids and androgens, adrenal and ovarian imaging and undergo CYP21A2 gene mutation analysis.

Konjenital Adrenal Hiperplazili Hastalarda Final Boyun Değerlendirilmesi

Purpose : Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease that occurs as a result of deficiency of any of the enzymes required for the synthesis of glucocorticoid, mineralocorticoid and sex steroid from cholesterol in the adrenal cortex .In this study, we aimed to evaluate the final height in patients with CAH due to 21-hydroxylase and 11 Beta hydroxylase deficiency and to investigate the factors affecting it.
 Material-method: The anthropometric, clinical and laboratory findings of the patients who were diagnosed with CAH in the Pediatric Endocrinology Clinic were evaluated retrospectively. A total of 39 patients with CAH who had regular controls, who did not have precocious puberty and no additional disease during their follow-up, and who reached the final height were included in the study.
 Results: The final height was 158.2±5.46 cm in female cases and 168.8±11.67 cm in male cases with classic simple virilizing CAD due to 21 hydroxylase deficiency, and it was 152.2±5.94 cm in salt-wasting female cases and 156.5±6.2 cm in salt-wasting male cases. It was found to be 155.9±7.59 cm in non-classic female cases and 157 cm in 1 non-classic male case. The final height of all classic type CAH cases is SD - 1.41±1.45 SD, and it was calculated as -0.81±1.12 (-2,30 - 0,80) in cases with simple virilizing type classic CAH and -1.79±1.53 (-3.70 - 0.70) in cases with salt-wasting type classic CAD. In non-classic CAH cases, final height SD was calculated as -1.65±1.69 SD. When patients with salt-wasting CAH and simple virilizing CAH were compared in terms of final height SD and genetically adjusted height SD, the final heights of patients with simple virilizing CAH were significantly longer (p

Hipobetalipoproteinemia familiar ApoB específica en una paciente con hiperplasia suprarrenal congénita no clásica

Familial hypobetalipoproteinaemia is a disorder of lipid metabolism characterized by low levels of total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B. ApoB-related familial hypolipoproteinemia is an autosomal condition with a codominance inheritance pattern. Non-classical congenital adrenal hyperplasia is an autosomal recessive disorder due to mutations in the CYP21A2, a gene encoding for the enzyme 21-hydroxylase, which results in an androgen excess production from adrenal source. We here present the case of a 25-year-old woman with NCAH showing decreased levels of total-cholesterol, low-density lipoprotein cholesterol and triglycerides. Her parent had digestive symptoms and severe hepatic steatosis with elevated liver enzymes, as well as decreased levels of total and low-density lipoprotein cholesterol. A genetic-molecular study of the proband identified a mutation in the APOB gene, which allowed a diagnosis of heterozygous ApoB-related hypolipoproteinaemia to be made.

A novel SMOC1 pathogenic homozygous variant in a fetus with mesomelia of the lower limbs, micrognathia and hypertelorism and an incidental finding of CYP21A2-related congenital adrenal hyperplasia.

Trio exome sequencing was performed on a fetus with bilateral mesomelia of the lower limbs with significant angulation of the tibial bones, micrognathia and hypertelorism detected on ultrasound scan at 19+0weeks gestation. The couple is consanguineous. A homozygous pathogenic frameshift variant in the SMOC1 gene (c.339_340del p.(Phe114Cysfs*40)) was detected and both parents were shown to be heterozygous. Pathogenic variants in the SMOC1 gene are associated with microphthalmia with limb anomalies which multidisciplinary team discussion determined to be causal of the scan anomalies detected. The fetus was also a compound heterozygote for CYP21A2 pathogenic variants, confirming a second diagnosis of non-classical congenital adrenal hyperplasia, which was felt incidental to the scan findings. The risk that this couple's next pregnancy would be affected by either of these disorders is 1 in 4 (25%) and demonstrates the importance of genetic diagnoses for the family and implications for future pregnancies.

Clinical-laboratory characteristics, psychological assessment and quality of life in patients with non-classical congenital adrenal hyperplasia

Clinical-laboratory characteristics, psychological assessment and quality of life in patients with non-classical congenital adrenal hyperplasia

Case series of non-classical congenital adrenal hyperplasia in childhood

Case series of non-classical congenital adrenal hyperplasia in childhood

SAT380 Clinical, Metabolic And Hormonal Profile In Women Carrying Cyp21a2 Mutations

Abstract Disclosure: S. Livadas: None. D.G. Goulis: None. E. Belardinelli: None. E. Armeni: None. B. Solmi: None. S. veneti: None. I. Lambrinoudaki: None. C. Cecchetti: None. D.P. Macut: None. A. Gambineri: None. Background: Heterozygote (HET) CYP21A2 gene mutations are present in 5-10% of the general Mediterranean population. Despite that homozygotes suffer from classical or non-classical congenital adrenal hyperplasia (NC-CAH), a survival advantage has been suggested for heterozygote carriers. The aim of this study was to describe the clinical, metabolic and hormonal profile in reproductive age women with CYP21A2 HET. Methods: Data from 56 HET women were compared with 105 controls, 64 untreated women with NC-CAH and 63 women with polycystic ovary syndrome (PCOS) of similar age and body mass index. Results: The prevalence of hirsutism (54 vs. 8%) and acne (44 vs. 4%) was higher in HET than controls. The degree of menstrual irregularities was similar between HET and NC-CAH and worse than controls. The lipid profile was better in HET than PCOS (Cholesterol 170.2±37.1 vs. 187. 7±39.3 mg/dl, HDL 61.4±26.1 vs. 46.8±8.6 mg/dl), but similar to NC-CAH. Testosterone (0.78±0.45 vs. 0.50±0.25 ng/dl), SHBG (38.2±20.1 vs. 56.2±31.4 nmol/l), FAI (9.56±3.45 vs. 5.37±1.24) and DHEAS concentrations (2.62±1.31 vs. 1.27±0.94 nmol/l) were similar to HET, NC-CAH and PCOS and significantly higher than controls as well as insulin (13.88±7.96 vs. 7.51±2.82 IU/l) and HOMA-IR (2.95±1.60 vs. 1.65±0.67). Δ4- androstenedione (5.97±2.88 vs. 8.80±3.45 ng/ml) and 17(OH)-progesterone (4.32±2.02 vs. 13.75±8.34 ng/ml) concentrations were lower in HET than in NC-CAH, but higher than PCOS and controls. Finally, ovarian PCO morphology prevalence was similar in HET than NC-CAH and PCOS. Conclusions: HET display a favorable lipidemic profile, but a similar degree of hyperandrogenic signs, menstrual disturbances, insulin resistance, hyperandrogenemia and ovarian morphology than women with PCOS or NC-CAH. Therefore, these women, when identified, should be followed-up. Presentation Date: Saturday, June 17, 2023

SAT287 Clinical And Biochemical Characteristics In Female Adolescents Diagnosed With Non-classic Congenital Adrenal Hyperplasia (NCCAH)

Abstract Disclosure: J. Hayes dorado: None. M. Calla Ayala: None. R. Zapata Lafuente: None. C. Ramos Bustencio: None. C. Gorena Montalvo: None. I. Chiri Porcel: None. The aim of this study was to evaluate the clinical and biochemical characteristics in female adolescents diagnosed with NCCAH in comparison to female age-matched healthy controls. A total of 39 female adolescents, aged 10-15 years, were enrolled in this study, including 24 patients with NCCAH (mean age 12.9±1.4 years) and 15 healthy controls (mean age 13.2±1.1 years). Data was collected on anthropometry, clinical features of hyperandrogenism (hirsutism, acne, alopecia) and menstrual irregularities, and ovarian ultrasound was performed. Hormonal and metabolic markers were assessed. Hirsutism was present in 91.7% of the NCCAH females and 46.7% of the controls (p<0.001), while acne and alopecia were defined in 83.3% and 66.7% of the NCCAH patients, respectively, compared to 33.3% and 26.7% of the healthy females (p acne <0.0001 and p alopecia =0.003). No significant difference was found in the rate of menstrual disorders between the groups. The BMI and waist circumference did not differ between NCCAH females and healthy controls. No significant difference was found in the parameters of lipid and glucose metabolism between the groups. Testosterone and basal levels of 17 OH Progesterone were significantly higher in NCCAH females (p<0.01). Polycystic ovaries were detected by ultrasound in 8.3% of the NCCAH and 6.7% of the controls, without significant difference between the groups. NCCAH in female adolescents is characterized by clinical and biochemical hyperandrogenism. No significant difference was found in the rate of menstrual disorders, the BMI, waist circumference and the parameters of lipid and glucose metabolism between the groups. Presentation: Saturday, June 17, 2023

FRI247 Case Of Metabolic Resolution Of Non-classic Congenital Adrenal Hyperplasia Post Roux-En-Y Gastric Bypass

Abstract Disclosure: K.G. Romo: None. S. Shu: None. M. Gabriel: None. S. Bhamre: None. Q.Z. Iqbal: None. A.A. Noor: None. G.I. Uwaifo: None. Background: Non-classic congenital adrenal hyperplasia (NCCAH) is an autosomal recessive disorder resulting from loss of function mutations of the 21-hydroxylase gene. It is characterized by mild cortisol deficiency, excess ACTH production, and androgen excess, often with various features of dysmetabolic syndrome. Elective bariatric surgery is one of the most effective long-term management strategies for morbid and complicated obesity. This case presents a woman with NCCAH and complicated morbid obesity who s/p Roux-en-Y Gastric Bypass (RYGB) had metabolic resolution of NCCAH and no longer required glucocorticoid (GC) therapy. Clinical Case: A 34-year-old G1P1 woman with NCCAH on glucocorticoid therapy, treated hypothyroidism with thyroid nodular disease, dyslipidemia, and morbid obesity (pre-RYGB BMI 60-69.9) initially presented to endocrinology on account of hirsutism and secondary amenorrhea attributed to PCOS. Work-up then confirmed diagnosis of NCCAH with 21-hydroxylase genetic testing showing deletion of one copy of CYP21A2 and the pathogenic variant p.V282L in the remaining copy. Outside the peripartum period, she was managed with OCP therapy, spironolactone, and metformin. She was additionally prescribed GC therapy of hydrocortisone 10mg TID following her diagnosis of NCCAH. She subsequently became pregnant unexpectedly. Post-partum course was complicated by significant weight gain, which led her to seek elective bariatric surgery for long-term weight management. At 5 months post-op, she had a weight deficit of ∼100lbs. Although she self-discontinued GC therapy due to fear of weight gain, her amenorrhea resolved, her hirsutism significantly improved, and lab testing revealed normalization of all NCCAH markers, including ACTH, 17-OHP, and androstenedione. Thus, GC therapy was not restarted. At 11 months post-op and still off GC therapy, she had a total weight deficit of ∼160lbs and continued metabolic resolution of NCCAH markers. Conclusions: This case presents a patient with NCCAH and morbid obesity who no longer required GC therapy post-RYGB. Presently, GC therapy remains the only available treatment for CAH; however, long-term GC therapy has the potential for myriad possible complications and side effects. Our case presents elective bariatric surgery as a potential and unique treatment option for patients with classic or non-classic CAH who have associated morbid obesity. The exact pathophysiologic basis for this effect and its potential role in long-term management of appropriate CAH patients requires further in-depth study. Presentation: Friday, June 16, 2023

FRI241 Late Diagnosis Of Non-classical CAH In An Elderly Male Previously Diagnosed With Estrogen Producing Adrenal Tumor

Abstract Disclosure: R. Kaval: None. J. Subauste: None. In 2013 a 66-year-old Caucasian male presented to the VA outpatient endocrinology clinic to establish care; the patient carried a diagnosis of estrogen producing left adrenal tumor in 1989 at the age of 42 at an outside facility. On review of records the patient was initially worked up for hypogonadism and was noted to have an elevated estrogen level and a “left adrenal tumor”. He subsequently underwent an unilateral left adrenalectomy for treatment and pathology reported with benign tumor findings. Following surgery, the patient was started on steroid and mineralocorticoid replacement for primary adrenal insufficiency (PAI) and topical testosterone gel for hypogonadism. The question was raised as to why this patient had PAI as he had an intact right adrenal gland on CT scan. On laboratory work-up in 2006 the patient had baseline cortisol of 3.4 ug/dl, ACTH was elevated at 99 pg/ml [7.2- 63.3], and adrenal antibodies (21-OH antibody] were negative. Renin was 2.35 ng/ml/hr [0.167-5.380], Estradiol was 41.8 pg/ml [7.6 - 42.6], LH was low at 0.20 mIU/ml [1.2-8.6] and total testosterone was low at 2.2 ng/ml [1.8-7.8]. Repeat testing yielded ACTH that was elevated at 686.7 pg/ml [7.2- 63.3], electrolytes including sodium and potassium were normal. On physical examination the patient had hyperpigmented skin, normal height, weight and otherwise unremarkable. On CT scan of the abdomen the right adrenal gland was mildly diffusely enlarged. In 2019, 30 years after his initial diagnosis the team questioned whether the adrenal tumor was truly an estrogen producing tumor. As a result, 17-OH progesterone was obtained, and the unstimulated value resulted as 3522 ng/dl [27-199]. With the elevated 17 OH >1000 ng/dL this was diagnostic for Non-classical CAH. The unilateral adrenalectomy likely unmasked the underlying impairment of cortisol production leading to primary AI that is seen with Non-classical CAH patients. The patient was lost to follow up during the pandemic, hence we were not able to perform and further testing. Presentation: Friday, June 16, 2023

SAT339 Osteopenia In The Setting of Mild Autonomous Cortisol Secretion

Abstract Disclosure: J.J. Mao: None. K.C. McCowen: None. C. Choe: None. Jimmy J. Mao, MD (1); Karen C. McCowen (1); Charles H. Choe (1)(1) Division of Endocrinology, Diabetes, and Metabolism, University of California San Diego, La Jolla, CA. Background: Over 80% of adrenal incidentalomas are benign adrenal cortical adenomas, of which 30-50% are found to have mild autonomous cortisol secretion (MACS). Bone fragility is a known complication of MACS. Clinical Case: A 57-year-old postmenopausal female with no prior history of fracture, venous thromboembolism, and atherosclerotic cardiovascular disease, was referred for incidental bilateral adrenal nodules. Body mass index was normal at 21 kg/m2, and no clinical stigmata of Cushing syndrome were noted on physical exam. Unenhanced computed tomography scan revealed a 4.6 cm right adrenal nodule and a 3.3 cm left adrenal nodule; both nodules measured less than -18 Hounsfield Units. Biochemical work-up for pheochromocytoma, primary aldosteronism, and non-classical congenital adrenal hyperplasia was negative. Evaluation for hypercortisolism revealed a morning cortisol of 20.3 mcg/dL (ref. 4-22 mcg/dL) with concurrent adrenocorticotropic hormone of <5 pg/mL (ref. 6-50 pg/mL), 24-hour urine free cortisol of 16.9 mcg (ref. 4-50 mcg), and midnight salivary cortisol of 0.07 mcg/dL (ref. <0.09 mcg/dL). A 1 mg dexamethasone suppression test measured on two separate occasions was elevated at 6.3 mcg/dL and 7.9 mcg/dL (ref. <1.8 mcg/dL). A subsequent 8 mg dexamethasone suppression test was also elevated at 6.1 mcg/dL (ref. <1.8 mcg/dL). The diagnosis of MACS was made. A bone mineral density (BMD) scan revealed T-scores at the right femoral neck, left femoral neck, and lumbar spine at -1.6, -1.3, and -0.8, respectively. Ten-year probability of major osteoporotic fracture and hip fracture were 8.3% and 1.0%, respectively. To reduce the risk for future fractures, the decision was made to proceed with adrenal vein sampling (AVS) in preparation for potential adrenalectomy. Conclusion: MACS is the most frequent hormonal abnormality in adrenal incidentalomas, with an estimated prevalence of 0.8-2 cases per 1000 persons. A previous prospective study found that surgical cure of unilateral MACS may lead to a substantial risk reduction (up to 15-fold) of future incident asymptomatic vertebral fractures. Additionally, the highest risk for clinical fracture in those with adrenal adenomas (either nonfunctional or with cortisol hypersecretion) appears to occur at 7-10 years after initial diagnosis. BMD does not perfectly correlate with fracture risk, so unilateral adrenalectomy (if lateralization is observed on AVS) and/or pharmacotherapy should be strongly considered in patients with an expected longevity of >10 years even with mild osteopenia and low fracture risk assessment tool scores. Presentation: Saturday, June 17, 2023

SAT378 Unusual Case of Hirsutism From Prolactinoma Induced Dihydrotestosterone Elevation

Abstract Disclosure: J. Ambalavanan: None. K. Alkwatli: None. L. Tranchito: None. D. Yogi-Morren: None. P.P. Rao: None. Introduction: Hirsutism, in women of reproductive age, is a clinical marker of hyperandrogenism. PCOS is the most common cause while non-classic congenital adrenal hyperplasia, adrenal/ovarian tumors are other causes. While various biomarkers of hyperandrogenism like total testosterone(T), 17-Hydroxyprogesterone(17-OHP), DHEA-S are obtained during evaluation, isolated elevation in dihydrotestosterone (DHT) is rarely seen. We present a unique case of hirsutism where elevated prolactin (PRL) levels from a prolactinoma led to an increase in DHT levels resulting in hirsutism. Case Report: A 31-year-old female presented to the endocrine clinic for hirsutism. Her symptoms included increased chin hair and loss of scalp hair. Symptoms were progressively worsening for a year. Initial biochemical evaluation by an endocrinologist in her home country was significant for subclinical hypothyroidism (SCH) with TSH of 8 mIU/ml (0.35-4.94), elevated PRL of 49 ng/ml(2.8-29.2) and elevated DHT of 871 pg/ml (24-368). T, 17-OHP, DHEA-S were normal. It was believed that her SCH was driving her high PRL and she was started on levothyroxine 12.5 mcg daily along with finasteride 2.5mg daily for high DHT. She denied galactorrhea, breast tenderness headache, vision changes, and menstrual abnormalities. Repeat biochemical testing was performed during the follicular phase of menstrual cycle, after stopping all her pills for 2 weeks. Labs were significant for PRL-102 ng/mL (4.5-26.8), TSH-3.49 mIU/mL (0.27-4.2), total T- 47 ng/dL (8-60), free testosterone - 0.9 ng/dL (0.13-1.03), 17- OHP-70.3 ng/dL (<206), androstenedione-1.7 ng/mL (0.3-3.3), DHT-272 pg/mL (24-208), DHEA-S-386.8 ug/dL (98.8-340), LH-9 mIU/mL, FSH-7.2 mIU/mL. Due to the high prolactin, MRI of the pituitary was obtained and showed a 1.1 cm pituitary adenoma with extension towards optic chiasm. Due to the macroadenoma, we started the patient on cabergoline 0.25 mg p.o. weekly. On repeat testing 1 month after cabergoline, her prolactin normalized to 2 ng/mL (4.5-26.8), dihydrotestosterone normalized to 175.2 pg/mL (24-208), DHEA-S normalized to 220.2 mcg/dL (98.8-340). Conclusion: Elevated DHT is a very rare cause of hirsutism. In our patient, the elevated PRL levels were associated with high DHT and DHEA-S level. Though the exact mechanism of is unclear, studies in rats have shown that prolactin has an activating effect on the 5 alpha reductase enzyme and increases DHT levels. Additionally, treatment of the high PRL levels resulted in normalization of DHT levels. The high DHEA-S was not thought to be a cause of hirsutism as it was normal in the initial labs. Moreover, peripheral conversion would have resulted in high T and androstenedione levels which were normal in our patient. In our review of literature, we could not find any similar reports in human beings and would like to educate the endocrine community of this possible association. Presentation Date: Saturday, June 17, 2023

FRI402 “An Unusual Presentation Of Polycystic Ovary Syndrome” - Isolated DHEA-S Elevation In A Patient With Difficulty Conceiving And Recent Onset of Hirsutism

Abstract Disclosure: C. Musurakis: None. J.L. Gilden: None. Background: Isolated DHEA-S levels and worsening hirsutism often prompt the clinician to investigate more serious causes for the elevation, such as an adrenal mass. Clinical Case: A 29-year-old female G0P0 with Norwegian and English heritage and familial hypertriglyceridemia, was referred for elevated DHEA-S levels, and difficulty conceiving for past three years. She had hirsutism of face, chest, and abdomen, worsening over the last two years. Acne had also progressively worsened to cystic type. Menarche was at age 12, and menses were regular. She had never used contraception. Medications: docosahexanoic acid, eicosapentanoic acid, topical azelaic acid, benzoyl peroxide, clindamycin, pantoprazole, prenatal vitamins, and cholecalciferol. There was a family history of acne, but not for hirsutism or menstrual irregularities. Vitals: BP 137/73, HR 81, Ht 165.10 cm, Wt 86.18 Kg, BMI 31.68. Ferriman-Gallwey score was 10 with normal genitalia. Labs (luteal phase): DHEA-S 756 mcg/dL with repeat of 596 mcg/dl(n=35-430), total testosterone 25 ng/dL(n=2-45), free testosterone 4.3 pg/mL(n=0.1-6.4), prolactin 6.6 ng/mL(n=2.2-30.3), LH 5.1 mIU/mL(n=0.6-16.6), FSH 4.7 mIU/mL(n=1.7-12.9), 17-OH progesterone 74 ng/dL(n=139-431), androstenedione 163 ng/dL(n=73-184), estradiol 59.79 pg/mL(n=55.8-214.2), AMH 1.38 ng/mL(n=0.69-13.39), midnight salivary cortisol <0.03 and 0.05 mcg/dL(n<5), IGF-1 258 ng/mL(n=63-373), ACTH 31 pg/mL(n=0-47), AM cortisol 12.58 ug/dL(n=5.3-22.5), TSH 1.27 uIU/mL(n=0.358-3.74), Free T4 0.88 ng/dL (n=0.76-1.46), peroxidase antibodies 49.8 U/m (n=0-60), thyroglobulin antibodies <15(n=0-60), HbA1c 5.5% (n<=5.6%), 25-OH vitamin D 42.7 ng/mL(n=30-100) and negative pregnancy urine test. US pelvis: small follicles in ovaries and normal size. MRI abdomen w/wo contrast: normal bilateral adrenal glands. Cosyntropin stimulation test: baseline cortisol 15.03 ug/dL,17-OH progesterone 168 ng/dL. 30 mins: Cortisol 30.39ug/dL(n>18),17-OH progesterone 130ng/dL(n<200). 60 mins: cortisol 38.95ug/dL(n>18), 17-OH progesterone 153ng/dL(n<200). Non-Classical Congenital Adrenal Hyperplasia was excluded. Polycystic Ovary Syndrome (PCOS) was diagnosed based on clinical and biochemical hyperandrogenism, lack of adrenal mass, and clinical signs of anovulation. Conclusion: As reported by Carmina et al, few patients with PCOS exhibit isolated increase of serum DHEA-S. It is important to recognize that non-classic forms of PCOS (normal ovaries or normal ovulatory cycles) can present with a higher prevalence of adrenal hyperandrogenism than the common classical forms of PCOS. Reference: Carmina E, Longo RA. Increased Prevalence of Elevated DHEAS in PCOS Women with Non-Classic (B or C) Phenotypes: A Retrospective Analysis in Patients Aged 20 to 29 Years. Cells. 2022 Oct 17;11(20):3255. doi: 10.3390/cells11203255. PMID: 36291122; PMCID: PMC9601254. Presentation: Friday, June 16, 2023

FRI245 Non-classic CAH Presenting As Bilateral Adrenal Incidentalomas

Abstract Disclosure: Y.A. Chin: None. T. Puar: None. T. King: None. Introduction: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive disorder. Non-classic CAH usually presents in late childhood or asymptomatic may remain undiagnosed. Adrenal incidentalomas have been reported as a presentation of CAH. Clinical Case: A 56-year-old man presented with a 4-day history of epigastric pain associated with chest discomfort and diaphoresis. There was no postural giddiness, vomiting, paroxysm or constitutional symptoms. He was a smoker, his parents were non-consanguineous and he had fathered 2 children. He was tachycardic at 114 bpm, but normotensive (129/89 mmHg) with no postural hypotension and no abnormal pigmentation. He had evidence of heart failure with bibasal crepitations and pedal oedema. Secondary sexual characteristics were normal and testicular volume was 15 mls bilaterally with no palpable mass. CT abdomen showed grossly enlarged bilateral adrenal glands with heterogenous nodular appearance with several focal hypodense cystic components, with absolute washout <60%. Biochemistry was consistent with primary adrenal insufficiency (PAI); 8am serum cortisol 188 nmol/L, with peak cortisol post 250mcg synacthen of 195 nmol/L. Serum ACTH was elevated at 254.6 ng/L, aldosterone and renin were normal and 24hr urinary normetanephrine was mildly elevated at 1982 nmol/d (NR 600-1900 nmol/d). Echocardiography revealed severe global hypokinesia (EF 20%) but myocardial perfusion imaging was negative for ischemia. In view of suspicion for tuberculosis, malignancy or infiltrative disease, CT guided adrenal biopsy was performed. Histology showed hyperplastic adrenal cortex with lipofuscin pigments, focal lymphohistiocytic infiltrates. No lymphoplasmacytic infiltrate with IgG 4 plasma cells, granuloma, malignant cells or amyloid deposits were seen. Serum 17-OHP level later came back elevated at 39.7 nmol/L (NR 1.8-10.4 nmol/L). DNA sequencing of CYP21 revealed compound heterozygous mutations in c.292+1G>A and c.518T>A, both of which have been reported to be causative of CAH. He was transitioned from stress dose to physiological glucocorticoid replacement and ACTH normalised on subsequent outpatient visits. Follow up imaging after 6 months and 2 1/2 years revealed no change in size or morphology of the adrenal glands. Follow up echocardiography showed no improvement in ejection fraction despite intensive heart failure treatment. Conclusion: Nodular adrenal hyperplasia is well described among CAH individuals, especially in those with inadequate glucocorticoid replacement and chronically elevated ACTH levels. There was no change in size of the adrenal lesions despite adequate glucocorticoid replacement. Improvement of cardiac function with glucocorticoid replacement has been reported in paediatric patients with CAH, but our case did not show any improvement on serial echocardiography. Presentation: Friday, June 16, 2023

SAT347 Surprising Turn Of Events In A Patient With Weight Gain: Simultaneous Diagnosis Of Macroprolactinoma And Polycystic Ovary Syndrome

Abstract Disclosure: A.N. Keskinkilic: None. D. Sistla: None. Background: The differential diagnoses of excess weight gain are broad and endocrinopathies constitute a small proportion of these etiologies. A pattern of associated symptoms, classical exam findings and hormonal testing can signal some endocrine causes. However, diagnosis can still be challenging due to overlapping clinical and biochemical features and concurrent presentations of endocrine disorders. Here, we present a diagnostically challenging rare case of a young female with weight gain who had simultaneous diagnosis of macroprolactinoma and PCOS. Clinical Case: A 34-year-old healthy female presented with one year of weight gain despite lifestyle changes. She also reported headaches, acne, hirsutism, stretch marks, excessive sweating, and had 10 years of amenorrhea while on oral contraceptives (OCs). Labs revealed mildly low free T4 of 0.72 ng/dl (n: 0.70-1.48 ng/dl) and significantly elevated prolactin (PRL) of 259.8 ng/ml (n: 1.2-29.9 ng/ml); normal FSH, LH, GH, IGF, TSH, ACTH, 1 mg dexamethasone suppression test, and 24-hour urinary cortisol. HbA1c, lipid panel, plasma metanephrine and androgen levels were normal. MRI pituitary revealed a 2.1 x 1.9 x 1.5 cm macroadenoma with mild compression to the optic chiasm. A low dose levothyroxine and cabergoline 0.25 mg twice weekly was started with dose increment to 0.5 mg twice weekly. At 6-month follow-up, PRL decreased to 30 ng/ml. Repeat MRI showed a decrease in size of the pituitary adenoma (1.5 x 1.4 x 1.3 cm). However, she could not tolerate cabergoline due to persistent headaches and depression. Hence, she elected to undergo transsphenoidal pituitary resection. Tumor pathology showed sparsely granulated lactotroph adenoma. Post op PRL level normalized, and MRI showed radiological cure of the adenoma. Headaches improved but amenorrhea persisted despite discontinuation of OCs for 6 months. Progesterone challenge tests resulted in withdrawal bleed suggesting anovulation. Repeat work-up ruled out nonclassical CAH, Cushing’s, and androgen-secreting tumors. However, subsequent pelvic ultrasound confirmed polycystic ovarian morphology, suggesting PCOS. The patient preferred to avoid OCs and could not tolerate metformin. She elected progesterone IUD placement for endometrial protection in combination with lifestyle changes with notable improvement in her symptoms. Conclusion: PCOS is a diagnosis of exclusion. Thorough evaluation of symptoms like weight gain, amenorrhea, clinical hyperandrogenism is recommended to rule out serious pathology like prolactinoma. Dual diagnosis of PCOS and macroprolactinoma is rare and should be suspected if menstrual abnormalities persist even after treatment of hyperprolactinemia. Presentation: Saturday, June 17, 2023

FRI261 A Case Of Cushing Syndrome And Hyperandrogenism Secondary To An Adrenal Cortical Oncocytoma

Abstract Disclosure: E. Hall: None. S. Gupta: None. J. Lee: None. Background: Adrenal cortical oncocytomas are rare neoplasms that are often non-functional, but there have been case reports of associated hypercortisolism, hyperandrogenism, and in even rarer cases, multiple hormonal excesses. Clinical Case: A 30 year old woman with history of hypertension, prediabetes and obesity presented with 3 years of oligomenorrhea, hirsutism, weight gain, and voice deepening. She did not take any medications and had no family history of endocrine diseases. Labs revealed hyperandrogenism: elevated total testosterone of 390 ng/dL and 435 ng/dL (nl 6-82), suppressed FSH of 0.2 mIU/mL (nl 1.7-21.5) and LH of <0.1 mIU/mL (nl 1.0-95.6), normal DHEA-S of 290 ug/dL (nl 98.8-340). Morning 17-hydroxyprogesterone was elevated to 944 ng/dL and increased to 1031 ng/dL (nl 23-431) on ACTH stimulation test, which did not meet diagnostic criteria for non-classical congenital adrenal hyperplasia. Also, genetic testing for CYP21A2 gene mutations was negative. Pelvic ultrasound was unremarkable. CT of the adrenal glands showed a 4.6 x 3.8 x 4.4 cm mildly heterogeneous left adrenal mass that measured 35 HU on non-contrast images with absolute washout of 50% and relative washout of 31%. The mass was concerning for malignancy based on HU >20, size >4cm, and 50% contrast washout (borderline). Overnight 1mg dexamethasone suppression test showed non-suppressed morning cortisol of 7.1 ug/dL (nl <1.8), with dexamethasone level of 246 ng/dL (nl 180-550) and ACTH of <5 pg/ml (nl 6-50). Twenty four hour urinary free cortisol level was slightly elevated to 52.3 mcg/24h (nl 4-50). Plasma metanephrines and aldosterone/renin ratio were normal. The patient underwent left laparoscopic adrenalectomy without complications. Pathology was consistent with adrenal cortical oncocytoma. Post-operatively, morning cortisol was <0.3 ug/dL, so she was started on hydrocortisone replacement twice daily but was tapered off within three months. Three weeks after surgery, total testosterone was <8 ng/dL. Two months after surgery, her menstrual cycles resumed. Fifteen months after surgery, she had regular menstrual cycles, 20 lb weight loss, resolution of hirsutism, hypertension and prediabetes. Conclusions: Adrenal cortical oncocytomas are rare tumors of the adrenal glands that should be considered in the differential for large adrenal tumors that appear suspicious for malignancy on imaging. They may or may not be functional, and in this case, the tumor secreted both androgens and cortisol. Although androgen-secreting tumors are frequently malignant, such as adrenocortical carcinomas, androgen-secreting oncocytomas are generally considered benign. However, there have been rare reports of malignant oncocytomas and oncocytomas of uncertain malignant potential. Presentation: Friday, June 16, 2023

THU187 Genotype-Phenotype Correlation, Clinical Presentation And Feminizing Surgery In Children With Congenital Adrenal Hyperplasia Due To 21-Hydroxylase Deficiency: A Nationwide Multi-Center Study

Abstract Disclosure: M. Lind-Holst: None. A. Berglund: None. M. Duno: None. G. Hvistendahl: None. M. Fossum: None. A. Juul: None. N. Jørgensen: None. K.M. Main: None. C.H. Gravholt: None. D. Hansen: None. Background: Congenital adrenal hyperplasia (CAH) due to 21 hydroxylase deficiency (21OHD) is a common autosomal recessive disorder caused by pathogenic variants in CYP21A2. Genotype cannot always predict severity and clinical consequences, and genotype-phenotype is only well correlated in the most severe clinical cases of CAH. Furthermore, non-classical CAH suffers from non-diagnosis, especially in males. Objective: Describe the genotype-phenotype correlation in Danish children with 21OHD and identify the most frequent pathogenic CYP21A2 variants. We describe the clinical manifestations at time of diagnosis and present data on virilization and feminizing surgery of females, stratified by genotype group during 20 years. Method: A national population-based study of all Danish children diagnosed with 21OHD, combining health registries and medical record data. We identified pathogenic variants in CYP21A2 and genotype-phenotype correlation. Clinical presentation at diagnosis and feminizing surgery in females was stratified by genotype group: Null, A, B, C and D, reflecting the preserved 21-hydroxylase activity in increasing order. Results: Variants frequency of 494 unique alleles: Deletion (31.8%) followed by I2G, Q318X, I172N, V281L, P30L, Cluster-E6, R356W and insT by 25.9%, 9.1%, 8.6%, 8.7%, 6.5%, 1.4%, 1.4% and 0.6%, respectively. Genotype-phenotype correlations: Null: 98%, A: 94%, B: 50%, C: 76%. Overall, 62 of the 159 children (67%) had evidence of pseudo-precocious puberty at time of diagnosis which was the most frequent group of symptoms in genotype group B: 8.2%, C: 23.3% and D: 3.8%. Bone age advancement was significantly more advanced at the time of diagnosis in males compared to females (p=0.0009). The most frequently reported symptom at diagnosis in the genotype group null (n=20) and A (n=31) were: clitoral hypertrophy in females: 62.7%, failure to thrive: 29% and salt-wasting crisis: 22%. Clitoral hypertrophy was also present in genotype group B, C and D and feminizing surgery was performed in 85% of prenatally virilized females and overall in 40% of females at a median age of 0.9 years [IQR 0.5-1.6]. Conclusion: Genotype groups only predict phenotype with high certainty in the null and A genotype groups. In a national cohort evidence of virilization in females and feminizing surgery were observed in every genotype group. Delayed or non-diagnosis in children with SV and NC CAH was substantial, especially in males. We suggest that children with even mild hyperandrogenic symptoms and normal biochemical markers for 21OHD may benefit from genetic testing for CAH to establish a diagnosis. Presentation: Thursday, June 15, 2023