Steroidogenic acute regulatory protein (STAR) deficiency: Our experience and systematic review for phenotype-genotype correlation.

OBJECTIVE: Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR. A systematic review of phenotype-genotype correlation and data on testicular histology in LCAH patients is unavailable. We aim to describe our experience and provide phenotype-genotype correlation. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective review of three genetically proven LCAH patients from our centre and per-patient data analysis from a systematic review of 292 probands. The phenotypic subgroups of 46,XY were Group A (typical female genitalia), Group B (atypical genitalia) and Group C (typical male genitalia). RESULTS: We report three new LCAH probands from India, all diagnosed post-infancy with preserved gonadal function and one novel variant. The systematic review reports 46,XY to 46,XX LCAH ratio of 1.1 (155:140). Patients with 46,XY LCAH in Group A were diagnosed in infancy (116/117) and had higher mineralocorticoid involvement than Group C (96.4% vs. 75%, p = 0.035), whereas Group C had preserved gonadal function. Hyperplastic adrenals are noted in ~60% of LCAH diagnosed with primary adrenal insufficiency in infancy. There was no report of gonadal germ cell cancer and rare reports of germ cell neoplasia in situ in adolescents, especially with intraabdominal gonads. Two-thirds of LCAH probands were East-Asian and 11/16 regional recurrent variants were from East Asia. There was minimal overlap between variants in Groups A (n = 55), B (n = 9) and C (n = 8). All nonsense and frameshift and most of the splice-site variants and deletion/insertions were present in Group A. CONCLUSIONS: We report three new cases of LCAH from India. We propose a phenotype-derived genotypic classification of reported STAR variants in 46,XY LCAH.

Hereditary Hypophosphatemic Rickets with Hypercalciuria Presenting with Enthesopathy, Renal Cysts, and High Serum c-Terminal FGF23: Single-Center Experience and Systematic Review.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of phosphate homeostasis. We describe a single-center experience of genetically proven HHRH families and perform systematic review phenotype-genotype correlation in reported biallelic probands and their monoallelic relatives. Detailed clinical, biochemical, radiological, and genetic data were retrieved from our center and a systematic review of Pub-Med and Embase databases for patients and relatives who were genetically proven. Total of nine subjects (probands:5) carrying biallelic SLC34A3 mutations (novel:2) from our center had a spectrum from rickets/osteomalacia to normal BMD, with hypophosphatemia and hypercalciuria in all. We describe the first case of genetically proven HHRH with enthesopathy. Elevated FGF23 in another patient with hypophosphatemia, iron deficiency anemia, and noncirrhotic periportal fibrosis led to initial misdiagnosis as tumoral osteomalacia. On systematic review of 58 probands (with biallelic SLC34A3 mutations; 35 males), early-onset HHRH and renal calcification were present in ~ 70% and late-onset HHRH in 10%. c.575C > T p.(Ser192Leu) variant occurred in 53% of probands without skeletal involvement. Among 110 relatives harboring monoallelic SLC34A3 mutation at median age 38 years, renal calcification, hypophosphatemia, high 1,25(OH)2D, and hypercalciuria were observed in ~30%, 22.3%, 40%, and 38.8%, respectively. Renal calcifications correlated with age but were similar across truncating and non-truncating variants. Although most relatives were asymptomatic for bone involvement, 6/12(50%) had low bone mineral density. We describe the first monocentric HHRH case series from India with varied phenotypes. In a systematic review, frequent renal calcifications and low BMD in relatives with monoallelic variants (HHRH trait) merit identification.

Long-Term Follow-Up Data of Tumor-Induced Osteomalacia Managed with Surgery and/or Radiofrequency Ablation from a Single Center.

Data on radiofrequency ablation (RFA) in tumor-induced osteomalacia (TIO) are restricted to case reports (~ 11 patients) and long-term follow-up data are further scarce. We describe our experience on managing TIO from a tertiary care center in India. Retrospective study of patients with localized TIO was performed and clinical, biochemical, treatment and follow-up details were retrieved. Normalization of serum phosphorus in absence of phosphate supplementation was defined as remission. Of 33 patients (23 males), 24 patients underwent surgery as first-line treatment, and early remission, delayed remission (> 1 month for phosphorus normalization) and persistence were observed 12, 3, and 9 patients at a median follow-up of 5 (4-9) years. The gender, age, tumor size, location of tumors and FGF23 levels were not statistically different in patients who were in remission after surgery versus those with persistent disease. Second/third line treatment included conventional medical treatment and/or repeat surgery (n = 3), radiotherapy (n = 3), peptide receptor radionuclide therapy (n = 1), RFA (n = 1). Two patients had transient worsening (weeks) of weakness post-surgery. 10 patients underwent RFA (first-line n = 9); at the last follow-up 5 (4-10) years, 7 are in remission. Two of three persistent disease patients had large tumors (5.6 and 3.6 cm). There were no RFA-related complications except local ulcer in one. Although persistent disease was present in a few patients in both arms, there was no recurrence in either RFA or surgical cohort. RFA provide durable response similar to surgery, persistence requires multi-modality treatment.

Pediatric Macrocorticotropinoma: Do They Differ from Microcorticotropinoma?

INTRODUCTION: Cushing's disease (CD) due to macrocorticotropinoma (MC) in children and adolescents is a rare entity with limited information regarding its characteristics. The objective of the study is to describe the clinical, biochemical, imaging, management, outcome, and genetic characteristics of children and adolescents with CD due to MC and compare them with those of microcorticotropinoma (mc). METHODS: This retrospective study was conducted at a single tertiary care center. Thirty-two patients with CD and MC (maximum tumor dimension ≥10 mm on imaging) and 65 patients with mc (<10 mm on imaging) aged ≤20 years at presentation were enrolled. RESULTS: Nineteen girls and 13 boys with MC presented at a median (IQR) age of 14.5 (12.0-17.9) years. Patients with MC had higher body mass index-standard deviation score (BMI-SDS) (3.70 ± 2.60 vs. 2.59 ± 2.01, p = 0.04), more frequent neuro-ophthalmic symptoms (25% vs. 9% p = 0.04) and short stature (59% vs. 34%, p = 0.049) but less frequent livid striae (53% vs. 77%, p = 0.01), hypokalemia (12% vs. 36%, p = 0.04), and lower cortisol (nmol/L) to corticotropin (pmol/L) ratio (41.20 vs. 55.74, p = 0.04) than those with mc. The remission (59% vs. 64%, p = 1.0) and relapse (53% vs. 37%, p = 0.26) rates after first-line surgery and remission rate after radiotherapy (RT) were comparable between the two cohorts, whereas time to remission after RT (27 vs. 13 months, p = 0.05) was longer in the MC group. A patient with MC had a pathogenic germline variant in CDH23. CONCLUSION: In this large monocentric series of pediatric CD, frequent mass effect symptoms and short stature, higher BMI-SDS, less frequent livid striae, and hypokalemia with lower effective cortisol secretion characterize the MC cohort. The outcomes of surgery and RT were similar between the groups except for a longer time to remission after RT in the MC cohort. Germline variants are rare (4%) in pediatric MC.

Inherited Fanconi renotubular syndromes: unveiling the intricacies of hypophosphatemic rickets/osteomalacia.

INTRODUCTION: Fanconi renotubular syndromes (FRTS) are a rare group of inherited phosphaturic disorders with limited Indian as well as global data on this condition. Here, we describe the experience of a single Endocrinology center from Western India on FRTS. MATERIALS AND METHODS: Comprehensive clinical, biochemical, radiological, management, and genetic details of FRTS patients managed between 2010 and 2023 were collected and analyzed. RESULTS: FRTS probands had mutations (eight novel) in six genes [CLCN5 (n = 4), SLC2A2 (n = 2), GATM, EHHADH, HNF4A, and OCRL (1 each)]. Among 15 FRTS patients (11 families), rickets/osteomalacia was the most common (n = 14) presentation with wide inter- and intra-familial phenotypic variability. Delayed diagnosis (median: 8.8 years), initial misdiagnosis (8/11 probands), and syndrome-specific discriminatory features (8/11 probands) were commonly seen. Hypophosphatemia, elevated alkaline phosphatase, normal parathyroid hormone (median: 36 pg/ml), high-normal/elevated 1,25(OH)2D (median: 152 pg/ml), hypercalciuria (median spot urinary calcium to creatinine ratio: 0.32), and variable proximal tubular dysfunction(s) were observed. Elevated C-terminal fibroblast growth factor 23 in two probands was misleading, till the genetic diagnosis was reached. Novel observations in our FRTS cohort were preserved renal function (till sixth decade) and enthesopathy in FRTS1 and FRTS3 families, respectively. CONCLUSION: Our findings underscore frequent under- and misdiagnosis of FRTS; hence, a high index of suspicion for FRTS in phosphopenic rickets/osteomalacia, with early consideration of genetic testing is essential to ensure timely diagnosis of FRTS. The novel variants and phenotypic manifestations described here expand the disease spectrum of FRTS.

Pituitary apoplexy: a comprehensive analysis of 93 cases across functioning and non-functioning pituitary adenomas from a single-center.

INTRODUCTION: Pituitary apoplexy (PA) is a rare clinical syndrome due to acute/subacute pituitary hemorrhage and/or infarction; data on PA in functioning pituitary adenoma (FPA) is scarce. METHODS: A retrospective record-review of details of PA in non-functioning (NFPA) and FPA managed at tertiary endocrine center. RESULTS: 93 patients [56 males; 33.3% FPA: 5 acromegaly, 14 prolactinoma, and 12 Cushing's Disease (CD)] diagnosed with PA were included. Median age was 40 years, with younger age of presentation in FPA. Type A (acute) [49.5%] and headache (78.5%) were the commonest presentations, with PA being the initial manifestation in 98.4% of NFPA. Median (range) Pituitary Apoplexy Score (PAS) was 2 (0-8). Median tumor diameter was 2.5 cm, with larger tumors in FPA (3.2 cm vs. 2.3 cm). 29 (46.7%) NFPA-PA and 14 (45.2%) FPA-PA patients [71% prolactinoma, 33% in CD, and none in acromegaly] were conservatively managed. In the NFPA cohort, those managed surgically had significantly higher PAS (4 vs. 1) and larger tumor size (2.6 vs. 1.8 cm); however, both arms had comparable recovery of neuro-visual, radiological, and hormonal outcomes. In FPA cohort, CD and acromegaly required definitive treatment, whereas prolactinomas were effectively managed (clinical and biochemical recovery) with oral cabergoline and glucocorticoids. Matching PAS cohorts (to overcome allocation bias for management approach) in macroadenomas (excluding prolactinoma) showed comparable neuro-deficit and hormonal recovery between surgical and conservative approaches. CONCLUSION: PA in FPA has distinct features and management issues. Carefully selected patients (PAS guided) in NFPA with PA for conservative management have comparable outcomes to surgery.

Pituitary apoplexy in cushing's disease: a single center study and systematic literature review.

INTRODUCTION: Pituitary apoplexy (PA) in Cushing's disease (CD) is rare with data limited to case reports/series. METHODS: We retrospectively reviewed case records of PA in CD managed at our center from 1987 to 2023 and performed a systematic literature review. RESULTS: We identified 58 patients (44 females), including twelve from our center (12/315 CD, yielding a PA prevalence in CD of 3.8%) and forty six from systematic review. The median age at PA diagnosis was 35 years. The most common presentation was type A (79.3%) and symptom was headache (89.6%), with a median Pituitary Apoplexy Score (PAS) of 2. Median cortisol and ACTH levels were 24.9 µg/dl and 94.1 pg/ml, respectively. Apoplexy was the first manifestation of underlying CD in 55.2% of cases, with 31.1% (14/45) presenting with hypocortisolemia (serum cortisol ≤ 5.0 µg/dl), underscoring the importance of recognizing clinical signs/symptoms of hypercortisolism. The median largest tumor dimension was 1.7 cm (53/58 were macroadenomas). PA was managed surgically in 57.8% of cases, with the remainder conservatively managed. All five PA cases in CD with microadenoma achieved remission through conservative management, though two later relapsed. Among treatment-naïve CD patients with macroadenoma, PA-related neuro-deficit improvement was comparable between surgical and conservative groups. However, a greater proportion of surgically managed patients remained in remission longer (70% vs. 38.5%; p = 0.07), for an average of 31 vs. 10.5 months. CONCLUSION: PA in CD is more commonly associated with macroadenomas, may present with hypocortisolemia, and surgical treatment tends towards higher and longer-lasting remission rates.

Luteinizing hormone ß-subunit deficiency: Report of a novel LHB likely pathogenic variant and a systematic review of the published literature.

CONTEXT: Selective deficiency of ß-subunit of luteinizing hormone (LHB) is a rare disease with scarce data on its characteristics. OBJECTIVES: To describe a male with LHB deficiency and systematically review the literature. DESIGN AND PATIENTS: Description of a male patient with LHB deficiency and a systematic review of LHB deficiency patients published to date (10 males and 3 females) as per PRISMA guidelines. RESULTS: A 36-year-old Asian Indian male presented with infertility. On evaluation, he had sexual maturity of Tanner's stage 3, low testosterone (0.23 ng/ml), low LH (0.44 mIU/ml), high follicle-stimulating hormone (FSH, 22.4 mIU/ml), and a novel homozygous missense likely pathogenic variant (p.Cys46Arg) in LHB. In the molecular dynamics simulation study, this variant interferes with heterodimerization of alpha-beta subunits. Eleven males with pathogenic variants in LHB reported to date, presented at a median age of 29 (17-38) years, most commonly with delayed puberty. Clinical and biochemical profiles were similar to those of our patient. In the majority, testosterone monotherapy modestly increased testicular volume whereas human chorionic gonadotropin (hCG) monotherapy also improved spermatogenesis. In females, oligomenorrhoea after spontaneous menarche was the most common manifestation. Ten pathogenic/likely pathogenic variants (three in-frame deletions, three missense, two splice-site, one nonsense, and one frameshift variants) have been reported in nine index patients. CONCLUSION: We report a novel likely pathogenic LHB variant in an Asian Indian patient. The typical phenotype in male patients with LHB deficiency is delayed puberty with low testosterone, low LH, and normal to high FSH and hCG monotherapy being the best therapeutic option.

Side-chain cleavage enzyme deficiency: Systematic review and case series.

OBJECTIVE: P450 side-chain cleavage deficiency (SCCD) patients present with primary adrenal insufficiency (PAI) with or without undervirilized external genitalia. The distinction between classic and nonclassic steroidogenic acute regulatory protein deficiency has been described, whereas in SCCD is unclear. The data on gonadal function and its correlation with SCCD genotype has not been studied. We describe our experience and perform a systematic review of genetically proven SCCD patients to determine the distinct phenotypic and genotypic characteristics of 46,XY SCCD patients with typical male external genitalia (SCCD-TMG) and atypical (SCCD-AG) external genitalia. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective review of three genetically proven SCCD patients from our centre and per-patient data analysis from a systematic review of 52 probands was performed. SCCD-TMG (n = 19) was defined as external genitalia of Sinnecker score 1 with 46,XY  karyotype; the rest (Sinnecker 2-5) were classified as SCCD-AG (n = 15). RESULTS: We report two new Indian cases of SCCD with three novel likely pathogenic variants and pubertal follow-up of a previously reported patient. In systematic review, age at diagnosis of PAI and elevated renin were not different between 46,XY  SCCD-TMG (n = 19) and SCCD-AG (n = 15), whereas spontaneous puberty (9/9 vs. 0/3, p = .0045), normal prepubertal (5/5 vs. 6/6, p = .002), pubertal gonadotropins (2/9 vs. 0/3, p = 1) and normal pubertal testosterone (9/11 vs. 0/3, p = .027) were more common in SCCD-TMG. Testicular adrenal rest tumours were exclusive to SCCD-TMG (n = 4). SCCD-TMG was associated with four particular genotypes [monoallelic p.Glu314Lys with another deleterious variant on the second allele (p.Glu314Lys/X-CHS: X-compound heterozygous state), biallelic p.Arg451Trp, p.Phe215Ser/p.Arg232Ter and monoallelic p.Val79Ile]. 46,XX SCCD  patients with p.Glu314Lys/X-CHS also had normal gonadotropins with spontaneous puberty. CONCLUSION: SCCD-TMG is associated with four specific genotypes and distinct gonadal characteristics from SCCD-AG with overlapping features of PAI.

Genotypic Spectrum and its Correlation with Alopecia and Clinical Response in Hereditary Vitamin D Resistant Rickets: Our Experience and Systematic Review.

Alopecia in hereditary vitamin D resistant rickets (HVDRR) has some correlation with severe rickets and poor overall response. However, these observations are based on small series. Hence, we aim to assess the genotypic spectrum of HVDRR and its correlation with alopecia and clinical response. Seven genetically-proven HVDDR patients from five unrelated families and 119 probands from systematic review were analysed retrospectively for phenotypic and genotypic data and overall response to therapy. In our cohort mean age at rickets onset was 12 (± 3.4) months. Alopecia was present in all patients but one. All patients had poor overall response to oral high-dose calcium and calcitriol and most required intravenous calcium. Genetic analyses revealed four novel variants. On systematic review, alopecia was present in majority (81.5%) and preceded the onset of rickets. Patients with alopecia had higher serum calcium (7.6 vs.6.9 mg/dl, p = 0.008), lower 1, 25(OH)2 D (200 vs.320 pg/ml, p = 0.03) and similar overall response to oral therapy (28.7% vs. 35.3%, p = 0.56). Alopecia was present in 51.4% of non-truncating (NT) ligand-binding domain (LBD) variants, whereas it was universal in truncating LBD and all DNA binding-domain (DBD) variants. Overall response to oral therapy was highest in LBD-NT (46.4%) as compared to 7.6% in LBD-truncating and 19% in DBD-NT variants. Among LBD-NT variants, those affecting RXR heterodimerization, but not those affecting ligand affinity, were associated with alopecia. Both alopecia and overall response have genotypic correlation. Age at diagnosis and overall response to oral therapy were similar between patients with and without alopecia in genetically proven HVDRR.

Acton-Prolongatum Stimulated Blood Steroid Profile in Apparently Healthy Asian Indian Women of Reproductive-Age Group.

Blood steroid profile is a recently introduced test in India that is commercially available through a few diagnostic laboratories. In adult women, ACTH-stimulated steroid panel helps to differentiate polycystic ovary syndrome (PCOS) from nonclassical forms of CAH. However, the interpretation of ACTH-stimulated steroid panels is often impeded by the limited availability of reference ranges. Here, we report the adrenal steroid levels after stimulation with Acton Prolongatum in Asian Indian women of reproductive age. This prospective study was conducted at a tertiary health care center in the Southern part of India. Apparently healthy women in the reproductive age group with regular menstrual cycles (21-35 days) at least over the last 6 months were included. All participants received intramuscular Acton Prolongatum® (Pfizer) in the morning hours during the follicular phase and the steroid profile was analyzed by liquid chromatography-tandem mass spectrometry in a blood sample collected 60-min later. The study included 32 apparently healthy women. The mean age of the study population was 22.19 ± 4.36 years. None of the participants experienced any adverse events during the procedure. The median (range) serum cortisol, 17α-hydroxyprogesterone, 11-deoxycortisol, and corticosterone were 22.65 (14.3-37.21) µg/dl, 99.72 (47.21-344.71) ng/dl, 287.2 (74.41-530.61) ng/dl and 728.04 (118.74-1708.2) respectively. In conclusion, this is the first report of the response of adrenal steroids measured by LC-MS/MS at 60 min after Acton Prolongatum in Asian Indian women of the reproductive age group. However, further larger studies are warranted to establish more robust ACTH-stimulated reference ranges for steroid profile in Indian women.

Prevalence of primary aldosteronism in type 2 diabetes mellitus and hypertension: A prospective study from Western India.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) and hypertension commonly coexist; however, underlying primary aldosteronism (PA) can lead to worsening of hypertension, glycemia and cardiovascular risk. We aim to screen patients with T2DM and hypertension for PA by conducting a prospective monocentric study from Western India, which included adults with T2DM and hypertension from the outpatient diabetes clinic. DESIGN: Prospective study. PATIENTS AND MEASUREMENTS: Patients with an aldosterone renin ratio of ≥1.6 ng/dl/µIU/ml with plasma aldosterone concentration (PAC) ≥ 10 ng/dl were considered to be positive on a screening test. A PAC ≥ 6 ng/dl on seated saline suppression test (SST) was used to confirm the diagnosis of PA. RESULTS: Four hundred and eighty-six patients were included in this study. Seventy-six (15.6%, 95% confidence interval [CI]: 12.7%-19.1%) patients had a positive screening test with positive confirmatory test in 20 of the 36 (55.5%, 95% CI: 39.3%-71.7%) screen-positive patients who underwent SST. Patients with positive screening test had a higher proportion of females (65.8% vs. 50%; p = .011), frequent history of hypertensive crises (21.1% vs. 8%; p = .001), uncontrolled blood pressure (51.3% vs. 34.6%; p = .006), diagnosis of hypertension before diabetes (32.9% vs. 21.7%; p = .035) and higher systolic (137.6 ± 6.9 vs. 131.2 ± 17.8 mmHg; p = .004) and diastolic (85.3 ± 11.1 vs. 81.7 ± 10.7 mmHg; p = .007) blood pressures. Patients with positive confirmatory test had longer duration of diabetes (108 [60-162] vs. 42 [24-87] months; p = .012), hypertension (84 [42-153] vs. 36 [15-81] months; p = .038) and higher creatinine (1.16 [1.02-1.42] vs. 0.95 [0.84-1.12] mg/dl; p = .021). CONCLUSIONS: PA is prevalent (at least 4.1%) in Asian Indian patients with T2DM and hypertension. Further studies are needed to assess the cost-effectiveness of routine screening.

Genetic spectrum of Kallmann syndrome: Single-center experience and systematic review.

OBJECTIVE: To study phenotype-genotype data of Asian-Indian Kallmann syndrome (KS) from our center and systematically review the studies analyzing multiple congenital hypogonadotropic hypogonadism (CHH) genes in KS cohorts using next-generation sequencing. DESIGN, PATIENTS, MEASUREMENT: Five hundred twenty-two KS probands (our center n = 78, published studies n = 444) were included in this systematic review. Molecular diagnosis was considered if the likely pathogenic/pathogenic variant in known CHH gene/s was reported in the appropriate allelic state. Varsome prediction tool (following American College of Medical Genetics standards) was used to analyze the variants. RESULT: For our center, the molecular diagnosis was seen in 20.5% of probands and was seen more often with severe than partial reproductive phenotype (28.3% vs. 4%, p = .0013). Our center data adds eight novel variants. The molecular diagnosis was seen in 31% as per the systematic review and analysis. It ranged from 16.6% to 72.2% at different centers. The affected genes were FGFR1 (9.8%), ANOS1 (7.5%), PROKR2 (6.1%), CHD7 (5.4%), oligogenic (2.1%), and others <1% each (FGF8, SOX10, PROK2, SEMA3A, IL17RD, and GNRHR). FGFR1 and ANOS1 were the commonly affected genes globally, whereas PROKR2 was commonest in studies from China and CHD7 from Japan, South Korea and Poland. CONCLUSION(S): This systematic review highlights that the genetic yield is 31% in KS probands, with distinct regional variations. The association of severe reproductive phenotype with the higher genetic yield needs further validation.

17ß hydroxysteroid dehydrogenase 3 deficiency in 46,XY disorders of sex development: Our experience and a gender role-focused systematic review.

OBJECTIVES: To describe Asian Indian patients with 17ß hydroxysteroid dehydrogenase 3 (17ßHSD3) deficiency and to perform a systematic review to determine the factors influencing gender role in 46,XY disorder of sex development (DSD) due to 17ßHSD3 deficiency. PATIENTS AND DESIGN: We present the phenotypic and genotypic data of 10 patients (9 probands and 1 affected family member) with 17ßHSD3 deficiency from our 46,XY DSD cohort (N = 150; Western India) and a systematic review of 152 probands with genetically proven, index 17ßHSD3 deficiency patients from the world literature to identify the determinants of gender role. RESULTS: 17ßHSD3 deficiency was the third most common (6%) cause of non-dysgenetic 46,XY DSD in our cohort. Five patients each had prepubertal (atypical genitalia) and pubertal (primary amenorrhoea) presentations. Six patients were initially reared as female of whom two (one each in prepubertal and pubertal age) changed their gender role. Ten pathogenic molecular variants (six novel) were observed. In the systematic review, initial male sex of rearing was uncommon (10.5%) and was associated with atypical genitalia, higher testosterone/androstenedione (T/A) ratio and Asian origin. Gender role change to male was seen in 10.3% of patients with initial female sex of rearing and was associated with Asian origin but unrelated to pubertal androgens or molecular variant severity. It has not been reported in patients of European origin. CONCLUSIONS: We report the first Indian case series of 17ßHSD3 deficiency, the third most common cause of 46,XY DSD, with six novel molecular variants. Distinct geographical differences in the frequency of initial male sex of rearing and gender role change to male in those initially reared as females in 17ßHSD3 deficiency were noted which needs further evaluation for the underlying molecular mechanisms.

Genotype-Phenotype Correlations in Asian Indian Children and Adolescents with Primary Hyperparathyroidism.

Childhood and adolescent primary hyperparathyroidism (PHPT) is a very rare disease. Data on its molecular genetics are scarce. We performed a retrospective analysis (January 2000-January 2021) to determine the deleterious germline variants and genotype-phenotype correlations in children and adolescents < 20 years diagnosed with PHPT from a single referral center. Clinical features, biochemistry, imaging, management, and genetics (clinical exome analyzed for 11 PHPT and 7 pancreatitis-associated genes, MLPA for CDC73) were recorded. Thirty-six patients (20 males; median age 17 years) were classified into those with familial and/or syndromic (F/S) or apparently sporadic (AS) presentation. Sixteen (44.4%) harbored pathogenic/likely pathogenic germline variants in PHPT-associated genes. The genetic yield in F/S group was 90% (MEN1:8/10; CDC73:1/10), and AS group was 26.9% (CDC73:4/26; CASR:3/26). F/S group had frequent asymptomatic presentation (60% vs none; P < 0.001), lower serum PTH (237.5 vs 1369.1 pg/mL; P = 0.001), and maximum parathyroid dimension (0.9 vs 2.2 cm; P = 0.01) than AS group. Among the AS group, renal involvement was higher in those with molecular diagnoses (71.4% vs 10.5%; P = 0.01). All those with novel CASR variants (including one homozygous) had hypercalciuria and histology-proven parathyroid adenoma/carcinoma. A missense CTRC VUS occurred in one patient with chronic pancreatitis. In summary, Asian Indian children and adolescents with PHPT have high genetic yield, even with apparently sporadic presentation. The phenotypic spectrum of CASR variants is expanded to include childhood/adolescent PHPT with hypercalciuria and single gland neoplasia. The proposed roles for renal involvement to predict molecular diagnosis among those with apparently sporadic presentation require further elucidation.

Early Pulse Glucocorticoid Therapy and Improved Hormonal Outcomes in Primary Hypophysitis.

INTRODUCTION: The role of glucocorticoids in primary autoimmune hypophysitis (PAH) has been fraught with variability in regimens, leading to inconsistent outcomes in terms of anterior pituitary (AP) hormonal recovery. Hence, we aimed to compare the clinical, hormonal, and radiological outcomes of a standardized high-dose glucocorticoid therapy group (GTG) in PAH with a matched clinical observation group (COG). METHODS: Thirty-nine retrospective patients with PAH evaluated and treated at a single center in western India from 1999 to 2019 with a median follow-up duration of 48 months were subdivided into the GTG (n = 18) and COG (n = 21) and compared for the outcomes. RESULTS: Baseline demographic, hormonal, and radiological features matched between the groups, except pituitary height, which was significantly higher in GTG. Cortisol, thyroid, and gonadal axes were affected in 25 (64%), 22 (56%), and 21 (54%) patients, respectively, and central diabetes insipidus was seen in 7 (18%) patients. Panhypophysitis (PH) was the most common radiological subtype (n = 33, 84.6%). Resolution of mass effects was similar in both groups. Overall and complete AP hormonal recovery was significantly higher in the GTG than in the COG (12/14 [85.7%) vs. 6/14 [42.8%], p = 0.02; 10/14 [71.4%] vs. 1/14 [7.7%], p = 0.0007, respectively). Proportion of cases with empty sella were significantly higher in the COG (9/20 [45%] vs 1/17 [5.9%], p = 0.001). Among PH patients in the GTG (n = 17), we found duration from symptoms onset to treatment as the predictor of recovery. CONCLUSION: In a PH subtype-predominant PAH cohort, a standardized high-dose glucocorticoid regimen resulted in higher overall and complete AP hormonal recovery than that in the COG. Initiation of glucocorticoids in the early disease course may have been contributory.

GNRH1 Variants in Congenital Hypogonadotropic Hypogonadism: Single-Center Experience and Systematic Literature Review.

OBJECTIVE: As GNRH1 genotype-phenotype correlation in CHH is not well studied, we aim to describe the GNRH1 variants in our CHH cohort and present a systematic review as well as genotype-phenotype analysis of all mutation-positive cases reported in the world literature. DESIGN: This is a retrospective study of GNRH1 mutation-positive patients from a western Indian center. PRISMA guidelines-based PubMed search of the published literature of all GNRH1 mutation-positive patients was conducted. SETTING: This study was conducted in an academic medical center. PATIENT(S): This study included 2 probands from our cohort and 19 probands from the world literature. MAIN OUTCOME MEASURE(S): Demographic details, clinical presentation, biochemistry, imaging, treatment details, and genotypic data were recorded. RESULT(S): Two probands in our cohort carried two novel pathogenic biallelic GNRH1 variants (p.Glu24Leu, c.238-2A>G). Both had a severe reproductive phenotype. We report successful gonadotropin therapy and fertility in 1 proband. We included 19 probands from 12 studies after the literature review. Ten CHH probands (inclusive 2 from this study) with biallelic GNRH1 variants had severe reproductive phenotype, low gonadotropin levels, low/normal prolactin, normal pituitary imaging, and no extra-reproductive phenotype. Of seven biallelic variants reported, three were frameshift, two were splice-site, and two were missense mutations. All of them were pathogenic/likely pathogenic without oligogenicity. Of seven monoallelic GNRH1 variants reported in 11 probands, 4 had nonreproductive phenotype, 3 were benign/likely benign, and 4 were oligogenic. CONCLUSION(S): GNRH1 biallelic variants lead to severe reproductive phenotype, with low gonadotropin levels without nonreproductive features or oligogenicity. However, the role of GNRH1 monoallelic variants in CHH pathophysiology for reported variants remains questionable.

Clinical Spectrum of Adrenal Cushing's Syndrome and the Caution for Interpretation of Adrenocorticotrophic Hormone: A Single-Center Experience.

To describe the differences in presentation, biochemistry, and radiological evaluation of various etiologies of adrenal Cushing's syndrome (CS) from a single center. To emphasize caution for interpretation of plasma adrenocorticotropic hormone (ACTH), as a spuriously unsuppressed ACTH level by immunometric assay may lead to therapeutic misadventures in adrenal CS. DESIGN: Retrospective, single-center, observational study. METHODS: Fifty-eight adrenal CS patients [Adrenocortical carcinoma (ACC), n=30; Adenoma (ACA), n=15; Primary pigmented nodular adrenocortical disease (PPNAD), n=10; ACTH independent macronodular adrenal hyperplasia (AIMAH), n=3) evaluated at a tertiary care center in western India between January 2006 to March 2020 were included. Data on demography, clinical evaluation, biochemistry, imaging, management, histopathology, and outcome were recorded in a standard format and analyzed. RESULTS: Cortisol secreting ACC presented at 38(1-50) years with abdominal mass in 26/30 (86.7%) and 16/30 (53.3%) had metastases at presentation. ACA with autonomous cortisol excess presented at 25(4.9-40) years with discriminating features of CS in 14/15 (93.3%), sex steroid production in 2/15, unenhanced HU <10 in only one, and relative washout >40% in 8/11 (72.7%). One ACA and eight ACC patients had plasma ACTH (by Siemens Immulite assay) > 20 pg/ml, despite hypercortisolemic state. CONCLUSIONS: Cortisol-secreting ACC and ACA most often present with mass effects and florid CS, respectively. Baseline HU has low sensitivity to differentiate cortisol-secreting ACA from ACC. Plasma ACTH measured by Seimens Immulite is often unsuppressed, especially in ACC patients, which can be addressed by measuring ACTH by more accurate assays.

Giant prolactinoma in children and adolescents: a single-center experience and systematic review.

PURPOSE: Giant prolactinoma (GP) in childhood and adolescence is a rare entity with scarce literature. We aimed to describe clinical features, biochemistry, radiology, genetics, management, and outcome in pediatric (≤ 20 years) GP. METHODS: Retrospective record review of 18 pediatric GP patients from our center and systematic review including these and 77 from the literature (total cohort: 95). RESULTS: GP constituted 20% of our pediatric prolactinoma cohort. In the total cohort (age: 15.4 ± 3.5 years), the majority (77, 82.8%) were males. Mass effect symptoms (88.6%), and pubertal delay/arrest in males (82.1%) were frequent. Median basal prolactin was 8649 (3246-17,532) ng/ml and the maximum tumor dimension was 5.5 ± 1.5 cm. MEN1 and AIP mutations were noted in 7 (21.9%) and 6 (18.8%) patients, respectively. Males with central hypogonadism had baseline bi-testicular volume of 20.2 ± 8.4 cc, lower LH than FSH (-2.04 ± 0.9 vs. -0.7 ± 1.6 SDS, p = 0.0075), and mostly, normal inhibin B. Majority (49/76, 64.5%) received dopamine agonist (DA) as first-line treatment with additional therapy in 35% (17/49). DA monotherapy arm had less frequent central hypothyroidism (42.9% vs 87.1%, p = 0.002) and central adrenal insufficiency (7.1% vs 66.7%, p = 0.0003) than multimodal therapy. A smaller tumor dimension (4.7 vs. 5.7 cm, p = 0.04) was associated with normoprolactinemia on DA monotherapy and AIP mutations (33.3% vs. nil, p = 0.02) with multimodal therapy. CONCLUSION: GP is characterized by male predominance with frequent delay/arrest of puberty (82%), but relative sparing of the FSH-inhibin B axis in boys. DA monotherapy may be preferred as the first-line therapy in pediatric GP.

Pituitary stalk interruption syndrome: phenotype, predictors, and pathophysiology of perinatal events.

PURPOSE: There is limited data regarding Pituitary Stalk Interruption Syndrome (PSIS) from India. Moreover, the pathophysiological link between perinatal events and PSIS is unclear. We aim to elucidate the predictors of PSIS among patients with growth hormone deficiency (GHD) and perinatal events in PSIS by comparing cohorts of PSIS and genetically proven GHD without PSIS. METHODS: Among 179 GHD patients, 56 PSIS and 70 genetically positive GHD (52-GHRHR, 15-POU1F1, and 3-PROP1) patients were included. Perinatal events, clinical anomalies, pituitary hormone deficiency, and imaging findings were recorded. We compared PSIS-isolated GHD (PSIS-IGHD) subgroup with GHRHR-IGHD and PSIS-combined pituitary hormone deficiency (PSIS-CPHD) subgroup with POU1F1/PROP1-CPHD. RESULTS: PSIS patients (45 males, median age: 12.5 years) most commonly presented with short stature. At last follow-up (median age: 17.35 years), gonadal (during pubertal-age), thyroid and cortisol axes were affected in 81.6%, 62.5%, and 62.5%. 10/13 (77%) of PSIS children with initial IGHD diagnosis manifested hypogonadism during pubertal age. Male predominance, sporadic presentation, and clinical anomalies were significantly higher in both PSIS subgroups than in the respective genetic subgroups. Breech presentation was higher in PSIS-CPHD than POU1F1/PROP1-CPHD (44.4% vs 5.5%, p = 0.004). Neonatal hypoglycemia (22% vs. 0%, p = 0.05) and jaundice (42 vs. 5%, p = 0.004) were higher in PSIS-CPHD than PSIS-IGHD. CONCLUSION: Later age at presentation and frequent hypogonadism were observed in our PSIS cohort. Male sex, sporadic presentation, clinical anomalies, and breech presentation predicted PSIS at presentation. Breech presentation in PSIS is likely due to stalk interruption rather than hormonal deficiency.