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.

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.

Overnight 1-mg DST Serum Cortisol in Various Stages of Chronic Kidney Disease-Normative Data and Underlying Mechanisms.

Context: Data on the overnight 1 mg-dexamethasone suppression test (ONDST) in renal dysfunction are limited. Objective: We aim to determine the normative range of ONDST cortisol across chronic kidney disease (CKD) stages and reasons for its alteration. Methods: Prospectively, 180 CKD (30 each in G2-G5/5D) patients and 30 healthy controls underwent ONDST 8 Am serum cortisol (chemiluminescent immunoassay [CLIA]). In an exploratory cohort, 45 (15 each: G3b/G4, G5/G5D, and healthy controls) individuals' blood biochemistry for basal (8 Am) cortisol and adrenocorticotropin (ACTH), post-ONDST 8 Am dexamethasone, ACTH, cortisol (CLIA and liquid chromatography-tandem mass spectrometry), and 4 Pm cortisol was collected. Results: Post-ONDST cortisol (µg/dL) correlated inversely (r = 0.47; P < .005) with estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2), with 95th percentile being 1.2 in controls, 3.0 in G2, 3.2 in G3a, 4.3 in G3b, 4.7 in G4, 5.7 in G5, and 7.1 in G5D. In the exploratory cohort, basal 8 Am cortisol and ACTH, and post-ONDST dexamethasone were similar among controls and CKD subgroups. ONDST ACTH (for evaluating the hypothalamo-pituitary-adrenal axis) was slightly higher in G5/5D vs controls (8.9 vs 6.1 pg/mL), while it was similar in G3b/G4 vs controls. Median 8 Am ONDST cortisol was similar on CLIA and LC-MS/MS in controls and higher on CLIA in G3b/4 (1.7 vs 1.1 µg/dL; P = .012) and G5/5D (2.4 vs 1.7 µg/dL; P = .002) than LC-MS/MS. Post-ONDST serum cortisol drop from 8 Am to 4 Pm was significant in controls (0.5-<0.2 µg/dL) and G3b/4 (1.7-1.2 µg/dL), but not in G5/5D (2.4-2.2 µg/dL). Conclusion: The normative data of ONDST serum cortisol with eGFR-based cutoffs are useful in evaluating Cushing syndrome in CKD. Prolonged cortisol half-life and immunoassay-related assay cross-reaction are likely contributors to higher ONDST cortisol.

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.

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.

Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement.

Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.

Giant prolactinoma in Asian-Indians: A single-center experience from Western India.

PURPOSE: Giant prolactinomas (GP) are rare tumors accounting for 4.3% of prolactinomas, with paucity of literature from India. We aim to describe clinical, biochemical, radiological, and treatment outcomes in a large series of Asian-Indian patients with GP. METHODS: A single-center retrospective analysis of GPs (n=84), age-based (adults: 66 versus pediatric: 18) and gender-based (males: 64 versus females: 20) comparison was done. RESULTS: The mean age at presentation was 34.1±13years, and 64 (76.2%) were males. Males were younger at presentation (32.1±12.2 versus 40.1±13.8years, P: 0.01). The majority presented with mass-effect-related manifestations (visual disturbances: 91.6%, headache: 84.5%) and/or hypogonadism (98.7%). At baseline, largest tumor dimension was 5.3±1.0cm, and serum prolactin was 8343 (3865.5-12,306) ng/mL; most (94.6%) had gonadal axis involvement. Dopamine-agonist (DA) as first-line therapy (45/67, 67.2%) achieved normoprolactinemia (maximum cabergoline dose: 2.0±1.2mg/week) in 36/45 (80%) and tumor response (≥50% reduction) in 36/37 (97.3%) patients at the last follow-up (median duration: 33 [14.5-53.5]months). Notably, gonadal axis recovery was poor (6/30, 20%) despite normoprolactinemia post-DA monotherapy. At latest follow-up, secondary hypothyroidism (32.5% versus 82.6%, P: 0.001) and central hypocortisolism (5.6% versus 42.9%, P: 0.007) were less frequent in DA monotherapy (n=43) than in multimodal therapy group (n=23). The proportion of males (94.4% versus 71.2%, P: 0.04) was higher in the pediatric age group, with DA-induced (first-line) normoprolactinemia observed in 66.7% of them. CONCLUSION: GP has male predominance, DA as first-line therapy normalized prolactin in four-fifths of patients with better preservation of HPT and HPA axes in patients with DA monotherapy.

Gonadotropin-Dependent Precocious Puberty: Single-Center Experience From Western India.

OBJECTIVE: To describe the characteristics of gonadotropin-dependent precocious puberty (GDPP) in Indian children. METHODS: Clinical profiles of GDPP (n=78, 61 females) and premature thelarche (n=12) from a single center in Western India were retrospectively studied. RESULTS: Pubertal onset was earlier in boys than girls (29 vs 75 months, respec-tively; P=0.008). The basal luteinizing hormone (LH) was ≥0.3 mIU/mL, except 18% of GDPP girls. At 60 minutes after GnRHa-stimulation, all patients (except one girl) had LH ≥5 mIU/mL. The GnRHa-stimulated LH/FSH ratio was ≥0.34 at 60 minutes in girls with GDPP unlike premature thelarche. Only one girl had an allergic reaction to long-acting GnRH agonist. Among GnRH agonist-treated girls (n=24), the predicted final adult height was -1.67±1.5 SDS, whereas the attained final height was -0.25±1.48 SDS. CONCLUSION: We establish the safety and efficacy of long acting GnRH agonist therapy in Indian children with GDPP. The 60-minute stimulated serum LH/FSH of ≥0.34 differentiated GDPP from premature thelarche.

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.

Glucocorticoid therapy as first-line treatment in primary hypophysitis: a systematic review and individual patient data meta-analysis.

Objectives: High-dose glucocorticoids are associated with improved recovery of deficits in primary autoimmune hypophysitis (PAH), but optimal dosing, route, and duration are unclear. Design: We reviewed literature for first-line glucocorticoid treatment in PAH until December 2021 and performed an individual patient data meta-analysis to analyze clinical, hormonal, and radiological outcomes with respect to route, dose, and duration (<6.5 vs 6.5-12 vs >12 weeks) of glucocorticoid treatment according to disease severity. Results: A total of 153 PAH patients from 83 publications were included. The median age at presentation was 41 (32.5-48) years with a female preponderance (70.3%). Visual field recovery was significantly better with i.v. (91.7%) as compared to oral (54.5%) route and high dose (100%) and very high dose (90.9%) as compared to medium dose (20%) of glucocorticoids. Corticotroph axis recovery was greater in i.v. (54.8% vs 28.1% oral, P = 0.033) route and increasing glucocorticoid dose group (0% vs 38.1% vs 57.1%), attaining statistical significance (P = 0.012) with very high-dose. A longer duration of treatment (>6.5 weeks) was associated with better corticotroph and thyrotroph recovery. The need for rescue therapy was lower with i.v. route (38% vs 17.5%, P = 0.012) and with increasing glucocorticoid doses (53.3% vs 34.3% vs 17.3%, P = 0.016). In severe disease, visual field and corticotroph axis recovery were significantly higher with i.v. route and very high-dose steroids. The adverse effects of glucocorticoids were independent of dose and duration of treatment. Conclusions: Very high-dose glucocorticoids by i.v. route and cumulative longer duration (>6.5 weeks) lead to better outcomes and could be considered as first-line treatment of severe PAH cases.

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.

Comparison of the Sensitivity of 68 Ga-DOTATATE PET/CT with Other Imaging Modalities in Detecting Head and Neck Paraganglioma: Experience from Western India.

Background This study aimed to compare the sensitivity of 68 Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) with other imaging modalities in the detection of head and neck paraganglioma (HNPGL). Methods The data of consecutive HNPGL patients ( n = 34) who had undergone at least 68 Ga-DOTATATE PET/CT and anatomical imaging (contrast-enhanced computed tomography/magnetic resonance imaging [CECT/MRI]) were retrospectively reviewed. The diagnosis of HNPGL (the primary tumor) was confirmed either by histopathology ( n = 10) or was based on clinical follow-up and correlation of anatomical with functional imaging in whom histopathology was not available ( n = 24). The sensitivities of 68 Ga DOTATATE PET/CT, 18F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT), 131 I-metaiodobenzylguanidine ( 131 I-MIBG) scintigraphy, and CECT/MRI for primary HNPGL, associated primary pheochromocytoma + sympathetic paraganglioma (PCC + sPGL), and metastatic lesions were analyzed. Results Thirty-four patients (males: 15) [isolated HNPGL: 26, HNPGL + PCC: 04, HNPGL+ sPGL: 03, HNPGL + PCC + sPGL: 01] harboring 50 primary lesions were included. For total lesions, 68 Ga-DOTATATE PET/CT (99.3%) had significantly higher lesion-wise sensitivity than 18 F-FDG PET/CT (81.6%, p = 0.0164), 131 I-MIBG (15.2%, p ≤0.0001), CECT (46.3%, p ≤ 0.0001) but similar sensitivity as MRI neck (97%, p = 0.79). On head-to-head comparison (21 primary HNPGL and 39 metastatic lesions), 68 Ga DOTATATE PET/CT had significantly higher lesion-wise sensitivities for the detection of metastatic (100 vs. 71.9%, p = 0.04) and total lesions (100 vs. 77.2%, p ≤ 0.0001). Conclusion 68 Ga-DOTATATE PET/CT was the most sensitive imaging modality for the detection of HNPGL and related lesions with significantly higher lesion-wise sensitivities than those of 18 F-FDG PET/CT, 131 I-MIBG, and CECT.

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.

Percentage arterial enhancement on 2D CT in the diagnosis of primary hyperparathyroidism: A prospective validation study and potential pitfalls.

BACKGROUND: Parathyroid lesions are identified by subjective enhancement and washout patterns on computed tomography (CT). We have previously proposed "percentage arterial enhancement" (PAE) as an objective index and now aim to validate its performance prospectively. METHODS: Dual-phase CT was performed in 40 consecutive primary hyperparathyroidism patients. PAE was calculated as [{arterial phase Hounsfield unit (HU)-unenhanced phase HU}/unenhanced phase HU] × 100. PAE > 128.9% was considered parathyroid. RESULTS: PAE had 94.2% sensitivity, 100% positive predictive value (PPV) in lateralization, and sensitivity and PPV of 93.9% in quadrant localization of single-gland disease. PAE failed to identify two lesions: an intrathyroidal parathyroid carcinoma in the background of multinodular goiter and another lower enhancing cystic parathyroid adenoma. PAE had 60% sensitivity, and 100% PPV to identify multigland disease. The mean effective dose was 2.74 mSV. CONCLUSIONS: PAE is a specific CT index for parathyroid lesions with less radiation exposure. Areas of caution include intrathyroidal and cystic lesions.

Regional genotypic variations in normosmic congenital hypogonadotropic hypogonadism: our experience and systematic review.

PURPOSE: To describe phenotype-genotype data of Asian-Indian normosmic congenital hypogonadotropic hypogonadism (nCHH) from our centre and perform a systematic review of genetic studies using next-generation sequencing (NGS) in nCHH. METHODS: Sixty-eight nCHH probands from our center, and 370 nCHH probands from published studies were included. Per-patient genetic variants were analyzed as per ACMG guidelines. Molecular diagnosis was defined as presence of a pathogenic or likely pathogenic variant in a known CHH gene following zygosity status as per known mode of genetic inheritance. RESULT: At our centre molecular diagnosis was observed in 35.3% of probands {GNRHR:16.2%, FGFR1:7.3%, KISS1R:4.4%, GNRH1:2.9%, TACR3:2.9%, CHD7:1.4%}. Molecular diagnosis was observed more often (44.7% vs 14.3%, p = 0.026) with severe than partial reproductive-phenotype. The study adds 12 novel variants and suggests GNRHR p.Thr32Ala variant may have a founder effect. In per-patient systematic review (including our cohort), the molecular diagnosis was reached in 23.2%, ranging from 3.5 to 46.7% at different centers. The affected genes were FGFR1:6.4%, GNRHR:4.3%, PROKR2:3.6%, TACR3:1.8%, CHD7:1.6%, KISS1R:1.4%, GNRH1:1.4% and others (PROK2, SOX3, SOX10, SOX11, IL17RD, IGSF10, TAC3, ANOS1, oligogenic): < 1% each. FGFR1 was the most commonly affected gene in most cohorts except Asia, whereas PROKR2 (in China and Japan) and GNRHR (in India) were the commonest. CONCLUSION: (s): The global molecular diagnosis rate was 23.2% in nCHH cohorts whereas that in our cohort was 35% with a higher rate (44.7%) in those with severe reproductive-phenotype. The most commonly affected gene in nCHH patients was FGFR1 globally while it was PROKR2 in East Asia and GNRHR in India.

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.

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.

17α-Hydroxylase/17,20-Lyase Deficiency in 46,XY: Our Experience and Review of Literature.

CONTEXT: There are more than 100 pathogenic variants in CYP17A1 that have been identified in patients with 17α-hydroxylase/17,20-lyase deficiency (17OHD). OBJECTIVE: We aimed to describe 46,XY patients with 17OHD from our center and review the literature. METHODS: We retrospectively analyzed genetically proven index cases of 17OHD from our 46,XY disorders of sex development cohort and reviewed similar cases from the literature (n = 150). Based on the phenotype, 17OHD probands were classified into combined severe deficiency (n = 128) and combined partial deficiency (n = 16). Additionally, patients with the apparent isolated 17,20-lyase deficiency (n = 7, from 6 families) were noted. Residual enzyme activities with the observed mutant enzymes were divided in 2 categories as < 1% and ≥ 1%, each for hydroxylase and lyase. RESULTS: We present 4 index cases of 46,XY 17OHD with a complete spectrum of undervirilization and 2 novel variants in CYP17A1. In the review, the combined severe deficiency was the most common form, with more frequent female sex of rearing, hypertension, hypokalemia, suppressed renin, higher plasma corticotropin, lower serum cortisol, and androgens. Immunoassay-measured serum aldosterone was frequently (68.2%) unsuppressed (>5 ng/dL). Elevated serum progesterone had high sensitivity for diagnosis of combined 17OHD, even in combined partial deficiency (83.3%). Among patients with clinical phenotype of combined severe deficiency, 11.5% had partial 17α-hydroxylase and complete 17,20-lyase deficiency (>1%/<1%) and had significantly higher serum cortisol than those with < 1%/<1% activity. CONCLUSION: We report the first monocentric case series of Asian Indian 46,XY patients with 17OHD. We propose that a phenotype of severe undervirilization with milder cortisol deficiency may represent a distinct subtype of combined severe 17OHD with residual 17α-hydroxylase activity but severe 17,20-lyase deficiency (>1%/<1%), which needs further validation.