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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. [ABSTRACT FROM AUTHOR]

Objective: To define the spectrum of genetic disorders in patients with short stature visiting the genetic out-patient department in a tertiary care hospital. Methods: A chart review was done for 455 individuals (10 months-16 yrs) with short stature, who were evaluated at the genetic clinic from 1 January, 2017 upto 31 October, 2018. 226 patients who needed detailed evaluation, the spectrum of genetic diagnosis is presented. Results: Proportionate short stature was identified in 63% individuals (n=142) of which 93 (65%) were recognizable syndromes such as Turner syndrome, and William syndrome, and RASopathies. In clinically undefined syndromes (39, 27%), a diagnosis could be made by karyotype (n=3/10), chromosomal microarray (6/12) and exome sequencing (1/6). In the 84 children in the disproportionate short stature group (37%), lysosomal storage disorders (LSDs) (45%, n=38) were identified by enzyme analysis in 86.8% and skeletal dysplasias (44%, n=37) identified by skeletal survey in 89% cases. Conclusions: In undefined syndromic short stature, chromosomal microarray may be the first investigation of choice if phenotyping is not suggestive of a specific genetic syndrome. Exome sequencing can be useful in identifying newer genes among idiopathic and familial short stature cohorts. [ABSTRACT FROM AUTHOR]

Introduction: The term 'Disorders of Sexual Differentiation' (DSD) is defined as a congenital discrepancy between external genitalia, gonadal and chromosomal sex. The Chicago consensus based on the primary genetic defect is used for current nomenclature and classification. A child with DSD, if identified and treated early, may grow to become a well-adjusted, functional member of the society. Patients with DSD carry a low but definite risk of developing germ cell tumours which necessitates a histological analysis in all cases. Aim: To describe the clinicopathological features of individuals with DSD and to classify the available cases according to the Chicago consensus which is based on karyotype and histopathology. Materials and Methods: The study was a retrospective descriptive study done at a tertiary referral centre in South India, for a period of four months from May to August 2016. Case charts and histopathology slides of cases received in the department of Pathology from January 2011 to May 2016 were included and reviewed. Cases where the histopathology slides/blocks were not retrievable/difficult to assess due to technical issues were excluded. Case charts and slides were reviewed retrospectively with a view to classify as per karyotypic or histological classification. The slides were reviewed by two pathologists to help in the classification wherever possible. Statistical measures like mean and percentages were used to describe the results. Results: A total of 22 cases of DSD were studied for which karyotype was available in 13 cases. Common clinical presentations were primary amenorrhoea, cryptorchidism and ambiguous genitalia. Age at presentation varied from nine months to 30 years. The initial diagnosis based on karyotype, clinical findings, hormonal assays and imaging were concordant with the final diagnosis in 11 cases. In two cases, histopathology was essential in arriving at a definitive diagnosis. Of the 13 cases with karyotype reports available, five were sex chromosome DSD, five were 46XY DSD and three were 46XX DSD. Gonadoblastoma was seen in three cases. Conclusion: Histopathological examination together with karyotype plays a crucial role in proper categorisation of disorders of sexual differentiation. A multidisciplinary team approach for early diagnosis and management of DSD is essential for the psychosexual development of these individuals. [ABSTRACT FROM AUTHOR]

Objectives: The etiology of primary amenorrhea is varied and can involve different organ systems. Gonadal dysgenesis and Mullerian agenesis are two most common disorders contributing to it. However, there is no consensus about the prevalence of different etiologies among studies reported from different parts of the world. The present study was carried out to evaluate different etiological factors responsible for primary amenorrhea in Western India. Materials and Methods: This was a prospective observational study carried out at a tertiary care hospital in Maharashtra. Thirty cases of primary amenorrhea were evaluated over a period of 2 years and data were analyzed regarding etiology and various management options. Results: Fourteen out of 30 cases had Mullerian agenesis and gonadal dysgenesis was reported in five cases. No case of genital tuberculosis was reported in our study. Most cases of Mullerian agenesis were managed with vaginoplasty, whereas cases of gonadal dysgenesis were managed with cyclical hormonal therapy. Conclusion: Mullerian agenesis was the most common etiology of primary amenorrhea followed by gonadal dysgenesis in our study. Diagnosis of patients of amenorrhea should be meticulous and their management depends on the underlying etiology. [ABSTRACT FROM AUTHOR]

Introduction: Idiopathic hypogonadotropic hypogonadism is a rare gonadal dysgenesis in which puberty does not take place naturally. It occurs due to insufficient pulsatile secretion of Gonadotrophin-Releasing Hormone (GnRH) and the resulting Follicle-Stimulating Hormone (FSH) and Luteinising Hormone (LH) deficiency leads to absence of or delayed sexual maturation. Kallmann syndrome is an uncommon genetic disorder characterised by hypogonadotropic hypogonadism associated with anosmia or hyposmia. When anosmia is absent, the same is referred as normosmic Idiopathic Hypogonadotropic hypogonadism (nIHH). Aim: To find out the significant differences between Kallmann syndrome and nIHH based on clinical features and biochemical assessment as a primary measure to initiate the treatment early. Materials and Methods: This hospital based cross-sectional observational cohort study was conducted in Department of Endocrinology, Nilratan Sircar Medical College and Hospital, Kolkata, India. The study was done on 55 cases of IHH presenting to the department with delayed secondary sexual characteristics. Results: Out of these 55 cases, 45 (81.8%) were nIHH and only ten (18.2%) cases were Kallmann Syndrome. It was found that both the conditions show male predominance. Smell abnormalities were present only in Kallmann group. The level of serum testosterone was significantly higher (p<0.05) in nIHH subjects (mean-35.59 ng/dL) than patients with Kallmann Syndrome (mean-14.90 ng/dL). Patients with Kallmann syndrome showed significantly reduced pubic and axillary hair development and absence of gonadal development. Conclusion: Absence puberty with anosmia/hyposmia with low serum FSH and LH, drastically reduced serum testosterone are factors that point towards the diagnosis of Kallmann syndrome even in absence of genetic study, which is helpful for initiation of hormone replacement therapy for treatment. [ABSTRACT FROM AUTHOR]

Objectives: To present the clinical profile, diagnostic work-up, and management of children with Disorders of Sexual Development (DSD).Materials and Methods: A retrospective study from a tertiary pediatric endocrine unit of western India. We included 39 patients who presented over a period of 9 years from June 2009 to June 2018. Results: Nineteen patients (48.7%) were diagnosed with 46 XY DSD, 16 (41%) with 46 XX DSD, and 4 (10.3%) with sex chromosomal DSD. Out of 46 XY DSD, androgen insensitivity was observed in 8 (42.1%) patients, 5 alpha-reductase deficiency in 5 (26.3%), gonadal dysgenesis in 3 (15.8%), ovotesticular DSD in 2 (10.5%) and 17 beta-hydroxylase (17γ-HSD3) deficiency in 1 (5.3%). Congenital adrenal hyperplasia was the most common cause in 46 XX DSD observed in 11 (68.75%) out of 16 patients, ovotesticular DSD was seen in 4 (25%) patients and testicular DSD in 1 (6.25%) patient. In sex chromosomal DSD 3 (75%) patients had mixed gonadal dysgenesis and 1 (25%) had ovotesticular DSD out of a total of 4 patients. At presentation gender of rearing was assigned as male in 16 (41%) patients, female in 20 (51.3%) patients, and no gender was assigned in 3 (7.7%). The gender of rearing was changed after diagnosis in 6 (16.7%) children. Conclusion: CAH was the most common etiology of 46 XX DSD whereas androgen insensitivity among 46 XY DSD. Assigning the sex of rearing should not be hurried and should be done only after diagnosis and parental counseling. A multidisciplinary and systematic approach is required for children with DSD. [ABSTRACT FROM AUTHOR]

Objective: To describe clinical features in Indian girls with Turner syndrome along with the phenotype-karyotype correlation. Methods: 103 girls with Turner syndrome were divided into karyotype-groups: Classic (45X), 45,X/46,XX mosaics, isochromosomeXq (46,X,iXq and 45,X/46,X,iXq mosaics), 45,X/46,XYmosaics and structural defects, and analyzed for phenotypic differences. Results: Majority (44.1%) had classic karyotype followed by isochromosome-Xq (26.5%). Classic Turner syndrome had higher prevalence of most skeletal and cutaneous stigmata, cubitus valgus (68.3%) and multiple nevi (68.2%) being the commonest. Bicuspid aortic valve was most common in 45,X/46,XX mosaics (5/15, 33.3%), and aortic coarctation in classic TS (3/42, 7.2%). Congenital renal anomalies occurred mostly in classic TS (6/42,14.3%). Overt hypothyroidism, conductive deafness and recurrent otitis media were commonest in isochromosomes (P<0.03). 45,X/46,XY mosaics had highest IQ (P<0.005). Conclusion: We report some novel associations of karyotype with non-endocrine parameters in Turner syndrome. In resource-limited settings, underlying karyotype may help prioritize screening investigations in girls with Turner syndrome. [ABSTRACT FROM AUTHOR]

Context: Primary Amenorrhea is worrisome for the adolescent as well as their guardian. It is essential to be able to identify the underlying pathology and initiate appropriate management strategies, well in time. Aims: To study the clinical features, with an aim to identify discriminatory clinical features to indicate a most probable diagnosis. Design: A prospective, observational study. Setting: The Gynecologic Endocrinology Clinic of Department of Obstetrics and Gynecology and Endocrinology Outpatient Department of a tertiary centre in North India. Methodology: In total 328 women with primary amenorrhea, registered during a duration of 10 years (January 2008 to December 2017), were enrolled for the study and a proforma was filled with their medical details. Results: It was observed that patients with normal stature and underdeveloped breasts were likely to be hypogonadotropic hypogonadism, whereas those with short stature and underdeveloped breasts were more likely to be gonadal failure with underlying chromosomal abnormality. The three most common causes of primary amenorrhea in the index population were hypogonadotropic hypogonadism (117/328 = 35.1%), gonadal dysgenesis (99/328 = 30.2%) and mullerian agenesis (53/328 = 16.2%). Conclusion: Age, height, and Tanner staging at presentation can provide a clue toward diagnosis, even before confirmatory tests are available. One of the largest studies reported on primary amenorrhea, we found hypogonadotropic hypogonadism to be the commonest cause, in contrast to previous studies. [ABSTRACT FROM AUTHOR]

We aimed to survey the monogenic causes of disorders of sex development (DSD) and thereby its prevalence in India. This study revealed mutations resulting in androgen insensitivity syndrome, 5α-reductase type 2 deficiency, and gonadal dysgenesis were commonly reported. Intriguingly, AR deficits were the most prevalent (32 mutations) and of 11/26 missense mutations were in exons 4-8 (encoding ligand binding domain). The unique features of SRD5A2 defects were p.R246Q (most prevalent) and p.G196S could be mutational hotspots, dual gene defects (p.A596T in AR and p.G196S in SRD5A2) in a patient with hypospadias and novel 8 nucleotide deletion (exon 1) found in a patient with perineal hypospadias. Deficits in SRY, WT1, DHH, NR5A1, and DMRT1 caused 46,XY gonadal dysgenesis. Notably, mutations in AR, SRD5A2, MAMLD1, WT1, and MAP3K1 have led to hypospadias and only one CYP19A1 mutation caused aromatase deficiency was reported to date. Data mining from various databases has not only reinforced the role of well-established genes (e.g., SRY, WT1, DHH, NR5A1, DMRT1, AR, SRD5A2, MAMLD1) involved in DSD but also provided us 12 more potential candidate genes (ACVR1, AMHR2, CTNNB1, CYP11A1, CYP19A1, FGFR2, FGF9, PRKACA, PRKACG, SMAD9, TERT, ZFPM2), which benefit from a close association with the well-established genes involved in DSD and might be useful to screen owing to their direct gene-phenotype relationship or through direct functional interaction. As more genes have been revealed in relation to DSD, we believe ultimately it holds a better scenario for therapeutic regimen. Despite the advances in translational medicine, hospitals are yet to adopt genetic testing and counseling facilities in India that shall have potential impact on clinical diagnosis. Abbreviations: 5α-RD2: 5α-Reductase type 2; AIS: androgen insensitivity syndrome; AMH: antimullerian hormone; AMHR: antimullerian hormone receptor; AR: androgen receptor gene; CAH: congenital adrenal hyperplasia; CAIS: complete AIS; CAH: congenital adrenal hyperplasia; CHH: congenital hypogonadotropic hypogonadism; CXORF6: chromosome X open reading frame 6 gene; CYP19A1: cytochrome P450 family 19 subfamily A member 1 gene; DHT: dihydrotestosterone; DMRT1: double sex and mab-3 related transcription factor 1 gene; DSD: disorders of sexual development; GD: gonadal dysgenesis; HGMD: human gene mutation database; IH: isolated hypospadias; MAMLD1: mastermind like domain containing 1 gene; MIS: mullerian inhibiting substance; NTD: N-terminal domain; OT DSD: ovotesticular DSD; PAIS: partial AIS; SOX9: SRY-related HMG-box 9 gene; SRY: sex-determining region Y gene; STAR: steroidogenic acute regulatory protein gene; SRD5A2: steroid 5 alpha-reductase 2 gene; T DSD: testicular DSD; T: testosterone; WNT4: Wnt family member 4 gene; WT1: Wilms tumor 1 gene; Δ4: androstenedione [ABSTRACT FROM AUTHOR]