Spectrum of Pathogenic Variants in &lt;b&gt;&lt;i&gt;SRD5A2&lt;/i&gt;&lt;/b&gt; in Indian Children with 46,XY Disorders of Sex Development and Clinically Suspected Steroid 5α-Reductase 2 Deficiency

Kumar, Anil; Sharma, Rajni; Faruq, Mohammed; Suroliya, Varun; Kumar, Manoj; Sharma, Shilpa; Werner, Ralf; Hiort, Olaf; Jain, Vandana

doi:10.1159/000509812

Cited by 9 publications

(7 citation statements)

References 44 publications

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“…In our cohort, 5α-reductase deficiency was more prevalent than AIS, which is similar to an Indian study including 46,XY DSD patients with normal to elevated baseline or hCG-stimulated testosterone (n = 75) but contrasts with the world literature [Hughes et al, 2019;Kumar et al, 2019;Yu et al, 2020]. This difference may be due to more frequent consanguineous/endogamous marriages in India or the frequent occurrence of a hotspot SRD5A2 mutation (p.Arg246Gln) in the Indian population [Bittles, 2002;Arya et al, 2020].…”

Section: Discussionsupporting

confidence: 82%

“…Elevated FSH in these patients may be due to surgical procedures or prolonged uncorrected cryptorchidism [Melo et al, 2003]. False-positive elevation of T/DHT ratio observed in a few of our AIS patients may be attributed to decreased activity of the enzyme secondary to a lack of androgen action (secondary 5α-reductase deficiency) [Imperato-Mc-Ginley et al, 1982;Kumar et al, 2019].…”

Section: Discussionmentioning

confidence: 98%

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Clinical, Hormonal, Genetic, and Molecular Characteristics in Androgen Insensitivity Syndrome in an Asian Indian Cohort from a Single Centre in Western India

Arya¹,

Barnabas²,

Lila³

et al. 2021

Sex Dev

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The study aimed to analyze clinical and hormonal phenotype,and genotype in patients with genetically proven androgen insensitivity syndrome (AIS) from Western India. Index patients with pathogenic variants in the androgen receptor (AR) gene were identified from a consecutive 46,XY DSD cohort (n = 150) evaluated with clinical exome sequencing, and their genetically-proven affected relatives were also included. In sum, 15 index cases (9 complete AIS [CAIS] and 6 partial AIS [PAIS]) were identified making AIS the second most common (10%) cause of 46,XY DSD, next to 5α-reductase 2 deficiency (n = 26; 17.3%). Most patients presented late in the postpubertal period with primary amenorrhoea in CAIS (89%) and atypical genitalia with gynecomastia in PAIS (71.4%). All CAIS were reared as females and 83.3% of PAIS as males with no gender dysphoria. Four of 6 patients with available testosterone to dihydrotestosterone ratio had a false elevation (>10). Metastatic dysgerminoma was seen in 1 patient in CAIS, while none in the PAIS group had malignancy. Fifteen different (including 6 novel) pathogenic/likely pathogenic variants in AR were found. Nonsense and frameshift variants exclusively led to CAIS phenotype, whereas missense variants led to variable phenotypes. In this largest, monocentric study from the Asian Indian subcontinent, AIS was the second most common cause of 46,XY DSD with similar phenotype but later presentation when compared to cases in the rest of the world. The study reports 6 novel pathogenic variants in AR.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 98%

Clinical, Hormonal, Genetic, and Molecular Characteristics in Androgen Insensitivity Syndrome in an Asian Indian Cohort from a Single Centre in Western India

Arya¹,

Barnabas²,

Lila³

et al. 2021

Sex Dev

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“…As the SRD5A2 gene is a smaller gene and a hotspot (p.R246Q in exon 5) has been described earlier in Indian patients, it was sequenced first in all these 75 subjects. Twenty-five children (including 2 with a clinical diagnosis of CAIS) were found to have pathogenic variants in the SRD5A2 gene [Kumar et al, 2019]. Sanger sequencing of the AR gene was performed in the remaining 50 patients.…”

Section: Methodsmentioning

confidence: 99%

“…The latter results from a lack of the enzyme 5α-reductase which converts testosterone to DHT and presents with a PAIS phenotype consisting of variable degrees of undervirilized genitalia, absence of müllerian structures, functioning testes, and a normal increase of testosterone in response to injection of human chorionic gonadotropin (hCG). Conventionally, a serum testosterone:dihydrotestosteron e (T:DHT) ratio >10 has been taken as a pointer towards 5-ARD rather than AIS, but several studies have documented the unreliability of this ratio [Maimoun et al, 2010;Chan et al, 2013;Akcay et al, 2014;Topcu et al, 2015;Kumar et al, 2019]. Making the correct diagnosis is essential for optimal management as the natural course of the disease, especially the expression of phenotype at puberty, as well as the mode of inheritance are different in AIS and 5-ARD.…”

Section: Introductionmentioning

confidence: 99%

Clinical, Biochemical, and Molecular Characterization of Indian Children with Clinically Suspected Androgen Insensitivity Syndrome

Kumar

Sharma

Faruq

et al. 2021

Sex Dev

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This study describes the clinical, biochemical, and molecular characteristics of Indian children with 46,XY DSD and suspected androgen insensitivity syndrome (AIS). Fifty children (median age 3.0 years, range 0–16.5 years) with 46,XY DSD and a suspected diagnosis of AIS were enrolled. Sanger sequencing was performed to identify pathogenic variants in the androgen receptor (AR) gene and to study genotype-phenotype correlations. All 5 (100%) patients with CAIS and 14/45 (31%) patients with PAIS had pathogenic/likely pathogenic variants in the AR gene (overall, 14 different variants in 19 patients; 38.8%). There was no significant difference in clinical (cryptorchidism, hypospadias, or external masculinizing score) or biochemical parameters (gonadotropins and testosterone) between patients with or without pathogenic variants. However, patients with AIS were more likely to have a positive family history, be assigned female gender at birth, and present with gynaecomastia at puberty. Three novel pathogenic/likely pathogenic variants, including one splice donor site variant c.2318+1G>A, one frameshift variant p.H790Lfs*40, and one missense variant p.G821E, were identified in 3 patients with CAIS. The missense variant p.G821E was predicted as deleterious, damaging, disease-causing, and likely functionally inactive by in silico analysis and protein modelling study. Two previously not reported pathogenic/likely pathogenic variants, including p.R386H and p.G396R, were identified in patients with PAIS. This study contributes in expanding the spectrum of pathogenic variants in the AR gene in patients with AIS. Only 31% patients with a provisional diagnosis of PAIS had pathogenic variants in the AR gene, suggesting other possible mechanisms or candidate genes may be responsible for such a phenotypic presentation.

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“…At puberty, there might be features of virilization along with Gender incongruence or Gender dysphoria. [ 2 ]…”

Section: W Hen To S Uspect Srd5...mentioning

confidence: 99%

“Congruency the ART of Being Real” - 46XY DSD Due to 5 α Reductase Deficiency - Challenges in Decision Making

Sridhar

Priyanka

Jayaraman

2021

Indian Journal of Endocrinology and Metabolism

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Disorders of sexual development (DSDs) are heterogenous group of disorders characterized by discrepancy in chromosomal, gonadal, and phenotypic sex. DSD is a Medico-Social Emergency. 5 α reductase type 2 deficiency is one of the rare causes of 46 XY DSD. The degree of under virilization varies from clinically female to a near male phenotype. Müllerian structures were absent. At puberty, there might be features of virilization. Gender incongruence or dysphoria occurs frequently during puberty. An important marker for diagnosis is an elevated testosterone to dihydrotestosterone ratio in the basal state or following HCG stimulation. All 46 XY DSD require an appropriate molecular diagnosis prior to gender assignment and gender reassignment surgery. Gender reassignment surgery and/or Gonadectomy should be performed only after 18 years if there are compelling indications like suspicion of malignancy or presence of gender dysphoria or gender incongruence.

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Spectrum of Pathogenic Variants in <b><i>SRD5A2</i></b> in Indian Children with 46,XY Disorders of Sex Development and Clinically Suspected Steroid 5α-Reductase 2 Deficiency

Cited by 9 publications

References 44 publications

Clinical, Hormonal, Genetic, and Molecular Characteristics in Androgen Insensitivity Syndrome in an Asian Indian Cohort from a Single Centre in Western India

Clinical, Hormonal, Genetic, and Molecular Characteristics in Androgen Insensitivity Syndrome in an Asian Indian Cohort from a Single Centre in Western India

Clinical, Biochemical, and Molecular Characterization of Indian Children with Clinically Suspected Androgen Insensitivity Syndrome

“Congruency the ART of Being Real” - 46XY DSD Due to 5 α Reductase Deficiency - Challenges in Decision Making

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