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

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.

The Spectrum of Ovotesticular Disorders of Sex Development in South Africa: A Single-Centre Experience.

OBJECTIVE: To describe the clinical characteristics, biochemistry, histopathology, and long-term outcomes in subjects with ovotesticular (OT) disorder of sex development (DSD). STUDY DESIGN: This is a retrospective subset analysis of 64 cases of histologically confirmed OT DSD. RESULTS: All subjects were South African; 97% (n = 62) were African and 92% (n = 59) were of Zulu ethnicity. The most common karyotype was 46,XX (88%; n = 56), followed by 46,XY (8%), 46,XY/45,X (3%), and 46,XX/46,XY (1%). The median age at presentation was 7 months (0.5 months to 5.1 years). Sixty-one of the subjects (95%) presented with DSD. The ovotestis was the most frequent gonad (56%), followed by the ovary (23%) and the testis (16%). Testes were more commonly located on the right and ovaries on the left (p < 0.0001). The male gender was the predominant sex of rearing in two-thirds of the subjects. Gender dysphoria was noted in 8 subjects (11%) at a median of 6.4 (4.3-9.3) years. Long-term follow-up (n = 14) revealed spontaneous puberty in 5 subjects, gender dysphoria in 2 subjects, and neuropsychiatric disorders in 4 subjects. CONCLUSION: OT DSD is an important differential diagnosis in Black South Africans with 46,XX DSD.

Phenotypic and molecular characteristics in eleven Chinese patients with 5α-reductase Type 2 deficiency.

CONTEXT: Steroid 5α-reductase type 2 deficiency (5α-RD2) is a male-limited, autosomal recessive inherited disease. Affected 46, XY individuals usually present with ambiguous genitalia at birth. An early and precise diagnosis is of great value to the long-term prognosis of the disease. OBJECTIVE: To describe the clinical features and molecular determinants in 11 Chinese patients with the SRD5A2 gene mutation and to investigate the functional alteration arising from a novel splicing site mutation identified in one of the patients. SUBJECTS AND METHODS: Eleven subjects born with abnormal external genitalia from 10 unrelated families were recruited. Among them, nine patients who were reared as girls underwent virilization and gender change after puberty. Genotyping analysis of the SRD5A2 gene was performed in each of the patients. Haplotype analysis was performed in five patients with a prevalent mutation of p.G203S to illustrate the founder effect in China. Functional impairment of the new variant was explored by an in vitro splicing study and enzymatic activity assay. RESULTS: Nine mutations in the SRD5A2 gene were detected in the eleven patients. In addition to the previously reported p.G203S, p.R227Q, p.N193S, p.R246Q, p.Q6X, p.A228V, c.655delT and IVS1-2 A>G, a novel splicing site mutation (IVS4 + 2 T>C) was identified. From an in vitro functional study, this mutation was found to result in a skipping of exon 4 in the course of mRNA splicing, leading to a truncated protein of 205 amino acids that lacks the catalysing activity. Two siblings with the same compound heterozygous mutation (IVS1-2A>G/p.G203S) exhibited differing phenotypes and opposite patterns of gender rearing. A prevalent variation p.V89L combined with c.655delT was revealed to cause a mild phenotype of 5α-RD2 with a micropenis. CONCLUSION: This cohort study describes the phenotypic, biochemical and long-term outcome in 11 Chinese patients with 5α-RD2 deficiency and defines the genotypic spectrum of SRD5A2 mutations in China.

Molecular analysis of the SRD5A2 in 46,XY subjects with incomplete virilization: the P212R substitution of the steroid 5alpha-reductase 2 may constitute an ancestral founder mutation in Mexican patients.

Inactivating mutations of the SRD5A2 gene result in steroid 5α-reductase 2 deficiency, an autosomal recessive disorder expressed as a male-limited disorder of sex development. Herein, genomic DNA was isolated from 11 new patients with apparent steroid 5α-reductase 2 deficiency. Coding sequence abnormalities in SRD5A2 were assessed by exon-specific polymerase chain reaction, single-stranded conformation polymorphism, and direct sequencing. Likewise, enzymatic activity of the P212R gene variant of SRD5A2 was assessed. DNA analysis revealed mutations in all patients (G115D, R171S, N193S, E197D, G203S, P212R). Three individuals were compound heterozygotes, 6 were homozygotes, and 2 more were single heterozygotes for SRD5A2 mutations; remarkably, 40% of the mutant alleles (9/22) contained the gene variant P212R. The results described in this study represent, along with our previous reports, the largest number of patients with steroid 5α-reductase 2 deficiency belonging to nonrelated families. Regarding the frequency of the p.P212R mutation in our population and its presence throughout all of our country, it allows us to hypothesize that the presence of this mutation may constitute a founder gene effect.