Differences/disorders of sex development (DSDs) are a diverse group of congenital conditions that result in disagreement between an individual's sex chromosomes, gonads, and/or anatomical sex. The 46, XY DSD group is vast and includes various conditions caused by genetic variants, hormonal imbalances, or abnormal sensitivity to testicular hormones, leading to varying degrees of under-virilization. A 19-year-old phenotypically normal female from Kakamega, Kenya, presented with primary amenorrhea. Physical examination revealed Tanner stage 3 breast development, Tanner stage 4 pubic hair, normal external genitalia, and a gynoid body shape. Hormonal profile tests indicated hypergonadotropic hypogonadism with normal 17-hydroxyprogesterone and testosterone levels. MRI revealed a hypoplastic uterus and absent ovaries. Karyotyping confirmed a 46, XY genotype, leading to the diagnosis of 46, XY complete gonadal dysgenesis (Swyer syndrome). Swyer syndrome is a rare disorder of sex development, characterized by unambiguous female genitalia, bilateral streak gonads, and elevated gonadotropin levels in individuals with a 46, XY karyotype. The condition results from abnormal gonadal development due to mutations in testis-determining factors, most commonly the SRY gene. Patients typically present with primary amenorrhea and seldom have secondary sexual characteristics as this patient had. Management includes hormone replacement therapy and gonadectomy because of the increased risk of gonadal tumors. The patient was educated about her condition, initiated on combined contraceptive pills, and counseled on exploratory laparoscopic gonadectomy. This case highlights the importance of a comprehensive diagnostic approach in patients with primary amenorrhea, keeping in mind that patients with disorders of sex development may have developed secondary sexual characteristics. The purpose of this overview is to: 1.. To describe the clinical characteristics of nonsyndromic disorders of testicular development; 2.. To review the genetic causes of nonsyndromic disorders of testicular development and conditions that may be in the differential diagnosis; 3.. To provide an evaluation strategy to identify the genetic cause of nonsyndromic disorders of testicular development (when possible); 4.. To inform management regarding sex of rearing, medical/surgical intervention (when appropriate), hormone therapy, and psychosocial aspects of care; 5.. To inform genetic risk assessment in family members of a proband.

Disorders of sex development (DSDs) are congenital conditions in which chromosomal, gonadal and sex is atypical. It is difficult to diagnose and manage patients with DSD in clinical practice, and the molecular etiology of DSD is still not completely understood. Here, we identified two novel pathogenic mutations from three unrelated Chinese patients with 46,XY complete gonadal dysgenesis (CGD) that is a clinical subgroup of DSD by whole exome sequencing. A novel mutation in the SRY gene (c.161delG) was identified in the first patient, and the second patient carried a novel missense mutation in the MAP3K1 gene (c.2117T>G). Bioinformatics analysis found that the deletion of SRY (c.161delG) led to a premature stop codon at amino acid 59 in the SRY protein, which resulted in lacking the DNA binding domain of SRY protein. Functional studies found that the missense mutation in the MAP3K1 gene (c.2117T>G) could interfere with the gene function through increasing the phosphorylation of the downstream targets of MAP3K1, ERK1/2 and p38, which resulted in reducing testis-determining factor SOX9 expression and increasing ovary-promoting factor β-catenin activity. According to the American college of medical genetics and genomics (ACMG) standards and guidelines, these mutations were categorized as "pathogenic" mutations. Thus, our findings provide two novel pathogenic mutations associated with 46,XY CGD that can improve the etiological diagnosis for 46,XY CGD. ABBREVIATIONS.

Complete gonadal dysgenesis (CGD) is characterized by an incomplete differentiation of the genital organs in a patient with a 46,XY karyotype. It is induced by mutations in the sex-determining region Y (SRY) gene which plays a key role in testis-determining pathways. The aim of this study was to investigate the possible pathogenic nature of a novel SRY mutation (p.Y127H) identified in a 46,XY female patient. To determine the effect of this mutation on SRY function, we studied its impact on DNA interaction by electrophoretic mobility shift assays. Since tyrosine 127 is close to the C-terminal nuclear localization signal of SRY, we conducted HA-SRY protein expression to observe the impact of the mutation on the nuclear import function in transfected cells. Our results showed that the Y127H mutation nearly abolishes the DNA-binding capacity of SRY and strongly impairs the nuclear localization of the mutated protein. Together with a previously described mutation analyzed in parallel in this paper (p.Y127C), our results highlight this tyrosine residue as a crucial structural determinant of the high mobility group box domain. This is the first report to explain the molecular mechanism of the Y127H mutation causing sex reversal and gives new insights for clinical practice to benefit patients with disorders of sex development.