Broad-spectrum XX and XY gonadal dysgenesis in patients with a homozygous L193S variant in PPP2R3C

Context: Homozygous and heterozygous variants in PPP2R3C are associated with syndromic 46,XY complete gonadal dysgenesis (MEGD syndrome), and impaired spermatogenesis, respectively. This study expands the role of PPP2R3C in the aetiology of gonadal dysgenesis (GD). Method: We sequenced the PPP2R3C gene in four new patients from three unrelated families. The clinical, laboratory and molecular characteristics were investigated. We have also determined the requirement for Ppp2r3c in mice (C57BL6/N) using CRISPR/Cas9 genome editing. Results: A homozygous c.578T>C (p.L193S) PPP2R3C variant was identified in one 46,XX girl with primary gonadal insufficiency, 2 girls with 46,XY complete GD, and one undervirilized boy with 46,XY partial GD. The patients with complete GD had low gonadal and adrenal androgens, low AMH, and high FSH and LH concentrations. All patients manifested characteristic features of MEGD syndrome. Heterozygous Ppp2r3c knockout mice appeared overtly normal and fertile. Inspection of homozygous embryos at 14.5, 9.5 and 8.5 days post coitum revealed evidence of dead embryos. We conclude that loss of function of Ppp2r3c is not compatible with viability in mice and results in embryonic death from 7.5 dpc or earlier. Conclusion: Our data indicate essential roles for PPP2R3C in mouse and human development. Germline homozygous variants in human PPP2R3C are associated with distinctive syndromic GD of varying severity in both 46,XY and 46,XX individuals.

The Desert Hedgehog Signalling Pathway in Human Gonadal Development and Differences of Sex Development

While the Hedgehog signalling pathway is implicated in numerous developmental processes and maladies, variants in the <i>Desert Hedgehog</i> (<i>DHH</i>) ligand underlie a condition characterised by 46,XY gonadal dysgenesis with or without peripheral neuropathy. We discuss here the role and regulation of <i>DHH</i> and its signalling pathway in the developing gonads and examine the current understanding of how disruption to this pathway causes this difference of sex development (DSD) in humans.

Expanding DSD Phenotypes Associated with Variants in the DEAH-Box RNA Helicase DHX37

Missense variants in the RNA-helicase DHX37 are associated with either 46,XY gonadal dysgenesis or 46,XY testicular regression syndrome (TRS). DHX37 is required for ribosome biogenesis, and this subgroup of XY DSD is a new human ribosomopathy. In a cohort of 140 individuals with 46,XY DSD, we identified 7 children with either 46,XY complete gonadal dysgenesis or 46,XY TRS carrying rare or novel DHX37 variants. A novel p.R390H variant within the RecA1 domain was identified in a girl with complete gonadal dysgenesis. A paternally inherited p.R487H variant, previously associated with a recessive congenital developmental syndrome, was carried by a boy with a syndromic form of 46,XY DSD. His phenotype may be explained in part by a novel homozygous loss-of-function variant in the <i>NGLY1</i> gene, which causes a congenital disorder of deglycosylation. Remarkably, a homozygous p.T477H variant was identified in a boy with TRS. His fertile father had unilateral testicular regression with typical male genital development. This expands the DSD phenotypes associated with DHX37. Structural analysis of all variants predicted deleterious effects on helicase function. Similar to all other known ribosomopathies, the mechanism of pathogenesis is unknown.

Sex Dimorphism of Birth Weight and Length: Evidence Based on Disorders of Sex Development

The aim of this study was to verify the influence of Y chromosome and intrauterine androgens production/action on birth weight and length of children with Disorders/Differences of Sex Development (DSD). This was a cross-sectional and retrospective study. Cases of Turner syndrome (TS), complete (XX and XY), mixed (45,X/46,XY) and partial (XY) gonadal dysgenesis (GD), complete (CAIS) and partial (PAIS) androgen insensitivity syndromes and XX and XY congenital adrenal hyperplasia (CAH) were included. Such conditions were grouped according to karyotype and to intrauterine production/action of androgens. The sample consisted of 293 cases, 50 with TS, 28 mixed GD, 117 CAH (49 XY and 68 XX), 18 CAIS, 10 PAIS, 30 partial GD, 10 XY and 30 XX complete GD. Birth weight and length were lower in TS and mixed GD when compared to XY and XX. In turn, patients with increased androgen production/action (117 cases) had higher birth weight and length when compared to those with absent (108 cases) and decreased (68 cases) production/action. It was observed a negative influence of the 45,X/46,XY karyotype in birth weight and a positive influence of increased androgen production/action. Regarding birth length, there was a negative influence of the TS karyotype and of decreased androgen production/action. In conclusion, in DSD, both karyotype, especially with a 45,X cell line, and intrauterine androgenic production/action influence sex dimorphism of birth weight and length. It can be inferred that in children with normal karyotype and without a DSD, this dimorphism is mainly due to intrauterine androgenic production or action.

Swyer Syndrome

A clinical observation of a patient with Swyer's syndrome is presented. The article presents anamnesis data, phenotypic signs, clinical symptoms and objective data of the patient, the results of instrumental and hormonal studies, on the basis of which doctors of different specialties may suspect a violation of sex formation with XY gonadal dysgenesis.