Ovarian Dysgenesis 7

A number sign (#) is used with this entry because of evidence that ovarian dysgenesis-7 (ODG7) is caused by homozygous mutation in the MRPS22 gene (605810) on chromosome 3q23.

Description

Ovarian dysgenesis-7 is characterized by primary amenorrhea, delayed puberty, elevated gonadotropic hormones, and small uterus and ovaries. Ovarian histology shows fibrotic ovaries without follicles (Chen et al., 2018).

For a discussion of genetic heterogeneity of ovarian dysgenesis, see ODG1 (233300).

Clinical Features

Chen et al. (2018) described 2 46,XX sisters and their female cousin from a large consanguineous Israeli-Christian Arab family, who had delayed puberty with elevated gonadotropins and small uterus and ovaries. At ages 16 and 19 years, the sisters exhibited Tanner stage 1 breast development and stage 2 pubic hair development, and both had delayed bone age of 13 years. At age 14 years, their similarly affected 46,XX cousin underwent ovarian biopsy, which demonstrated fibrotic ovaries without follicles. The authors also reported a 46,XX 20-year-old Turkish woman who presented at age 14.75 years with amenorrhea and Tanner stage 3 breast development, without pubic or axillary hair. Bone age was 10 years. She exhibited mild facial dysmorphism, including deep-set eyes with mild hypotelorism and mild ptosis, hypoplastic nares, and thin upper lip. Blood lactate levels were slightly elevated, and she showed bilateral axonal polyneuropathy of the lower extremities, with absent sural, peroneal, and tibial evoked potentials. Endocrine evaluation showed hypergonadotropic hypogonadism, and ultrasound revealed a small uterus with nonvisualization of the ovaries; repeat ultrasound at age 20 showed small uterus and hypoplastic ovaries. Echocardiography results reported in 3 of the patients were normal, and the Turkish woman underwent brain MRI with normal results.

Mapping

In a large consanguineous Israeli-Christian Arab family in which 3 46,XX females had ovarian dysgenesis, Chen et al. (2018) performed SNP analysis and identified a 3-Mb interval on chromosome 3, defined by SNP markers rs2737735 and rs16850488, that segregated with the disorder. Analysis of whole-exome data also showed an absence of heterozygosity within this interval.

Molecular Genetics

In a large consanguineous Israeli-Christian Arab family in which 3 46,XX females had ovarian dysgenesis, Chen et al. (2018) performed whole-exome sequencing and identified a homozygous missense mutation in the MRPS22 gene (R202H; 605810.0003) that segregated fully with disease. The authors noted that this family had previously been studied by Rosler et al. (1996), who demonstrated that 2 46,XY family members with 17-beta hydroxysteroid dehydrogenase III deficiency (264300) were homozygous for a missense mutation in the HSD17B3 gene (R80Q; 605573.0003). However, among the 3 46,XX family members with ODG, 1 was homozygous for the R80Q mutation, 1 was heterozygous, and 1 did not carry the HSD17B3 mutation. In addition, other 46,XX R80Q homozygotes had been reported as asymptomatic, suggesting an independent genetic etiology for the ODG phenotype within the family. Chen et al. (2018) also identified a 46,XX proband from a consanguineous Turkish family with ovarian dysgenesis in whom previous exome variant analysis had revealed 5 candidate homozygous variants, including an R135Q missense mutation in MRPS22 (605810.0004).