Ovarian Dysgenesis 1

A number sign (#) is used with this entry because of evidence that ovarian dysgenesis-1 (ODG1) is caused by homozygous or compound heterozygous mutation in the gene encoding follicle-stimulating hormone receptor (FSHR; 136435) on chromosome 2p16.

Description

Hypergonadotropic ovarian failure is a heterogeneous disorder that, in the most severe forms, is a result of ovarian dysgenesis. Ovarian dysgenesis accounts for about half the cases of primary amenorrhea (Timmreck and Reindollar, 2003).

Genetic Heterogeneity of Ovarian Dysgenesis

Even in its isolated form, 46,XX ovarian dysgenesis is etiologically heterogeneous. See ODG2 (300510), caused by mutation in the BMP15 gene (300247); ODG3 (614324), caused by mutation in the PSMC3IP gene (608665); ODG4 (616185), caused by mutation in the MCMDC1 gene (610098); ODG5 (617690), caused by mutation in the SOHLH1 gene (610224); ODG6 (618078), caused by mutation in the NUP107 gene (607617); ODG7 (618117), caused by mutation in the MRPS22 gene (605810); and ODG8 (618187), caused by mutation in the ESR2 gene (601663).

See also ovarian dysgenesis with sensorineural deafness, or Perrault syndrome (233400).

Clinical Features

Elliott et al. (1959) reported the condition in 3 sisters who had normal stature and sex chromatin but had never menstruated and had severe osteoporosis. The parents were first cousins in the case of the 2 affected sisters (with normal stature and sex-chromatin positivity) reported by Klotz et al. (1956). Christakos et al. (1969) observed gonadal dysgenesis in 3 sisters whose parents were second cousins. Each had a normal female 46,XX karyotype. Somatic features of Turner syndrome were not found. All 3 had elevated gonadotropins, and laparotomy on the 2 older sisters showed streak gonads and unstimulated mullerian structures. Gonadal dysgenesis, often with somatic abnormalities, has been reported in sibs by several other authors and in some of these reports the parents were consanguineous. Simpson et al. (1971) pointed out that only affected sibs have been described and parental consanguinity is frequent. Vesely et al. (1980) reported 3 affected sisters and expressed the opinion that only the family reported by Elliott et al. (1959) was similar in having sisters above 152 cm in height, with no associated congenital anomalies. Aleem (1981) described affected sisters, aged 16 and 17, who presented with secondary amenorrhea.

In a nationwide population-based study of women born between 1950 and 1976 in Finland, Aittomaki (1994) identified 75 patients with XX gonadal dysgenesis. In 1 family, 4 daughters were affected; in 6 families, 2 daughters were affected; and 57 cases were isolated. In 1 additional family, there were 2 affected females in successive generations. Consanguinity was detected in 8 of 66 families (12%). When only females were considered, the segregation analysis yielded a proportion of 0.23 affected. The relatively high incidence of 1 in 8,300 liveborn girls implied a high gene frequency in the Finnish population. The geographic distribution was highly uneven, with most families originating in the sparsely populated north-central part of Finland. The findings supported the existence of an autosomal recessive XXGD gene, which Aittomaki (1994) symbolized ODG1 (for ovarian dysgenesis-1), that is highly enriched in Finland. This is, thus, one of the examples of 'Finnish diseases' of which some 30 have been defined (de la Chapelle, 1993).

To elucidate the proportion of cases due to an autosomal recessive gene or genes, Meyers et al. (1996) analyzed 17 published and 8 unpublished pedigrees with at least 2 female offspring. To minimize ascertainment bias, the analysis was restricted to cases in which ovarian failure was documented by the presence of streak ovaries (published cases) or elevated gonadotropins (unpublished cases), and published cases included only those reported before 1982. Meyers et al. (1996) showed that 32% of these cases were sporadic and 68% segregated in an autosomal recessive pattern.

Mapping

By linkage studies in Finnish multiplex families with hypergonadotropic ovarian dysgenesis and normal karyotype, Aittomaki et al. (1995) mapped the ODG1 locus to chromosome 2p.

Molecular Genetics

In the Finnish population in which ovarian dysgenesis with normal XX karyotype is relatively common (approximately 1 in 8,300 females), Aittomaki et al. (1995) demonstrated that affected females are homozygous for a missense mutation in the FSHR gene (A189V; 136435.0001).

In a 30-year-old Armenian woman with oligomenorrhea followed by secondary amenorrhea, who had high FSH levels and normal-sized ovaries without maturing follicles or corpus luteum, Beau et al. (1998) identified compound heterozygosity for missense mutations in the FSHR gene (136435.0003-136435.0004).

In a Finnish woman with primary amenorrhea and hypergonadotropic ovarian failure, Doherty et al. (2002) identified compound heterozygosity for A189V and another missense mutation in the FSHR gene (136435.0007).

Kuechler et al. (2010) studied a 17-year-old girl with primary amenorrhea and incomplete pubertal development, who had elevated FSH and LH levels with low estradiol levels. Diagnostic laparoscopy revealed normal-sized ovaries and small uterus. Histologic examination of ovarian tissue showed disturbed folliculogenesis with a high number of primordial follicles, but complete absence of secondary or tertiary follicles. In this patient, Kuechler et al. (2010) identified compound heterozygosity for a missense mutation in the FSHR gene (136435.0014) and a seemingly balanced translocation in which analysis of the breakpoints demonstrated a 162.7-kb deletion encompassing exons 9 and 10 of FSHR gene.