Alternative titles; symbols
ORPHA: 243; DO: 0080493;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p16.3 | Ovarian dysgenesis 1 | 233300 | Autosomal recessive | 3 | FSHR | 136435 |
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.
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); ODG8 (618187), caused by mutation in the ESR2 gene (601663); ODG9 (619665), caused by mutation in the SPIDR gene (615384); and ODG10 (619834), caused by mutation in the ZSWIM7 gene (614535).
See also ovarian dysgenesis with sensorineural deafness, or Perrault syndrome (233400).
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).
Aittomaki et al. (1996) studied 22 Finnish women with ovarian dysgenesis and the A189V mutation in the FSHR gene (136435.0001). All had primary amenorrhea, and pubertal development was reported as delayed in 6. Gonadotropin levels were elevated in all. Pelvic ultrasound, performed in 12 patients, showed streak or hypoplastic ovaries, with identifiable ovarian tissue always present. Ovarian biopsy was obtained in 9 of the patients and revealed consistently hypoplastic histology. Follicles were present in all ovaries, but the number of follicles was very low, and there was much more fibrosis compared to the normal prepubertal ovary. The authors noted that the birthplaces of mutation carriers (parents of patients) were almost entirely within the more lately settled parts of Finland, consistent with a recent founder effect, suggesting that enrichment of the A189V variant occurred mainly during the past 300 to 500 years.
The transmission pattern of ODG1 in the families reported by Aittomaki et al. (1996) was consistent with autosomal recessive inheritance.
To elucidate the proportion of cases of ovarian dysgenesis 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.
By linkage studies in 6 Finnish multiplex families with hypergonadotropic ovarian dysgenesis and normal karyotype, Aittomaki et al. (1995) mapped the ODG1 locus to chromosome 2p.
In 15 affected individuals from 6 Finnish multiplex families with hypergonadotropic ovarian dysgenesis mapping to chromosome 2p, Aittomaki et al. (1995) identified homozygosity for a missense mutation in the FSHR gene (A189V; 136435.0001). All parents studied were heterozygous for the mutation. In patient interviews, no male sibs were reported to have hypogonadism, but genetic analysis of 6 brothers from 2 of the families (family 2 and family 6) revealed 3 homozygotes, who were all more than 40 years of age: 2 had 2 children each, whereas the third was childless and had sought treatment for infertility. The authors suggested that spermatogenesis in male homozygotes might range from normospermia to azoospermia.
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.
Aittomaki et al. (1996) compared the phenotype of 22 Finnish ODG patients with the A189V mutation (136435.0001) to that of 30 patients with ODG of unknown origin. Clinically, both groups of subjects had primary or early secondary amenorrhea, variable development of secondary sex characteristics, and high serum levels of FSH and LH. Notable differences were seen in median adult height, with A189V-positive patients being significantly shorter than those with ODG of unknown etiology. In addition, follicles were detected by transvaginal sonography in 6 of 8 with the mutation as opposed to 1 of 11 without the mutation. Ovarian histology was present in all 9 with the mutation compared with 1 of 4 without the mutation. These findings suggested that a subset of individuals with ovarian dysgenesis are phenotypically distinct in having ovarian follicles, perhaps due to residual FSHR activity that is associated with this mutation.
Aittomaki et al. (1995) stated that the incidence of ovarian dysgenesis with normal XX karyotype in the Finnish population had been estimated as approximately 1 in 8,300 females.
Layman et al. (1998) screened 35 American (30 white, 3 African American, 1 Indian, and 1 Hispanic) women with 46,XX premature ovarian failure and 10 normal controls for the Finnish A189V mutation in the FSHR gene. The mutation was not present in any patient or control.
Aittomaki, K., Herva, R., Stenman, U.-H., Juntunen, K., Ylostalo, P., Hovatta, O., de la Chapelle, A. Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene. J. Clin. Endocr. Metab. 81: 3722-3726, 1996. [PubMed: 8855829] [Full Text: https://doi.org/10.1210/jcem.81.10.8855829]
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Aleem, F. A. Familial 46,XX gonadal dysgenesis. Fertil. Steril. 35: 317-320, 1981. [PubMed: 7202756] [Full Text: https://doi.org/10.1016/s0015-0282(16)45378-1]
Beau, I., Touraine, P., Meduri, G., Gougeon, A., Desroches, A., Matuchansky, C., Milgrom, E., Kuttenn, F., Misrahi, M. A novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor. J. Clin. Invest. 102: 1352-1359, 1998. [PubMed: 9769327] [Full Text: https://doi.org/10.1172/JCI3795]
Boczkowski, K. Pure gonadal dysgenesis and ovarian dysplasia in sisters. Am. J. Obstet. Gynec. 106: 626-628, 1970. [PubMed: 5412860] [Full Text: https://doi.org/10.1016/0002-9378(70)90056-6]
Christakos, A. C., Simpson, J. L., Younger, J. B., Christian, C. D. Gonadal dysgenesis as an autosomal recessive condition. Am. J. Obstet. Gynec. 104: 1027-1030, 1969. [PubMed: 5794832] [Full Text: https://doi.org/10.1016/0002-9378(69)90697-8]
de la Chapelle, A. Disease gene mapping in isolated human populations: the example of Finland. J. Med. Genet. 30: 857-865, 1993. [PubMed: 8230163] [Full Text: https://doi.org/10.1136/jmg.30.10.857]
Doherty, E., Pakarinen, P., Tiitinen, A., Kiilavuori, A., Huhtaniemi, I., Forrest, S., Aittomaki, K. A novel mutation in the FSH receptor inhibiting signal transduction and causing primary ovarian failure. J. Clin. Endocr. Metab. 87: 1151-1155, 2002. [PubMed: 11889179] [Full Text: https://doi.org/10.1210/jcem.87.3.8319]
Elliott, G. A., Sandler, A., Rabinowitz, D. Gonadal dysgenesis in three sisters. J. Clin. Endocr. 19: 995-1003, 1959. [PubMed: 13819997] [Full Text: https://doi.org/10.1210/jcem-19-8-995]
Klotz, H. P., Merger, R., Avril, J. Syndrome de Turner chez deux soeurs issues de cousins germains. Consideration pathogeniques. Ann. Endocr. 17: 43-46, 1956. [PubMed: 13340295]
Kuechler, A., Hauffa, B. P., Koninger, A., Kleinau, G., Albrecht, B., Horsthemke, B., Gromoll, J. An unbalanced translocation unmasks a recessive mutation in the follicle-stimulating hormone receptor (FSHR) gene and causes FSH resistance. Europ. J. Hum. Genet. 18: 656-661, 2010. [PubMed: 20087398] [Full Text: https://doi.org/10.1038/ejhg.2009.244]
Layman, L. C., Amde, S., Cohen, D. P., Jin, M., Xie, J. The Finnish follicle-stimulating hormone receptor gene mutation is rare in North American women with 46,XX ovarian failure. Fertil. Steril. 69: 300-302, 1998. [PubMed: 9496345] [Full Text: https://doi.org/10.1016/s0015-0282(97)00480-9]
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Simpson, J. L., Christakos, A. C., Horwith, M., Silverman, F. S. Gonadal dysgenesis in individuals with apparently normal chromosomal complements: tabulation of cases and compilation of genetic data. Birth Defects Orig. Art. Ser. 7: 215-228, 1971. [PubMed: 5173165]
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