Other entities represented in this entry:
DO: 0080864;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q33.3 | Adrenocortical insufficiency | 612964 | Autosomal dominant | 3 | NR5A1 | 184757 |
| 9q33.3 | Premature ovarian failure 7 | 612964 | Autosomal dominant | 3 | NR5A1 | 184757 |
A number sign (#) is used with this entry because of evidence that premature ovarian failure-7 (POF7) is caused by heterozygous mutation in the NR5A1 gene (184757) on chromosome 9q33. Additionally, adrenal insufficiency without evidence of ovarian insufficiency can be caused by homozygous mutation in the NR5A1 gene.
For a general phenotypic description and a discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360).
Premature Ovarian Failure 7
Lourenco et al. (2009) studied 4 families with a history of 46,XY disorders of sex development (DSD) and 46,XX ovarian insufficiency and 25 subjects with 46,XX sporadic ovarian insufficiency. They identified 6 patients with primary ovarian insufficiency; 4 of the patients were first-degree relatives of a proband with 46,XY DSD. The subjects showed variation in expressivity and penetrance of the phenotype. There was no evidence of adrenal dysfunction in any subject.
NR5A1-Related Adrenal Insufficiency
Biason-Lauber and Schoenle (2000) described a phenotypically normal girl who presented at age 14 months with adrenal insufficiency. The clinical picture of severe 'slackness,' muscular hypotonia, and typical laboratory findings of decreased sodium, increased potassium, and elevated ACTH made the diagnosis of adrenocortical insufficiency. With appropriate treatment, the patient's clinical signs normalized, and growth and psychomotor development were normal thereafter. Normal female chromosomal pattern (46,XX) and normal luteinizing hormone (LH; see 152780) and follicle-stimulating hormone (FSH; see 136530) serum levels were found. Ultrasonography failed to reveal the adrenals but showed a normal infantile uterus and infantile ovaries of normal size and structure. Magnetic resonance imaging (MRI) confirmed the presence of normal ovaries.
In a discussion of NR5A1 mutations in 46,XX subjects, Domenice et al. (2016) remarked that a follow-up description of the patient of Biason-Lauber and Schoenle (2000) addressing ovarian function at postpubertal age was lacking.
Guran et al. (2016) described a 2-week-old girl with primary adrenal insufficiency who presented with hyperpigmentation, salt-wasting crisis, prolonged jaundice, hypoglycemia, and vomiting. Glucocorticoid and mineralocorticoid deficiencies were noted. MRI revealed hypoplastic right adrenal gland. The karyotype was 46,XX and no DSD was present. The family was reported as nonconsanguineous, and the mode of inheritance sporadic.
Premature Ovarian Failure 7
Lourenco et al. (2009) identified missense, frameshift, and in-frame mutations in the NR5A1 gene in patients with anomalies of ovarian development and function. Four of the mutations were familial (184757.0011-184757.0014); in each of these families, the same mutation was identified in a relative with a 46,XY disorder of sex development (SRXY3; 612965). Two other mutations (184757.0015-184757.0016) were identified in 2 of 25 patients with isolated premature ovarian failure. In all of those affected, there was no evidence of adrenal dysfunction.
By microarray analysis in a mother with premature ovarian failure and her 46,XY son with partial gonadal dysgenesis, Harrison et al. (2013) identified heterozygosity for a 0.232-Mb microdeletion of chromosome band 9q33.3, involving NR5A1 and 4 other genes. There was no family history of disorders of sex development (DSD) or POF, and the mutation appeared to have arisen de novo in the mother. The authors stated that this was the first NR5A1 microdeletion transmitted in a pedigree with both DSD (see 612965) and POF, and the first report of an NR5A1 copy number variation (CNV) associated with POF. To assess the frequency of NR5A1 CNVs in DSD states, Harrison et al. (2013) used MPLA to screen 11 patients with 46,XY DSD phenotypes, 21 patients with proximal hypospadias with or without cryptorchidism, and 35 patients with POF, but did not identify any more NR5A1 CNVs.
NR5A1-Related Adrenal Insufficiency
Biason-Lauber and Schoenle (2000) described a female patient with adrenal insufficiency and no apparent defect in ovarian maturation, despite a heterozygous mutation in the NR5A1 gene (R255L; 184757.0002). The authors concluded that NR5A1 has a crucial role in adrenal gland formation in both sexes.
In a 46,XX patient with normal female phenotype and primary adrenal insufficiency, Guran et al. (2016) detected homozygosity for an arg92-to-gln mutation (R92Q; 184757.0003). This mutation had been reported by Achermann et al. (2002) in homozygosity in a 46,XY phenotypic female with adrenal insufficiency.
Achermann, J. C., Ozisik, G., Ito, M., Orun, U. A., Harmanci, K., Gurakan, B., Jameson, J. L. Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner. J. Clin. Endocr. Metab. 87: 1829-1833, 2002. [PubMed: 11932325] [Full Text: https://doi.org/10.1210/jcem.87.4.8376]
Biason-Lauber, A., Schoenle, E. J. Apparently normal ovarian differentiation in a prepubertal girl with transcriptionally inactive steroidogenic factor 1 (NR5A1/SF-1) and adrenocortical insufficiency. Am. J. Hum. Genet. 67: 1563-1568, 2000. [PubMed: 11038323] [Full Text: https://doi.org/10.1086/316893]
Domenice, S., Machado, A. Z., Ferreira, F. M., Ferraz-de-Souza, B., Lerario, A. M., Lin, L., Nishi, M. Y., Gomes, N. L., da Silva, T. E., Silva, R. B., Correa, R. V., Montenegro, L. R., Narciso, A., Costa, E. M. F., Achermann, J. C., Mendonca, B. B. Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals. Birth Defects Res. C Embryo Today 108: 309-320, 2016. [PubMed: 28033660] [Full Text: https://doi.org/10.1002/bdrc.21145]
Guran, T., Buonocore, F., Saka, N., Ozbek, M. N., Aycan, Z., Bereket, A., Bas, F., Darcan, S., Bideci, A., Guven, A., Demir, K., Akinci, A., and 21 others. Rare causes of primary adrenal insufficiency: genetic and clinical characterization of a large nationwide cohort. J. Clin. Endocr. Metab. 101: 284-292, 2016. [PubMed: 26523528] [Full Text: https://doi.org/10.1210/jc.2015-3250]
Harrison, S. M., Campbell, I. M., Keays, M., Granberg, C. F., Villanueva, C., Tannin, G., Zinn, A. R., Castrillon, D. H., Shaw, C. A., Stankiewicz, P., Baker, L. A. Screening and familial characterization of copy-number variations in NR5A1 in 46,XY disorders of sex development and premature ovarian failure. Am. J. Med. Genet. 161A: 2487-2494, 2013. [PubMed: 23918653] [Full Text: https://doi.org/10.1002/ajmg.a.36084]
Lourenco, D., Brauner, R., Lin, L., De Perdigo, A., Weryha, G., Muresan, M., Boudjenah, R., Guerra-Junior, G., Maciel-Guerra, A. T., Achermann, J. C., McElreavey, K., Bashamboo, A. Mutations in the NR5A1 associated with ovarian insufficiency. New Eng. J. Med. 360: 1200-1210, 2009. [PubMed: 19246354] [Full Text: https://doi.org/10.1056/NEJMoa0806228]