A number sign (#) is used with this entry because of evidence that 46,XX sex reversal is caused by heterozygous mutation in the NR5A1 gene (184757) on chromosome 9q33.

For a discussion of genetic heterogeneity of 46,XX sex reversal, see 400045.

Bashamboo et al. (2016) reported 4 unrelated families with 46,XX sex reversal. The first family, of European-American ancestry, had two 46,XX children with ovotestes. The first child presented with ambiguous genitalia at birth. Gonads were palpable in the right inguinal region and in the left labioscrotal fold. The karyotype was SRY-negative. Vaginoscopy revealed a rudimentary vagina and uterine cervix. Gonadal histology showed a left dysgenetic testis and a right ovotestis. The second child had ambiguous genitalia, abdominal gonads that were both ovotestes, and a uterus. The mother had no known androgenization but had menopause at age 40. The second family, of Latino-Hispanic origin, had a boy referred at 7 months of age for small penis with palpable gonads; by 9 months, the gonads were no longer palpable. Karyotype was 46,XX, SRY-negative. By ultrasound, 2 structures were identified in the inguinal region that had the morphology and Doppler appearance of testes. AMH (600957) and inhibin B (see 147290) levels were in the normal range. There was a good testosterone response to 3-day hCG (see 118860) stimulation. Family 3, of African and African-American ancestry, had a son presenting with small testes and low testosterone at age 16. At age 30, he was found to have bilateral atrophic testes and a small penis. Karyotype was 46,XX, SRY-negative. Endocrine evaluation showed primary testicular failure, but normal adrenal function. Semen analysis showed azoospermia. Family 4, of South Asian ancestry, had a girl who presented with labial fusion and mild clitoral enlargement at age 6 years. Karyotype was 46,XY, SRY-positive. Palpable inguinal gonads were dysgenetic testes. There was no uterus. A younger brother was born with severe penoscrotal hypospadias but palpable gonads in the scrotum. Biopsy of the right testis showed dysgenetic testicular tissue. The karyotype was 46,XX, SRY-negative. The mother had no reported androgenization but had very irregular periods all her life.

Baetens et al. (2017) reported 3 unrelated Northern European children with 46,XX sex reversal. The first case was the second child of healthy, nonconsanguineous parents. Mild hypertrophy of the clitoris was noted at birth, and vaginoscopy showed a cervix and right hemiuterus, a left epididymis, and male vasculature. Biopsy of the left gonad revealed testicular differentiation with germ cells present; the right gonad contained only fibrotic tissue. An hCG stimulation test showed elevated testosterone and AMH level between the male and female reference levels. A chromosome microarray showed a normal female pattern, and FISH for SRY was negative. The second case was a 22-year-old woman who presented with ambiguous genitalia at birth and a short, blind-ending vagina. At age 4, she underwent clitoroplasty and bilateral gonadectomy of abdominal ovotestes. FISH for SRY was negative. Chromosome microarray showed a female pattern and a small benign chromosome 8 duplication. The third case was a 23-year-old man with 46,XX testicular DSD. Micropenis, hypospadias, and bilateral scrotal but atrophic testes were noted at birth. Gonadal biopsies at age 2 years showed bilateral testicular differentiation without germ cells. Hypergonadotrophic hypogonadism developed, requiring testosterone supplementation at age 13. FISH for SRY was negative and array CGH was normal. Two younger brothers were unaffected.

Igarashi et al. (2017) reported 2 unrelated Japanese patients with 46,XX sex reversal. The first patient presented with ambiguous genitalia and was found to have no uterus or vagina. Abdominal gonads were testis-like on the right and ovotesticular on the left. The ovotestis was both SOX9 (608160)- and FOXL2 (605597)-positive. The second patient was raised as male and presented with hypospadias and bifid scrotum. Gonads were palpable, and biopsy revealed testicular tissue and spermatic cord. There was no uterus or vagina. Gonadotropin and testosterone levels were almost comparable to those of unaffected boys. At 14 years and 10 months, the patient had descended testes of 2 ml in volume and Tanner stage 2-3 pubic hair.

Swartz et al. (2017) reported a 3-year-old 46,XX child of European ancestry with clitoromegaly, rugated labia, no palpable gonads, and a small uterus. Abdominal gonads were ovotestes with dysgenetic testicular tissue lacking germ cells.

Baetens et al. (2017) hypothesized that in the female embryo, the arg92-to-trp mutation in NR5A1 (see MOLECULAR GENETICS) downregulates the pro-ovarian WNT4 (603490)/beta-catenin (116806) pathway, resulting in loss of stable SOX9 repression and tipping the balance toward male development.

Using whole-exome, whole-genome, or direct sequencing, Bashamboo et al. (2016) showed that a specific recurrent heterozygous missense mutation, arg92 to trp (R92W; 184757.0019) in the accessory DNA-binding region of NR5A1 is associated with a variable degree of testis development in 46,XX children and adults from 4 unrelated families. Remarkably, in 1 family a sib of the proband, raised as a girl and carrying the R92W mutation, was found to have a 46,XY karyotype and partial testicular dysgenesis. Bashamboo et al. (2016) concluded that these findings highlighted how a specific variant in a developmental transcription factor can switch organ fate from the ovary to testis in mammals and represented the first missense mutation causing isolated, nonsyndromic 46,XX testicular/ovotesticular DSD in humans.

Baetens et al. (2017) screened a cohort of 11 unrelated cases and 2 sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD) using whole-exome sequencing in 9 patients, targeted resequencing in 4, and haplotyping. Immunohistochemistry of sex-specific markers was performed on patients' gonads. The consequences of mutation were investigated using luciferase assays, localization studies, and RNA-seq. Baetens et al. (2017) identified a heterozygous NR5A1 mutation, c.274C-T (R92W; 184757.0019), in 3 unrelated patients. The arg92 residue is highly conserved and located in the Ftz-F1 region, which is thought to be involved in DNA-binding specificity and stability. There were no consistent changes in transcriptional activation or subcellular localization. Transcriptomics in patient-derived lymphocytes showed upregulation of MAMLD1 (300120), a direct NR5A1 target previously associated with 46,XY DSD. In gonads of affected individuals, ovarian FOXL2 (605597) and testicular SRY-independent SOX9 (608160) expression was observed. Baetens et al. (2017) proposed NR5A1, previously associated with 46,XY DSD and 46,XX primary ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD and hypothesized that the R92W mutation results in decreased inhibition of the male developmental pathway through downregulation of female antitestis genes, thereby tipping the balance toward testicular differentiation in 46,XX individuals. Baetens et al. (2017) concluded that their study supported a role for NR5A1 in testis differentiation in the XX gonad. In the first family reported by Baetens et al. (2017), the proband's healthy sister, father, paternal uncle and grandfather all carried the R92W mutation in NR5A1. A younger sister of the second proband carried the same mutation and displayed normal puberty. In the third family, the proband's 2 younger brothers and mother, all unaffected, carried the R92W mutation. All affected mutation carriers shared a common haplotype spanning a 1.5-Mb region. No other known variants associated with 46,XX sex reversal were identified in any of the probands.

Igarashi et al. (2017) detected the R92W mutation in the NR5A1 gene in 2 unrelated Japanese patients with 46,XX sex reversal. The mutation was absent from the clinically normal mothers and from 200 unaffected Japanese individuals.

In a 46,XX patient with bilateral ovotestes, Swartz et al. (2017) identified a heterozygous arg92-to-gln (R92Q; 184757.0003) mutation, inherited from the unaffected father. This mutation had previously been reported in a patient with 46,XY DSD (SRXY3; 612965) and in a 46,XX infant with normal female phenotype and adrenal insufficiency (see 612964).