Mullerian Aplasia And Hyperandrogenism

A number sign (#) is used with this entry because of evidence that mullerian aplasia and hyperandrogenism can be caused by heterozygous mutation in the WNT4 gene (603490) on chromosome 1p36.

Clinical Features

Biason-Lauber et al. (2004) reported an 18-year-old 46,XX woman, referred for evaluation of primary amenorrhea, who on examination had normal height and weight, acne, Tanner stage 5 pubic hair and breasts with a clitoris of normal size, and a small, short vaginal introitus. Serum androstenedione and dehydroepiandrosterone levels were elevated, and total and free testosterone levels were repeatedly slightly elevated, but levels of LH, FSH, and other sex hormones were all normal. Abdominopelvic MRI revealed that the vagina and uterus were absent, both ovaries were of normal size but ectopic (retroperitoneal), and the right kidney was aplastic with compensatory hypertrophy of the left kidney. The authors noted that this phenotype resembled that of patients with the Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH syndrome; 277000), and was strikingly similar to that of Wnt4 (603490)-knockout female mice.

Biason-Lauber et al. (2007) described a 19.5-year-old 46,XX woman who was referred for primary amenorrhea and dysmorphic features. She was obese and short, and had an abnormal anterior hairline, bushy eyebrows and synophrys, short philtrum, high palate, prominent ears, short neck, brachydactyly, cubitus valgus, and broad chest. Signs of androgen excess were present, including acne on the forehead and chest and mild facial hirsutism. The clitoral size was normal, but the vaginal introitus was small and short. Her total testosterone was repeatedly elevated, but other hormone levels, including androstenedione and dehydroepiandrosterone, were normal. Pelvic ultrasonography revealed uterine agenesis and normal-sized but ectopic ovaries, with a pattern of solid tissue on the left gonad that had no apparent follicular structure, and kidneys of normal size and location.

Philibert et al. (2008) studied a 16-year-old 46,XX girl who presented with primary amenorrhea and clinical hyperandrogenism, with microcystic acne of the face, back, and chest and Tanner IV pubertal development. Hormone analysis showed a high normal testosterone level, slightly elevated androstenedione, and normal dehydroepiandrosterone and 17-alpha-hydroxyprogesterone. The LHRH stimulation test showed an increased LH response, whereas the FSH response was only slightly elevated. Pelvic ultrasonography revealed a hypoplastic uterus, normal left ovary and a 'subnormal' right ovary, with no visible ovarian follicles. At surgery, the fallopian tubes were present but covered with fibrous tissue, and the ovaries were whitish and dystrophic; biopsy of the left ovary revealed only a few follicles.

Molecular Genetics

In an 18-year-old woman with mullerian duct regression, unilateral renal agenesis, and virilization, who was negative for mutation in TCF2 (see 189907.0002), Biason-Lauber et al. (2004) identified a heterozygous missense mutation in the WNT4 gene (E226G; 603490.0001) The mutation was not found in her unaffected mother or sister or in 100 controls; the father was unavailable for study.

In a 19.5-year-old woman with absence of mullerian duct derivatives and clinical and biochemical androgen excess, who was negative for mutation in the TCF2 gene, Biason-Lauber et al. (2007) identified heterozygosity for a missense mutation in the WNT4 gene (R83C; 603490.0003). The mutation was not found in her unaffected mother, sibs, or 100 controls. No mutations in the TCF2 or WNT4 genes were identified in 5 additional patients with varying degrees of mullerian abnormalities but no hyperandrogenism (see MRKH, 277000).

In a 16-year-old girl with uterine hypoplasia, follicle depletion, and hyperandrogenism, Philibert et al. (2008) identified heterozygosity for a missense mutation in the WNT4 gene (L12P; 603490.0004). The mutation was not found in 27 additional adolescent girls with primary amenorrhea, XX karyotype, and mullerian duct abnormalities without hyperandrogenism, or in 100 ethnically matched female controls.