WNT4 deficiency—a clinical phenotype distinct from the classic Mayer–Rokitansky–Kuster–Hauser syndrome: A Case Report

• Published in: Human reproduction (Oxford) Vol. 22; no. 1; pp. 224 - 229
• Main Authors: Biason-Lauber, A., De Filippo, G., Konrad, D., Scarano, G., Nazzaro, A., Schoenle, E.J.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-01-2007; Oxford Publishing Limited (England)
• Subjects: Abnormalities, Multiple - diagnosis; Adolescent; Adult; Amino Acid Sequence; Amino Acid Substitution; Biological and medical sciences; Child; Child, Preschool; Female; Gonadal Dysgenesis - diagnosis; Gynecology. Andrology. Obstetrics; Humans; Infant; Kidney - abnormalities; Medical sciences; Molecular Sequence Data; Mullerian Ducts - abnormalities; Ovary - abnormalities; Phenotype; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - genetics; Sequence Alignment; Syndrome; Tumor Cells, Cultured; Uterus - abnormalities; Wnt Proteins - deficiency; Wnt Proteins - genetics; Wnt4 Protein; WNT; Mayer–Rokitansky–Kuster–Hauser syndrome; gonad; sex determination; Agenesis; Deficiency; Genital system; gonad/Mayer-Rokitansky-Kuster-Hauser syndrome/sex determination/WNT; Female genital diseases; Case study; Vertebrata; Phenotype; Mammalia; Malformation; Sex determination; Gonad; Rokitansky Kuster Hauser syndrome; Uterine diseases
• ISSN: 0268-1161; 1460-2350
• DOI: 10.1093/humrep/del360

The pathways leading to female sexual determination in mammals are incompletely defined. Loss-of-function mutations in the WNT4 gene appear to cause developmental abnormalities of sexual differentiation in women and mice. We recruited six patients with different degrees of Müllerian abnormalities, with or without renal aberrations and a normal female 46,XX karyotype. A clear androgen excess was found only in one patient. This 19-year-old woman was affected by primary amenorrhoea, absence of Müllerian ducts derivatives, clinical (acne and hirsutism) and biochemical (repeatedly high levels of testosterone) signs of androgen excess. Direct sequencing of her WNT4 gene followed by functional studies in human ovarian cells (OVCAR3) was performed. This patient carried the novel R83C loss-of-function dominant negative mutation in her WNT4, confirming the role of WNT4 in the development and maintenance of the female phenotype in women. Our study can also help refine the phenotype of WNT4 deficiency in humans. In fact, it appears that at least in this limited casuistic small group of patients, the absence of a uterus (and not other Müllerian abnormalities) and the androgen excess are the pathognomonic signs of WNT4 defects, suggesting that this might be a clinical entity distinct from the classic Mayer–Rokitansky–Kuster–Hauser syndrome.