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Hum. Reprod. Advance Access published online on September 7, 2006
Human Reproduction, doi:10.1093/humrep/del360
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received January 27, 2006
Revised June 6, 2006
Accepted July 5, 2006

Article

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

A. Biason-Lauber 1 *, G. De Filippo 2, D. Konrad 1, G. Scarano 2, A. Nazzaro 2, and E.J. Schoenle 1

1 University Children’s Hospital, Zurich, Switzerland
2 Gaetano Rummo Hospital, Benevento, Italy

* To whom correspondence should be addressed.
A. Biason-Lauber, E-mail: anna.lauber{at}kispi.unizh.ch


  Abstract

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.

Keywords: gonad/Mayer-Rokitansky-Kuster-Hauser syndrome/sex determination/WNT.
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