The discovery of a single-gene mutation in an 18-year-old female patient who lacks a uterus and vagina suggests that, as with the male, much of female sexual development is directed by a single gene, reported Dr. Anna Biason-Lauber and colleagues.
The notion held by experts up until now was that male development was determined by sex-specific genes, while the female was the basic human gender.
The patient initially was seen for primary amenorrhea, said Dr. Biason-Lauber of University Children's Hospital, Zurich, Switzerland. On physical examination, she had a normal weight, mature breast and body-hair development, and a normal-sized clitoris. But her vaginal introitus was small and short, and she had acne that was being treated with antiandrogen therapy (N. Engl. J. Med. 351:792-98, 2004).
Endocrine studies showed that she had increased androgen production, and magnetic resonance imaging revealed that she was missing a vagina and uterus, and that her right kidney was aplastic. She had normal-sized but ectopic ovaries.
The phenotype was consistent with Mayer-Rokitansky-Kuster-Hauser syndrome, which occurs with an estimated frequency of 1 in 5,000 females and is the second most common cause of primary amenorrhea after gonadal dysgenesis.
Previous studies with mice had shown that inactivating a single gene, known as WNT4, prevents the development of mullerian ducts in embryos, results in ovaries depleted of oocytes, and affects kidney development. Moreover, in males, a single gene on the Y chromosome, known as SRY, is critical for testis development, and translocation of the SRY gene to the X chromosome explains testis development in 90% of XX males.
Genetic analysis of this 18-year-old patient showed that she had 46 chromosomes, with two X chromosomes, but had a single guanine-for-adenosine substitution in one exon of her WNT4 gene. Her mother did not have this mutation, suggesting it was either a spontaneous mutation or came from the father (who was not available for study).
In an editorial accompanying the article, Dr. Ieuan A. Hughes of the University of Cambridge (England) said that this finding counters the long-held notion that a fetus is basically female and becomes a woman by default, while the male gender is switched on by specific genes. Instead, the development of both sexes appears to be guided by very specific genes. The absence of WNT4 appears to result in some masculinization, he noted.
The case indicates that WNT4 is a major player in the development and maintenance of the female phenotype; however, other cases need to be identified, Dr. Biason-Lauber said.
BY TIMOTHY F. KIRN
COPYRIGHT 2004 International Medical News Group
COPYRIGHT 2004 Gale Group