46,xx Sex Reversal With Dysgenesis Of Kidneys, Adrenals, And Lungs

A number sign (#) is used with this entry because of evidence that 46,XX sex reversal with dysgenesis of kidney, adrenals, and lungs (SERKAL) is caused by homozygous mutation in the WNT4 gene (603490) on chromosome 1p36. One such family has been reported.

Clinical Features

Mandel et al. (2008) studied a consanguineous kindred of Arab Muslim origin. The family had been followed since the birth of an infant who died of type 1 citrullinemia (215700) at age 4 days. The parents were second cousins. Three affected fetuses showed largely overlapping features including female sex reversal and dysgenesis of kidneys, adrenals, and lungs, given the acronym of SERKAL syndrome. In the case of all 3 affected fetuses, pregnancy was terminated because of the finding of renal agenesis.

Molecular Genetics

Given the similarities between the findings in these cases and a WNT4 knockout mouse model (Vainio et al., 1999; Heikkila et al., 2005), Mandel et al. (2008) genotyped all available family members for microsatellite markers spanning the WNT4 locus. The affected fetus from which DNA was available displayed a homozygous haplotype, which was found to be carried in heterozygous state by all parents and unaffected sibs, suggesting the existence of a homozygous mutation in WNT4 in the affected fetus. The mutation was found to be a homozygous transition resulting in the amino acid substitution A114V (603490.0002). The mutation resulted in markedly reduced WNT4 mRNA levels in vivo and in vitro and downregulated WNT4-dependent inhibition of beta-catenin (116806) degradation.