CASE REPORT An N-terminal WT1 mutation (P181S) in an XY patient with ambiguous genitalia, normal testosterone production, absence of kidney disease and associated heart defect: enlarging the phenotypic spectrum of WT1 defects

Objective: This study reports the clinical and molecular data of an XY patient with a very unusual phenotype due to a Wilms’ tumor-suppressor (WT1) gene mutation. The genotype-phenotype relationship of different WT1 mutations is then discussed. Patient: The patient presented at birth with micropenis, severe hypospadias and cryptorchidism. Normal androgen production and an absence of clinical response to a testosterone treatment trial suggested partial androgen resistance. Eventually, female sex of rearing was chosen. At the beginning of puberty, normal male androgen production occurred, and subsequent gonadectomy did not show gonadal dysgenesis. It is notable that the patient, now 20 years of age, has not developed kidney disease. In addition to the genital malformation, the patient displayed an associated congenital heart defect, consisting of a coarctation of the aorta and a patent ductus arteriosis (PDA). Results: No mutations were detected in the androgen receptor or 5a-reductase genes. Direct sequencing of the WT1 gene identified a heterozygous proline to serine substitution at position 181 (P181S). The same heterozygous mutation was found in the mother. Interestingly, the mother shows no signs of kidney disease at her present age of 49. Conclusion: This is the first germline missense mutation in the N-terminal part of WT1 identified in a patient with the very particular phenotype of ambiguous genitalia with absence of gonadal dysgenesis and kidney disease. The possible molecular mechanisms leading to the patient’s phenotype are considered. The high frequency of PDA in newborns and the absence of heart abnormalities in XX females carrying the P181S mutation, however, suggest that the heart defect was most likely a coincidental association. This case enlarges the clinical spectrum of WT1 defects and may provide new insights into the complex functions of WT1 in genital and kidney development. European Journal of Endocrinology 150 825–830