Lourenco et al. (2011) described a French family in which 2 brothers and their male cousin had a 46,XY disorder of sex development (DSD) with variable clinical presentation but consistent with defects in testicular differentiation and function; all ... Lourenco et al. (2011) described a French family in which 2 brothers and their male cousin had a 46,XY disorder of sex development (DSD) with variable clinical presentation but consistent with defects in testicular differentiation and function; all 3 were raised as males. The proband presented at birth with ambiguous genitalia; genitography showed a 15-mm diameter cavity communicating with the urethra at the verumontanum, and no uterus. He had fused hypoplastic labioscrotal folds, perineal hypospadias, and hypoplasia of the corpus cavernosum, as well as bilateral inguinal hernias containing gonads. He underwent surgical repair of his cryptorchidism at 1 year of age, which revealed bilateral disjunction between the epididymis and testis and a perforation in the left tunica albuginea. Plasma levels of adrenal steroids before and after adrenocorticotropic hormone (ACTH; 176830) stimulation were normal. No cardiac anomalies were apparent by echocardiography. Testicular ultrasonography at 10 years of age showed diffuse calcifications. At 20 years of age, he was sexually active but azoospermic. His older brother had micropenis and bilateral inguinal hernias containing gonads at birth; testicular ultrasound at 12.5 years of age showed calcifications. Echocardiography prompted by a minor systolic murmur revealed a normal left ventricle and slightly dilated, hypokinetic right ventricle. Their maternal male cousin was also born with ambiguous genitalia; genitography showed a cavity of 15 by 8 mm communicating with the urethra at the verumontanum, and no uterus. He had bilateral inguinal hernias containing gonads; during surgery at 7 months of age, 4-mm gonads surrounded by an epididymis and vas deferens were removed, and histologic examination showed bilateral dysgenetic testes. He was noted to have a minor systolic murmur. His 10-year-old sister was born with tetralogy of Fallot, underwent repair, and was in good health. A maternal aunt had congenital cyanotic heart disease that was well tolerated and she did not undergo medical intervention; she had 2 healthy daughters and 1 son who had no history of medical interventions.
In 2 brothers and their male cousin from a French family with testicular anomalies and congenital heart disease, Lourenco et al. (2011) identified heterozygosity for a missense mutation in the GATA4 gene (G221R; 600576.0018). Their apparently unaffected mothers ... In 2 brothers and their male cousin from a French family with testicular anomalies and congenital heart disease, Lourenco et al. (2011) identified heterozygosity for a missense mutation in the GATA4 gene (G221R; 600576.0018). Their apparently unaffected mothers also carried the mutation; DNA samples from other family members were not available. The mutation was not found in 450 European controls, including 342 of French ancestry. Analysis of 7 other known sex-determining genes in the 2 brothers showed no pathogenic mutations, and high-resolution CGH in the proband showed no rearrangements known to be associated with 46,XY disorders of sex development.