Close relationship, similar phenotype of GATA4 and NR5A1 mutations: gonadal dysgenesis and puberty development

Sex differentiation is a complex process controlled by several genes. GATA4 and NR5A1 interact at all stages of this process, starting from bipotential gonad development to testicular differentiation. Mutations in these two genes, which are in close relationship to each other in both Leydig and Sertoli cell development and function, may cause similar phenotypes. There have been reports in the literature of patients with the NR5A1 mutation becoming virilized at puberty, but no reports of GATA4 virilizing at puberty. We evaluated the characteristics of 46, XY gonadal dysgenesis patients with NR5A1 and GATA4 mutations, which we follow in our clinic to determine diagnostic clues.

We had ten 46, XY cases with NR5A1 and/or GATA4 mutations (10 from 8 different families). Clinical and hormonal features of all cases were compatible with gonadal dysgenesis. The phenotype was variable, such as ambiguous genitalia, amenorrhea, or pubertal virilization. Six out of 10 cases were raised as girls. A broad range of 46, XY DSD phenotypes, including isolated hypospadias, ambiguous external genitalia with a bifid scrotum, and/or micropenis up to fully female external genitalia, have been linked to GATA4 and NR5A1 variations. In our study, we have one case with a GATA4 mutation and two cases with NR5A1 mutation that became virilized at puberty.

In cases of DSD, abnormal expression of the GATA4 gene should be considered even if there is no congenital heart disease (CHD). The NR5A1 and GATA4 gene mutations should be included in the differential diagnosis of DSD patients when virilization during puberty has been identified.