New syndromic association of male pseudohermaphroditism with female external genitalia and adrenal hypoplasia congenita suggests additional sex determining gene(s)

Abstract

Genetic mechanisms of sex determination involve a network of interacting genes. Molecular analyses of rare patients with sex reversal or sexual ambiguities have been critical in the identification of new genes for sexual development. SRY, an HMG-box transcription factor, triggers male sex determination. When the dosage sensitive sex reversal (DSS) locus, containing the nuclear hormone receptor DAX1, is duplicated, the result is XY sex reversal and hypogonadotropic hypogonadism (HH); mutations in DAX1 cause adrenal hypoplasia congenita (AHC). Here we describe two patients with a new clinical association of male pseudohermaphroditism with sex-reversed external genitalia and AHC. In both patients, normal female genitalia were noted at birth and each had an episode of adrenal insufficiency before two months of age. They had absent steroidogenesis, AHC and HH. Abdominal magnetic resonance imaging (MRI) showed adrenal hypoplasia or aplasia, and pelvic MRI revealed neither gonads nor any Mullerian structures. The patients' karyotypes were 46,XY. Molecular genetic studies revealed no mutations in SRY, DAX1, or SF1, another nuclear hormone receptor. We present alternative hypotheses to explain this unusual association: (1) one or more additional sex-determining genes within the DSS locus, possibly acting in synergy with DAXl; or (2) one or more genes not linked to DSS involved in both gonadal and adrenal development.