Abstract 827

Sex determination orients development in sexually dimorphic individuals. In humans, genetic mechanisms of sex determination involve a network of genes that interact with each other. Molecular analysis of rare patients with sex reversal or sexual ambiguities has been critical in the identification of new genes for sexual development. SRY, an HMG-box transcription factor, triggers male sex determination. DAX1, a member of the nuclear hormone receptor superfamily, is responsible for Adrenal Hypoplasia Congenita (AHC) when mutated. When the Dosage Sensitive Sex reversal (DSS) locus containing DAX1 is duplicated, the result is XY sex reversal. Recent transgenic experiments with the mouse DAX1 homolog, Ahch, suggest that it may be a sex-determining gene since it antagonizes Sry action, but only in a specific mouse strain (Poschiavinus) carrying a "weak" Sry.

Here we describe two patients with a new clinical association of AHC, and male pseudohermaphroditism with sex-reversed external male genitalia. In both patients, normal female genitalia were noted at birth. They both suffered an episode of adrenal insufficiency within the first two months of life. Endocrine studies and abdominal ultrasound and/or MRI were consistent with absent steroidogenesis and adrenal hypoplasia. They also exhibited hypogonadotropic hypogonadism. MRI scan of their pelves revealed neither gonads nor any Mullerian structures. Their karyotype was 46, XY. Molecular genetic studies revealed no mutations in SRY, DAX1 or SF1, another orphan nuclear receptor. StAR mutations are unlikely since their adrenals are not enlarged. We present alternative hypothesis to explain this unusual association: (1) it may reflect the presence of one or more additional sex-determining genes within the DSS locus, possibly acting in synergy with DAX1; or (2) there may be one or more genes not linked to the DSS locus involved in both gonadal and adrenal development.