Gonadal dysgenesis without adrenal insufficiency in a 46, XY patient heterozygous for the nonsense C16X mutation: a case of SF1 haploinsufficiency.

Targeted disruption of the orphan nuclear receptor SF1 results in the absence of adrenals and gonads, establishing that this transcription factor is implicated in gonadal determination and adrenal development. Four human SF1 gene mutations have been described to date: three (G35E, R92Q, R255L) were responsible for adrenal insufficiency associated with a gonadal dysgenesis in two 46, XY individuals, one (8 bp deletion in exon 6) resulted in gonadal dysgenesis without adrenal insufficiency. We identified a new heterozygous SF1 gene mutation, C16X, in a 46, XY patient showing gonadal dysgenesis with normal adrenal function: low basal levels of AMH and testosterone (T), weak T response to hCG, hypoplastic testes with abundant seminiferous tubules but rare germ cells. This mutation causes premature termination of translation and should abolish all SF1 activity. Therefore haploinsufficiency could explain the deleterious effect of this mutation in our patient suggesting that testis development is more SF1 dose-dependent than adrenal development. Although the same mechanism explains the deleterious effects of SF1 missense mutations, recent studies have demonstrated an additional dominant negative effect. These data suggest that heterozygous mutation impaired adrenal development only if the two mechanisms, gene dosage and dominant negative effects occur.