X-linked adrenal hypoplasia congenita caused by a novel intronic mutation of the DAX-1 gene.

OBJECTIVE: X-linked adrenal hypoplasia congenita (AHC) associated with hypogonadotropic hypogonadism (HHG) is caused by mutations of the DAX-1 gene. A novel intronic mutation of the gene and the results of in vitro expression analysis are reported. PATIENT AND METHODS: The patient is a 13-year-old boy who presented with severe dehydration and salt loss in the neonatal period, when he lacked cutaneous pigmentation and elevation of plasma ACTH level. He had been diagnosed and treated as adrenal hypoplasia. The DAX-1 gene was analyzed by direct DNA sequencing in the patient and his parents. In vitro expression analysis was applied to confirm the consequent missplicing of mRNA caused by the mutation.
RESULTS: The substitution of guanine for cytosine at the splice donor site (IVS1 + 1G>C) was observed in our patient and his mother. Expression analysis suggested that this mutation may hinder splicing of the adjacent intron and cause alternative activation of three cryptic splice donor sites within exon 1 leading to the aberrant splicing of mRNA and production of truncated proteins.
CONCLUSION: To our knowledge, this is the first case report of AHC associated with HHG caused by an intronic mutation of the DAX-1 gene. The clinical course of our patient may suggest that the onset of mineralocorticoid deficiency can precede that of glucocorticoid deficiency in some patients with AHC, and thus appear to suffer from aldosterone synthase deficiency at the onset of the disease. Copyright 2009 S. Karger AG, Basel.