Unusual presentation of familial glucocorticoid deficiency with a novel MRAP mutation.

CONTEXT: Mutations in MRAP, an interacting partner of the ACTH receptor, have been shown recently to cause familial glucocorticoid deficiency (FGD) in kindreds with confirmed FGD and no ACTH receptor mutations.

OBJECTIVE: We describe a Jewish-Ethiopian family with FGD caused by a novel MRAP mutation.

PATIENTS: Our index patient presented at the age of 19 months with hypocortisolism, severe psychomotor retardation, myoclonic seizures, spastic quadriparesis, and microcephaly. Before the definite diagnosis was made, a female sibling was born in another hospital and succumbed during the neonatal period due to sepsis and adrenal crisis.

METHODS: DNA was extracted from peripheral blood samples from the index case and his mother and from fibroblasts obtained from the female patient. The DAX-1, ACTH receptor (MC2R), and MRAP genes were analyzed.

RESULTS: The index patient was diagnosed with FGD and was found to be homozygous for a novel MRAP mutation, a seven-base deletion in exon 3 of the MRAP gene. This deletion causes a frame shift, resulting in a stop codon after 23 amino acids (L31X). Postmortem analysis of fibroblasts obtained from the female patient revealed that she harbored the same mutation.

CONCLUSIONS: This is the first report of MRAP mutations after the recent identification of the gene. Whether the novel MRAP mutation described by us is associated with a particularly severe phenotype remains to be investigated.