ADRENOCORTICOTROPIN RECEPTOR GENE-MUTATIONS IN FAMILIAL GLUCOCORTICOID DEFICIENCY - RELATIONSHIPS WITH CLINICAL-FEATURES IN 4 FAMILIES

Familial glucocorticoid deficiency is an autosomal recessive syndrome of adrenal unresponsiveness to ACTH characterized by glucocorticoid de ficiency, high plasma ACTH levels, and a normal renin-aldosterone axis . Defects of the ACTH receptor have been suggested as a possible cause , and we have previously reported a number of novel mutations of the A CTH receptor gene in some, but not all, cases, suggesting that familia l glucocorticoid deficiency may have a heterogeneous molecular etiolog y. Here we report the clinical features and ACTH receptor gene analysi s in four patients from different families. We found that two patients were compound heterozygotes for the S74I and R128C mutations (patient A) and I44M and L192fs frame shift mutations (patient B). The other t wo patients (C and D) were of different ethnic ancestry, but were both homozygous for a R146H mutation. Segregation studies within families revealed heterozygosity in the parents and several other family member s. Human CRH tests in the parents of patients A and B showed normal co rtisol and ACTH responses in the S74I, R128C, and I44M heterozygotes a nd exaggerated cortisol and ACTH responses in the L192fs heterozygote, suggesting that the physiological ACTH increment induced in this test did not reveal evidence of subclinical ACTH resistance, and that this test may not be of value in ascertaining heterozygosity.