FAMILIAL ADRENOCORTICOTROPIN UNRESPONSIVENESS ASSOCIATED WITH ALACRIMA AND ACHALASIA - BIOCHEMICAL AND MOLECULAR STUDIES IN 2 SIBLINGS WITHCLINICAL HETEROGENEITY

The syndrome of familial adrenocorticotropin (ACTH) unresponsiveness i s a rare form of primary adrenal insufficiency, usually without minera locorticoid deficiency. It is characterized by elevated plasma ACTH co ncentrations and undetectable plasma cortisol levels not responding to exogenous ACTH. Alacrima and achalasia have also been occasionally as sociated with adrenal insufficiency (triple A syndrome). Pathogenetic mutations have been identified in the ACTH receptor gene in families w ith isolated familial ACTH unresponsiveness. Whether the ACTH receptor represents the locus of the defect for the triple A syndrome is not k nown. Here we report two siblings with familial ACTH unresponsiveness who were discrepant for skin pigmentation and mineralocorticoid functi on. In addition, achalasia and alacrima were documented only in the ol der sibling. The boy, studied at the age of 2 years, was hyperpigmente d, in contrast to his normally pigmented sister, studied at the age of 9 years; basal plasma a-melanocyte stimulating hormone immunureactivi ty levels were 79 and 38 pg/ml, respectively (normal <40 pg/ml). Furos emide-induced diuresis resulted in normal rises of plasma renin activi ty in both patients; however, plasma aldosterone levels increased only in the boy and not in his sister. Screening for abnormalities of the ACTH receptor gene by single strand conformation polymorphism analysis revealed no abnormality. Direct sequencing of the entire coding area of the ACTH receptor gene was also normal. Conclusion The syndrome of familial ACTH unresponsiveness can vary clinically and biologically wi thin the same family. In contrast to results from some families with i solated familial ACTH unresponsiveness, the ACTH receptor gene does no t appear to be the locus of the defect in this pedigree, suggesting a different molecular aetiology for the triple A syndrome which associat es adrenal insufficiency, alacrima and achalasia.