Familial adrenocortiocotropin unresponsiveness associated With alacrima and achalasia: Biochemical and molecular studies in two siblings with clincial heterogeneity

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Abstract
The syndrome of familial adrenocorticotropin (ACTH) unresponsiveness is a rare form of primary adrenal insufficiency, usually without mineralocorticoid deficiency. It is characterized by elevated plasma ACTH concentration and undetectable plasma cortisol levels not responding to exogenous ACTH. Alacrima and achalasia have also been occasionally associated with adrenal insufficiency (triple A syndrome). Pathogenetic mutations have beein indentified in the ACTH receptor gene in families with isolated familial ACTH unresponsiveness. Whether the ACTH receptor represents the locus of the defect for the triple A syndrome is not known. Here we report two siblings with familial ACTH unresponsiveness who were discrenant for skin pigmentation and mineralocorticoid function. In addition, achalasia and alacrima wer documented only in the older sibling. The boy, studied at the age of 2 years, was hyperpigmented, in contrast to his normally pigmented siter, studied at the age of 9 years; basal plasma α-melanocyte stimulating hormone immunure-acitivity levels wer 79 and 38 pg/ml, respectively (normal <40 pg/ml). Furosemide-induced diuresis resulted in normal rises of plasma rein activity 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 conding area of the ACTH receptor gene was also normal. Conclusion The syndrome of familial ACTH unresponsiveness can vary clinically and biologically within the same family. In contrast to results from some families with isolated familial ACTH unresponsiveness, the ACTH receptor gene does not appear to be the locus of the defect in this pedigree, suggesting a different molecular aetiology for the triple A syndrome which assciates adrenal insuficiency alacrima and achalasia.