Familial vasopressin-sensitive ACTH-independent macronodular adrenal hyperplasia (VPs-AIMAH): clinical studies of three kindreds.

OBJECTIVE

Cushing's syndrome due to familial ACTH-independent macronodular adrenal hyperplasia (AIMAH) has been reported in small kindreds. In vasopressin-sensitive AIMAH (VPs-AIMAH), VP stimulates an aberrant, ACTH-independent increase in cortisol. The aims of this study were to (i) delineate the preclinical phenotype of VPs-AIMAH in a three-generation kindred (AIMAH-01) and two smaller kindreds (AIMAH-02 and AIMAH-03) and (ii) investigate the aetiology of VP sensitivity in AIMAH-01.

DESIGN

Clinical studies of three kindreds for adrenal tumours or early Cushing's and molecular studies of adrenal tumours (AIMAH-01).

PATIENTS: Thirty-three individuals, from three kindreds, were screened for perturbations of the hypothalamic-pituitary-adrenal axis or adrenal tumours.

MEASUREMENTS: Patients underwent clinical, biochemical and adrenal imaging investigations. Evaluation included low-dose (1 IU/70 kg) VP stimulation. Adrenal VP receptor (AVPR1A, AVPR1B, AVPR2) expression (AIMAH-01) was assessed using RT-PCR and immunohistochemistry (IHC). IHC for VP was also performed.

RESULTS

AIMAH-01 had three siblings with Cushing's, and four individuals with suppressed ACTH/aberrant VP responses and/or adrenal nodules. In AIMAH-02, a father and son were affected. AIMAH-03 had three siblings with Cushing's. RT-PCR showed adrenal overexpression of AVPR1A and AVPR1B. IHC detected AVPR1A. The adrenal tumour from one patient also stained weakly for VP and AVPR2.

CONCLUSION

Adrenal nodules, suppressed ACTH and increased VP sensitivity may represent preclinical disease, allowing early detection, and treatment, of affected individuals. In AIMAH-01, increased VP sensitivity may be due to adrenal VP receptor overexpression. In these kindreds, VPs-AIMAH is familial, and autosomal dominant inheritance is most likely.