Endocrine Abstracts

ACTH independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of Cushing’s syndrome. Both Phosphodiesterase 11A4 (PDE11A4) mutations and inactivating mutations of armadillo repeat containing 5(ARMC5) have been associated with familial AIMAH. A family with autosomal dominant AIMAH was studied trying to elucidate the involved genetic basis.

Methods and results: Adrenal hypercortisolism with giant bilateral AH was diagnosed in three adult members of the family, a mother and two sons. Further evaluation excluded the presence of aberrant receptors. Bilateral adrenalectomy of the index case was performed showing huge adrenal glands (460 g). DNA were extracted from peripheral blood lymphocytes. Sequencing of ARMC5 coding region in the proband revealed a novel heterozygote mutation, S767X. Interestingly, sequencing of PDE11A4 coding region revealed a heterozygote rare variant R867G, that has frequency of 2–3% in the general population. PDE11A4 gene defects have been associated with Carney complex and AIMAH, including R867G, probably acting as a phenotype modifier. Inmunohistochemical studies of the excised adrenal tissue showed a very low expression of PDE11A4 and ARMC5 compared to normal adrenals. The family was screened for hypercortisolism, adrenal hyperplasia (MRI) and genetic testing. All the patients with AIMAH carried both variants. Other siblings carrying either one mutation or none were healthy, with normal adrenal size. A 15 years old daughter of the index case harbored both variants, but her HPA axis evaluation was normal and the adrenals showed a normal size.

Conclusions: A family with ADAIMAH causing giant adrenal hyperplasia associated with a novel mutation in ARMC5 in conjunction with PDE11A4 mutation, causing low protein expression is reported. Coexistence of PDE11A4 variant in all three affected individuals may indicate a phenotype modifier role. Because clinical and biochemical abnormalities appear during adulthood, young phenotypically normal mutation carriers may be at risk of developing clinical disease in the future.