Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?

Abstract

Long-term consequences of cortisol excess are frequent despite appropriate treatment after cure of Cushing's syndrome. This might be due to diagnostic delay, often difficult to reduce in rare diseases. The identification of a genetic predisposing factor might help to improve early diagnosis by familial screening. Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Hypercortisolism in PBMAH is most often diagnosed between the fifth and sixth decades of life. The bilateral nature of the adrenocortical tumors and the occurrence of rare clear familial forms suggest a genetic origin. Indeed, a limited subset of PBMAH can be observed as part of multiple tumors syndromes due to alterations of the APC, Menin or Fumarate Hydratase genes. Rare variants of the phosphodiesterases PDE11A have been associated with PBMAH. The recent identification of ARMC5 germline alterations in 25-50% of PBMAH patients without obvious familial history or associated tumors opens new perspectives. ARMC5 alterations follow the model of a tumor suppressor gene: a first germline inactivating mutation of this 16p located gene is followed by a somatic secondary hit on the other allele (inactivating mutation or allelic loss). Functional studies demonstrate that ARMC5 controls apoptosis and steroid synthesis. The phenotype of index cases patients with the mutation seems more severe than the one of WT index cases. However, phenotype variability within a family is often observed. This review summarizes the genetics of PBMAH, focusing on ARMC5, which offer new perspectives for early diagnosis of Cushing's syndrome.

Newly Diagnosed Carney Complex in 3 Young Adults with Primary Adrenal Cushing Syndrome – A Case Series and Review of the Literature

“…First was the earlier age of CS diagnosis in CNC as compared to other primary adrenal etiologies for CS, such as primary bilateral macronodular adrenocortical hyperplasia, which is usually diagnosed later in life between the age of 50 and 60 (13). Second, primary adrenal CS in the absence of bilateral macronodular disease or unilateral adrenal lesion might indicate the diagnosis of PPNAD.…”

DIAGNOSIS OF ENDOCRINE DISEASE: Differentiation of pathologic/neoplastic hypercortisolism (Cushing’s syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing’s syndrome)

“…Nonetheless, adrenal imaging is not an index of adrenal function. In fact, adrenal size evaluated by imaging can be remarkably discordant with cortisol secretion (81,82).…”

ENDOCRINE TUMOURS: The genomics of adrenocortical tumors

“…Indeed only rare families have been reported, and mutations in several genes (PRKAR1A, PDE11A, PDE8B, GNAS, PRKACB, MEN1 or FH among others; review in (4,24,25)) have been identified only in rare instances and or specific subtypes of these diseasessuch as PRKAR1A mutations in PPNAD.…”

“…ARMC5 inactivating mutations were shown to decrease steroidogenesis and to reduce apoptosis in adrenocortical cells (24). Its precise role remains to be established.…”