Alterations in Primary Macronodular Adrenal Hyperplasia (PMAH) and the Clinical State of Variant Carriers.

Context: Primary macronodular adrenal hyperplasia (PMAH) is a rare type of Cushing or subclinical Cushing syndrome and is associated with bilateral multinodular formation. is one of the responsible genes for PMAH.

Objectives: This study was performed to identify the genotype-phenotype correlation of in a cohort of Japanese patients.

Patients And Methods: Fourteen patients with clinically diagnosed PMAH and family members of selected patients were studied for gene alteration and clinical phenotype. The associated nonadrenal tumor tissues were also studied.

Results: Of fourteen patients with PMAH, 10 had pathogenic or likely pathogenic variants of . We found two variants. Five unrelated patients had identical variants (p.R619*). In two patients, the variant was found in offspring with the asymptomatic or presymptomatic state. Six of ten patients who tested positive for the pathogenic or likely pathogenic variant carried nonadrenal tumors; however, no loss of heterozygosity (LOH) or second hit of the gene was evident. The variant-positive group showed a significantly higher basal cortisol level. Furthermore, age-dependent cortisol hypersecretion was seen in the variant-positive group.

Conclusions: pathogenic variants are common (71%) in Japanese patients with PMAH. p.R619* might be a hot spot in Japanese patients with PMAH. Asymptomatic or presymptomatic pathogenic variant carriers were found among the family members of the patients. Although 50% of variant carriers had nonadrenal neoplastic lesions, no LOH or second hit of in the tumor tissues was evident. The variant-positive mutant group showed a higher basal cortisol level than the negative group.