The ARMC5 gene shows extensive genetic variance in primary macronodular adrenocortical hyperplasia

Abstract

Objective Primary macronodular adrenal hyperplasia (PMAH) is a rare type of Cushing’s syndrome (CS) that results in increased cortisol production and bilateral enlargement of the adrenal glands. Recent work showed that the disease may be caused by germline and somatic mutations in the ARMC5 gene, a likely tumor-suppressor gene (TSG). We investigated 20 different adrenal nodules from one patient with PMAH for ARMC5 somatic sequence changes. Design All of the nodules where obtained from a single patient who underwent bilateral adrenalectomy. DNA was extracted by standard protocols and the ARMC5 sequence was determined by the Sanger method. Results Sixteen of 20 adrenocortical nodules harbored, in addition to what appeared to be the germline mutation, a second somatic variant. The p.Trp476* sequence change was present in all 20 nodules, as well as in normal tissue from the adrenal capsule, identifying it as the germline defect; each of the 16 other variants were found in different nodules: 6 were frame shift, 4 were missense, 3 were nonsense, and 1 was a splice site variation. Allelic losses were confirmed in 2 of the nodules. Conclusion This is the most genetic variance of the ARMC5 gene ever described in a single patient with PMAH: each of 16 adrenocortical nodules had a second new, “private”, and -in most cases- completely inactivating ARMC5 defect, in addition to the germline mutation. The data support the notion that ARMC5 is a TSG that needs a second, somatic hit, to mediate tumorigenesis leading to polyclonal nodularity; however, the driver of this extensive genetic variance of the second ARMC5 allele in adrenocortical tissue in the context of a germline defect and PMAH remains a mystery.

The genetic background of acromegaly

“…XLAG: All gene carriers develop pituitary disease, 83% adenoma and 17% hyperplasia and all have gigantism [15]. Carney complex: 80% of gene carriers will have biochemical GH abnormality and 10% will manifest clinical acromegaly [16]. A few patient have been described with gigantism.…”

“…Carney complex (CNC) is a syndrome characterized by the presence of acromegaly (10–12%), cardiac and cutaneous myxomas, primary pigmented nodular adrenocortical disease (PPNAD) and pigmented lesions of the skin and mucosae (can vary from lentigines to blue nevi) [16]. CNC presents as familial disease in 70% of the cases and is inherited in an autosomal dominant manner with an overall full penetrance.…”

“…GH excess is present in 80% of the cases and is mainly consequence of a pituitary somatotroph hyperplasia and not due to a pituitary adenoma (Fig. 1) [16]. …”

Diagnosis and Clinical Genetics of Cushing Syndrome in Pediatrics

“…This work identified that PBMAH/MMAD is frequently a genetic disorder, most often due to ARMC5-inactivating mutations, a putative tumor-suppressor gene. Subsequent studies have confirmed the high frequency of ARMC5 mutations in this disorder (43, 44). …”

Genetics of tumors of the adrenal cortex

“…In addition to what appeared to be the germline mutation p.Trp476*, sixteen of the 20 nodules harbored a second somatic ARMC5 variant, each of them being unique and specific to one nodule. Allelic losses were identified in two of them (Correa et al 2015).…”