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Studies offer insight into rare adrenal disorder
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New data from two studies have shed light on the genetic nature of macronodular adrenal hyperplasia that may affect screening for and treatment of the condition.
In particular, the first study indicates that corticotropin-independent macronodular adrenal hyperplasia may be linked to mutations in the ARMC5 gene while the second study suggests that the hypercortisolism observed in bilateral macronodular adrenal hyperplasia is corticotropin-dependent.
Role of genetics
The bilateral nature of adrenal tumors and reports of familial cases suggest that macrodolar adrenal hyperplasia may have genetic origins, researchers wrote in The New England Journal of Medicine.
“Because they often don’t cause any obvious symptoms, adrenal tumors may go undiagnosed for many years,” study researcher Constantine A. Stratakis, MD, of the division of intramural research at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, said in a press release. “If we could screen family members for the ARMC5 gene, we could monitor their cortisol levels and treat them after the first sign of Cushing’s syndrome and avoid the long-term consequences of the disorder.”
To investigate this further, the researchers genotyped blood and tumor DNA of 12 men and 21 women aged 30 to 73 years with corticotropin-independent macronodular adrenal hyperplasia.
Loss of heterozygosity at 16p, which occurred in eight of the 33 patients, was the most frequent somatic chromosome alteration, according to the study results. The researchers also found that the most frequently identified mutation via whole-genome sequencing was in ARMC5, located at 16p11.2. Further, ARMC5 mutations were found in 18 of the 33 patients. All 26 specimens obtained from these 18 patients had two genetic alterations — one germline and one somatic — in the ARMC5 locus.
In four patients with an ARMC5 germline mutation in whom two or more nodules from one or both adrenal glands were analyzed, different, nodule-specific, somatic ARMC5 alterations were associated with the same germline ARMC5 mutation, according to the researchers.
Results also showed that mutated tumors’ transcriptome was enriched in genes related to RNA processing, indicating that ARMC5 mutations significantly affect gene expression and identify a subgroup of patients with corticotropin-independent macronodular adrenal hyperplasia.
Inactivation of ARMC5 reduced steroidogenesis in vitro, and its overexpression changed cell survival.
These data suggest that corticotropin-independent macronodular adrenal hyperplasia may have a common genetic cause, according to the researchers.
Role of corticotropin
In a second study, also published in The New England Journal of Medicine, researchers evaluated corticotropin production in adrenal glands with macronodular adrenal hyperplasia and decreased levels of peripheral corticotropin.
“In [bilateral macronodular adrenal hyperplasia], hypersecretion of cortisol suppresses the release of corticotropin by pituitary corticotrophs, which results in low plasma corticotropin levels,” the researchers wrote. “Thus, the disease has been termed corticotropin-independent macronodular adrenal hyperplasia,” the researchers wrote.
However, results from the study suggest that this term may be inappropriate, according to the researchers.
In all hyperplastic macronodular adrenal tissue specimens from 30 patients with primary adrenal disease, the researchers detected expression of proopiomelanocortin mRNA. They also found corticotropin in clusters of steroidogenic cells disseminated throughout the specimens.
Adrenal corticotropin levels were higher in adrenal venous blood samples vs. peripheral venous samples, which is consistent with local production, the researchers wrote. Results also showed that ligands of aberrant membrane receptors, but not corticotropin-releasing hormone or dexamethasone, stimulated the release of adrenal corticotropin.
Corticotropin-receptor antagonists also significantly inhibited cortisol secretion during in vitro studies.
“From a pathophysiological point of view, the term ‘corticotropin-independent,’ which has been used to designate cases of bilateral adrenal macronodular hyperplasia with hypercortisolism and low plasma corticotropin levels, appears to be inappropriate,” the researchers wrote
Clinical implications
In an accompanying editorial, André Lacroix, MD, of the Centre Hospitalier de l’Unversité de Montréal, highlighted the impact that results from these two studies may have on clinical practice.
“Screening family members of patients with mutations may identify affected silent carriers,” Lacroix wrote. “The further development of specific aberrant receptor and corticotropin-receptor antagonists could, if confirmed to be effective in vivo, provide individualized specific therapies for hypercotisolism, eliminate the need for bilateral adrenalectomy (the current standard therapy), and possibly prevent disease progression in genetically affected family members.”
For more information:
Assié G. N Engl J Med. 2013;369:2105-2114.
Lacroix A. N Engl J Med. 2013;369:2147-2149.
Louiset E. N Engl J Med. 2013;369:2115-2125.
Disclosure: See the studies for a full list of relevant financial disclosures. Lacroix reports having financial ties to EMD Serono, the European Journal of Endocrinology, EMD Serono, and Novartis.