We consider the description of this mutation relevant due to its novelty and its association with the presence of tumors not previously associated with the ARMC5 gene.
Recent studies published on mutations in the ARMC5 gene show that adrenal nodes in patients with HAMB tend to be more aggressive and have a larger size when compared to patients without genetic alteration5. At the same time, a correlation between phenotype and genotype has been described6. The evolution from a subclinical CS stages (PACS and ACS) to a more open form of hypercortisolism as described in the index case is consistent with other published studies, in which initially there are no functional alterations8, with a later slow progression towards subclinical and even aggressive clinical forms.
The characteristic slow development of the hormonal hypersecretion determines this diseases diagnosis to be usually delayed until between 40 and 70 years of age and also determines a correlation between the size of the nodules, the basal cortisol levels, the ACTH concentration and the age of the patient4,6,8,9. Thus, the follow-up of patients genetically affected by an ARMC5 mutation must be carried out indefinitely. The underestimation of the penetrance of the disease would be in line with what has been commented10.
Knudson's "two-hit" theory11, described for tumor suppressor genes such as ARMC512, implies that the heterozygous germline mutation needs to add a somatic mutation to express phenotypically. In the absence of somatic mutation, the phenotypic expression either does not appear, or it does so late, since due to the inefficiency in the synthesis of cortisol of the adrenal nodules, these would need to reach a large size to cause SC10. This would explain that not all members of the same family suffer from the disease despite carrying the mutation. In the cases reported in this paper, the mutation could be studied in the germ line, but not the somatic one. Other cases have been described in which the somatic mutation was not found either4,6,8,13,14.
Somatic mutations in genes such as ARMC5 could contribute to the appearance of neoplasms in other locations, although with mechanisms that are not well clarified8. Meningiomas15,16, breast cancer8, thyroid cancer8 and parathyroid cancer8 have been described in patients with ARMC5 mutations. Kyo C et al8 recently described the existence of extra-adrenal tumors in patients with ARMC5 germline mutation without somatic mutation. In the family described in our publication, 4 carriers of the mutation presented with neoplasms, specifically prostate, larynx, lung and stomach cancer. The high prevalence of neoplastic processes among first-generation family members and what has been referenced above, makes us suspect the existence of a possible relationship between this novel ARMC5 mutation and the incidental presence of these tumors. It remains to be determined whether patients with ARMC5 mutations, and specifically the ARMC5 c.2162T > C p mutation (Leu721Pro), should be screened for the early detection of certain neoplasms.