ARMC5-associated Bilateral Macronodular Adrenocortical Hyperplasia: A Novel Germline Variant Associated with Concomitant Papillary Thyroid Carcinoma and Meningioma. (28th October 2021)

• Record Type: Journal Article
• Authors: Strauss, K; Smith, S; Grover, A
• Is Part Of: American journal of clinical pathology. Volume 156(2021)Supplement 1
• Page Start: S54
• Page End: S55
• Publication Date: 2021-10-28
• Subjects: Diagnosis, Laboratory -- Periodicals; Pathology -- Periodicals; 616.07
• DOI: 10.1093/ajcp/aqab191.111
• Languages: English
• ISSNs: 0002-9173

Abstract

Abstract: Introduction/Objective: Germline mutations in the tumor suppressor gene Armadillo-containing repeat protein 5 gene (ARMC5) have been very recently recognized as a cause for a familial form of bilateral macronodular adrenocortical hyperplasia (BMAH), itself a rare cause of Cushing syndrome. In patients with ARMC5 mutations, scattered case reports have also shown an association with meningiomas and cancers of the pancreas, breast, colon, and thyroid. Methods/Case Report: We present the case of BMAH, arising in a 61-year-old female with a history of metastatic papillary thyroid carcinoma and meningioma. The patient presented with bilateral but asymmetric adrenal enlargement (right greater than left) and Cushing syndrome. Given history of thyroid cancer and meningioma, genetics referral was ordered. Counseling revealed a pedigree without a strongly evident familial pattern of hereditary endocrine neoplasia characteristic of any of the more common inherited dispositions to endocrine neoplasia. Additionally, a targeted capture-based NGS germline genetic sequencing study for variants in 12 genes associated with associated with hereditary thyroid cancer was performed and negative. However, based on recent scholarship regarding ARMC5, follow-up germline NGS and Sanger sequencing studies encompassing the entire coding sequences of ARMC5 were ordered. These identified a germline, heterozygous, novel (not in ClinVar) but likely pathogenic variant in (c.802C>T, p.Arg268*), providing a likely explanation for the patient's BMAH. In attempt to control the patient's Cushing symptoms, right-sided adrenalectomy was performed, revealing a 220g adrenal gland with marked multinodular hyperplasia with solid, nested, and tubular architecture. Results (if a Case Study enter NA): NA Conclusion: While case reports exist describing an association between other ARMC5 mutations and BMAH with concomitant meningiomas and/or malignancies, greater study is needed in order to better characterize the phenotypic spectrum of this disease. Our experience with this case not only reports a novel, apparently pathogenic mutation, but it documents its association with BMAH and, additionally, papillary thyroid carcinoma and meningioma.