MEN 2A-related cutaneous lichen amyloidosis: report of three kindred and systematic literature review of clinical, biochemical and molecular characteristics

Abstract

Multiple endocrine neoplasia type 2A (MEN2A) may be rarely associated with cutaneous lichen amyloidosis (CLA), a skin lesion located in the interescapular region. Here, we describe 3 MEN2A-related CLA kindred and perform a systematic review (SR) of the literature on clinical, biochemical and molecular characteristics of MEN2A-related CLA patients. Thirty-eight patients with MEN2A-related CLA followed at our institution were evaluated. The median age at MEN2A diagnosis in our cohort was 25 (13-41) years, 68 % were women and all harbored codon 634 RET mutations. The literature search resulted in 20 publications that contributed with 25 MEN2A families and 214 individuals. The mean age of MEN2A diagnosis was 31 ± 17 years, with 77 % women. The mean age reported by patients to initial skin lesion suggestive to CLA was 20 ± 13 years. All but two kindred harbored mutations at codon 634: C634R 7 kindred (35 %), C634Y 5 kindred (25 %), C634W 3 kindred (15 %), C634G 1 kindred (5 %), V804M 1 kindred (5 %) and S891A 1 kindred (5 %). Most interesting, the standardized CLA prevalence was higher in women (2.3/1.0, P < 0.005). The overall reported prevalence of medullary thyroid carcinoma, CLA, pheochromocytoma and hyperparathyroidism was 94, 51, 30 and 16 %, respectively. SR of literature indicates that MEN2A-related CLA is more frequent in women and presents a high penetrance, being the second most frequent manifestation of the syndrome, preceded only by MTC.

Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives

“…The clinical course of MTC in patients with MEN 2A is variable, and the disease progression is associated with codon-specific mutations in the RET proto-oncogene (Eng et al 1996a, Machens et al 2003. Approximately 98% of MEN 2A is associated with RET mutations in the cysteinerich extracellular domain, particularly in exons 10 and 11, codons 609, 611, 618, 620, and 634, which is responsible for at least 85% of MEN 2A cases and correlated with the presence of PHEO, HPT, and CLA (Eng et al 1996b, Raue & Frank-Raue 2009, Scapineli et al 2016, Maciel et al 2019. Amino acid change in the intracellular domain of RET in exon 13 (codons 768,790 and 791), exon 14 (codons 804 and 844) and exon 15 (codon 891) are less frequent.…”

An Atypical Presentation of Insulin Amyloidosis: An Uncommon but Important Complication of Insulin Therapy

“…Localized amyloidosis can form from focal production of immunoglobulin light chains or can be caused by proteins produced by an affected organ. The most common type of primary, cutaneous amyloidosis is lichen amyloidosis which may be associated with rheumatologic conditions, such as systemic lupus erythematosus, and can additionally be seen in patients with multiple endocrine neoplasia type 2a (4). Notably, symptoms may be present prior to the diagnosis of multiple endocrine neoplasia type 2a, with interscapular pruritus, and subsequent lichen amyloidosis occurring at the same region secondary to chronic inflammation from scratching (4).…”

“…The most common type of primary, cutaneous amyloidosis is lichen amyloidosis which may be associated with rheumatologic conditions, such as systemic lupus erythematosus, and can additionally be seen in patients with multiple endocrine neoplasia type 2a (4). Notably, symptoms may be present prior to the diagnosis of multiple endocrine neoplasia type 2a, with interscapular pruritus, and subsequent lichen amyloidosis occurring at the same region secondary to chronic inflammation from scratching (4). Once the diagnosis of amyloidosis is made, immunohistochemistry is often used for subtype analysis, with other methods including liquid chromatography in tandem with mass spectrometry and amino acid sequencing to confirm the subtype of disease (3).…”

Persistently itchy papules

“…2,3 Lichen amyloidosis may be associated with atopic dermatitis, multiple endocrine neoplasia type 2 and autoimmune disorders such as rheumatoid arthritis and thyroiditis. [4][5][6][7]…”