Dermal Hyperneury and Multiple Sclerotic Fibromas in Multiple Endocrine Neoplasia Type 2A Syndrome

Abstract

IMPORTANCE Multiple endocrine neoplasia type 2 (MEN 2) syndrome is an autosomal dominant, hereditary cancer disorder caused by germline mutations in the RET (formerly MEN2A, MEN2B) proto-oncogene located on chromosomal band 10q11.21. Two distinct clinical forms have been described as the following phenotypes: multiple endocrine neoplasia type 2A (MEN 2A) and multiple endocrine neoplasia type 2B (MEN 2B) syndromes. The common and necessary nexus that defines these 2 phenotypes is the presence of medullary thyroid carcinoma (MTC). The familial MTC type of MEN 2 syndrome was included within the spectrum of MEN 2A syndrome. Cutaneous manifestations of MEN 2A syndrome include macular amyloidosis, whereas MEN 2B syndrome is traditionally linked to multiple mucosal neuromas.OBJECTIVES To describe a family with cutaneous manifestations not previously described in patients with MEN 2A syndrome and to discuss the association of this disorder with Cowden syndrome.DESIGN, SETTING, AND PARTICIPANTS Clinicopathologic correlation of cutaneous lesions and genetic studies in 11 members of a family with familial MTC.INTERVENTIONS Cutaneous lesions were histopathologically and immunohistochemically studied. Genetic screening for a germline mutation at the RET gene was performed in 11 family members.MAIN OUTCOMES AND MEASURES Identification of cutaneous lesions not previously described in patients with MEN 2A syndrome. RESULTSThis family of 11 individuals with familial MTC type of MEN 2A syndrome demonstrated the moderate risk RET p.Val804Met (protein valine at residue 804 replaced by methionine) genetic mutation, with 2 of the relatives presenting with dermal hyperneury, cutaneous lesions classically described in MEN 2B syndrome, and 1 relative also showing multiple sclerotic fibromas, a cutaneous manifestation of PTEN (phosphatase and tensin homologue) hamartoma-tumor syndrome.CONCLUSIONS AND RELEVANCE Dermal hyperneury and multiple sclerotic fibromas should be added to the list of cutaneous manifestations of patients with the familial MTC type of MEN 2A syndrome.

Approach of Multiple Endocrine Neoplasia Type 1 (MEN1) Syndrome–Related Skin Tumors

“…Finally, the present topic of following the skin tumors in MEN1 represents a fraction of a more complex picture that includes cutaneous aspects in association with various tumor-related hormonal issues as seen in acromegaly, primary hyperparathyroidism, or similar findings in pancreatic NETs in addition to heterogeneous anomalies in MEN2 syndrome (involving both MEN2A and MEN2B type, such as dermal hyperneury, cutaneous lichen amyloidosis, sclerotic fibromas, atypical rash, macular amyloidosis, etc. ), but also, clinical expression of carcinoid syndrome caused by gastroenteropancreatic NETs or metastatic medullary thyroid cancer [ 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 ]. A good dermatological—endocrinological collaboration is required to benefit our patients.…”

Dermatologic Manifestations of Endocrine Disorders

“…Additionally, patients with MEN2B can also have café-au-lait macules. The presence of dermal hyperneury, a cutaneous manifestation classically described in MEN2B syndrome, and multiple sclerotic fibromas has been reported as an associated clinical finding in a family of 11 individuals with familial medullary thyroid cancer-type of MEN2A syndrome [20].…”

Expanding the clinical spectrum of dermal hyperneury: report of nine new cases and a review of the literature

“…Recently, dermal hyperneury has been demonstrated in two of 11 patients with familial MEN 2A thyroid cancer, 4 and in a case of probable 'forme fruste' of MEN 2B syndrome. 3 The latter presented with striated pigmentation, marfanoid habitus, abnormal electromyography, and corneal nerve hypertrophy, without endocrine tumours.…”

“…It can be seen throughout normal‐appearing skin in multiple endocrine neoplasia type 2B (MEN 2B) and Cowden syndrome patients . It has also been described in lesional skin in patients with MEN 2B syndrome, type II neurofibromatosis, a ‘forme fruste’ of MEN 2B syndrome, and multiple endocrine neoplasia type 2A (MEN 2A) syndrome, and in one case of medullary thyroid carcinoma accompanied by macular amyloidosis . In addition, dermal hyperneury can be encountered locally in areas of trauma, chronic rubbing or scratching, nodular prurigo, neurocristic hamartoma and notalgia paraesthetica …”