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Brief Report
December 2017

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

Author Affiliations
  • 1Department of Dermatology, Fundación Jiménez Diaz, Universidad Autónoma, Madrid, Spain
  • 2Department of Pathology, Fundación Jiménez Diaz, Universidad Autónoma, Madrid, Spain
  • 3Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
JAMA Dermatol. 2017;153(12):1298-1301. doi:10.1001/jamadermatol.2017.3959
Key Points

Question  Is there a phenotypic association between the cutaneous manifestations of multiple endocrine neoplasia type 2A and PTEN (phosphatase and tensin homologue) hamartoma-tumor syndromes?

Findings  A kindred of 11 individuals with familial medullary thyroid carcinoma variant of multiple endocrine neoplasia type 2A syndrome showed a moderate risk RET p.Val804Met (protein valine at residue 804 replaced by methionine) genetic mutation. Two family members had dermal hyperneury lesions characteristically seen in multiple endocrine neoplasia type 2B syndrome; 1 family member also showed multiple sclerotic fibromas, a cutaneous manifestation previously described in PTEN hamartoma-tumor syndrome, but not in multiple endocrine neoplasia type 2A syndrome.

Meaning  PTEN hamartoma-tumor and multiple endocrine neoplasia type 2 syndromes show considerable overlap in the signaling pathways regulated by PTEN and RET genes, respectively, which may explain the clinical overlap between the 2 syndromes.

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.

Results  This 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.

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