Germ Line Mutations in the Thyroid Hormone Receptor Alpha Gene Predispose to Cutaneous Tags and Melanocytic Nevi

Emery Di Cicco, Carla Moran, W. Edward Visser, Annarita Nappi, Erik Schoenmakers, Pamela Todd, Greta Lyons, Mehul Dattani, Raffaele Ambrosio, Silvia Parisi, Domenico Salvatore, Krishna Chatterjee*, Monica Dentice*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Background: Many physiological effects of thyroid hormone (TH) are mediated by its canonical action via nuclear receptors (TH receptor α and β [TRα and TRβ]) to regulate transcription of target genes. Heterozygous dominant negative mutations in human TRα mediate resistance to thyroid hormone alpha (RTHα), characterized by features of hypothyroidism (e.g., skeletal dysplasia, neurodevelopmental retardation, constipation) in specific tissues, but near-normal circulating TH concentrations. Hitherto, 41 RTHα cases have been recorded worldwide. Methods: RTHα cases (n = 10) attending a single center underwent cutaneous assessment, recording skin lesions. Lesions excised from different RTHα patients were analyzed histologically and profiled for cellular markers of proliferation and oncogenic potential. Proliferative characteristics of dermal fibroblasts and inducible pluripotent stem cell (iPSC)-derived keratinocytes from patients and control subjects were analyzed. Results: Multiple skin tags and nevi were recorded in all cases, mainly in the head and neck area with a predilection for flexures. The affected patients had highly deleterious mutations (p.E403X, p.E403K, p.F397fs406X, p.A382PfsX7) involving TRα1 alone or mild/moderate loss-of-function mutations (p.A263V, p.L274P) common to TRα1 and TRα2 isoforms. In four patients, although lesions excised for cosmetic reasons were benign intradermal melanocytic nevi histologically, they significantly overexpressed markers of cell proliferation (K17, cyclin D1) and type 3 deiodinase. In addition, oncogenic markers typical of basal cell carcinoma (Gli-1, Gli-2, Ptch-1, n = 2 cases) and melanoma (c-kit, MAGE, CDK4, n = 1) were markedly upregulated in skin lesions. Cell cycle progression and proliferation of TRα mutation-containing dermal fibroblasts and iPSC-derived keratinocytes from patients were markedly increased. Conclusions: Our observations highlight frequent occurrence of skin tags and benign melanocytic nevi in RTHα, with cutaneous cells from patients being in a hyperproliferative state. Such excess of skin lesions, including nevi expressing oncogenic markers, indicates that dermatologic surveillance of RTHα patients, monitoring lesions for features that are suspicious for neoplastic change, is warranted.

Original languageEnglish
Pages (from-to)1114-1126
Number of pages13
Issue number7
Publication statusPublished - Jul 2021

Bibliographical note

Funding Information:
K.C. is supported by the Wellcome Trust (Investigator Award 210755/Z/18/Z) and NIHR Cambridge Biomedical Research Centre (C.M., K.C.). MD is supported by the AIRC-Associazione Italiana per la Ricerca sul Cancro (grant ID: IG 13065), and D.S. and M.D. by a grant from the European Research Council under the European Union's Horizon2020 Programme??"EU FP7 contract Thyrage (grant number 666869).

Publisher Copyright:
© Emery Di Cicco et al., 2021; Published by Mary Ann Liebert, Inc.


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