Abstract
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.
Highlights
Thyroid hormones (TH: thyroxine [T4] and triiodothyronine [T3]) are key endocrine regulators of diverse biologic functions
We have provided evidence that patients with resistance to thyroid hormone alpha (RTHa) due to mutations in THRA develop cutaneous lesions, which could be at increased risk of neoplastic transformation
We have documented skin tags and nevi occurring principally in the head and neck region, in 10 RTHa patients harboring mild, moderate, and severe loss-of-function mutations affecting TRa1 alone or both TRa1 and TRa2, that are representative of the molecular genetic spectrum of the disorder
Summary
Thyroid hormones (TH: thyroxine [T4] and triiodothyronine [T3]) are key endocrine regulators of diverse biologic functions (e.g., growth, central nervous system [CNS] development, energy homeostasis, cardiac function, intestinal motility). The skin is a recognized target tissue of TH action, with TH mediating fetal epidermal differentiation, barrier formation, hair growth, wound healing, keratinocyte proliferation, and keratin gene expression [3]. Both TRa1 and TRb1 are expressed in human skin and contribute to cutaneous homeostasis [4,5]. Conclusions: Our observations highlight frequent occurrence of skin tags and benign melanocytic nevi in RTHa, 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 RTHa patients, monitoring lesions for features that are suspicious for neoplastic change, is warranted
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