Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Thyroid. 2021 Jul;31(7):1114-1126. doi: 10.1089/thy.2020.0391. Epub 2021 Mar 13.
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. RTHα cases ( = 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. 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, = 2 cases) and melanoma (c-kit, MAGE, CDK4, = 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. 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.
许多甲状腺激素 (TH) 的生理作用是通过其核受体 (TRα 和 TRβ) 的经典作用介导的，以调节靶基因的转录。人类 TRα 的杂合显性负性突变导致对甲状腺激素 alpha (RTHα) 的抵抗，其特征是特定组织中出现甲状腺功能减退 (如骨骼发育不良、神经发育迟缓、便秘) 的特征，但循环 TH 浓度接近正常。迄今为止，全世界已记录了 41 例 RTHα 病例。在单一中心就诊的 10 例 RTHα 患者接受了皮肤评估，记录了皮肤损伤。从不同 RTHα 患者中切除的病变进行了组织学分析，并对增殖和致癌潜能的细胞标志物进行了分析。分析了患者和对照受试者的真皮成纤维细胞和诱导多能干细胞 (iPSC) 衍生的角质形成细胞的增殖特征。所有病例均记录了多个皮肤标签和痣，主要位于头颈部，易发生弯曲处。受影响的患者有高度有害的突变 (p.E403X、p.E403K、p.F397fs406X、p.A382PfsX7)，仅涉及 TRα1 或 TRα1 和 TRα2 同工型中常见的轻度/中度功能丧失突变 (p.A263V、p.L274P)。在 4 名患者中，尽管出于美容原因切除的病变在组织学上是良性的真皮黑素细胞痣，但它们显著过度表达细胞增殖标志物 (K17、cyclin D1) 和 3 型脱碘酶。此外，皮肤病变中显著上调了基底细胞癌 (Gli-1、Gli-2、Ptch-1，2 例) 和黑色素瘤 (c-kit、MAGE、CDK4，1 例) 的典型致癌标志物。含有 TRα 突变的真皮成纤维细胞和患者来源的 iPSC 衍生角质形成细胞的细胞周期进展和增殖明显增加。我们的观察结果强调了 RTHα 中皮肤标签和良性黑素细胞痣的频繁发生，并且患者的皮肤细胞处于过度增殖状态。这些皮肤病变过多，包括表达致癌标志物的痣，表明需要对 RTHα 患者进行皮肤科监测，监测病变是否具有可疑的肿瘤变化特征。
