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

Abstract

Background: Many physiological effects of thyroid hormone (TH) are mediated by its canonical action via nuclear receptors (TH receptor a and b [TRa and TRb]) to regulate transcription of target genes. Heterozygous dominant negative mutations in human TRa mediate resistance to thyroid hormone alpha (RTHa), characterized by features of hypothyroidism (e.g., skeletal dysplasia, neurodevelopmental retardation, constipation) in specific tissues, but near-normal circulating TH concentrations. Hitherto, 41 RTHa cases have been recorded worldwide. Methods: RTHa cases (n = 10) attending a single center underwent cutaneous assessment, recording skin lesions. Lesions excised from different RTHa 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 TRa1 alone or mild/moderate loss-of-function mutations (p.A263V, p.L274P) common to TRa1 and TRa2 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 TRa 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 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.

Thyroid Hormone Receptor Isoforms Alpha and Beta Play Convergent Roles in Muscle Physiology and Metabolic Regulation

“…In detail, TRαKO mice (due to the disruption of both TRα1 and TRα2 isoforms) display progressive hypothyroidism, with clear growth retardation together with multiple disorders, such as a lower body temperature, a strongly delayed maturation of bone and intestine, thus leading to death shortly after the weaning period [ 25 , 27 ]. This phenotype is in agreement with the phenotype observed in patients with mutations in the THRα gene, which are characterized by highly variable phenotypic features of hypothyroidism with skeletal dysplasia, poor growth, neurodevelopmental retardation, low metabolic rate and constipation [ 28 , 29 , 30 ].…”

Is Melanoma Progression Affected by Thyroid Diseases?

“…It is thus clear from this study that TH have antiproliferative and differentiating effects of TH on zebrafish melanophores [ 123 , 124 ]. In line with these experimental observations are those of Di Cicco and colleagues, obtained in patients affected by resistance to TH due to mutations in the THRA gene [ 125 ]. These patients are characterized by signs of hypothyroidism and exhibit numerous skin lesions.…”

“…These patients are characterized by signs of hypothyroidism and exhibit numerous skin lesions. Histological and molecular analyses of skin nevi from four of them evidenced the expression of keratin 17 and type 3 deiodinase, indicative of unbalanced, increased cellular proliferation versus differentiation, along with a higher expression of molecular markers suggestive of different skin malignancies, including melanoma ( Figure 1 ) [ 125 ]. All together, these data appear to fit well with those of Ellerhorst and colleagues, reported above, showing an increased prevalence of hypothyroidism among melanoma patients, as well as with the outcome of a Sweden cohort study on patients receiving levothyroxine therapy [ 126 ].…”

Genetic disorders of thyroid development, hormone biosynthesis and signalling

“…Some features of CH (e.g., macroglossia, poor feeding and hoarse cry), have been recorded at birth. Abnormal physical characteristics include macrocephaly, dysmorphic facies with a flattened nose, prominent tongue and thick lips, together with an excess of skin tags and moles, especially in adults 64,65 …”

“…Abnormal physical characteristics include macrocephaly, dysmorphic facies with a flattened nose, prominent tongue and thick lips, together with an excess of skin tags and moles, especially in adults. 64,65 Growth retardation, affecting the lower segment disproportionately, resulting in childhood short stature, is a major mode of presentation.…”