Sum m a r yThyroid hormones exert their effects through alpha (TRα1) and beta (TRβ1 and TRβ2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental retardation, skeletal dysplasia, and severe constipation) but only borderline-abnormal thyroid hormone levels. Using wholeexome sequencing, we identified a de novo heterozygous nonsense mutation in a gene encoding thyroid hormone receptor alpha (THRA) and generating a mutant protein that inhibits wild-type receptor action in a dominant negative manner. Our observations are consistent with defective human TRα-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues.T hyroid hormones have diverse actions, which include regulation of skeletal growth, maturation of the central nervous system, cardiac and gastrointestinal function, and energy homeostasis. In addition, thyroid hormones control their own production by feedback inhibition of hypothalamic thyrotropinreleasing hormone and pituitary thyroid-stimulating hormone, which direct their synthesis or release. These physiological effects are principally mediated by hormone action through nuclear receptor proteins that act as ligand-inducible transcription factors and either positively or negatively regulate the expression of target genes in different tissues in a hormone-dependent manner.The receptors are encoded by two genes (THRA and THRB), each of which undergoes alternate splicing to generate receptor subtypes (TRα1, TRβ1, and TRβ2), with differing tissue distributions. TRα1 is the predominant subtype in bone, the gastrointestinal tract, cardiac and skeletal muscle, and the central nervous system; TRβ1 is most abundant in the liver and kidney; and TRβ2 is more discretely expressed in the hypothalamus, pituitary, cochlea, and retina. 1 In the absence of hormone, thyroid receptors that are not bound to ligands repress or silence targetgene transcription by recruiting multiprotein complexes containing corepressors (e.g., nuclear receptor corepressor and silencing mediator of retinoic acid and thyroid hormone receptor), with histone deacetylase activity; triiodothyronine occupancyThe New England Journal of Medicine Downloaded from nejm.org on May 10, 2018. For personal use only. No other uses without permission.

Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Using exome and candidate gene sequencing, we identified eight distinct mutations and two deletions in IGSF1 in males from eleven unrelated families with central hypothyroidism, testicular enlargement, and variably low prolactin concentrations. IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary gland and the identified mutations impair its trafficking to the cell surface in heterologous cells. Igsf1-deficient male mice show diminished pituitary and serum thyroid-stimulating hormone (TSH) concentrations, reduced pituitary thyrotropin-releasing hormone (TRH) receptor expression, decreased triiodothyronine concentrations, and increased body mass. Collectively, our observations delineate a novel X-linked disorder in which loss-of-function mutations in IGSF1 cause central hypothyroidism, likely secondary to an associated impairment in pituitary TRH signaling.

Selenium, a trace element that is fundamental to human health, is incorporated into some proteins as selenocysteine (Sec), generating a family of selenoproteins. Sec incorporation is mediated by a multiprotein complex that includes Sec insertion sequence-binding protein 2 (SECISBP2; also known as SBP2). Here, we describe subjects with compound heterozygous defects in the SECISBP2 gene. These individuals have reduced synthesis of most of the 25 known human selenoproteins, resulting in a complex phenotype. Azoospermia, with failure of the latter stages of spermatogenesis, was associated with a lack of testis-enriched selenoproteins. An axial muscular dystrophy was also present, with features similar to myopathies caused by mutations in selenoprotein N (SEPN1). Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular ROS, and susceptibility to ultraviolet radiation-induced oxidative damage may mediate the observed photosensitivity. Reduced levels of selenoproteins in peripheral blood cells were associated with impaired T lymphocyte proliferation, abnormal mononuclear cell cytokine secretion, and telomere shortening. Paradoxically, raised ROS in affected subjects was associated with enhanced systemic and cellular insulin sensitivity, similar to findings in mice lacking the antioxidant selenoenzyme glutathione peroxidase 1 (GPx1). Thus, mutation of SECISBP2 is associated with a multisystem disorder with defective biosynthesis of many selenoproteins, highlighting their role in diverse biological processes.

Objectives: Central hypothyroidism (CeH) is a rare form of hypothyroidism characterized by insufficient thyroid stimulation due to disturbed pituitary and/or hypothalamic functioning. Due to its origin and the whole clinical context, CeH represents a challenging condition in clinical practice as it is characterized by suboptimal accuracy of clinical and biochemical parameters for diagnosis and management. Since no expert consensus or guidance for this condition is currently available, a task force of experts received the commitment from the European Thyroid Association (ETA) to prepare this document based on the principles of clinical evidence. Study Design: The task force started to work in February 2017 and after a careful selection of appropriate references (cohort studies, case reports, expert opinions), a preliminary presentation and live discussion during the 2017 ETA meeting, and several revision rounds, has prepared a list of recommendations to support the diagnosis and management of patients with CeH. Results: Due to the particular challenges of this rare condition in the different ages, the target users of this guidance are pediatric and adult endocrinologists. Experts agreed on the need to recognize and treat overt CeH at all ages, whereas treatment of milder forms may be dispensable in the elderly (> 75 years). Conclusions: Despite the lack of randomized controlled clinical trials, the experts provide 34 recommendations supported by variable levels of strength that should improve the quality of life of the affected patients and reduce the metabolic and hormonal consequences of inadequate management.