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Context:Mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene cause the X-linked IGSF1 deficiency syndrome consisting of central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency, and occasionally transient partial GH deficiency. Since our first reports, we discovered 20 new families with 18 new pathogenic IGSF1mutations.Objective:We aimed to share data on the largest cohort of patients with IGSF1 deficiency to date and formulate recommendations for clinical management.Methods:We collected clinical and biochemical characteristics of 69 male patients (35 children, 34 adults) and 56 female IGSF1mutation carriers (three children, 53 adults) from 30 unrelated families according to a standardized clinical protocol. At evaluation, boys were treated with levothyroxine in 89%, adult males in 44%, and females in 5% of cases.Results:Additional symptoms in male patients included small thyroid gland volume (74%), high birth weight (25%), and large head circumference (20%). In general, the timing of pubertal testicular growth was normal or even premature, in contrast to a late rise in T levels. Late adrenarche was observed in patients with prolactin deficiency, and adult dehydroepiandrosterone concentrations were decreased in 40%. Hypocortisolism was observed in 6 of 28 evaluated newborns, although cortisol concentrations were normal later. Waist circumference of male patients was increased in 60%, but blood lipids were normal. Female carriers showed low free T4(FT4) and low-normal FT4in 18% and 60%, respectively, delayed age at menarche in 31%, mild prolactin deficiency in 22%, increased waist circumference in 57%, and a negative correlation between FT4concentrations and metabolic parameters.Conclusion:IGSF1 deficiency represents the most common genetic cause of central hypothyroidism and is associated with multiple other characteristics. Based on these results, we provide recommendations for mutational analysis, endocrine work-up, and long-term care.

Context:Isolated central congenital hypothyroidism (CCH) is rare and evades diagnosis on TSH-based congenital hypothyroidism (CH) screening programs in the United Kingdom. Accordingly, genetic ascertainment facilitates diagnosis and treatment of familial cases. Recognized causes include TSH β subunit (TSHB) and Ig superfamily member 1 (IGSF1) mutations, with only two previous reports of biallelic, highly disruptive mutations in the TRH receptor (TRHR) gene.Case Description:A female infant presenting with prolonged neonatal jaundice was found to have isolated CCH, with TSH of 2.2 mU/L (Reference range, 0.4–3.5) and free T4of 7.9 pmol/L (0.61 ng/dL) (Reference range, 10.7–21.8 pmol/L). Because TSHBor IGSF1mutations are usually associated with profound or X-linked CCH, TRHRwas sequenced, and a homozygous mutation (p.P81R) was identified, substituting arginine for a highly conserved proline residue in transmembrane helix 2. Functional studies demonstrated normal cell membrane expression and localization of the mutant TRHR; however, its ability to bind radio-labelled TRH and signal via Gqα was markedly impaired, likely due to structural distortion of transmembrane helix 2.Conclusions:Two previously reported biallelic, highly disruptive (nonsense; R17*, in-frame deletion and single amino acid substitution; p.[S115-T117del; A118T]) TRHRmutations have been associated with CCH; however, we describe the first deleterious, missense TRHRdefect associated with this phenotype. Importantly, the location of the mutated amino acid (proline 81) highlights the functional importance of the second transmembrane helix in mediating hormone binding and receptor activation. Future identification of other naturally occurring TRHRmutations will likely offer important insights into the molecular basis of ligand binding and activation of TRHR, which are still poorly understood.

Abstract: Syncope is a common problem in the older patient. Sometimes syncope is caused by extreme bradycardia secondary to atrioventricular (AV) block. We describe a case in which a 90-year-old woman presented with complete AV block due to severe hypothyroidism. After suppletion with levothyroxine, AV conduction was restored. (Neth Heart J 2008;16:57-9.)

BackgroundCongenital central hypothyroidism occurs either as isolated thyroid-stimulating hormone (TSH) deficiency or in conjunction with other pituitary hormone deficits. Undetected central hypothyroidism is associated with developmental delay in children and adverse cardiometabolic sequelae in adults. Hitherto, mutations in the thyrotropin-releasing hormone receptor gene (TRHR) or the TSHb subunit gene (TSHB) are the only known causes of isolated TSH deficiency.