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Development and differentiation of the thyroid gland is directed by expression of specific transcription factors in the thyroid follicular cell which mediates hormone biosynthesis. Membrane transporters are rate-limiting for cellular entry of thyroid hormones (TH) (T4 and T3) into some tissues, with selenocysteine-containing, deiodinase enzymes (DIO1 and DIO2) converting T4 to the biologically active hormone T3. TH regulate expression of target genes via hormone-inducible nuclear receptors (TRα and TRβ) to exert their physiological effects. Primary congenital hypothyroidism (CH) due to thyroid dysgenesis may be mediated by defects in thyroid transcription factors or impaired thyroid stimulating hormone receptor function. Dyshormonogenic CH is usually due to mutations in genes mediating thyroidal iodide transport, organification or iodotyrosine synthesis and recycling. Disorders of TH signalling encompass conditions due to defects in membrane TH transporters, impaired hormone metabolism due to deficiency of deiodinases and syndromes of Resistance to thyroid hormone due to pathogenic variants in either TRα or TRβ. Here, we review the genetic basis, pathogenesis and clinical features of congenital, dysgenetic or dyshormonogenic hypothyroidism and disorders of TH transport, metabolism and action.

Objective Congenital hypothyroidism (CH) is known to be due to thyroid dyshormonogenesis (DH), which is mostly inherited in an autosomal recessive inheritance pattern or thyroid dysgenesis (TD), whose inheritance pattern is controversial and whose molecular etiology remains poorly understood. Design and methods The variants in 37 candidate genes of CH, including 25 genes related to TD, were screened by targeted exon sequencing in 205 Chinese patients whose CH cannot be explained by biallelic variants in genes related to DH. The inheritance pattern of the genes was analyzed in family trios or quartets. Results Of the 205 patients, 83 patients carried at least one variant in 19 genes related to TD, and 59 of those 83 patients harbored more than two variants in distinct candidate genes for CH. Biallelic or de novo variants in the genes related to TD in Chinese patients are rare. We also found nine probands carried only one heterozygous variant in the genes related to TD that were inherited from a euthyroid either paternal or maternal parent. These findings did not support the monogenic inheritance pattern of the genes related to TD in CH patients. Notably, in family trio or quartet analysis, of 36 patients carrying more than two variants in distinct genes, 24 patients carried these variants inherited from both their parents, which indicated that the oligogenic inheritance pattern of the genes related to TD should be considered in CH. Conclusions Our study expanded the variant spectrum of the genes related to TD in Chinese CH patients. It is rare that CH in Chinese patients could be explained by monogenic germline variants in genes related to TD. The hypothesis of an oligogenic origin of the CH should be considered.

Thyroid hormone levels have a crucial role for optimal brain development from gestation through the first 2 postnatal years. However, thyroid hormones vary with gestational age, and their levels vary between term and preterm infants. Preterm newborns are prone to thyroid dysfunction which is now more frequently observed with the advances of neonatal care and improved survival of extremely premature infants. Thus, hypothyroxinaemia of prematurity associated with delayed TSH elevation is very common in low birth weight premature infants most likely due to the immaturity of the hypothalamic-pituitary thyroid axis. Furthermore, postnatal illness, medications and iodine status may contribute to the thyroid dysfunction or affect the interpretation of the thyroid function tests. Despite available guidelines, timing of screening and optimal treatment of thyroid dysfunction in premature infants remains controversial. Furthermore, it is unknown whether untreated thyroid dysfunction in premature babies affects neurodevelopmental outcome. In the vast majority of preterm infants, hypothyroxinaemia is transient; however, permanent hypothyroidism due to thyroid dysgenesis or enzyme defects might also occur. Therefore, careful monitoring of thyroid function and long-term follow-up is needed to assess an appropriate therapeutic approach. This article reviews thyroid physiology in preterm infants, the influences of gestation and other neonatal conditions on thyroid function tests, optimal timing of screening and possible predictors to differentiate transient hypothyroxinaemia from permanent hypothyroidism.

SummaryBackground Whether serum TSH undergoes seasonal fluctuations in euthyroid and hypothyroid residents of temperate climates is controversial. Methods Monthly TSH and thyroid hormone levels were cross-sectionally analysed in a large cohort of euthyroid subjects (n=11 806) and L-thyroxine (L-T4)-treated athyreotic patients (n=3 934). Moreover, in a small group (n=119) of athyreotic patients treated with an unchanged dosage of L-T4 monotherapy, hormones were measured both in the coldest and in the hottest seasons of the same year (longitudinal study). Results No seasonal hormone change was observed in the euthyroid subjects except for a small FT3 increase in winter (+2.9%, P

Summary Background Congenital hypothyroidism (CH) is a common endocrine disease that occurs in about 1:3000 newborns. In 80–85% of the cases, CH is presumably secondary to thyroid dysgenesis (TD), a defect in the organogenesis of the gland leading to an ectopic (30–45%), absent (agenesis, 35–40%) or hypoplastic (5%) thyroid gland. The pathogenesis of TD is still largely unknown. Most cases of TD are sporadic, although familial occurrences have occasionally been described. Recently, mutations in the PAX8 transcription factor have been identified in patients with TD. Objective Our aim was to identify and functionally characterize novel PAX8 mutations with autosomal dominant transmission responsible for TD. Design The PAX8 gene was sequenced in a mother and child both suffering from congenital hypothyroidism (CH) because of thyroid hypoplasia. Subsequently, expression vectors encoding the mutated PAX8 were generated, and the effects of the mutation on both the DNA-binding capability and the transcriptional activity were evaluated. Results PAX8 gene sequencing revealed a heterozygous mutation that consists of the substitution of a histidine residue with a glutamine at position 55 of the PAX8 protein (H55Q). When tested in cotransfection experiments with a thyroglobulin promoter reporter construct, the mutant protein turned out to be still able to bind DNA in Electrophoretic Mobility Shift Assay assays but transcriptionally inactive. Conclusions Our findings confirm the important role of PAX8 in normal thyroid development and support the evidence that in humans haploinsufficiency of PAX8 is associated with TD.

Context: Thyroid dysgenesis may be associated with mutations in the paired box transcription factor 8 (PAX8) gene and is characterized by congenital hypothyroidism transmitted in an autosomal dominant mode. Objectives: The aim of this study was to identify new mutations in the PAX8 gene. Sixty congenital hypothyroidism-affected individuals with dysgenetic (agenesis, ectopia and hypoplasia) and eutopic thyroid glands were studied. Methods: The 12 exons of the PAX8 gene along with their exon-intron boundaries were amplified from genomic DNA and a mutational screening was performed by single-strand conformational polymorphism (SSCP) followed by direct sequencing of samples with abnormal migration patterns. The PAX8 mutations were functionally characterized by transient transfection experiments. Results: Molecular analysis of the PAX8 gene indicated that four affected individuals had four sequence differences: three novel variations [c.699C>T (p.L233L), c.1006G>A (p.G336S) and c.1317A>G (p.A439A)] and one recently reported [c.674C>T (p.T225M)], whereas the 56 remaining patients showed only wild-type alleles of PAX8. p.T225M, p.L233L and p.G336S variants were not detected in 530 chromosomes from 265 subjects randomly selected from the general population, whereas the p.A439A variant was identified in only one of the 530 chromosomes analysed. Functional analysis of the nonsynonymous substitutions showed that the p.T225M and p.G336S proteins had not lost their ability to bind a specific DNA sequence and to activate the transcription of the thyroglobulin (TG) promoter in synergy with thyroid transcription factor 1 (TTF1). Conclusions: We report the occurrence of two nonsynonymous substitutions, one recently reported (p.T225M) and one novel (p.G336S), and two novel synonymous substitutions (p.L233L and p.A439A) in the PAX8 gene. p.T225M and p.G336S are rare sequence variants or may act by inhibiting an unknown particular function. Our study also confirms the very low prevalence of PAX8 mutations in thyroid dysgenesis. Fil: Esperante, Sebastian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Rivolta, Carina Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina Fil: Miravalle, Lucrecia. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; Argentina Fil: Herzovich, Viviana. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; Argentina Fil: Iorcansky, Sonia. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; Argentina Fil: Baralle, Marco. International Centre For Genetic Engineering And Biotechnology.; Italia. Instituto Cent.for Genetic Engineering ; Italia Fil: Targovnik, Hector Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina

Monoallelic microdeletion of chromosome 22q11 (22q11DS) is considered to be the commonest human microdeletion syndrome. Abnormalities of thyroid function are sporadically reported in this syndrome, but very few studies have specifically assessed this issue, and thyroid morphology has not been systematically studied.To evaluate the prevalence of abnormalities of thyroid function and morphology in a cohort of paediatric and adult patients with 22q11DS.Thirty patients with 22q11DS (median age 9.7, range 1.5-43.9 years) were studied. In all subjects, serum free-T(3), free-T(4), TSH, thyroperoxidase, thyroglobulin, and TSHr auto-antibodies, as well as thyroid ultrasonographic data, were evaluated and compared with age- and sex-matched healthy control groups, for paediatric and adult patients.Fourteen (46.6%) patients showed thyroid hypoplasia involving the entire gland. In all the patients, the volume of the left lobe of the thyroid was significantly reduced (P0.01). Among the subjects with thyroid hypoplasia, 10 out of 14 (71%) showed a concomitant heart malformation, a condition that was present in five (31%) of the subjects with a normal thyroid volume (P0.05). Seven (23.3%) cases of subclinical hypothyroidism and one (3.3%) case of overt hypothyroidism were identified. Three (10%) patients were positive for thyroid auto-antibodies. Of the patients with overt and subclinical hypothyroidism, five out of eight (62.5%) patients showed thyroid hypoplasia.This study confirms the presence of alterations of thyroid function in 22q11DS, and also suggests a frequent occurrence of abnormalities in thyroid morphology in these subjects. Patients with 22q11DS should be monitored for thyroid function, and thyroid ultrasound screening should be considered, especially in those patients with changes in thyroid function or congenital heart malformations. The possible relationship between developmental abnormalities in the heart and the thyroid gland should be confirmed.