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Context: Thyroid dysgenesis may be associated with loss-of-function mutations in the thyrotropin receptor (TSHR) gene., Objectives: The aim of this study was to characterize a novel TSHR gene variant found in one patient harboring congenital hypothyroidism (CH) from a cohort of patients with various types of thyroid defects., Materials and Methods: This cross-sectional cohort study involved 118 patients with CH and their family members, including 45 with familial and 73 with sporadic diseases. The thyroid gland was normal in 23 patients, 25 patients had hypoplasia, 25 hemithyroid agenesis, 21 had athyreosis, and 21 had ectopy. Genomic DNA was extracted, and 10 exons of the TSHR gene were amplified and sequenced. Mutations in other candidate genes were investigated. Ortholog alignment was performed, and TSHR functional assays were evaluated., Results: We identified one previously unknown missense variation in the hinge region (HinR) of the TSHR gene (p.S304R) in one patient with thyroid hypoplasia. This variant is conserved in our ortholog alignment. However, the p.S304R TSHR variant presented a normal glycosylation pattern and signal transduction activity in functional analysis., Conclusion: We report the ocurrence of a novel nonsynonymous substitution in the HinR of the large N-terminal extracellular domain of the TSHR gene in a patient with thyroid hypoplasia. In contrast with four others in whom TSHR mutations of the hinge portion were previously identified, the p.S304R TSHR variation neither affected TSH binding nor cAMP pathway activation. This TSHR gene variant was documented in a CH patient, but the current data do not support its role in the clinical phenotype.

Background/objective: Normally sited glands account for increasing congenital hypothyroidism (CH). Mechanisms often remain unknown. To report the incidence of CH with in situ thyroid gland (ISTG) and describe the natural history of the disease without known etiology., Method: Clinical, biochemical and imaging data at diagnosis were retrospectively analyzed in 285 children positively screened for CH in Ile-de-France between 2005 and 2008. If treatment was discontinued, management of hormonal substitution and follow-up of biochemical thyroid function was performed., Results: 93 full-term CH neonates displayed ISTG (40.6%), including 50 with unexplained mechanism. Follow-up data were available in 32 of them. Therapy was withdrawn from 20 children at a median age of 23.5 months (6-66), among whom 18 remained still untreated over a median duration of 15.3 months (4.4-29.6). In 11 children, levothyroxine (L-T4) dosage was increased over time to maintain biochemical euthyroidism. No statistical differences in initial TSH or FT4 levels, iodine status or birth weight were found between children with transient and permanent hypothyroidism., Conclusion: Withdrawal of L-T4 substitution was feasible in 56.2% of full-term children with CH with ISTG but unexplained mechanism, emphasizing the need for systematic therapy withdrawal. However, further studies are warranted to standardize withdrawal protocol., (© 2015 S. Karger AG, Basel.)

Context: Within the last two decades, heterozygous loss-of-function PAX8 mutations have been reported in patients with a wide degree of thyroid gland dysfunction and growth despite the presence of identical mutations., Objectives: To search for PAX8 mutations in a cohort of patients with congenital hypothyroidism (CH) and various types of thyroid gland defects., Design: A cross-sectional study was conducted in a cohort of patients., Setting: The French neonatal screening program was used for recruiting patients., Patients: A total of 118 patients with CH, including 45 with familial and 73 with sporadic diseases, were included in this study. The thyroid gland was normal in 23 patients had hypoplasia, 25 had hemithyroid agenesis, 21 had athyreosis, and 21 had ectopy., Results: We found four different PAX8 mutations (p.R31C, p.R31H, p.R108X, and p.I47T) in ten patients (six patients with CH and four family members), two with sporadic and eight with familial diseases. Imaging studies performed in the index cases showed ectopic thyroid gland (n=2), hypoplasia (n=2), eutopic lobar asymmetry (n=1), and eutopic gland compatible with dyshormonogenesis (n=1). The previously reported p.R31C and the novel p.I47T PAX8 mutations are devoid of activity., Conclusion: Four different PAX8 mutations were detected in six index patients with CH (ten total subjects). The p.R31C, p.R31H, and p.R108X mutations have been reported. The novel p.I47T PAX8 mutation presented loss of function leading to CH. Thyroid ectopy was observed in two cases of PAX8 (p.R31H) mutation, a finding that has not been reported previously. We observed a high inter-individual and intra-familial variability of the phenotype in PAX8 mutations, underlining that population genetic studies for CH should include patients with various clinical presentations., (© 2014 European Society of Endocrinology.)

Background: NKX2.1 mutations have been identified in patients displaying complete or partial brain-lung-thyroid syndrome, which can include benign hereditary chorea (BHC), hypothyroidism and/or lung disease., Aims and Methods: We evaluated the recently developed Multiplex Ligation-dependent Probe Amplification (MLPA) method to assess the relative copy number of genes. The goal was to determine if MLPA could improve, in addition to direct sequencing, the detection rate of NKX2.1 mutations in a phenotype-selected cohort of 24 patients affected by neurological, thyroid and/or pulmonary disorders., Results: Direct sequencing revealed two heterozygous mutations. Using MLPA, we identified two further heterozygous NKX2.1 gene deletions. MLPA increased the detection rate by 50%. All patients with gene deletions identified were affected by BHC and congenital hypothyroidism., Conclusion: MLPA should be considered as a complementary tool in patients with partial or total brain-lung-thyroid syndrome when direct sequencing failed to identify NKX2.1 mutations. All patients with an NKX2.1 mutation had BHC and congenital hypothyroidism, emphasizing the high prevalence of these signs associated with defective NKX2.1 alleles., (Copyright © 2012 S. Karger AG, Basel.)

Context: Homozygous loss-of-function mutations in forkhead box E1/thyroid transcription factor 2 (FOXE1/TTF-2) cause syndromic congenital hypothyroidism, with thyroid dysgenesis, cleft palate, spiky hair, and variable choanal atresia and bifid epiglottis in three cases reported hitherto. We have elucidated the molecular basis of the disorder in a female with a similar clinical phenotype, born to nonconsanguineous parents., Objective and Design: The FOXE1 gene, located on chromosome 9q22, was sequenced in the proband and family members. Microsatellite marker and multiplex ligation probe amplification analyses determined chromosomal inheritance patterns and FOXE1 copy number. Mutant FOXE1 function was predicted by structural modeling and tested in transfection assays., Results: The proband was homozygous for a novel missense (c.412T-->C; F137S) FOXE1 mutation, but her mother showed heterozygous and father wild-type alleles for this gene sequence. However, the proband was also homozygous for 10 microsatellite markers spanning chromosome 9 with exclusively maternal inheritance. Multiplex ligation probe amplification assays showed two copies of FOXE1 in the proband, indicating maternal isodisomy for chromosome 9. Consistent with structural modeling, the F137S mutant FOXE1 protein failed to bind DNA and showed negligible transcriptional activity., Conclusion: We have described the first case of uniparental disomy causing homozygosity for a novel, loss-of-function FOXE1/TTF-2 mutation in dysgenetic congenital hypothyroidism.

Background: Congenital central hypothyroidism (CCH) is a rare condition that is often diagnosed in late childhood in countries where neonatal screening programs rely solely on detecting thyrotropin (TSH) elevation. TSHbeta gene mutation is one of the causes of CCH. We describe two cases of c.Q49X mutation and three cases of c.C105Vfs114X mutation in exon 3 of the TSH beta-subunit gene., Summary: We found two different TSHbeta gene mutations in two families. In one family, we identified a missense mutation in exon 3 leading to a premature stop at position 49 (c.Q49X) in the two affected twins. In the other family, the three affected siblings had a 313delT nucleotide deletion leading to a frame shift responsible for premature termination at codon 114 (c.C105Vfs114X); neonatal screening showed very low TSH levels in all three patients. The presence of inappropriately low TSH levels at birth in the three affected members of the second family raises questions about the value of the TSH level for CCH screening., Conclusions: The marked phenotypic variability in patients with the c.Q49X mutation suggests modulation by interacting genes and/or differences in the genetic background. TSHbeta gene mutations should be suspected in neonates with inappropriately low TSH levels.

Context: Nonimmune fetal goitrous hypothyroidism is a rare condition that can induce obstetrical and/or neonatal complications and neurodevelopmental impairments such as those still seen in some patients with congenital hypothyroidism. Prenatal treatment to prevent these adverse outcomes is appealing, but experience is limited and the risk to benefit ratio controversial., Objective: The objective of the study was to evaluate the feasibility, safety, and effectiveness of intrauterine l-thyroxine treatment in a large cohort with nonimmune fetal goitrous hypothyroidism., Design: This was a retrospective study of 12 prenatally treated fetuses diagnosed between 1991 and 2005 in France., Methods: During pregnancy, goiter size and thyroid hormone levels were compared before and after prenatal treatment. At birth, clinical, laboratory, and ultrasound data were evaluated., Results: Prenatal treatment varied widely in terms of l-thyroxine dosage (200-800 microg/injection), number of injections (one to six), and frequency (every 1-4 wk). No adverse events were recorded. During pregnancy, thyroid size decreased in eight of nine cases and amniotic-fluid TSH levels decreased in the six investigated cases, returning to normal in four. However, at birth, all babies had hypothyroidism, indicating that intraamniotic TSH levels did not reliably reflect fetal thyroid function., Conclusion: Our data confirm the feasibility and safety of intraamniotic l-thyroxine treatment for nonimmune fetal goitrous hypothyroidism. Although goiter size reduction is usually obtained, thyroid hormone status remains deficient at birth. Amniocentesis seems inadequate for monitoring fetal thyroid function. Further studies are needed to determine the optimal management of this disorder.

Aims: To describe the phenotype of a large group of children with congenital hypothyroidism (CH) and iodide organification defect (IOD), suspected based on normal thyroid position and abnormal perchlorate discharge test, as first step of a project evaluating correlations between phenotypes and genotypes., Methods: 71 children born in Paris between 1980 and 2006 were included. Two groups were defined according to perchlorate discharge: total IOD (TIOD) when the release was above 90% and partial IOD (PIOD) between 10 and 90%. Comparisons between groups were performed using SPSS 14.0 for Windows., Results: The incidence of IOD over the 2003-2006 period was 1:20,660. Of the 71 children, 61 had PIOD and 10 TIOD. Compared to PIOD, TIOD was characterized by greater clinical severity. A wide spectrum of clinical features was seen in the PIOD group. Evolution showed transient hypothyroidism in 10/61 patients with PIOD and 1/10 TIOD patients., Conclusions: Severe presentation in the majority of TIOD patients suggests dysfunction of a key iodide-organification enzyme. In contrast, the variety of clinical features in PIOD group suggests that diverse mechanisms may lead to PIOD, such as delayed or reduced activity of enzymes involved in hormonogenesis or defects in iodine storage and release., (Copyright 2008 S. Karger AG, Basel.)

Thyroid dysgenesis is the most common cause of congenital hypothyroidism (CH) and its genetic basis is largely unknown. Here, we describe the second homozygous missense mutation in TTF-2 (or FOXE1), a transcription factor that has been implicated in thyroid development. Two male siblings, born to consanguineous parents, presented with CH, athyreosis and cleft palate and were found to be homozygous for a mutation corresponding to a serine to asparagine substitution at codon 57 (S57N) in the forkhead DNA binding domain of TTF-2. Their heterozygous parents were unaffected and this mutation was not found in 31 unrelated cases of athyreosis or normal controls. Consistent with its location, the S57N TTF-2 mutant protein showed impaired DNA binding and partial loss of transcriptional function. Such incomplete loss of TTF-2 function may account for the absence of choanal atresia and bifid epiglottis in our patients, anomalies which were present together with CH and cleft palate in two other individuals with the only other, more deleterious, TTF-2 mutation (A65V) described previously. Our observations support the role of TTF-2 in both thyroid and palate development but suggest phenotypic heterogeneity of this syndromic form of CH.

Although a few familial forms of congenital hypothyroidism (CH) due to thyroid dysgenesis (TD) have been reported, this disorder is usually considered to be sporadic. Recently, we reported that 2% of CH patients with TD have a positive familial history. The aim of this study was to describe the clinical characteristics of these familial cases and to compare them with sporadic cases. We used the French national population-based registry of the first 19-yr screening program, which included 14,416,428 screened neonates with a 100% recovery rate. Familial history of CH with TD was investigated by means of a questionnaire sent to the pediatricians (n = 592) who provided ongoing clinical care for the 4049 CH patients detected during this period, including 2863 CH cases due to TD. Information was obtained from 73% of these pediatricians who were following up 2472 CH patients with TD (86%). In all, 67 patients with a positive family history of CH with TD were referred, belonging to 32 multiplex families (i.e. including at least 2 affected members). Families were identified with ectopic gland (n = 12), athyreosis (n = 7), or both (n = 13). Comparison of familial with isolated cases showed a similar etiological diagnosis distribution of CH (40% vs. 33% for athyreosis and 60% vs. 67% for ectopic thyroid gland, respectively), whereas a significantly lower predominance of females was found in familial than in isolated cases (1.4 vs. 2.7; P < 0.03). Extrathyroidal congenital malformations were found with a similarly higher incidence in familial and isolated CH populations compared with the general population (respectively, 9% and 8.2% vs. 2.5%). In conclusion, although familial cases represent a minority of cases of congenital hypothyroidism caused by thyroid dysgenesis, they were observed in a significantly higher proportion (>15-fold) than would be expected from chance alone. This familial clustering, including athyreosis and ectopic thyroid gland, strongly suggests that genetic factors could be involved in thyroid dysgenesis with a common underlying mechanism for both etiological groups. Moreover, the high proportion of extrathyroidal congenital malformations in a population affected by CH due to TD suggests that the potential genetic factors involved in thyroid gland organogenesis are also involved in the development of other organs.