RESUMO
Background and Objectives: Congenital thyroid dyshormonogenesis is caused by alterations in the synthesis of thyroid hormones in a newborn. Additionally, 10 to 20% of these cases are hereditary, caused by defects in proteins involved in hormonal synthesis. One of the most common causes is mutations in the thyroid peroxidase (TPO) enzyme gene, an autosomal recessive disease. We aimed to detect mutations of the TPO gene in 12 Chilean patients with congenital hypothyroidism due to dyshormonogenesis (CHD) and to characterize these patients clinically and molecularly. Materials and Methods: Twelve patients under 20 years of age with CHD, controlled at San Juan de Dios Hospital in Santiago, Chile, were selected according to the inclusion criteria: elevated neonatal TSH, persistent hypothyroidism, and thyroid normotopic by imaging study. Those with deafness, Down syndrome, and central or transient congenital hypothyroidism were excluded. Blood samples were taken for DNA extraction, and the 17 exons and exon-intron junctions of the TPO gene were amplified by PCR. The PCR products were sequenced by Sanger. Results: Two possibly pathogenic mutations of the TPO gene were detected: c.2242G>A (p.Val748Met) and c.1103C>T (p.Pro368Leu). These mutations were detected in 2 of 12 patients (16.6%): 1 was compound heterozygous c.1103C>T/c.2242G>A, and the other was heterozygous for c.2242G>A. In the diagnostic confirmation test, both patients presented diffuse hyper-uptake goiter on thyroid scintigraphy and high TSH in venous blood (>190 uIU/mL). Conclusions: The frequency of patients with possibly pathogenic mutations in TPO with CHD was 16.6%. Its study would allow for genetic counseling to be offered to the families of affected patients.
Assuntos
Hipotireoidismo Congênito , Iodeto Peroxidase , Proteínas de Ligação ao Ferro , Mutação , Humanos , Hipotireoidismo Congênito/genética , Hipotireoidismo Congênito/sangue , Chile , Iodeto Peroxidase/genética , Feminino , Masculino , Proteínas de Ligação ao Ferro/genética , Autoantígenos/genética , Lactente , Criança , Adolescente , Pré-Escolar , Recém-Nascido , Disgenesia da Tireoide/genética , Disgenesia da Tireoide/complicações , Disgenesia da Tireoide/sangueRESUMO
Congenital hypothyroidism (CH) may be caused by biallelic variants in the TSHR gene. CH due to thyroid dysgenesis has also been linked to pathogenic variants of the nucleotide kinase 2, homeobox 5 (NKX2-5) gene, which can also cause sudden cardiac death from ventricular arrhythmia. In particular, the NKX2-5 p.Arg25Cys missense variant has been repeatedly reported in patients with congenital heart defects and, more rarely, with hypogonadism. We report the case of a 7 year old boy with ventricular arrhythmias, thyroid dysgenesis and intellectual disability, born from consanguineous Tunisian parents. Exome sequencing and segregation analysis revealed two potentially relevant variants: the NKX2-5 p.Arg25Cys variant (maternally inherited), as well as a single heterozygous TSHR p.Gln90Pro variant (paternally inherited). Of note, a male sibling of the proband, presenting with intellectual disability only, carried the same two variants. No other TSHR variants, or other potentially relevant variants were identified. In this proband, despite the identification of variants in two genes potentially correlated to the phenotype, a definite genetic diagnosis could not be reached. This case report highlights the complexity of exome data interpretation, especially when dealing with families presenting complex phenotypes and variable expression of clinical traits.
Assuntos
Hipotireoidismo Congênito , Deficiência Intelectual , Disgenesia da Tireoide , Masculino , Humanos , Hipotireoidismo Congênito/diagnóstico , Disgenesia da Tireoide/genética , Fenótipo , Arritmias Cardíacas , MutaçãoRESUMO
OBJECTIVE: To evaluate the candidate genes PAX-8, NKX2-5, TSH-R and HES-1 in 63 confirmed cases of thyroid dysgenesis. SUBJECTS AND METHODS: Characterization of patients with congenital hypothyroidism into specific subtypes of thyroid dysgenesis with hormone levels (TT4 and TSH), thyroid ultrasound and scintigraphy. DNA was extracted from peripheral blood leukocytes and the genetic analysis was realized by investigating the presence of mutations in the transcription factor genes involved in thyroid development. RESULTS: No mutations were detected in any of the candidate genes. In situ thyroid gland represented 71.1% of all cases of permanent primary congenital hypothyroidism, followed by hypoplasia (9.6%), ectopia (78%), hemiagenesis (6.0%) and agenesis (5.5%). The highest neonatal screening TSH levels were in the agenesis group (p < 0.001). CONCLUSIONS: Thyroid dysgenesis is possibly a polygenic disorder and epigenetic factors could to be implicated in these pathogeneses.
Assuntos
Proteína Homeobox Nkx-2.5/genética , Mutação/genética , Fator de Transcrição PAX8/genética , Receptores da Tireotropina/genética , Disgenesia da Tireoide/genética , Brasil , Pré-Escolar , Estudos de Coortes , Hipotireoidismo Congênito/diagnóstico por imagem , Hipotireoidismo Congênito/etiologia , Hipotireoidismo Congênito/genética , Análise Mutacional de DNA , Feminino , Testes Genéticos , Humanos , Lactente , Recém-Nascido , Masculino , Triagem Neonatal , Disgenesia da Tireoide/complicações , Disgenesia da Tireoide/diagnóstico por imagem , Tireotropina/sangue , Tiroxina/sangue , Fatores de Transcrição HES-1/genética , UltrassonografiaRESUMO
ABSTRACT Objective: To evaluate the candidate genes PAX-8, NKX2-5, TSH-R and HES-1 in 63 confirmed cases of thyroid dysgenesis. Subjects and methods: Characterization of patients with congenital hypothyroidism into specific subtypes of thyroid dysgenesis with hormone levels (TT4 and TSH), thyroid ultrasound and scintigraphy. DNA was extracted from peripheral blood leukocytes and the genetic analysis was realized by investigating the presence of mutations in the transcription factor genes involved in thyroid development. Results: No mutations were detected in any of the candidate genes. In situ thyroid gland represented 71.1% of all cases of permanent primary congenital hypothyroidism, followed by hypoplasia (9.6%), ectopia (78%), hemiagenesis (6.0%) and agenesis (5.5%). The highest neonatal screening TSH levels were in the agenesis group (p < 0.001). Conclusions: Thyroid dysgenesis is possibly a polygenic disorder and epigenetic factors could to be implicated in these pathogeneses.
Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Receptores da Tireotropina/genética , Proteína Homeobox Nkx-2.5/genética , Fator de Transcrição PAX8/genética , Mutação/genética , Brasil , Análise Mutacional de DNA , Testes Genéticos , Estudos de Coortes , Ultrassonografia , Hipotireoidismo Congênito/etiologia , Hipotireoidismo Congênito/genética , Hipotireoidismo Congênito/diagnóstico por imagem , Disgenesia da Tireoide/genéticaRESUMO
Context: Thyroid dysgenesis (TD) is the leading cause of congenital hypothyroidism (CH). The etiology of TD remains unknown in â¼90% of cases, the most common form being thyroid ectopia (TE) (48% to 61%). Objective: To search for candidate genes in hypothyroid children with TE. Design, Setting, and Participants: We followed a cohort of 268 children with TD and performed whole-exome sequencing (WES) in three children with CH with TE (CHTE) and compared them with 18 thyroid-healthy controls. We then screened an additional 41 children with CHTE by Sanger sequencing and correlated the WES and Sanger molecular findings with in vitro functional analysis. Main Outcome Measures: Genotyping, mutation prediction analysis, and in vitro functional analysis. Results: We identified seven variants in the DUOX2 gene, namely G201E, L264CfsX57, P609S, M650T, E810X, M822V, and E1017G, and eight known variations. All children carrying DUOX2 variations had high thyroid-stimulating hormone levels at neonatal diagnosis. All mutations were localized in the N-terminal segment, and three of them led to effects on cell surface targeting and reactive oxygen species generation. The DUOX2 mutants also altered the interaction with the maturation factor DUOXA2 and the formation of a stable DUOX2/DUOXA2 complex at the cell surface, thereby impairing functional enzymatic activity. We observed no mutations in the classic genes related to TD or in the DUOX1 gene. Conclusion: Our findings suggest that, in addition to thyroid hormonogenesis, the DUOX2 N-terminal domain may play a role in thyroid development.
Assuntos
Hipotireoidismo Congênito/genética , Oxidases Duais/genética , Mutação , Disgenesia da Tireoide/genética , Estudos de Coortes , Hipotireoidismo Congênito/complicações , Análise Mutacional de DNA , Oxidases Duais/química , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Células HEK293 , Humanos , Recém-Nascido , Masculino , Domínios Proteicos/genética , Disgenesia da Tireoide/complicações , Glândula Tireoide/embriologiaRESUMO
SUMMARY Resistance to thyroid hormone (RTH) coexisting with ectopic thyroid is rare. Here we report a case of RTH with ectopic thyroid. A ten-year-old girl had been misdiagnosed as congenital hypothyroidism and treated with levothyroxine since she was born. Ten-year follow-up showed that the elevated thyrotropin was never suppressed by levothyroxine and no signs indicating hyperthyroidism or hypothyroidism despite elevated FT3 and FT4 levels. Therefore the girl developed no defects in physical and cognitive development. Pituitary adenoma was excluded by magnetic resonance imaging. Ultrasonography did not find the thyroid gland in the normal place, while the thyroid scan found a large lingual thyroid gland. The octreotide inhibition test showed a reduction in thyrotropin by 41.98%. No mutation was detected in the thyroid hormone receptor (THR) β, THRα, thyrotropin receptor (TSHR), and GNAS1 genes. To our knowledge, it is an interesting RTH case coexisting with lingual thyroid.
Assuntos
Humanos , Feminino , Criança , Receptores dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/complicações , Disgenesia da Tireoide/complicações , Tiroxina/uso terapêutico , Fatores de Tempo , Doenças da Língua/diagnóstico por imagem , DNA/isolamento & purificação , Tireotropina/análise , Análise Mutacional de DNA , Seguimentos , Síndrome da Resistência aos Hormônios Tireóideos/genética , Hipotireoidismo Congênito/diagnóstico , Erros de Diagnóstico , Disgenesia da Tireoide/genética , Disgenesia da Tireoide/diagnóstico por imagemRESUMO
Resistance to thyroid hormone (RTH) coexisting with ectopic thyroid is rare. Here we report a case of RTH with ectopic thyroid. A ten-year-old girl had been misdiagnosed as congenital hypothyroidism and treated with levothyroxine since she was born. Ten-year follow-up showed that the elevated thyrotropin was never suppressed by levothyroxine and no signs indicating hyperthyroidism or hypothyroidism despite elevated FT3 and FT4 levels. Therefore the girl developed no defects in physical and cognitive development. Pituitary adenoma was excluded by magnetic resonance imaging. Ultrasonography did not find the thyroid gland in the normal place, while the thyroid scan found a large lingual thyroid gland. The octreotide inhibition test showed a reduction in thyrotropin by 41.98%. No mutation was detected in the thyroid hormone receptor (THR) ß, THRα, thyrotropin receptor (TSHR), and GNAS1 genes. To our knowledge, it is an interesting RTH case coexisting with lingual thyroid.
Assuntos
Receptores dos Hormônios Tireóideos/genética , Disgenesia da Tireoide/complicações , Síndrome da Resistência aos Hormônios Tireóideos/complicações , Criança , Hipotireoidismo Congênito/diagnóstico , DNA/isolamento & purificação , Análise Mutacional de DNA , Erros de Diagnóstico , Feminino , Seguimentos , Humanos , Disgenesia da Tireoide/diagnóstico por imagem , Disgenesia da Tireoide/genética , Síndrome da Resistência aos Hormônios Tireóideos/genética , Tireotropina/análise , Tiroxina/uso terapêutico , Fatores de Tempo , Doenças da Língua/diagnóstico por imagemRESUMO
Objective To search for genetic alteration in NKX2.5 gene in patients presenting both congenital heart disease (CHD) and TD. Subjects and methods Individual phenotypes were carefully analyzed in 86 children with thyroid dysgenesis (TD) using thyroid function tests, scintigraphy, ultrasound and echocardiography. DNA was extracted and NKX2.5 gene coding region was amplified by polymerase chain reaction (PCR) and sequenced. Results CHD were found in 8.1% of patients with TD. The mutation screening revealed two known polymorphisms in patients with isolated TD or TD associated with CHD. None of them are predicted to result in codon change in conserved domain. The c.63A>G polymorphism was detected in 54/86 patients (49 with isolated TD and 5 with TD combined with CHD). There was a significant association of c.63A>G polymorphism with hypoplasia (p < 0.036). The c.541G>A polymorphism was observed in only one patient with isolated thyroid hypoplasia. Conclusion NKX2.5 mutations were not found. The c.63A>G polymorphism might be associated with thyroid hypoplasia.
Assuntos
Feminino , Humanos , Recém-Nascido , Masculino , Proteínas de Homeodomínio/genética , Polimorfismo Genético , Disgenesia da Tireoide/genética , Glândula Tireoide/anormalidades , Fatores de Transcrição/genética , Estudos de Associação Genética , Linhagem , Testes de Função TireóideaRESUMO
OBJECTIVE: To search for genetic alteration in NKX2.5 gene in patients presenting both congenital heart disease (CHD) and TD. SUBJECTS AND METHODS: Individual phenotypes were carefully analyzed in 86 children with thyroid dysgenesis (TD) using thyroid function tests, scintigraphy, ultrasound and echocardiography. DNA was extracted and NKX2.5 gene coding region was amplified by polymerase chain reaction (PCR) and sequenced. RESULTS: CHD were found in 8.1% of patients with TD. The mutation screening revealed two known polymorphisms in patients with isolated TD or TD associated with CHD. None of them are predicted to result in codon change in conserved domain. The c.63A>G polymorphism was detected in 54/86 patients (49 with isolated TD and 5 with TD combined with CHD). There was a significant association of c.63A>G polymorphism with hypoplasia (p < 0.036). The c.541G>A polymorphism was observed in only one patient with isolated thyroid hypoplasia. CONCLUSION: NKX2.5 mutations were not found. The c.63A>G polymorphism might be associated with thyroid hypoplasia.