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1.
Eur J Endocrinol ; 178(6): 623-633, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29650690

RESUMO

OBJECTIVE: Congenital hypothyroidism (CH), the most common neonatal metabolic disorder, is characterized by impaired neurodevelopment. Although several candidate genes have been associated with CH, comprehensive screening of causative genes has been limited. DESIGN AND METHODS: One hundred ten patients with primary CH were recruited in this study. All exons and exon-intron boundaries of 21 candidate genes for CH were analyzed by next-generation sequencing. And the inheritance pattern of causative genes was analyzed by the study of family pedigrees. RESULTS: Our results showed that 57 patients (51.82%) carried biallelic mutations (containing compound heterozygous mutations and homozygous mutations) in six genes (DUOX2, DUOXA2, DUOXA1, TG, TPO and TSHR) involved in thyroid hormone synthesis. Autosomal recessive inheritance of CH caused by mutations in DUOX2, DUOXA2, TG and TPO was confirmed by analysis of 22 family pedigrees. Notably, eight mutations in four genes (FOXE1, NKX2-1, PAX8 and HHEX) that lead to thyroid dysgenesis were identified in eight probands. These mutations were heterozygous in all cases and hypothyroidism was not observed in parents of these probands. CONCLUSIONS: Most cases of congenital hypothyroidism in China were caused by thyroid dyshormonogenesis rather than thyroid dysgenesis. This study identified previously reported causative genes for 57/110 Chinese patients and revealed DUOX2 was the most frequently mutated gene in these patients. Our study expanded the mutation spectrum of CH in Chinese patients, which was significantly different from Western countries.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Hipotireoidismo Congênito/genética , China , Oxidases Duais/genética , Feminino , Fatores de Transcrição Forkhead/genética , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/genética , Humanos , Lactente , Recém-Nascido , Iodeto Peroxidase/genética , Masculino , Proteínas de Membrana/genética , Mutação , Fator de Transcrição PAX8/genética , Linhagem , Receptores da Tireotropina/genética , Análise de Sequência de DNA , Tireoglobulina/genética , Disgenesia da Tireoide/genética , Fator Nuclear 1 de Tireoide/genética , Fatores de Transcrição/genética
2.
J Endocrinol Invest ; 41(6): 711-717, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29159607

RESUMO

BACKGROUND: Congenital hypothyroidism is a frequent disease occurring with an incidence of about 1/1500 newborns/year. In about 75% of the cases, CH is caused by alterations in thyroid morphogenesis, defined "thyroid dysgenesis" (TD). TD is generally a sporadic disease but in about 5% of the cases a genetic origin has been demonstrated. Previous studies indicate that Dnajc17 as a candidate modifier gene for hypothyroidism, since it is expressed in the thyroid bud, interacts with NKX2.1 and PAX8 and it has been associated to the hypothyroid phenotype in mice carrying a single Nkx2.1 and Pax8 genes (double heterozygous knock-out). PURPOSE: The work evaluates the possible involvement of DNAJC17 in the pathogenesis of TD. METHODS: High-resolution DNA melting analysis (HRM) and direct sequencing have been used to screen for mutations in the DNAJC17 coding sequence in 89 patients with TD. RESULTS: Two mutations have been identified in the coding sequence of DNAJC17 gene, one in exon 5 (c.350A>C; rs79709714) and one in exon 9 (c.610G>C; rs117485355). The last one is a rare variant, while the rs79709714 is a polymorphism. Both are present in databases and the frequency of the alleles is not different between TD patients and controls. CONCLUSIONS: DNAJC17 mutations are not frequently present in patients with TD.


Assuntos
Biomarcadores/análise , Proteínas de Choque Térmico HSP40/genética , Mutação , Fator de Transcrição PAX8/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Disgenesia da Tireoide/genética , Fator Nuclear 1 de Tireoide/genética , Criança , Análise Mutacional de DNA , Feminino , Humanos , Fenótipo , Prognóstico , Disgenesia da Tireoide/diagnóstico
3.
Cell Mol Biol (Noisy-le-grand) ; 63(8): 93-94, 2017 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-28886330

RESUMO

Cornelia de Lange syndrome (CdLs), which is also called Brachmann de Lange syndrome, is a congenital disorder characterized by distinctive facial features, prenatal and postnatal growth deficiency, feeding difficulties, psychomotor delay, behavioral problems, and associated malformations that mainly involve the upper extremities. The prevalence ranges from 1:100,000 to as high as 1:10,000. Most cases (50-60%) were carried mutation in NIPBL gene. To our knowledge this is the first CdLs Indonesian case that reported with molecular analysis study. We present an 11 months old female Indonesian patient with classic CdLs with congenital hypothyroid. Genetics studies were performed in intron 1, exon 2, exon 10 and exon 22 of NIPBL gene. Thyroid studies (T3, T4, TSH and thyroid scan) were performed. Low level of T3 and T4, and high level of TSH were observed. Thyroid agenesis was found in thyroid scan examination. We detected thyroid agenesis which has been never reported in CdLs patients. We could not find any mutation in intron 1, exon 2, exon 10 and exon 22 of NIPBL gene. Further genetics examinations were necessary whether there is mutation in other locus.


Assuntos
Hipotireoidismo Congênito/diagnóstico , Síndrome de Lange/diagnóstico , Disgenesia da Tireoide/diagnóstico , Hipotireoidismo Congênito/genética , Hipotireoidismo Congênito/patologia , Síndrome de Lange/genética , Síndrome de Lange/patologia , Feminino , Expressão Gênica , Humanos , Indonésia , Lactente , Proteínas/genética , Proteínas/metabolismo , Disgenesia da Tireoide/genética , Disgenesia da Tireoide/patologia , Tireotropina/genética , Tireotropina/metabolismo , Tiroxina/deficiência , Tiroxina/genética , Tri-Iodotironina/deficiência , Tri-Iodotironina/genética , Regulação para Cima
4.
J Pediatr Endocrinol Metab ; 30(8): 857-862, 2017 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-28749785

RESUMO

BACKGROUND: The embryonic development of the thyroid gland is regulated by the expression of several candidate genes which are related to congenital hypothyroidism. These genes include the numerous critical thyroid transcription factors such as NKX2.1, NKX2.5, FOXE1, and PAX8. The molecular analysis of these loci will be essential to the explanation of the participation of these transcription activators in the etiology of hypothyroidism. Among them, the role of NKX2.5 is important during the early thyroid morphogenesis and in controlling thyroidal cell differentiation and migration. Importantly, NKX2.5 change nucleotides are recognized to be central to the genesis of congenital hypothyroidism. METHODS: A case-control study was conducted in 65 unrelated patients, diagnosed with primary congenital hypothyroidism and all of them were diagnosed according to the clinical presentations of thyroid hypoplasia and without cardiovascular defects. Mutational screening of the entire NKX2-5 coding sequence was performed in a cohort of pediatric patients by PCR-SSCP and direct sequencing. RESULTS: We identified two known variations 73C>T (R25C) and 63A>G (E21E) in patients with thyroid hypothyroidism. Both of them are located in conserved region of the gene and previously reported in cases with thyroid dysgenesis and congenital heart defects. There was a significance association between 63A>G variation with primary hypothyroidism (p=0.003). CONCLUSIONS: These SNPs are probably related to thyroid hypoplasia because the allele frequency of the 63A>G polymorphism was significantly different in patients and controls and also R25C variation not observed in healthy cases.


Assuntos
Hipotireoidismo Congênito/genética , Proteína Homeobox Nkx-2.5/genética , Mutação , Polimorfismo de Nucleotídeo Único , Disgenesia da Tireoide/genética , Alelos , Estudos de Casos e Controles , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Frequência do Gene , Genótipo , Humanos , Irã (Geográfico) , Masculino
5.
J Clin Endocrinol Metab ; 102(11): 4060-4071, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28666341

RESUMO

Context: Thyroid dysgenesis (TD) is the leading cause of congenital hypothyroidism (CH). The etiology of TD remains unknown in ∼90% 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/embriologia
6.
Best Pract Res Clin Endocrinol Metab ; 31(2): 143-159, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28648504

RESUMO

Developmental anomalies of the thyroid gland, defined as thyroid dysgenesis, underlie the majority of cases of congenital hypothyroidism. Thyroid dysgenesis is predominantly a sporadic disorder although a reported familial enrichment, variation of incidence by ethnicity and the monogenic defects associated mainly with athyreosis or orthotopic thyroid hypoplasia, suggest a genetic contribution. Of note, the most common developmental anomaly, thyroid ectopy, remains unexplained. Ectopy may result from multiple genetic or epigenetic variants in the germline and/or at the somatic level. This review provides a brief overview of the monogenic defects in candidate genes that have been identified so far and of the syndromes which are known to be associated with thyroid dysgenesis.


Assuntos
Morfogênese/fisiologia , Disgenesia da Tireoide/genética , Glândula Tireoide/embriologia , Animais , Hipotireoidismo Congênito/epidemiologia , Hipotireoidismo Congênito/genética , Feminino , Estudos de Associação Genética , Humanos , Hipotireoidismo/epidemiologia , Hipotireoidismo/etiologia , Incidência , Masculino , Doenças da Glândula Tireoide/complicações , Doenças da Glândula Tireoide/epidemiologia , Doenças da Glândula Tireoide/genética , Disgenesia da Tireoide/embriologia , Disgenesia da Tireoide/epidemiologia , Glândula Tireoide/anormalidades , Glândula Tireoide/crescimento & desenvolvimento
7.
Best Pract Res Clin Endocrinol Metab ; 31(2): 183-194, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28648507

RESUMO

Resistance to thyrotropin (RTSH) is broadly defined as reduced sensitivity of thyroid follicle cells to stimulation by biologically active TSH due to genetic defects. Affected individuals have elevated serum TSH in the absence of goiter, with the severity ranging from nongoitrous isolated hyperthyrotropinemia to severe congenital hypothyroidism with thyroid hypoplasia. Conceptually, defects leading to RTSH impair both aspects of TSH-mediated action, namely thyroid hormone synthesis and gland growth. These include inactivating mutations in the genes encoding the TSH receptor and the PAX8 transcription factor. A common third cause has been genetically mapped to a locus on chromosome 15, but the underlying pathophysiology has not yet been elucidated. This review provides a succinct overview of currently defined causes of nonsyndromic RTSH, their differential diagnoses (autoimmune; partial iodine organification defects; syndromic forms of RTSH) and implications for the clinical approach to patients with RTSH.


Assuntos
Hipotireoidismo Congênito/complicações , Resistência a Medicamentos , Disgenesia da Tireoide/complicações , Tireotropina/fisiologia , Hipotireoidismo Congênito/genética , Humanos , Mutação , Receptores da Tireotropina/genética , Síndrome , Disgenesia da Tireoide/genética , Hormônios Tireóideos/metabolismo , Tireotropina/genética
8.
Clin Chim Acta ; 470: 36-41, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28455095

RESUMO

BACKGROUND: The abnormal expression of certain transcription factors (NKX2.1, FOXE1, NKX2.5, and PAX8) and thyroid stimulating hormone receptor (TSHR) genes has been associated with athyreosis, which is a form of thyroid dysgenesis (TD). We aimed to identify candidate gene mutations in CH patients with athyreosis and to establish the genotype-phenotype correlations in a Chinese population. METHODS: The exons and flanking sequences of NKX2.1, FOXE1, NKX2.5, PAX8, and TSHR were screened by next-generation sequencing and further confirmed by direct Sanger sequencing. The mutation frequencies were calculated and compared against databases. The relationship between genotype and phenotype was also determined. RESULTS: Seven variants were detected in TSHR-p.P52T, p.G132R, p.M164K, p.R450H, p.C700E, p.A522V, and p.R528S. The p. G132R, p. M164K and p. R528S variants were first identified in public databases. Five variants (p.G44D, p.G360V, p.R401Q, p.L418I, and p.E453Q) were found in NKX2.1 and one variant (p.P243T) was detected in FOXE1. In addition, one variant (p.N291I) was found in NKX2.5 and two variants (p.A355V and c.-26G>A) were detected in PAX8. CONCLUSIONS: Our study indicated that TSHR mutations have phenotypic variability and has further expanded the mutation spectrum of TSHR. We also revealed that the rate of NKX2.1, FOXE1, NKX2.5, and PAX8 mutations were low in patients with CH and athyreosis, in contrast to the higher rate of TSHR mutations.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Hipotireoidismo Congênito/genética , Análise Mutacional de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Receptores da Tireotropina/genética , Disgenesia da Tireoide/genética , Fatores de Transcrição/genética , Sequência de Bases , Criança , Pré-Escolar , Feminino , Fatores de Transcrição Forkhead/genética , Genótipo , Proteína Homeobox Nkx-2.5/genética , Humanos , Masculino , Fator de Transcrição PAX8/genética , Fenótipo , Glândula Tireoide/metabolismo , Fator Nuclear 1 de Tireoide/genética
9.
Am J Med Genet A ; 173(6): 1690-1693, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28398607

RESUMO

Wilm's tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome, a rare genetic disorder, is caused by the loss of 11p13 region including PAX6 and WT1. We report novel findings in a 28-month-old boy with aniridia, Wilm's tumor, congenital hypothyroidism, and sublingual thyroid ectopia. He was found to have a mosaic 5.28 Mb interstitial deletion of chromosome 11p13 deleting PAX6 and WT1. In order to clarify the mechanism underlying his thyroid dysgenesis, sequence analysis of candidate thyroid developmental genes was performed. We identified a FOXE1: c.532_537delGCCGCC p.(Ala178_Ala179del) variant that predisposes to thyroid ectopia. Taken together, this is the first report of mosaic 11p13 deletion in association with thyroid dysgenesis. We also propose a model of complex interactions of different genetic variants for this particular phenotype in the present patient.


Assuntos
Hipotireoidismo Congênito/genética , Fatores de Transcrição Forkhead/genética , Disgenesia da Tireoide/genética , Síndrome WAGR/genética , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 11 , Hipotireoidismo Congênito/fisiopatologia , Humanos , Hibridização in Situ Fluorescente , Masculino , Mosaicismo , Fator de Transcrição PAX6/genética , Fenótipo , Disgenesia da Tireoide/fisiopatologia , Síndrome WAGR/fisiopatologia , Proteínas WT1/genética
10.
Endocrine ; 56(2): 279-285, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28390009

RESUMO

PURPOSE: Human thyroid development is a complex and still unexplained process. Thyroid hemiagenesis is a congenital anomaly, where one of the thyroid lobes fails to develop. In the majority of patients with thyroid hemiagenesis, the genetic background remains unknown. The aim of the study was to search for novel genetic contributors to the etiology of thyroid hemiagenesis. METHODS: A cohort of 34 sporadic patients diagnosed with thyroid hemiagenesis and one three-generation family were subjected to comprehensive genomic examination. Initially, targeted screening of associated transcription factors, known to be linked to thyroid development, was performed. As a next step, genomic examinations were applied using high-resolution microarrays, whereas for the thyroid hemiagenesis family, additionally the whole exome sequencing was performed. RESULTS: Screening of transcription factors revealed no causative mutations in the studied cohort. Genomic examinations revealed the presence of four recurrent defects (three deletions and one duplication) affecting highly conservative proteasome genes PSMA1, PSMA3, and PSMD3. In a thyroid hemiagenesis family a splice site mutation in a proteasome gene PSMD2 (c.612T > C cDNA.1170T > C, g.3271T > C) was found in both affected mother and daughter. CONCLUSIONS: Our results shed a new light on etiology of thyroid hemiagenesis, so far suspected to be linked only to mutations in the genes directly involved in the thyroid development. We demonstrated, for the first time, that genomic alterations in proteasome-associated genes co-occur in patients presenting this developmental anomaly.


Assuntos
Predisposição Genética para Doença , Complexo de Endopeptidases do Proteassoma/genética , Fator 2 Associado a Receptor de TNF/genética , Disgenesia da Tireoide/genética , Deleção de Genes , Duplicação Gênica , Estudos de Associação Genética , Humanos , Mutação
11.
Hum Mol Genet ; 26(3): 599-610, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28025328

RESUMO

Congenital hypothyroidism is the most common neonatal endocrine disorder and is primarily caused by developmental abnormalities otherwise known as thyroid dysgenesis (TD). We performed whole exome sequencing (WES) in a consanguineous family with TD and subsequently sequenced a cohort of 134 probands with TD to identify genetic factors predisposing to the disease. We identified the novel missense mutations p.S148F, p.R114Q and p.L177W in the BOREALIN gene in TD-affected families. Borealin is a major component of the Chromosomal Passenger Complex (CPC) with well-known functions in mitosis. Further analysis of the missense mutations showed no apparent effects on mitosis. In contrast, expression of the mutants in human thyrocytes resulted in defects in adhesion and migration with corresponding changes in gene expression suggesting others functions for this mitotic protein. These results were well correlated with the same gene expression pattern analysed in the thyroid tissue of the patient with BOREALIN-p.R114W. These studies open new avenues in the genetics of TD in humans.


Assuntos
Proteínas de Ciclo Celular/genética , Predisposição Genética para Doença , Mutação de Sentido Incorreto/genética , Disgenesia da Tireoide/genética , Proteínas de Ciclo Celular/biossíntese , Movimento Celular/genética , Exoma/genética , Feminino , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mitose/genética , Linhagem , Disgenesia da Tireoide/patologia
12.
Arch Endocrinol Metab ; 60(6): 601-604, 2016 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27737329

RESUMO

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 imagem
13.
Endocrinol Metab Clin North Am ; 45(2): 243-54, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27241962

RESUMO

Thyroid dysgenesis (TD) is the most common cause of congenital hypothyroidism in iodine-sufficient regions and includes a spectrum of developmental anomalies. The genetic components of TD are complex. Although a sporadic disease, advances in developmental biology have revealed monogenetic forms of TD. Inheritance is not based on a simple Mendelian pattern and additional genetic elements might contribute to the phenotypic spectrum. This article summarizes the key steps of normal thyroid development and provides an update on responsible genes and underlying mechanisms of TD. Up-to-date technologies in genetics and biology will allow us to advance in our knowledge of TD.


Assuntos
Hipotireoidismo Congênito/genética , Genes Controladores do Desenvolvimento , Disgenesia da Tireoide/genética , Humanos , Iodo/deficiência , Glândula Tireoide/embriologia
14.
Pediatr Endocrinol Rev ; 13(3): 612-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27116848

RESUMO

Thyroid hemiagenesis (TH) is a rare congenital abnormality of the thyroid gland, characterised by the absence of one lobe. The true prevalence of this congenital abnormality is not known because the absence of one thyroid lobe usually does not cause clinical symptoms by itself. Between 1970 and 2010, 329 cases of TH have been reported. It is interesting to note that most cases have an agenesis of the left lobe (80% of cases) followed by the isthmus (44-50% of cases). Although the female to male ratio was 1:1.4 in 24,032 unselected 11-to 14-yr-old schoolchildren from South-eastern Sicily, several other reports have documented a higher prevalence in women, which may indicate a possible gender association. Most cases of TH are diagnosed when patients present a lesion in the functioning lobe. The functioning lobe of the thyroid gland can be a site of pathological changes similar to a normally developed gland and may present a spectrum of diseases like multinodular goiter, colloid goiter, follicular adenoma, thyroiditis, hypothyroidism and hyperthyroidism. In three of our patients, TH was associated with Hashimoto thyroiditis (n = 1) and with subclinical hypothyroidism (n = 2). The frequency of thyroid abnormalities in patients with TH varies with age, due to the longer exposure of the hemi-agenetic gland to TSH overstimulation in older patients. This could explain the controversy about the benign character of this anomaly. Other extrathyroidal lesions, such as parathyroid adenoma or hyperplasia, cervical thymic cysts, ectopic sublingual thyroid gland and thyroglossal duct cyst have been reported with TH. Therefore, systematic follow-up of all identified cases is recommended.


Assuntos
Envelhecimento/fisiologia , Disgenesia da Tireoide , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Estudos Retrospectivos , Disgenesia da Tireoide/diagnóstico , Disgenesia da Tireoide/epidemiologia , Disgenesia da Tireoide/genética , Disgenesia da Tireoide/terapia , Glândula Tireoide/embriologia , Glândula Tireoide/crescimento & desenvolvimento
15.
J Clin Endocrinol Metab ; 101(3): 861-70, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26760175

RESUMO

CONTEXT: The pathogenesis of congenital hypothyroidism (CH) is still largely unexplained. We previously reported that perturbations of the Notch pathway and knockdown of the ligand jagged1 cause a hypothyroid phenotype in the zebrafish. Heterozygous JAG1 variants are known to account for Alagille syndrome type 1 (ALGS1), a rare multisystemic developmental disorder characterized by variable expressivity and penetrance. OBJECTIVE: Verify the involvement of JAG1 variants in the pathogenesis of congenital thyroid defects and the frequency of unexplained hypothyroidism in a series of ALGS1 patients. DESIGN, SETTINGS, AND PATIENTS: A total of 21 young ALGS1 and 100 CH unrelated patients were recruited in academic and public hospitals. The JAG1 variants were studied in vitro and in the zebrafish. RESULTS: We report a previously unknown nonautoimmune hypothyroidism in 6/21 ALGS1 patients, 2 of them with thyroid hypoplasia. We found 2 JAG1 variants in the heterozygous state in 4/100 CH cases (3 with thyroid dysgenesis, 2 with cardiac malformations). Five out 7 JAG1 variants are new. Different bioassays demonstrate that the identified variants exhibit a variable loss of function. In zebrafish, the knock-down of jag1a/b expression causes a primary thyroid defect, and rescue experiments of the hypothyroid phenotype with wild-type or variant JAG1 transcripts support a role for JAG1 variations in the pathogenesis of the hypothyroid phenotype seen in CH and ALGS1 patients. CONCLUSIONS: clinical and experimental data indicate that ALGS1 patients have an increased risk of nonautoimmune hypothyroidism, and that variations in JAG1 gene can contribute to the pathogenesis of variable congenital thyroid defects, including CH.


Assuntos
Síndrome de Alagille/genética , Proteínas de Ligação ao Cálcio/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Disgenesia da Tireoide/genética , Adulto , Animais , Criança , Pré-Escolar , Biologia Computacional , Feminino , Imunofluorescência , Humanos , Proteína Jagged-1 , Masculino , Proteínas Serrate-Jagged , Peixe-Zebra , Proteínas de Peixe-Zebra
16.
World J Pediatr ; 12(2): 215-8, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26684308

RESUMO

BACKGROUND: Familial clustering in patients with permanent congenital hypothyroidism (CH) caused by thyroid dysgenesis (TD) has been reported in developed countries. There is no information on familial TD from developing countries. METHODS: A total of 312 first degree relatives belonging to 80 families of children with TD (group 1) and 40 families of age-matched normal children (group 2) were screened by thyroid ultrasonography, serum total thyroxine (T4) and thyroid stimulating hormone (TSH). RESULTS: Thyroid scintigraphy revealed agenesis in 78.7% of the patients, ectopic gland in 15%, and hypoplasia in 6.2%. The mean thyroid volumes were similar in parents and siblings of both groups. Eight (10.6%) mothers in group 1 were identified to have thyroid hypoplasia as compared with none in group 2 (P=0.03). Serum TSH was significantly higher in group 1 than in group 2 (P=0.004). Sixteen (7.8%) subjects (6 mothers, 5 fathers, and 5 siblings) in group 1 were found to have subclinical hypothyroidism as compared to none in group 2 (P<0.05). Four families were identified to have thyroid developmental anomalies and abnormal thyroid functions accounting for 5% of cases of familial TD in our cohort. CONCLUSION: Thyroid developmental anomalies and thyroid function abnormalities are more frequent in first degree relatives of children with TD as compared with a control population. These findings suggest that possibly there is a genetic component of TD in Indian patients.


Assuntos
Disgenesia da Tireoide/genética , Glândula Tireoide/anormalidades , Glândula Tireoide/crescimento & desenvolvimento , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Masculino , Doenças da Glândula Tireoide/sangue , Doenças da Glândula Tireoide/etiologia , Doenças da Glândula Tireoide/fisiopatologia , Disgenesia da Tireoide/sangue , Disgenesia da Tireoide/complicações , Disgenesia da Tireoide/fisiopatologia , Glândula Tireoide/fisiopatologia , Tireotropina/sangue , Tiroxina/sangue
17.
Int J Clin Exp Pathol ; 8(9): 11434-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26617871

RESUMO

BACKGROUND: Thyroid dysgenesis (TD) is the most frequent cause of congenital hypothyroidism (CH), but its pathogenesis remains unclear. As a thyroid transcription factor, paired box transcription factor 8 (PAX8) is essential for thyroid organogenesis and development. AIM: To screen PAX8 mutations and characterize the features of these mutations in Chinese TD patients. MATERIALS AND METHODS: Blood samples were collected from 63 TD patients in Shandong Province, China, and genomic DNA was extracted from peripheral blood leukocytes. Exon 3~4 of PAX8 were analyzed by PCR and direct sequencing. RESULTS: Direct sequencing of PAX8 revealed a heterozygous missense mutation (c.155G/C, P.Arg52Pro) in one child with agenesis. Genetic screening of the child's family revealed that the clinically unaffected parents do not carry the mutation, suggesting that the identified sequence change is a de novo mutation. CONCLUSION: We report a heterozygous missense de novo mutation in PAX8 in one out of 63 unrelated Chinese TD patients, showing that the PAX8 mutation rate is very low in TD patients in China. However, de novo mutation and epigenetic mechanisms need to be considered in the future study.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Mutação de Sentido Incorreto , Fator de Transcrição PAX8/genética , Disgenesia da Tireoide/genética , Criança , Pré-Escolar , Hipotireoidismo Congênito/genética , Feminino , Humanos , Lactente , Masculino , Linhagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
Arch. endocrinol. metab. (Online) ; 59(6): 562-567, Dec. 2015. tab, graf
Artigo em Inglês | LILACS | ID: lil-767919

RESUMO

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 Tireóidea
19.
Arch Endocrinol Metab ; 59(6): 562-7, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26421664

RESUMO

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
Proteínas de Homeodomínio/genética , Polimorfismo Genético , Disgenesia da Tireoide/genética , Glândula Tireoide/anormalidades , Fatores de Transcrição/genética , Feminino , Estudos de Associação Genética , Proteína Homeobox Nkx-2.5 , Humanos , Recém-Nascido , Masculino , Linhagem , Testes de Função Tireóidea
20.
Endocr J ; 62(5): 393-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25797365

RESUMO

Genetic defects of hormone receptors are the most common form of end-organ hormone resistance. One example of such defects is TSH resistance, which is caused by biallelic inactivating mutations in the TSH receptor gene (TSHR). TSH, a master regulator of thyroid functions, affects virtually all cellular processes involving thyroid hormone production, including thyroidal iodine uptake, thyroglobulin iodination, reuptake of iodinated thyroglobulin and thyroid cell growth. Resistance to TSH results in defective thyroid hormone production from the neonatal period, namely congenital hypothyroidism. Classically, clinical phenotypes of TSH resistance due to inactivating TSHR mutations were thought to vary depending on the residual mutant receptor activity. Nonfunctional mutations in the two alleles produce severe thyroid hypoplasia with overt hypothyroidism (uncompensated TSH resistance), while hypomorphic mutations in at least one allele produce normal-sized thyroid gland with preserved hormone-producing capacity (compensated TSH resistance). More recently, a new subgroup of TSH resistance (nonclassic TSH resistance) that is characterized by paradoxically high thyroidal iodine uptake has been reported. In this article, the pathophysiology and clinical features of TSH resistance due to inactivating TSHR mutations are reviewed, with particular attention to the nonclassic form.


Assuntos
Síndrome da Resistência aos Hormônios Tireóideos , Tireotropina , Alelos , Hipotireoidismo Congênito/genética , Genótipo , Humanos , Iodo/metabolismo , Mutação , Fenótipo , Receptores da Tireotropina/química , Receptores da Tireotropina/genética , Receptores da Tireotropina/fisiologia , Disgenesia da Tireoide/genética , Glândula Tireoide/patologia , Glândula Tireoide/fisiopatologia , Síndrome da Resistência aos Hormônios Tireóideos/complicações , Síndrome da Resistência aos Hormônios Tireóideos/genética , Hormônios Tireóideos/biossíntese
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