RESUMO
BACKGROUND: The study aimed to compare the growth responses to 3 years of growth hormone (GH) treatment in children and adolescents with GH deficiency (GHD) according to idiopathic, organic, isolated (IGHD), and multiple pituitary hormone deficiency (MPHD). METHODS: Total 163 patients aged 2-18 years (100 males and 63 females; 131 idiopathic and 32 organic GHD; 129 IGHD and 34 MPHD) were included from data obtained from the LG Growth Study. Parameters of growth responses and biochemical results were compared during the 3-year GH treatment. RESULTS: The baseline age, bone age (BA), height (Ht) standard deviation score (SDS), weight SDS, mid-parental Ht SDS, predicted adult Ht (PAH) SDS, and insulin like growth factor-1 (IGF-1) SDS were significantly higher in the organic GHD patients than in the idiopathic GHD patients, but peak GH on the GH-stimulation test, baseline GH dose, and mean 3-year-GH dosage were higher in the idiopathic GHD patients than in the organic GHD patients. The prevalence of MPHD was higher in the organic GHD patients than in the idiopathic GHD patients. Idiopathic MPHD subgroup showed the largest increase for the ΔHt SDS and ΔPAH SDS during GH treatment, and organic MPHD subgroup had the smallest mean increase after GH treatment, depending on ΔIGF-1 SDS and ΔIGF binding protein-3 (IGFBP-3) SDS. The growth velocity and the parental-adjusted Ht gain were greater in the idiopathic GHD patients than the organic GHD patients during the 3-year GH treatment, which may have been related to the different GH dose, ΔIGF-1 SDS, and ΔIGFBP-3 SDS between two groups. Multiple linear regression analysis revealed that baseline IGF-1 SDS, BA, and MPH SDS in idiopathic group and baseline HT SDS in organic group are the most predictable parameters for favorable 3-year-GH treatment. CONCLUSION: The 3-year-GH treatment was effective in both idiopathic and organic GHD patients regardless of the presence of MPHD or underlying causes, but their growth outcomes were not constant with each other. Close monitoring along with appropriate dosage of GH and annual growth responses, not specific at baseline, are more important in children and adolescents with GHD for long-term treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01604395.
Assuntos
Estatura/efeitos dos fármacos , Hipotireoidismo Congênito/tratamento farmacológico , Hipotireoidismo Congênito/fisiopatologia , Nanismo Hipofisário/tratamento farmacológico , Nanismo Hipofisário/fisiopatologia , Hormônio do Crescimento Humano/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , MasculinoRESUMO
Congenital hypothyroidism (CH) is an endocrine disease commonly found in newborns and is related to the absence or reduction of thyroid hormones (THs), which are essential for development since intrauterine life. Children with CH can develop hearing problems as THs are crucial for the auditory pathway's development and maturation. Sensory deprivations, especially in hearing disorders at early ages of development, can impair language skills, literacy, and behavioral, cognitive, social, and psychosocial development. In this review we describe clinical and molecular aspects linking CH and hearing loss.
Assuntos
Hipotireoidismo Congênito/complicações , Perda Auditiva/etiologia , Audição/fisiologia , Transtornos da Linguagem/etiologia , Idioma , Criança , Hipotireoidismo Congênito/fisiopatologia , Perda Auditiva/fisiopatologia , Humanos , Transtornos da Linguagem/fisiopatologiaRESUMO
OBJECTIVE: This study aimed to look for a possible relationship between thyrotropin (TSH) values from neonatal bloodspot screening testing and newborn lower auditory pathway myelinization evaluated using the brainstem evoked response audiometry (ABR) test. METHODS: Sixty-two healthy full-term newborns without perinatal problems were enrolled in the study. TSH results were collected from neonatal bloodspot screening data and were below the test cut-off level (15µUI/mL). The TSH test was performed between three and seven days, and the ABR test was performed in the first 28 days of life. The newborns were divided into two groups: Group 1 (n = 35), TSH between 0 and 5µUI/mL, and group 2 (n = 27), TSH between 5 and 15µUI/mL. Data are presented as mean ± SD, median, or percentage, depending on the variable. RESULTS: Wave latency and interpeak interval values for Groups 1 and 2 were as follows: Wave I: 1.8 ± 0.1 and 1.7 ± 0.1; Wave III: 4.4 ± 0.1 and 4.4 ± 0.1; Wave V: 6.9 ± 0.1 and 6.9 ± 0.1; interval I-III: 2.6 ± 0.1 and 2.6 ± 0.1; interval I-V: 5.1 ± 0.1 and 5.1 ± 0.1; interval III-V: 2.4 ± 0.1 and 2.4 ± 0.1. There were no significant differences in ABR parameters between groups 1 and 2 (p > 0.05). Multiple regression analysis showed a slight significant negative correlation between TSH and wave I values (standardized ß = -0.267; p = 0.036), without observing any relationship with the other ABR waves recorded. CONCLUSIONS: This study investigated the relationship of TSH and auditory myelinization evaluated by ABR. It did not show a significant change in lower auditory pathway myelinization according to TSH levels in newborns with TSH screening levels lower than 15 µUI/mL.
Assuntos
Vias Auditivas , Tireotropina/sangue , Adulto , Audiometria de Resposta Evocada , Vias Auditivas/crescimento & desenvolvimento , Vias Auditivas/fisiologia , Hipotireoidismo Congênito/sangue , Hipotireoidismo Congênito/fisiopatologia , Estudos Transversais , Feminino , Humanos , Recém-Nascido , MasculinoRESUMO
CONTEXT: Children with congenital hypothyroidism (CH) are at risk for suboptimal neurodevelopment. OBJECTIVES: To evaluate neurocognitive function and white matter microstructure in children with permanent or transient CH and to correlate these findings with disease severity. DESIGN, PARTICIPANTS AND METHODS: A retrospective and prospective observational study was conducted in 39 children with permanent or transient CH, and in 39 healthy children. Cognitive function was assessed by Wechsler Intelligence Scale, Fourth Edition, and by other tests; the white matter microstructure was investigated by 3 Tesla magnetic resonance imaging. RESULTS: Children with permanent CH have lower cognitive scores at a median age of 9.5 years than those with transient CH and controls. An IQ score between 71 and 84 was found in 28.6% of permanent CH and of <70 (Pâ =â 0.06) in 10.7%. The Processing Speed Index (PSI; Pâ =â 0.004), sustained visual attention (Pâ =â 0.02), reading speed (Pâ =â 0.0001), written calculations (Pâ =â 0.002), and numerical knowledge (Pâ =â 0.0001) were significantly lower than controls. Children born to mothers with Hashimoto's thyroiditis have significantly lower IQ values (Pâ =â 0.02), Working Memory Index (Pâ =â 0.03), and PSI (Pâ =â 0.02). Significantly lower IQ and Verbal Comprehension Index values were found in children with a family history of thyroid disorders (Pâ =â 0.004 and Pâ =â 0.009, respectively). In children with permanent CH, significant correlations between abnormalities in white matter microstructural, clinical, and cognitive measures were documented. CONCLUSIONS: These findings indicate that children with CH are at risk of neurocognitive impairment and white matter abnormalities despite timely and adequate treatment. The association between offspring cognitive vulnerability and maternal thyroid disorders requires careful consideration.
Assuntos
Cognição/fisiologia , Hipotireoidismo Congênito/psicologia , Doenças da Glândula Tireoide/psicologia , Substância Branca/patologia , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Estudos de Coortes , Hipotireoidismo Congênito/tratamento farmacológico , Hipotireoidismo Congênito/patologia , Hipotireoidismo Congênito/fisiopatologia , Feminino , Terapia de Reposição Hormonal , Humanos , Testes de Inteligência , Itália , Masculino , Transtornos Neurocognitivos/etiologia , Estudos Retrospectivos , Doenças da Glândula Tireoide/tratamento farmacológico , Doenças da Glândula Tireoide/genética , Doenças da Glândula Tireoide/patologia , Testes de Função Tireóidea , Tiroxina/uso terapêutico , Substância Branca/crescimento & desenvolvimento , Adulto JovemRESUMO
INTRODUCTION: Congenital hypothyroidism (CH) is the most common cause of preventable intellectual disability in the pediatric population. Early diagnosis and treatment during the first month of life are essential to avoid delaying the neuropsychological development of these patients. OBJECTIVE: to describe the social, cognitive, and psychomotor development of children with CH treated at the National Institute of Child Health (INSN) in Lima, Peru. PATIENTS AND METHOD: Retrospective analysis of 26 CH pa tients seen during 2012-2017 at INSN were reviewed. The aspects of neuropsychological development studied were: cognitive development (IQ), social development (social category), and psychomotor development (gait, speech, and chest control). The IQ was classified according to the result of the Weschler IV scale. An analysis was carried out with the Fisher-Freeman-Halton test to verify if there was a difference in the frequency of the variables according to the age of diagnosis and beginning of treatment. RESULTS: Most of the patients presented a borderline IQ (38.5%), the most frequent social category was educable (88.7%), and most of the patients presented delay in developing the speech (88.5%). In the Fisher-Freeman-Halton test, there was only a statistically significant increase in the number of cases of speech delay in patients treated between 22 days and 12 months of age (c2 = 11.246, p = 0.002, V of Cramer = 0.778). CONCLUSION: Neuropsychological developmental delay was more frequent in patients with CH diagnosed and treated after 21 days of age.
Assuntos
Desenvolvimento Infantil/fisiologia , Cognição/fisiologia , Hipotireoidismo Congênito/fisiopatologia , Habilidades Sociais , Criança , Linguagem Infantil , Pré-Escolar , Hipotireoidismo Congênito/complicações , Hipotireoidismo Congênito/diagnóstico , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/etiologia , Deficiência Intelectual/prevenção & controle , Inteligência , Transtornos do Desenvolvimento da Linguagem , Masculino , Peru , Desempenho Psicomotor , Estudos RetrospectivosRESUMO
PURPOSE: Thyroid dyshormonogenesis is a heterogeneous group of hereditary diseases produced by a total/partial blockage of the biochemical processes of thyroid-hormone synthesis and secretion. Paired box 8 (PAX8) is essential for thyroid morphogenesis and thyroid hormone synthesis. We aimed to identify PAX8 variants in patients with thyroid dyshormonogenesis and to analyze them with in vitro functional studies. PATIENTS AND METHODS: Nine pediatric patients with a eutopic thyroid gland were analyzed by the Catalan screening program for congenital hypothyroidism. Scintigraphies showed absent, low, or normal uptake. Only one patient had a hypoplastic gland. On reevaluation, perchlorate discharge test was negative or compatible with partial iodine-organization deficit. After evaluation, 8 patients showed permanent mild or severe hypothyroidism. Massive-sequencing techniques were used to detect variants in congenital hypothyroidism-related genes. In vitro functional studies were based on transactivating activity of mutant PAX8 on a TG-gene promoter and analyzed by a dual-luciferase assays. RESULTS: We identified 7 heterozygous PAX8 exonic variants and 1 homozygous PAX8 splicing variant in 9 patients with variable phenotypes of thyroid dyshormonogenesis. Five were novel and 5 variants showed a statistically significant impaired transcriptional activity of TG promoter: 51% to 78% vs the wild type. CONCLUSIONS: Nine patients presented with PAX8 candidate variants. All presented with a eutopic thyroid gland and 7 had deleterious variants. The phenotype of affected patients varies considerably, even within the same family; but, all except the homozygous patient presented with a normal eutopic thyroid gland and thyroid dyshormonogenesis. PAX8 functional studies have shown that 6 PAX8 variants are deleterious. Our studies have proven effective in evaluating these variants.
Assuntos
Hipotireoidismo Congênito/genética , Fator de Transcrição PAX8/genética , Glândula Tireoide/fisiologia , Adolescente , Variação Biológica da População , Criança , Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/tratamento farmacológico , Hipotireoidismo Congênito/fisiopatologia , Feminino , Seguimentos , Terapia de Reposição Hormonal , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Triagem Neonatal , Fenótipo , Testes de Função Tireóidea , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/patologia , Tiroxina/uso terapêuticoRESUMO
Objectives Adequate treatment of congenital hypothyroidism (CH) is required for normal growth and sexual development. To evaluate pubertal development in patients with permanent CH detected by a statewide Neonatal Screening Program of Paraná and, secondly, to evaluate adult height (AH) in a subgroup of patients. Methods Clinical, laboratory, and auxological data obtained from medical records of 174 patients (123 girls). Results Median chronological age (CA) at treatment initiation was 24 days, and mean initial levothyroxine dose was 11.7 ± 1.9 µg/kg/day; mean CA at puberty onset was 11.5 ± 1.3 years (boys) and 9.7 ± 1.2 years (girls); mean CA in girls who underwent menarche (n=81) was 12.1 ± 1.1 years. Thyroid-stimulating hormone (TSH) values above the normal range were observed in 36.4% of the boys and 32.7% of the girls on puberty onset, and in 44.6% around menarche. Among 15 boys and 66 girls who had reached the AH, the median height z-score value was significantly greater than the target height (TH) z-score value in boys (p=0.01) and in girls (p<0.001). Boys with normal TSH values at puberty onset had greater mean AH z-score compared with boys with TSH values above the normal range (p=0.04). Conclusions In this group, pubertal development in girls with CH was not different from that reported in healthy girls in the general Brazilian population. Boys with higher TSH at puberty onset may have an increased risk of not reaching their potential height compared with those with normal TSH during this period. In a subgroup who attained AH, the median AH z-score was greater than the median TH z-score.
Assuntos
Desenvolvimento do Adolescente/fisiologia , Hipotireoidismo Congênito/fisiopatologia , Puberdade/fisiologia , Adolescente , Desenvolvimento do Adolescente/efeitos dos fármacos , Adulto , Estatura/efeitos dos fármacos , Estatura/fisiologia , Brasil/epidemiologia , Criança , Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/tratamento farmacológico , Hipotireoidismo Congênito/epidemiologia , Feminino , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Triagem Neonatal , Puberdade/efeitos dos fármacos , Valores de Referência , Tiroxina/uso terapêuticoRESUMO
Objectives We evaluated the spectrum of diseases accompanying congenital hypothyroidism (CH) in the United Arab Emirates and compared them with internationally studied patterns. Methods The presented retrospective cross-sectional study took place in two government tertiary care centres. In total, 204 patients with a confirmed diagnosis of CH and a minimum period of follow-up of 1 year were included. Patients with Down syndrome, infants born at <35 weeks of gestation, and babies with TORCH (Toxoplasma gondii, Other viruses [HIV, measles, etc.], Rubella, Cytomegalovirus, and Herpes simplex) infections were subsequently excluded from the study. Results Of the subjects with CH, 39% had associated extrathyroidal anomalies (ETAs); among these, 25% had a single anomaly. A significant proportion of Arab males were affected by CH as compared to other ethnic groups. Dyshormonogenesis was the commonest aetiological cause (55%) of CH. Males with an ectopic lingual thyroid gland had significant ETAs as compared to females of the same cohort. The most common ETAs were congenital heart disease (16%), followed by urogenital tract anomalies (14%). Conclusions Detection of a high rate and variability of ETAs associated with CH necessitates the formulation of a structured screening programme including appropriate clinical, laboratory, and imaging tools to detect ETAs at an earlier stage.
Assuntos
Hipotireoidismo Congênito/fisiopatologia , Cardiopatias Congênitas/epidemiologia , Disgenesia da Tireoide/epidemiologia , Anormalidades Urogenitais/epidemiologia , Adolescente , Biomarcadores/análise , Criança , Pré-Escolar , Estudos Transversais , Feminino , Seguimentos , Cardiopatias Congênitas/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Estudos Retrospectivos , Disgenesia da Tireoide/patologia , Emirados Árabes Unidos/epidemiologiaRESUMO
BACKGROUND: Congenital hypothyroidism (CH) is reported to be more common in preterm infants than in term infants, especially in sick preterm infants. Though a frequent possibility of transitory thyroidal alterations in this category of neonates, the evolution of CH to transient or permanent forms is unpredictable. METHODS: We retrospectively analyzed medical records of 28 preterm infants (<37 weeks gestation) who had exhibited a positive screening for CH at birth during the period 2000-2015 followed in our Center. Children were divided into three groups: permanent CH (PCH) with thyroid dysgenesis, PCH with eutopic normal-sized thyroid gland, and transient CH (TCH) with eutopic normal-sized thyroid gland. In all groups we described clinical and biochemical characteristics. Secondly, we analyzed the differences between patients with thyroid dysgenesis and patients with eutopic normal-sized gland and we compared PCH and TCH groups with normal-sized thyroid gland in order to identify clinical or biochemical data for early detection of transient forms. RESULTS: Of all patients, 21.4% showed thyroid dysgenesis while 78.6% presented eutopic normal-sized gland. Infants with thyroid dysgenesis had higher median (IQR) baseline s-TSH and levothyroxine (L-T4) dose per weight at 12 months (12 m-dose) than patients with eutopic normal-sized gland. At re-evaluation of the patients with eutopic normal-sized gland, 36% showed PCH and 64% had TCH. The age of the patients at the beginning of L-T4 treatment, gestational age (GA), birth weight, blood thyroid stimulating hormone levels (b-TSH) at first newborn screening (NBS), baseline serum thyroid stimulating hormone (s-TSH), and L-T4 12 m-dose were statistically different between the two groups. CONCLUSIONS: Our results demonstrate that factors as GA, birth weight, b-TSH levels at first NBS, baseline s-TSH, L-T4 12 m-dose and age at the start of the treatment may be considered useful predictive elements for the evolution of CH.
Assuntos
Hipotireoidismo Congênito/diagnóstico , Doenças do Prematuro/diagnóstico , Criança , Hipotireoidismo Congênito/patologia , Hipotireoidismo Congênito/fisiopatologia , Hipotireoidismo Congênito/terapia , Progressão da Doença , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/patologia , Doenças do Prematuro/fisiopatologia , Doenças do Prematuro/terapia , Masculino , Triagem Neonatal , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: To compare the performance in gross motor, fine motor-adaptive, language, cognitive and personal-social development skills of girls with a mean age of 36 to 71 months with Congenital Hypothyroidism treated from the neonatal period with that of their peers without thyroid alterations. METHODS: The participants included in the study were 30 children aged between 36 and 70 months divided into two groups paired for chronological age and socioeconomic status: 15 girls diagnosed with Congenital Hypothyroidism - Experimental Group (EG) and 15 girls without thyroid changes - Control Group (CG). The following assessment instruments were used: Interview with parents, Peabody Picture Vocabulary Test - Revised (PPVT-R), and Denver Developmental Screening Test - 2nd edition (DDST-II). Psychological testing of intellectual functioning was conducted with application of the Stanford-Binet Intelligence Scale (SBIS). The descriptive statistical analysis was performed using Student's t-test and the Mann-Whitney test at a significance level of 5% (p<0.05). RESULTS: Comparison of the PPVT-R and SBIS results showed a statistically significant difference between the EG and CG. Comparison of the DDST-II results showed a statistically significant difference between the groups for the fine motor-adaptive, language and gross motor areas. CONCLUSION: The present study confirms that Congenital Hypothyroidism affects child development, even when children are diagnosed and treated early, leading to alterations that can impair their motor, cognitive and language development.
OBJETIVO: Comparar o desempenho das habilidades motora grossa, motora fina-adaptativa, linguagem, cognitiva e pessoal-social de meninas entre 36 e 70 meses com hipotireoidismo congênito tratado no período pós-natal com seus pares sem alterações tireoidianas. MÉTODO: Participaram 15 meninas com diagnóstico de hipotireoidismo congênito, com idade cronológica variando de 36 a 70 meses no Grupo Experimental (GE); e 15 meninas sem alterações tireoidianas no Grupo Comparativo (GC), pareadas por idade cronológica e nível socioeconômico. Os instrumentos de avaliação utilizados foram: Entrevista com os pais; Teste de Vocabulário por Imagem Peabody (TVIP-R); e Teste de Triagem do Desenvolvimento de Denver II (TTDD-II). Foi realizada a avaliação psicológica, quanto ao nível intelectual, com a aplicação da Stanford-Binet Intelligence Scale (SBIS). A estatística foi realizada por meio de análise descritiva, teste "t" de Student e Teste de Mann-Whitney, nível de significância de p <5%. RESULTADOS: Na comparação do TVIP-R e SBIS, houve diferença estatisticamente significante entre o GE e o GC. Na comparação entre as áreas do TTDD-II, houve diferença estatisticamente significante entre os grupos para as áreas de Linguagem, Motora Grossa e Motora Fina-Adaptativa. CONCLUSÃO: O presente estudo confirmou a interferência do Hipotireoidismo Congênito no desenvolvimento infantil, mesmo quando diagnosticado e tratado precocemente, levando a mudanças no desenvolvimento que podem trazer prejuízos nas áreas motora, cognitiva e linguística.
Assuntos
Cognição/fisiologia , Comunicação , Hipotireoidismo Congênito/fisiopatologia , Destreza Motora/fisiologia , Estudos de Casos e Controles , Criança , Desenvolvimento Infantil , Linguagem Infantil , Pré-Escolar , Transtornos Cognitivos , Feminino , Humanos , Desenvolvimento da Linguagem , Habilidades SociaisRESUMO
Transient congenital hypothyroidism (TCH) has long-lasting consequences on the cardiovascular system during adulthood. The aim of this study was to determine whether nitric oxide (NO) and NO-producing enzymes are involved in impaired cardiac function as well as decreased tolerance to ischemia-reperfusion (IR) injury in adult male rats with TCH. Pregnant rats were divided into control and hypothyroid groups. Male offspring rats were categorized in control and hypothyroid (TCH) groups at week 16. Levels of NOx (nitrate+nitrite) and neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS) were measured in hearts of rats and isolated perfused hearts from both groups were subjected to IR. Levels of NOx and NOSs were also measured in both groups after ischemia. Compared with controls, heart NOx levels were higher at baseline (48.0 ± 4.9 vs. 35.0 ± 2.6 µmol/L; P = 0.034) and following IR (103.6 ± 4.2 vs. 70.2 ± 2.7 µmol/L; P < 0.001) in rat with TCH. At baseline, compared with controls, heart iNOS and nNOS levels were significantly higher in rats with TCH (6.12 ± 0.34 vs. 4.78 ± 0.27 ng/mg protein; P = 0.008 for iNOS and 4.87 ± 0.28 vs. 3.55 ± 0.23 ng/mg protein; P = 0.003 for nNOS). Following IR, in rats with TCH, heart iNOS levels increased (11.75 ± 2.02 vs. 6.12 ± 0.34, ng/mg protein; P = 0.015) whereas nNOS level decreased (4.10 ± 0.25 vs. 4.87 ± 0.28 ng/mg protein; P = 0.063). Adverse effects of TCH on cardiac function are associated with increased ratio of iNOS/eNOS; in addition, increased heart nNOS levels are involved in impaired cardiac function while its decrease is associated with decreased tolerance to IR injury.
Assuntos
Hipotireoidismo Congênito/fisiopatologia , Coração/fisiopatologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Óxido Nítrico Sintase/fisiologia , Animais , Feminino , Hemodinâmica , Masculino , Óxido Nítrico Sintase/análise , Ratos , Ratos Wistar , Hormônios Tireóideos/sangueRESUMO
Objective: To elucidate the molecular cause in a well-characterized cohort of patients with Congenital Hypothyroidism (CH) and Dyshormonogenesis (DH) by using targeted next-generation sequencing (TNGS). Study design: We studied 19 well-characterized patients diagnosed with CH and DH by targeted NGS including genes involved in thyroid hormone production. The pathogenicity of novel mutations was assessed based on in silico prediction tool results, functional studies when possible, variant location in important protein domains, and a review of the recent literature. Results: TNGS with variant prioritization and detailed assessment identified likely disease-causing mutations in 10 patients (53%). Monogenic defects most often involved TG, followed by DUOXA2, DUOX2, and NIS and were usually homozygous or compound heterozygous. Our review shows the importance of the detailed phenotypic description of patients and accurate analysis of variants to provide a molecular diagnosis. Conclusions: In a clinically well-characterized cohort, TNGS had a diagnostic yield of 53%, in accordance with previous studies using a similar strategy. TG mutations were the most common genetic defect. TNGS identified gene mutations causing DH, thereby providing a rapid and cost-effective genetic diagnosis in patients with CH due to DH.
Assuntos
Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/genética , Adolescente , Adulto , Criança , Pré-Escolar , Hipotireoidismo Congênito/fisiopatologia , Oxidases Duais/genética , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Linhagem , Simportadores/genética , Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo , Adulto JovemRESUMO
RESUMO Objetivo Comparar o desempenho das habilidades motora grossa, motora fina-adaptativa, linguagem, cognitiva e pessoal-social de meninas entre 36 e 70 meses com hipotireoidismo congênito tratado no período pós-natal com seus pares sem alterações tireoidianas. Método Participaram 15 meninas com diagnóstico de hipotireoidismo congênito, com idade cronológica variando de 36 a 70 meses no Grupo Experimental (GE); e 15 meninas sem alterações tireoidianas no Grupo Comparativo (GC), pareadas por idade cronológica e nível socioeconômico. Os instrumentos de avaliação utilizados foram: Entrevista com os pais; Teste de Vocabulário por Imagem Peabody (TVIP-R); e Teste de Triagem do Desenvolvimento de Denver II (TTDD-II). Foi realizada a avaliação psicológica, quanto ao nível intelectual, com a aplicação da Stanford-Binet Intelligence Scale (SBIS). A estatística foi realizada por meio de análise descritiva, teste "t" de Student e Teste de Mann-Whitney, nível de significância de p <5%. Resultados Na comparação do TVIP-R e SBIS, houve diferença estatisticamente significante entre o GE e o GC. Na comparação entre as áreas do TTDD-II, houve diferença estatisticamente significante entre os grupos para as áreas de Linguagem, Motora Grossa e Motora Fina-Adaptativa. Conclusão O presente estudo confirmou a interferência do Hipotireoidismo Congênito no desenvolvimento infantil, mesmo quando diagnosticado e tratado precocemente, levando a mudanças no desenvolvimento que podem trazer prejuízos nas áreas motora, cognitiva e linguística.
ABSTRACT Objective To compare the performance in gross motor, fine motor-adaptive, language, cognitive and personal-social development skills of girls with a mean age of 36 to 71 months with Congenital Hypothyroidism treated from the neonatal period with that of their peers without thyroid alterations. Methods The participants included in the study were 30 children aged between 36 and 70 months divided into two groups paired for chronological age and socioeconomic status: 15 girls diagnosed with Congenital Hypothyroidism - Experimental Group (EG) and 15 girls without thyroid changes - Control Group (CG). The following assessment instruments were used: Interview with parents, Peabody Picture Vocabulary Test - Revised (PPVT-R), and Denver Developmental Screening Test - 2nd edition (DDST-II). Psychological testing of intellectual functioning was conducted with application of the Stanford-Binet Intelligence Scale (SBIS). The descriptive statistical analysis was performed using Student's t-test and the Mann-Whitney test at a significance level of 5% (p<0.05). Results Comparison of the PPVT-R and SBIS results showed a statistically significant difference between the EG and CG. Comparison of the DDST-II results showed a statistically significant difference between the groups for the fine motor-adaptive, language and gross motor areas. Conclusion The present study confirms that Congenital Hypothyroidism affects child development, even when children are diagnosed and treated early, leading to alterations that can impair their motor, cognitive and language development.
Assuntos
Humanos , Feminino , Pré-Escolar , Criança , Linguagem Infantil , Transtornos Cognitivos , Hipotireoidismo Congênito/fisiopatologia , Destreza Motora/fisiologia , Estudos de Casos e Controles , Desenvolvimento Infantil , Cognição , Habilidades Sociais , Desenvolvimento da LinguagemRESUMO
This study assessed white matter microstructural integrity and behavioral correlates for children with severe congenital hypothyroidism (CH) who were identified and treated early following newborn screening. Eighteen children with severe CH and 21 healthy controls underwent a battery of behavioral measures of hearing, language and communication, along with diffusion MR imaging. Tract-based spatial statistics were performed on standard diffusion parameters of fractional anisotropy and diffusivity metrics. Microscopic diffusion anisotropy mapping based on the Spherical Mean Technique was also used to evaluate biologically specific metrics. Compared with age-matched controls, children with severe CH had poorer hearing and communication skills, albeit generally within normal limits. Children with severe CH had fractional anisotropy that was significantly lower in the cerebellum, bilateral thalami and right temporal lobe, and radial diffusivity that was significantly higher in the cerebellum and bilateral thalami. Microscopic fractional anisotropy and intra-neurite volume fraction were also significantly decreased, and transverse microscopic diffusivity was significantly increased, in the CH group in areas including the cerebellum, thalamus, occipital lobe, and corpus callosum, and in the white matter adjacent to sensorimotor cortex, particularly in the left hemisphere. Significant and widespread correlations were observed between behavioral measures and measures of white matter microstructural integrity in children with CH. The results indicate that children with severe CH who are identified through newborn screening may have significant brain white matter microstructural abnormalities despite early treatment.
Assuntos
Disfunção Cognitiva/fisiopatologia , Transtornos da Comunicação/fisiopatologia , Hipotireoidismo Congênito/patologia , Hipotireoidismo Congênito/fisiopatologia , Perda Auditiva/fisiopatologia , Transtornos da Linguagem/fisiopatologia , Substância Branca/patologia , Adolescente , Criança , Disfunção Cognitiva/etiologia , Transtornos da Comunicação/etiologia , Hipotireoidismo Congênito/complicações , Hipotireoidismo Congênito/diagnóstico por imagem , Imagem de Tensor de Difusão , Feminino , Perda Auditiva/etiologia , Humanos , Transtornos da Linguagem/etiologia , Masculino , Índice de Gravidade de Doença , Substância Branca/diagnóstico por imagemRESUMO
OBJECTIVE: To investigate the signal amplitudes of transient evoked otoacoustic emissions (TEOAE) in neonates and infants diagnosed with congenital hypothyroidism (HC) and verify their association with clinical and laboratory aspects. METHODS: A cross-sectional study with a convenience sample of 22 individuals with congenital hypothyroidism and a group of 22 individuals without the disease, neonates and infants, aged 0-12 months. The TEOAE amplitudes were evaluated in both groups and compared using the Mann-Whitney test. The existence of association between TEOAE amplitudes and clinical-laboratory variables was verified through the Spearman correlation coefficient. RESULTS: There were no statistically significant differences between TEOAE amplitudes between the two groups. There was an association between the amplitudes of TEOAE and serum levels of thyroid stimulating hormone (TSH) and free thyroxine (T4) in the diagnostic test. CONCLUSIONS: The existence of an association between serum levels of TSH and free T4 in the diagnostic test and the amplitudes of TEOAE suggests the influence of these hormones on the auditory function.
Assuntos
Cóclea/fisiopatologia , Hipotireoidismo Congênito/fisiopatologia , Hipotireoidismo Congênito/complicações , Estudos Transversais , Potenciais Evocados Auditivos/fisiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Emissões Otoacústicas Espontâneas/fisiologia , Testes de Função Tireóidea , TiroxinaRESUMO
INTRODUCTION: The investigation of amplitudes of otoacoustic emissions in congenital hypothyroidism can provide information on cochlear function with more sensibility, when compared to other methods of auditory evaluation. AIM: To investigate cochlear function through the amplitude of distortion product otoacoustic emissions in individuals with congenital hypothyroidism and to correlate with clinical aspects. METHODS: An exploratory, analytical, cross-sectional study with a convenience sample, composed of 50 individuals with congenital hypothyroidism and a group of 42 individuals without the disease, mean age of 8.4 (±3.1) years. The subjects of the research were evaluated by means of tonal and speech audiometry, immittance and distortion product otoacoustic emissions (DPOAEs). Continuous variables were described as mean or median and standard deviation. The Spearman test evaluated the correlations between the variables. RESULTS: Otoacoustic emission amplitudes were significantly reduced in the exposed group, with congenital hypothyroidism, when compared to the group of individuals without the disease, especially in the medium frequencies. The Spearman test showed a slight correlation between the amplitude values of the otoacoustic emissions of some frequencies and the variables: disease time, diagnostic age, irregular serum free thyroxine hormone levels and thyroid stimulating hormone, especially in the condition of less treatment, whose correlation was negative. CONCLUSION: There was a correlation between the levels of signal amplitudes of otoacoustic emissions with clinical conditions and hormonal follow-up, suggesting probable subclinical auditory impairment in this population, as well as influence of some clinical aspects of congenital hypothyroidism on auditory function.
Assuntos
Doenças Cocleares/fisiopatologia , Hipotireoidismo Congênito/fisiopatologia , Emissões Otoacústicas Espontâneas , Audiometria de Tons Puros , Audiometria da Fala , Estudos de Casos e Controles , Criança , Pré-Escolar , Doenças Cocleares/etiologia , Hipotireoidismo Congênito/complicações , Estudos Transversais , Humanos , Tireotropina/sangue , Tiroxina/sangueRESUMO
Six patients are described with bi-allelic DUOX2 variants and widely variable phenotypes. Patient 1 is an infant with a compressive hypothyroid goiter causing respiratory distress, which was promptly alleviated by levothyroxine (LT4). He was a compound heterozygote for DUOX2 variants, including a novel deletion of 540 base pairs. Patients 2 and 3 are siblings with the same compound heterozygous mutations of DUOX2, yet one had overt hypothyroidism at 14 months and the other lifelong euthyroidism. Patient 4 is a compound heterozygote individual and has mild persistent congenital hypothyroidism; his sister (patient 5) only had a borderline thyrotropin elevation at newborn screening, consistent with homozygous DUOX2 variants with a mild impact on enzyme activity. Their euthyroid mother (patient 6) is a compound heterozygote for the same DUOX2 mutations as her son. Targeted exome sequencing did not reveal any relevant modifiers. It is concluded that (i) prompt LT4 replacement in infants with respiratory distress due to a hypothyroid goiter makes surgery unnecessary; and (ii) the clinical expression of DUOX2 deficiency varies widely between individuals and over time, justifying periodic reevaluation of the need for LT4 replacement.
Assuntos
Hipotireoidismo Congênito/genética , Oxidases Duais/genética , Bócio/genética , Hipotireoidismo/genética , Tiroxina/uso terapêutico , Adolescente , Adulto , Obstrução das Vias Respiratórias/diagnóstico por imagem , Obstrução das Vias Respiratórias/etiologia , Criança , Pré-Escolar , Hipotireoidismo Congênito/sangue , Hipotireoidismo Congênito/fisiopatologia , Oxidases Duais/deficiência , Feminino , Bócio/complicações , Bócio/diagnóstico por imagem , Bócio/tratamento farmacológico , Heterozigoto , Homozigoto , Humanos , Hipotireoidismo/sangue , Hipotireoidismo/tratamento farmacológico , Hipotireoidismo/fisiopatologia , Lactente , Recém-Nascido , Masculino , Triagem Neonatal , Linhagem , Fenótipo , Tireotropina/sangue , Tiroxina/sangueRESUMO
Variants have been identified in the embryonic ectoderm development (EED) gene in seven patients with syndromic overgrowth similar to that observed in Weaver syndrome. Here, we present three additional patients with missense variants in the EED gene. All the missense variants reported to date (including the three presented here) have localized to one of seven WD40 domains of the EED protein, which are necessary for interaction with enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). In addition, among the seven patients reported in the literature and the three new patients presented here, all of the reported pathogenic variants except one occurred at one of four amino acid residues in the EED protein. The recurrence of pathogenic variation at these loci suggests that these residues are functionally important (mutation hotspots). In silico modeling and calculations of the free energy changes resulting from these variants suggested that they not only destabilize the EED protein structure but also adversely affect interactions between EED, EZH2, and/or H3K27me3. These cases help demonstrate the mechanism(s) by which apparently deleterious variants in the EED gene might cause overgrowth and lend further support that amino acid residues in the WD40 domain region may be mutation hotspots.
Assuntos
Anormalidades Múltiplas/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Deformidades Congênitas da Mão/genética , Histona-Lisina N-Metiltransferase/genética , Complexo Repressor Polycomb 2/genética , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Criança , Simulação por Computador , Hipotireoidismo Congênito/etiologia , Hipotireoidismo Congênito/fisiopatologia , Anormalidades Craniofaciais/etiologia , Anormalidades Craniofaciais/fisiopatologia , Proteína Potenciadora do Homólogo 2 de Zeste/química , Feminino , Deformidades Congênitas da Mão/etiologia , Deformidades Congênitas da Mão/fisiopatologia , Histona-Lisina N-Metiltransferase/química , Humanos , Masculino , Simulação de Dinâmica Molecular , Taxa de Mutação , Mutação de Sentido Incorreto/genética , Complexo Repressor Polycomb 2/química , Conformação Proteica , Repetições WD40/genética , Sequenciamento do ExomaRESUMO
RESUMO Objetivo: Investigar a manifestação de sintomas do transtorno do processamento auditivo central em crianças com hipotireoidismo congênito. Métodos: Estudo de caráter exploratório, descritivo e transversal com 112 pacientes com hipotireoidismo congênito com idade ≥5 anos. Realizou-se entrevista com os pais/cuidadores no momento da espera da consulta médica. Portadores de outras afecções médicas foram excluídos. Como instrumento de pesquisa utilizou-se o protocolo estruturado de anamnese para avaliação do processamento auditivo rotineiramente empregado por audiologistas. A análise estatística utilizou o teste Qui-quadrado. Resultados: A distribuição por sexo foi semelhante (meninas: 53,3%). Os casos não-disgenesia constituíram a forma fenotípica mais prevalente para o hipotireoidismo congênito (88,4%), e verificou-se que 65,3% das crianças apresentavam algum episódio de níveis séricos irregulares de hormônio tireoestimulante. Dentre as manifestações mais frequentes dos sintomas do transtorno do processamento auditivo central, as queixas relaciondas às funções cognitivas auditivas, como: figura-fundo (83,0%), atenção auditiva (75,9%) e memória auditiva (33,0%) foram as mais evidentes. Reclamações relacionadas ao rendimento escolar foram reportadas em 62,3%. Conclusões: Os dados obtidos evidenciaram altas frequências de sintomas de defasagem nas funções cognitivas relacionadas ao processamento auditivo central, em especial na atenção auditiva, figura-fundo e memória auditiva nos portadores do hipotireoidismo congênito.
ABSTRACT Objective: To investigate the presence of central auditory processing disorder symptoms in children with congenital hypothyroidism. Methods: An exploratory, descriptive, cross-sectional study of 112 patients with congenital hypothyroidism aged ≥5 years old. An interview was held with the parents/caregivers at the time of the medical consultation. Patients with other medical conditions were excluded. As a research instrument, the structured protocol of anamnesis was used to evaluate the auditory processing routinely used by audiologists. For statistical analysis, the chi-square test was used. Results: Sex distribution was similar in both boys and girls (girls: 53.3%). The most prevalent phenotypic form of congenital hypothyroidism was no dysgenesis (88.4%), and 65.3% of the children had an episode of irregular serum thyroid-stimulating hormone (TSH) levels. Among the manifestations of the most frequent central auditory processing disorder symptoms, problems were reported with regard to cognitive functions, as they related to hearing, such as figure-background ability (83.0%), auditory attention (75.9%) and auditory memory (33.0%). Complaints related to school performance were reported in 62.3% of the cases. Conclusions: The data obtained show a high frequency of lag symptoms in cognitive functions related to central auditory processing, particularly with regard to auditory attention, figure-background ability and auditory memory in patients with congenital hypothyroidism.
Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Tireotropina/sangue , Cognição , Brasil/epidemiologia , Fatores Sexuais , Estudos Transversais , Fatores de Risco , Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/fisiopatologia , Hipotireoidismo Congênito/sangue , Hipotireoidismo Congênito/epidemiologia , Bócio Nodular/diagnóstico , Bócio Nodular/etiologia , Bócio Nodular/psicologia , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Neurossensorial/psicologia , Testes Auditivos/métodos , Testes Auditivos/estatística & dados numéricosRESUMO
Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and Genitopatellar syndrome (GTPTS) are very rare conditions caused by KAT6B truncating variants. Because of both syndromes often share common features the associated phenotypes are usually grouped under the term "KAT6B-related disorders." However, particular signs of each syndrome have been reported and their appearance seems to be dependent on where the KAT6B variant is located. Thus, whereas truncating variants associated with SBBYSS have their highest density in the distal part of exon 18, those resulting in GTPTS are distributed between the end of exon 17 and beginning of exon 18. Here, we reported two de novo heterozygous KAT6B truncating variants. The first variant (c.5802delA; p.A1935Pfs*16), identified in a boy with SSBYSS phenotype, resulting in the most distal KAT6B truncating variant reported up-to-date in the scientific literature. The second variant (c.3152delG; p.S1051Tfs*63), located in a region hitherto defined as specific of SBBYSS, seems to cause an overlapping SBBYSS/GTPTS phenotype. The clinical and genetic characterization of these patients could contribute to the understanding of the KAT6B-related disorders.