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Frontiers in Endocrinology 2021Resistance to thyroid hormone (RTH) is a clinical syndrome defined by impaired sensitivity to thyroid hormone (TH) and its more common form is caused by mutations in the... (Review)
Review
Resistance to thyroid hormone (RTH) is a clinical syndrome defined by impaired sensitivity to thyroid hormone (TH) and its more common form is caused by mutations in the gene, termed RTHβ. The characteristic biochemical profile is that of elevated serum TH levels in absence of thyrotropin suppression. Although most individuals are considered clinically euthyroid, there is variability in phenotypic manifestation among individuals harboring different mutations and among tissue types in the same individual due in part to differential expression of the mutant TRβ protein. As a result, management is tailored to the specific symptoms of TH excess or deprivation encountered in the affected individual as currently there is no available therapy to fully correct the TRβ defect. This focused review aims to provide a concise update on RTHβ, discuss less well recognized associations with other thyroid disorders, such as thyroid dysgenesis and autoimmune thyroid disease, and summarize existing evidence and controversies regarding the phenotypic variability of the syndrome. Review of management addresses goiter, attention deficit disorder and "foggy brain". Lastly, this work covers emerging areas of interest, such as the relevance of variants of unknown significance and novel data on the epigenetic effect resulting from intrauterine exposure to high TH levels and its transgenerational inheritance.
Topics: Humans; Inheritance Patterns; Mutation; Thyroid Hormone Receptors beta; Thyroid Hormone Resistance Syndrome
PubMed: 33868182
DOI: 10.3389/fendo.2021.656551 -
Thyroid : Official Journal of the... Mar 2021An ENDO-European Reference Network (ERN) initiative was launched that was endorsed by the European Society for Pediatric Endocrinology and the European Society for... (Review)
Review
Congenital Hypothyroidism: A 2020-2021 Consensus Guidelines Update-An ENDO-European Reference Network Initiative Endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology.
An ENDO-European Reference Network (ERN) initiative was launched that was endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology with 22 participants from the ENDO-ERN and the two societies. The aim was to update the practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). A systematic literature search was conducted to identify key articles on neonatal screening, diagnosis, and management of primary and central CH. The evidence-based guidelines were graded with the Grading of Recommendations, Assessment, Development and Evaluation system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. The recommendations include the various neonatal screening approaches for CH as well as the etiology (also genetics), diagnostics, treatment, and prognosis of both primary and central CH. When CH is diagnosed, the expert panel recommends the immediate start of correctly dosed levothyroxine treatment and frequent follow-up including laboratory testing to keep thyroid hormone levels in their target ranges, timely assessment of the need to continue treatment, attention for neurodevelopment and neurosensory functions, and, if necessary, consulting other health professionals, and education of the child and family about CH. Harmonization of diagnostics, treatment, and follow-up will optimize patient outcomes. Lastly, all individuals with CH are entitled to a well-planned transition of care from pediatrics to adult medicine. This consensus guidelines update should be used to further optimize detection, diagnosis, treatment, and follow-up of children with all forms of CH in the light of the most recent evidence. It should be helpful in convincing health authorities of the benefits of neonatal screening for CH. Further epidemiological and experimental studies are needed to understand the increased incidence of this condition.
Topics: Benchmarking; Congenital Hypothyroidism; Consensus; Endocrinology; Evidence-Based Medicine; Humans; Infant, Newborn; Neonatal Screening; Predictive Value of Tests; Prognosis; Risk Factors; Transition to Adult Care
PubMed: 33272083
DOI: 10.1089/thy.2020.0333 -
Frontiers in Endocrinology 2022Preterm newborns are forced to adapt to harsh extrauterine conditions and endure numerous adversities despite their incomplete growth and maturity. The inadequate... (Review)
Review
Preterm newborns are forced to adapt to harsh extrauterine conditions and endure numerous adversities despite their incomplete growth and maturity. The inadequate thyroid hormones secretion as well as the impaired regulation of hypothalamus-pituitary-thyroid axis may lead to hypothyroxinemia. Two first weeks after birth are pivotal for brain neurons development, synaptogenesis and gliogenesis. The decreased level of thyroxine regardless of cause may lead to delayed mental development. Congenital hypothyroidism (CH) is a disorder highly prevalent in premature neonates and it originates from maternal factors, perinatal and labor complications, genetic abnormalities, thyroid malformations as well as side effects of medications and therapeutic actions. Because of that, the prevention is not fully attainable. CH manifests clinically in a few distinctive forms: primary, permanent or transient, and secondary. Their etiologies and implications bear little resemblance. Therefore, the exact diagnosis and differentiation between the subtypes of CH are crucial in order to plan an effective treatment. Hypothyroxinemia of prematurity indicates dynamic changes in thyroid hormone levels dependent on neonatal postmenstrual age, which directly affects patient's maintenance and wellbeing. The basis of a successful treatment relies on an early and accurate diagnosis. Neonatal screening is a recommended method of detecting CH in preterm newborns. The preferred approach involves testing serum TSH and fT4 concentrations and assessing their levels according to the cut-off values. The possible benefits also include the evaluation of CH subtype. Nevertheless, the reference range of thyroid hormones varies all around the world and impedes the introduction of universal testing recommendations. Unification of the methodology in neonatal screening would be advantageous for prevention and management of CH. Current guidelines recommend levothyroxine treatment of CH in preterm infants only when the diagnose is confirmed. Moreover, they underline the importance of the re-evaluation among preterm born infants due to the frequency of transient forms of hypothyroidism. However, results from multiple clinical trials are mixed and depend on the newborn's gestational age at birth. Some benefits of treatment are seen especially in the preterm infants born <29 weeks' gestation. The discrepancies among trials and guidelines create an urgent need to conduct more large sample size studies that could provide further analyses and consensus. This review summarizes the current state of knowledge on congenital hypothyroidism in preterm infants. We discuss screening and treatment options and demonstrate present challenges and controversies.
Topics: Congenital Hypothyroidism; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Neonatal Screening; Pregnancy; Thyroid Dysgenesis; Thyroxine
PubMed: 35370986
DOI: 10.3389/fendo.2022.860862 -
Frontiers in Endocrinology 2020Thyroid dysgenesis (TD), which is caused by gland developmental abnormalities, is the most common cause of congenital hypothyroidism (CH). In addition, advances in...
Thyroid dysgenesis (TD), which is caused by gland developmental abnormalities, is the most common cause of congenital hypothyroidism (CH). In addition, advances in diagnostic techniques have facilitated the identification of mild CH patients with a gland- (GIS) with normal thyroid morphology. Therefore, TD and GIS account for the vast majority of CH cases. Sixteen known genes to be related to CH were sequenced and screened for variations by next-generation sequencing (NGS) in a cohort of 377 CH cases, including 288 TD cases and 89 GIS cases. In our CH cohort, we found that (21.22%) was the most commonly variant pathogenic gene, while was prominent in TD (18.75%) and was prominent in GIS (34.83%). Both biallelic and triple variants of were found to be most common in children with TD and children with GIS. The most frequent combination was with among the 61 patients who carried digenic variants. We also found for the first time that biallelic , and variants participate in the pathogenesis of TD. In addition, the variant p.Y246X in was the most common variant hotspot, with 58 novel variants identified in our study. We meticulously described the types and characteristics of variants from sixteen known gene in children with TD and GIS in the Chinese population, suggesting that and variants may confer susceptibility to TD and GIS via polygenic inheritance and multiple factors, which further expands the genotype-phenotype spectrum of CH in China.
Topics: Child; China; Cohort Studies; Congenital Hypothyroidism; Dual Oxidases; Genetic Predisposition to Disease; High-Throughput Nucleotide Sequencing; Humans; Membrane Proteins; Mutation; Phenotype; Prognosis; Thyroid Dysgenesis
PubMed: 32425884
DOI: 10.3389/fendo.2020.00237 -
Frontiers in Endocrinology 2023Published data on the relationship between polycystic ovary syndrome (PCOS) and thyroid dysfunction are sparse and confusing. (Review)
Review
BACKGROUND
Published data on the relationship between polycystic ovary syndrome (PCOS) and thyroid dysfunction are sparse and confusing.
OBJECTIVE
To comprehensively review data available in the literature regarding the relationship between PCOS and the thyroid function, and its abnormalities.
METHODS
Nine main areas of interest were identified and analyzed according to the available evidence: 1) Evaluation of thyroid function for PCOS diagnosis; 2) Epidemiology data on thyroid function/disorders in patients with PCOS, and vice versa; 3) Experimental data supporting the relationship between thyroid function/disorders and PCOS; 4) Effects of thyroid function/disorders on PCOS features, and vice versa; 5) Effect of thyroid alterations on the cardiometabolic risk in women with PCOS; 6) Effect of thyroid abnormalities on reproductive outcomes in women with PCOS; 7) Relationship between thyroid function/abnormalities in patients with PCOS who are undergoing fertility treatment; 8) Effect of treatments for thyroid diseases on PCOS; and 9) Effect of treatments for PCOS on thyroid function. An extensive literature search for specific keywords was performed for articles published from 1970 to March 2023 using PubMed and Web of Science. Data were reported in a narrative fashion.
RESULTS
PCOS is a diagnosis of exclusion for which diagnosis is possible only after excluding disorders that mimic the PCOS phenotype, including thyroid dysfunctions. However, the tests and the cutoff values used for this are not specified. Many experimental and clinical data suggest a relationship between perturbations of the thyroid function and PCOS. Direct and unequivocal evidence on the effects of thyroid function/disorders on PCOS features are lacking. High thyroid-stimulating hormone levels and subclinical hypothyroidism may be associated with significant worsening of several intermediate endpoints of cardiometabolic risk in women with PCOS. Thyroid abnormalities may worsen reproductive outcomes, especially in patients undergoing fertility treatment. To date, there are no data demonstrating the efficacy of thyroid medications on fertility and cardiometabolic risk in women with PCOS. Lifestyle modification changes, metformin, and vitamin D seem to improve thyroid function in the general population.
CONCLUSION
PCOS and thyroid disorders are closely related, and their coexistence may identify patients with a higher reproductive and metabolic risk. Regular screening for thyroid function and thyroid-specific autoantibodies in women with PCOS, particularly before and during pregnancy, is highly recommended.
Topics: Female; Humans; Pregnancy; Polycystic Ovary Syndrome; Thyroid Diseases; Hypothyroidism; Thyroid Dysgenesis; Antibodies; Cardiovascular Diseases
PubMed: 37635968
DOI: 10.3389/fendo.2023.1251866 -
Endocrine Journal Oct 2018To identify the spectrum and prevalence of thirteen causative genes mutations in congenital hypothyroidism (CH) patients, we collected blood samples and extracted...
To identify the spectrum and prevalence of thirteen causative genes mutations in congenital hypothyroidism (CH) patients, we collected blood samples and extracted genomic DNA of 106 CH patients, and designed a customized targeted next-generation sequencing panel containing 13 CH-causing genes to detect mutations. A total of 132 mutations were identified in 65.09% of patients (69/106) on the following nine genes: DUOX2, TG, TPO, TSHR, TTF1, TTF2, NKX2-5, PAX8 and GNAS. 69.70% (92/132) mutations related to thyroid dyshormonogenesis genes, including DUOX2 (n = 49), TG (n = 35), and TPO (n = 8). 21.21% (28/132) mutations related to thyroid dysgenesis genes, including TSHR (n = 19), TTF1 (n = 5), TTF2 (n = 1), PAX8 (n = 2), and NKX2-5 (n = 1). 9.09% (12/132) mutations related to GNAS, which was associated with thyrotropin resistance. No mutation of THRA, TSHB, IYD or SLC5A5 was detected. Among 69 mutations detected patients, 41 (59.42%) patients were two or more mutations detected, and mutations of 30 (43.48%) patients related to two or three genes. According to the pathomechanism of the mutant genes, 57.97% CH patients were classified as thyroid dyshormonogenesis. Overall, DUOX2, TG and TSHR mutations were the most common genetic defects in Chinese CH patients, and thyroid dyshormonogenesis could be the first genetic etiology of CH in Chinese. Besides, multiple mutations accounts for a part of genetic pathogenesis.
Topics: Adenosine Triphosphatases; Asian People; Autoantigens; China; Chromogranins; Congenital Hypothyroidism; DNA-Binding Proteins; Dual Oxidases; GTP-Binding Protein alpha Subunits, Gs; High-Throughput Nucleotide Sequencing; Homeobox Protein Nkx-2.5; Humans; Iodide Peroxidase; Iron-Binding Proteins; Microfilament Proteins; Muscle Proteins; Mutation; PAX8 Transcription Factor; Phenotype; Receptors, Thyrotropin; Transcription Factors
PubMed: 30022773
DOI: 10.1507/endocrj.EJ18-0156 -
European Journal of Endocrinology Jun 2018Congenital hypothyroidism (CH), the most common neonatal metabolic disorder, is characterized by impaired neurodevelopment. Although several candidate genes have been...
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 (, , , , and ) involved in thyroid hormone synthesis. Autosomal recessive inheritance of CH caused by mutations in , , and was confirmed by analysis of 22 family pedigrees. Notably, eight mutations in four genes (, , and ) 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 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.
Topics: Asian People; China; Congenital Hypothyroidism; Dual Oxidases; Female; Forkhead Transcription Factors; Genetic Association Studies; High-Throughput Nucleotide Sequencing; Homeodomain Proteins; Humans; Infant; Infant, Newborn; Iodide Peroxidase; Male; Membrane Proteins; Mutation; PAX8 Transcription Factor; Pedigree; Receptors, Thyrotropin; Sequence Analysis, DNA; Thyroglobulin; Thyroid Dysgenesis; Thyroid Nuclear Factor 1; Transcription Factors
PubMed: 29650690
DOI: 10.1530/EJE-17-1017 -
Indian Journal of Endocrinology and... 2015Congenital hypothyroidism (CH) is the one of the most common preventable cause of mental retardation. In the majority of patients, CH is caused by an abnormal... (Review)
Review
Congenital hypothyroidism (CH) is the one of the most common preventable cause of mental retardation. In the majority of patients, CH is caused by an abnormal development of the thyroid gland (thyroid dysgenesis) that is a sporadic disorder and accounts for 85% of cases and the remaining 15% of cases are caused by dyshormonogenesis. The clinical features of congenital hypothyroidism are so subtle that many newborn infants remain undiagnosed at birth and delayed diagnosis leads to the most severe outcome of CH, mental retardation, emphasizing the importance of neonatal screening. Dried capillary blood is used for screening and it is taken from heel prick optimally between 2 and 5 days of age. Blood spot TSH or thyroxine (T4) or both are being used for CH screening in different programs around the world. Neonates with abnormal thyroid screening tests should be recalled immediately for examination and a venipuncture blood sample should be drawn for confirmatory serum testing. Confirmatory serum should be tested for TSH and free T4, or total T4. Serum TSH and T4 undergo dynamic changes in the first weeks of life; it is important to compare serum results with age-normal reference ranges. Treatment should be started promptly and infant should be rendered euthyroid as early as possible, as there is an inverse relationship between intelligence quotient (IQ) and the age at diagnosis. Levothyroxine (l-thyroxine) is the treatment of choice and American academy of pediatrics and European society of pediatric endocrinology recommend 10-15μgm/kg/day as initial dose. The immediate goal of therapy is to normalize T4 within 2 weeks and TSH within one month. The overall goal of treatment is to ensure growth and neurodevelopmental outcomes as close as possible to their genetic potential.
PubMed: 25729683
DOI: 10.4103/2230-8210.131748