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Clinical Genetics Jan 2020Congenital hypothyroidism (CH) is a neonatal endocrine disorder that might occur as itself or be associated to congenital extra-thyroidal defects. About 85% of affected... (Review)
Review
Congenital hypothyroidism (CH) is a neonatal endocrine disorder that might occur as itself or be associated to congenital extra-thyroidal defects. About 85% of affected subjects experience thyroid dysgenesis (TD), characterized by defect in thyroid gland development. In vivo experiments on null mice paved the way for the identification of genes involved thyroid morphogenesis and development, whose mutation has been strongly associated to TD. Most of them are thyroid-specific transcription factors expressed during early thyroid development. Despite the arduous effort in unraveling the genetics of TD in animal models, up to now these data have been discontinuously confirmed in humans and only 5% of TD have associated with known null mice-related mutations (mainly PAX8 and TSHR). Notwithstanding, the advance in genetic testing represented by the next-generation sequencing (NGS) approach is steadily increasing the list of genes whose highly penetrant mutation predisposes to TD. In this review we intend to outline the molecular bases of TD, summarizing the current knowledge on thyroid development in both mice and humans and delineating the genetic features of its monogenetic forms. We will also highlight current strategies to enhance the insight into the non-Mendelian mechanisms of abnormal thyroid development.
Topics: Animals; Congenital Hypothyroidism; Genotype; High-Throughput Nucleotide Sequencing; Humans; Mice; Mutation; Thyroid Dysgenesis; Thyroid Gland
PubMed: 31432505
DOI: 10.1111/cge.13627 -
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 -
Hormones (Athens, Greece) Jun 2021Congenital primary hypothyroidism (CH) is a state of inadequate thyroid hormone production detected at birth, caused either by absent, underdeveloped or ectopic thyroid... (Review)
Review
PURPOSE
Congenital primary hypothyroidism (CH) is a state of inadequate thyroid hormone production detected at birth, caused either by absent, underdeveloped or ectopic thyroid gland (dysgenesis), or by defected thyroid hormone biosynthesis (dyshormonogenesis). A genetic component has been identified in many cases of CH. This review summarizes the clinical and biochemical features of the genetic causes of primary CH.
METHODS
A literature review was conducted of gene defects causing congenital hypothyroidism.
RESULTS
Mutations in five genes have predominantly been implicated in thyroid dysgenesis (TSHR, FOXE1, NKX2-1, PAX8, and NKX2-5), the primary cause of CH (85%), and mutations in seven genes in thyroid dyshormonogenesis (SLC5A5, TPO, DUOX2, DUOXA2, SLC6A4, Tg, and DEHAL1). These genes encode for proteins that regulate genes expressed during the differentiation of the thyroid, such as TPO and Tg genes, or genes that regulate iodide organification, thyroglobulin synthesis, iodide transport, and iodotyrosine deiodination. Besides thyroid dysgenesis and dyshormonogenesis, additional causes of congenital hypothyroidism, such as iodothyronine transporter defects and resistance to thyroid hormones, have also been associated with genetic mutations.
CONCLUSION
The identification of the underlying genetic defects of CH is important for genetic counseling of families with an affected member, for identifying additional clinical characteristics or the risk for thyroid neoplasia and for diagnostic and management purposes.
Topics: Congenital Hypothyroidism; Dual Oxidases; Forkhead Transcription Factors; Humans; Infant, Newborn; Iodides; Mutation; Serotonin Plasma Membrane Transport Proteins; Thyroid Dysgenesis; Thyroid Hormones
PubMed: 33400193
DOI: 10.1007/s42000-020-00267-x -
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 -
Best Practice & Research. Clinical... Mar 2017Developmental anomalies of the thyroid gland, defined as thyroid dysgenesis, underlie the majority of cases of congenital hypothyroidism. Thyroid dysgenesis is... (Review)
Review
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.
Topics: Animals; Congenital Hypothyroidism; Female; Genetic Association Studies; Humans; Hypothyroidism; Incidence; Male; Morphogenesis; Thyroid Diseases; Thyroid Dysgenesis; Thyroid Gland
PubMed: 28648504
DOI: 10.1016/j.beem.2017.04.008 -
Nihon Rinsho. Japanese Journal of... May 2006
Review
Topics: Animals; Congenital Hypothyroidism; Diagnosis, Differential; Humans; Infant, Newborn; Neonatal Screening; Thyroid Dysgenesis; Thyroid Gland; Thyroid Hormone Resistance Syndrome; Thyroid Hormones; Thyrotropin
PubMed: 16776209
DOI: No ID Found -
Endocrinology Dec 2005
Review
Topics: Animals; Genes, Developmental; Humans; Thyroid Dysgenesis
PubMed: 16291637
DOI: 10.1210/en.2005-1238 -
Clinics in Perinatology Mar 2018Congenital hypothyroidism is common and can cause severe neurodevelopmental morbidity. Prompt diagnosis and treatment are critical to optimizing long-term outcomes.... (Review)
Review
Congenital hypothyroidism is common and can cause severe neurodevelopmental morbidity. Prompt diagnosis and treatment are critical to optimizing long-term outcomes. Universal newborn screening is an important tool for detecting congenital hypothyroidism, but awareness of its limitations, repeated screening in high-risk infants, and a high index of clinical suspicion are needed to ensure that all affected infants are appropriately identified and treated. Careful evaluation will usually reveal the etiology of congenital hypothyroidism, which may inform treatment and prognosis. Early and adequate treatment with levothyroxine results in excellent neurodevelopmental outcomes for most patients with congenital hypothyroidism.
Topics: Congenital Hypothyroidism; Deficiency Diseases; Disease; Early Diagnosis; Early Medical Intervention; Hormone Replacement Therapy; Humans; Infant, Newborn; Iodine; Neonatal Screening; Prognosis; Thyroid Dysgenesis; Thyroid Gland; Thyroxine
PubMed: 29405999
DOI: 10.1016/j.clp.2017.10.004 -
Current Topics in Developmental Biology 2013Thyroid dysgenesis is the most common cause of congenital hypothyroidism that affects 1 in 3000 newborns. Although a number of pathogenetic mutations in thyroid... (Review)
Review
Thyroid dysgenesis is the most common cause of congenital hypothyroidism that affects 1 in 3000 newborns. Although a number of pathogenetic mutations in thyroid developmental genes have been identified, the molecular mechanism of disease is unknown in most cases. This chapter summarizes the current knowledge of normal thyroid development and puts the different developmental stages in perspective, from the time of foregut endoderm patterning to the final shaping of pharyngeal anatomy, for understanding how specific malformations may arise. At the cellular level, we will also discuss fate determination of follicular and C-cell progenitors and their subsequent embryonic growth, migration, and differentiation as the different thyroid primordia evolve and merge to establish the final size and shape of the gland.
Topics: Animals; Body Patterning; Cell Movement; Endoderm; Gene Expression Regulation, Developmental; Humans; Models, Anatomic; Mutation; Thyroid Dysgenesis; Thyroid Gland
PubMed: 24290349
DOI: 10.1016/B978-0-12-416021-7.00004-3 -
QJM : Monthly Journal of the... Jul 2023
Topics: Humans; Thyroid Dysgenesis; Ultrasonography
PubMed: 37021964
DOI: 10.1093/qjmed/hcad054