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Endocrine Journal 2015Genetic 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... (Review)
Review
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.
Topics: Alleles; Congenital Hypothyroidism; Genotype; Humans; Iodine; Mutation; Phenotype; Receptors, Thyrotropin; Thyroid Dysgenesis; Thyroid Gland; Thyroid Hormone Resistance Syndrome; Thyroid Hormones; Thyrotropin
PubMed: 25797365
DOI: 10.1507/endocrj.EJ15-0131 -
Ugeskrift For Laeger Apr 2023Lingual thyroid is a rare congenital disorder displaying ectopic thyroid tissue at the base of the tongue. This is the most common location for ectopic thyroid tissue...
Lingual thyroid is a rare congenital disorder displaying ectopic thyroid tissue at the base of the tongue. This is the most common location for ectopic thyroid tissue and is usually the only thyroid tissue present. This is a case report of a 16-year-old female who presented with nasal congestion. Fiberoptic laryngoscopy showed swelling at the base of the tongue and an ultrasound examination of the neck was without visible thyroid tissue. A 99mTc-pertechnetate scintigraphy confirmed the clinical diagnosis. As the patient was euthyroid and without symptoms active surveillance was planned.
Topics: Female; Humans; Adolescent; Lingual Thyroid; Neck; Tongue; Thyroid Dysgenesis
PubMed: 37114580
DOI: No ID Found -
Orphanet Journal of Rare Diseases Jun 2010Congenital hypothyroidism (CH) occurs in approximately 1:2,000 to 1:4,000 newborns. The clinical manifestations are often subtle or not present at birth. This likely is... (Review)
Review
Congenital hypothyroidism (CH) occurs in approximately 1:2,000 to 1:4,000 newborns. The clinical manifestations are often subtle or not present at birth. This likely is due to trans-placental passage of some maternal thyroid hormone, while many infants have some thyroid production of their own. Common symptoms include decreased activity and increased sleep, feeding difficulty, constipation, and prolonged jaundice. On examination, common signs include myxedematous facies, large fontanels, macroglossia, a distended abdomen with umbilical hernia, and hypotonia. CH is classified into permanent and transient forms, which in turn can be divided into primary, secondary, or peripheral etiologies. Thyroid dysgenesis accounts for 85% of permanent, primary CH, while inborn errors of thyroid hormone biosynthesis (dyshormonogeneses) account for 10-15% of cases. Secondary or central CH may occur with isolated TSH deficiency, but more commonly it is associated with congenital hypopitiutarism. Transient CH most commonly occurs in preterm infants born in areas of endemic iodine deficiency. In countries with newborn screening programs in place, infants with CH are diagnosed after detection by screening tests. The diagnosis should be confirmed by finding an elevated serum TSH and low T4 or free T4 level. Other diagnostic tests, such as thyroid radionuclide uptake and scan, thyroid sonography, or serum thyroglobulin determination may help pinpoint the underlying etiology, although treatment may be started without these tests. Levothyroxine is the treatment of choice; the recommended starting dose is 10 to 15 mcg/kg/day. The immediate goals of treatment are to rapidly raise the serum T4 above 130 nmol/L (10 ug/dL) and normalize serum TSH levels. Frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome. Serum TSH and free T4 should be measured every 1-2 months in the first 6 months of life and every 3-4 months thereafter. In general, the prognosis of infants detected by screening and started on treatment early is excellent, with IQs similar to sibling or classmate controls. Studies show that a lower neurocognitive outcome may occur in those infants started at a later age (> 30 days of age), on lower l-thyroxine doses than currently recommended, and in those infants with more severe hypothyroidism.
Topics: Congenital Hypothyroidism; Humans; Infant, Newborn; Neonatal Screening; Thyroid Dysgenesis; Thyroid Function Tests; Thyrotropin; Thyroxine
PubMed: 20537182
DOI: 10.1186/1750-1172-5-17 -
Best Practice & Research. Clinical... Mar 2017Resistance to thyrotropin (RTSH) is broadly defined as reduced sensitivity of thyroid follicle cells to stimulation by biologically active TSH due to genetic defects.... (Review)
Review
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.
Topics: Congenital Hypothyroidism; Drug Resistance; Humans; Mutation; Receptors, Thyrotropin; Syndrome; Thyroid Dysgenesis; Thyroid Hormones; Thyrotropin
PubMed: 28648507
DOI: 10.1016/j.beem.2017.03.004 -
Orphanet Journal of Rare Diseases Jul 2022Turner syndrome (TS; ORPHA 881) is a rare condition in which all or part of one X chromosome is absent from some or all cells. It affects approximately one in every...
Turner syndrome (TS; ORPHA 881) is a rare condition in which all or part of one X chromosome is absent from some or all cells. It affects approximately one in every 1/2500 liveborn girls. The most frequently observed karyotypes are 45,X (40-50%) and the 45,X/46,XX mosaic karyotype (15-25%). Karyotypes with an X isochromosome (45,X/46,isoXq or 45,X/46,isoXp), a Y chromosome, X ring chromosome or deletions of the X chromosome are less frequent. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins) is to provide health professionals with information about the optimal management and care for patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Growth and Developmental Endocrine disorders, is available from the French Health Authority website. Turner Syndrome is associated with several phenotypic conditions and a higher risk of comorbidity. The most frequently reported features are growth retardation with short adult stature and gonadal dysgenesis. TS may be associated with various congenital (heart and kidney) or acquired diseases (autoimmune thyroid disease, celiac disease, hearing loss, overweight/obesity, glucose intolerance/type 2 diabetes, dyslipidemia, cardiovascular complications and liver dysfunction). Most of the clinical traits of TS are due to the haploinsufficiency of various genes on the X chromosome, particularly those in the pseudoautosomal regions (PAR 1 and PAR 2), which normally escape the physiological process of X inactivation, although other regions may also be implicated. The management of patients with TS requires collaboration between several healthcare providers. The attending physician, in collaboration with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are designed to provide such support.
Topics: Adult; Chromosomes, Human, X; Diabetes Mellitus, Type 2; Female; Humans; Karyotype; Karyotyping; Turner Syndrome
PubMed: 35821070
DOI: 10.1186/s13023-022-02423-5 -
Clinical Endocrinology Oct 2022Development and differentiation of the thyroid gland is directed by expression of specific transcription factors in the thyroid follicular cell which mediates hormone... (Review)
Review
Development and differentiation of the thyroid gland is directed by expression of specific transcription factors in the thyroid follicular cell which mediates hormone biosynthesis. Membrane transporters are rate-limiting for cellular entry of thyroid hormones (TH) (T4 and T3) into some tissues, with selenocysteine-containing, deiodinase enzymes (DIO1 and DIO2) converting T4 to the biologically active hormone T3. TH regulate expression of target genes via hormone-inducible nuclear receptors (TRα and TRβ) to exert their physiological effects. Primary congenital hypothyroidism (CH) due to thyroid dysgenesis may be mediated by defects in thyroid transcription factors or impaired thyroid stimulating hormone receptor function. Dyshormonogenic CH is usually due to mutations in genes mediating thyroidal iodide transport, organification or iodotyrosine synthesis and recycling. Disorders of TH signalling encompass conditions due to defects in membrane TH transporters, impaired hormone metabolism due to deficiency of deiodinases and syndromes of Resistance to thyroid hormone due to pathogenic variants in either TRα or TRβ. Here, we review the genetic basis, pathogenesis and clinical features of congenital, dysgenetic or dyshormonogenic hypothyroidism and disorders of TH transport, metabolism and action.
Topics: Humans; Hypothyroidism; Iodide Peroxidase; Signal Transduction; Thyroid Hormones; Transcription Factors
PubMed: 35999191
DOI: 10.1111/cen.14817 -
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 -
Orphanet Journal of Rare Diseases Feb 2016Vici syndrome [OMIM242840] is a severe, recessively inherited congenital disorder characterized by the principal features of callosal agenesis, cataracts, oculocutaneous... (Review)
Review
Vici syndrome [OMIM242840] is a severe, recessively inherited congenital disorder characterized by the principal features of callosal agenesis, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and a combined immunodeficiency. Profound developmental delay, progressive failure to thrive and acquired microcephaly are almost universal, suggesting an evolving (neuro) degenerative component. In most patients there is additional variable multisystem involvement that may affect virtually any organ system, including lungs, thyroid, liver and kidneys. A skeletal myopathy is consistently associated, and characterized by marked fibre type disproportion, increase in internal nuclei, numerous vacuoles, abnormal mitochondria and glycogen storage. Life expectancy is markedly reduced.Vici syndrome is due to recessive mutations in EPG5 on chromosome 18q12.3, encoding ectopic P granules protein 5 (EPG5), a key autophagy regulator in higher organisms. Autophagy is a fundamental cellular degradative pathway conserved throughout evolution with important roles in the removal of defective proteins and organelles, defence against infections and adaptation to changing metabolic demands. Almost 40 EPG mutations have been identified to date, most of them truncating and private to individual families.The differential diagnosis of Vici syndrome includes a number of syndromes with overlapping clinical features, neurological and metabolic disorders with shared CNS abnormalities (in particular callosal agenesis), and primary neuromuscular disorders with a similar muscle biopsy appearance. Vici syndrome is also the most typical example of a novel group of inherited neurometabolic conditions, congenital disorders of autophagy.Management is currently largely supportive and symptomatic but better understanding of the underlying autophagy defect will hopefully inform the development of targeted therapies in future.
Topics: Agenesis of Corpus Callosum; Autophagy-Related Proteins; Cataract; Chromosomes, Human, Pair 18; Humans; Lysosomal Membrane Proteins; Mutation; Proteins; Vesicular Transport Proteins
PubMed: 26927810
DOI: 10.1186/s13023-016-0399-x -
Journal of Endocrinological... Jan 2018Thyroid hormones are essential for skeletal development and are important regulators of bone maintenance in adults. Childhood hypothyroidism causes delayed skeletal... (Review)
Review
Thyroid hormones are essential for skeletal development and are important regulators of bone maintenance in adults. Childhood hypothyroidism causes delayed skeletal development, retarded linear growth and impaired bone mineral accrual. Epiphyseal dysgenesis is evidenced by classic features of stippled epiphyses on X-ray. In severe cases, post-natal growth arrest results in a complex skeletal dysplasia. Thyroid hormone replacement stimulates catch-up growth and bone maturation, but recovery may be incomplete dependent on the duration and severity of hypothyroidism prior to treatment. A severe phenotype characteristic of hypothyroidism occurs in children with resistance to thyroid hormone due to mutations affecting THRA encoding thyroid hormone receptor α (TRα). Discovery of this rare condition recapitulated animal studies demonstrating that TRα mediates thyroid hormone action in the skeleton. In adults, thyrotoxicosis is well known to cause severe osteoporosis and fracture, but cases are rare because of prompt diagnosis and treatment. Recent data, however, indicate that subclinical hyperthyroidism is associated with low bone mineral density (BMD) and an increased risk of fracture. Population studies have also shown that variation in thyroid status within the reference range in post-menopausal women is associated with altered BMD and fracture risk. Thus, thyroid status at the upper end of the euthyroid reference range is associated with low BMD and increased risk of osteoporotic fragility fracture. Overall, extensive data demonstrate that euthyroid status is required for normal post-natal growth and bone mineral accrual, and is fundamental for maintenance of adult bone structure and strength.
Topics: Bone and Bones; Fractures, Bone; Humans; Hypothyroidism; Mutation; Osteoporosis; Receptors, Thyroid Hormone; Thyroid Hormones; Thyrotoxicosis
PubMed: 28853052
DOI: 10.1007/s40618-017-0753-4