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Hypothyroidism due to TSH receptor mutations(CHNG1; RTSH)

MedGen UID:
487729
Concept ID:
C3493776
Disease or Syndrome
Synonyms: HYPOTHYROIDISM DUE TO UNRESPONSIVENESS TO THYROTROPIN; HYPOTHYROIDISM, CONGENITAL, DUE TO TSH RESISTANCE; Hypothyroidism, congenital, nongoitrous, 1; HYPOTHYROIDISM, NONAUTOIMMUNE; THYROID-STIMULATING HORMONE, RESISTANCE TO; TSH RESISTANCE
SNOMED CT: Hypothyroidism due to TSH receptor mutation (1230272009); Congenital hypothyroidism due to thyroid stimulating hormone receptor mutation (1230272009); Hypothyroidism due to TSHR (thyroid stimulating hormone receptor) mutation (1230272009)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): TSHR (14q31.1)
 
Monarch Initiative: MONDO:0010142
OMIM®: 275200
Orphanet: ORPHA90673

Definition

Resistance to thyroid-stimulating hormone (TSH; see 188540), a hallmark of congenital nongoitrous hypothyroidism, causes increased levels of plasma TSH and low levels of thyroid hormone. Only a subset of patients develop frank hypothyroidism; the remainder are euthyroid and asymptomatic (so-called compensated hypothyroidism) and are usually detected by neonatal screening programs (Paschke and Ludgate, 1997). Genetic Heterogeneity of Congenital Nongoitrous Hypothyroidism Also see CHNG2 (218700), caused by mutation in the PAX8 gene (167415) on chromosome 2q14; CHNG3 (609893), mapped to chromosome 15q25.3; CHNG4 (275100), caused by mutation in the TSHB gene (188540) on chromosome 1p13; CHNG5 (225250), caused by mutation in the NKX2-5 gene (600584) on chromosome 5q35; CHNG6 (614450), caused by mutation in the THRA gene (190120) on chromosome 17q21; CHNG7 (618573), caused by mutation in the TRHR gene (188545) on chromosome 8q24; CHNG8 (301033), caused by mutation in the TBL1X gene (300196) on chromosome Xp22; and CHNG9 (301035), caused by mutation in the IRS4 gene (300904) on chromosome Xq22. [from OMIM]

Additional description

From MedlinePlus Genetics
Congenital hypothyroidism is a partial or complete loss of function of the thyroid gland (hypothyroidism) that affects infants from birth (congenital). The thyroid gland is a butterfly-shaped tissue in the lower neck. It makes iodine-containing hormones that play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). People with congenital hypothyroidism have lower-than-normal levels of these important hormones.

Congenital hypothyroidism occurs when the thyroid gland fails to develop or function properly. In 80 to 85 percent of cases, the thyroid gland is absent, severely reduced in size (hypoplastic), or abnormally located. These cases are classified as thyroid dysgenesis. In the remainder of cases, a normal-sized or enlarged thyroid gland (goiter) is present, but production of thyroid hormones is decreased or absent. Most of these cases occur when one of several steps in the hormone synthesis process is impaired; these cases are classified as thyroid dyshormonogenesis. Less commonly, reduction or absence of thyroid hormone production is caused by impaired stimulation of the production process (which is normally done by a structure at the base of the brain called the pituitary gland), even though the process itself is unimpaired. These cases are classified as central (or pituitary) hypothyroidism.

Congenital hypothyroidism can also occur as part of syndromes that affect other organs and tissues in the body. These forms of the condition are described as syndromic. Some common forms of syndromic hypothyroidism include Pendred syndrome, Bamforth-Lazarus syndrome, and brain-lung-thyroid syndrome.

Signs and symptoms of congenital hypothyroidism result from the shortage of thyroid hormones. Affected babies may show no features of the condition, although some babies with congenital hypothyroidism are less active and sleep more than normal. They may have difficulty feeding and experience constipation. If untreated, congenital hypothyroidism can lead to intellectual disability and slow growth. In the United States and many other countries, all hospitals test newborns for congenital hypothyroidism. If treatment begins in the first two weeks after birth, infants usually develop normally.  https://medlineplus.gov/genetics/condition/congenital-hypothyroidism

Clinical features

From HPO
Goiter
MedGen UID:
42270
Concept ID:
C0018021
Disease or Syndrome
An enlargement of the thyroid gland.
Hypothyroidism
MedGen UID:
6991
Concept ID:
C0020676
Disease or Syndrome
Deficiency of thyroid hormone.
Thyroid hypoplasia
MedGen UID:
57720
Concept ID:
C0151516
Disease or Syndrome
Developmental hypoplasia of the thyroid gland.
Elevated circulating thyroid-stimulating hormone concentration
MedGen UID:
108325
Concept ID:
C0586553
Finding
Increased concentration of thyroid-stimulating hormone (TSH) in the blood circulation.

Term Hierarchy

Professional guidelines

PubMed

Mariani G, Tonacchera M, Grosso M, Orsolini F, Vitti P, Strauss HW
J Nucl Med 2021 Mar;62(3):304-312. Epub 2020 Oct 2 doi: 10.2967/jnumed.120.243170. PMID: 33008929
Sun F, Zhang JX, Yang CY, Gao GQ, Zhu WB, Han B, Zhang LL, Wan YY, Ye XP, Ma YR, Zhang MM, Yang L, Zhang QY, Liu W, Guo CC, Chen G, Zhao SX, Song KY, Song HD
Eur J Endocrinol 2018 Jun;178(6):623-633. Epub 2018 Apr 12 doi: 10.1530/EJE-17-1017. PMID: 29650690Free PMC Article
LaFranchi S
Thyroid 1999 Jul;9(7):735-40. doi: 10.1089/thy.1999.9.735. PMID: 10447022

Recent clinical studies

Etiology

Da DZ, Wang Y, Wang M, Long Z, Wang Q, Liu J
Inquiry 2021 Jan-Dec;58:469580211067943. doi: 10.1177/00469580211067943. PMID: 34919466Free PMC Article
Mariani G, Tonacchera M, Grosso M, Orsolini F, Vitti P, Strauss HW
J Nucl Med 2021 Mar;62(3):304-312. Epub 2020 Oct 2 doi: 10.2967/jnumed.120.243170. PMID: 33008929
Hernandez BY, Rahman M, Loo LWM, Chan OTM, Horio D, Morita S, Bryant-Greenwood G
J Cancer Res Clin Oncol 2021 Jan;147(1):183-194. Epub 2020 Sep 29 doi: 10.1007/s00432-020-03401-9. PMID: 32995956Free PMC Article
Vigone MC, Di Frenna M, Guizzardi F, Gelmini G, de Filippis T, Mora S, Caiulo S, Sonnino M, Bonomi M, Persani L, Weber G
Clin Endocrinol (Oxf) 2017 Nov;87(5):587-596. Epub 2017 Jul 6 doi: 10.1111/cen.13387. PMID: 28561265
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Handb Clin Neurol 2021;180:161-169. doi: 10.1016/B978-0-12-820107-7.00010-0. PMID: 34225927
Mariani G, Tonacchera M, Grosso M, Orsolini F, Vitti P, Strauss HW
J Nucl Med 2021 Mar;62(3):304-312. Epub 2020 Oct 2 doi: 10.2967/jnumed.120.243170. PMID: 33008929
Sun H, Cao L, Zheng R, Xie S, Liu C
Ital J Pediatr 2020 Nov 11;46(1):168. doi: 10.1186/s13052-020-00929-x. PMID: 33176840Free PMC Article
Grasberger H, Refetoff S
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Therapy

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Prognosis

Giannone M, Dalla Costa M, Sabbadin C, Garelli S, Salvà M, Masiero S, Plebani M, Faggian D, Gallo N, Presotto F, Bertazza L, Nacamulli D, Censi S, Mian C, Betterle C
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Hernandez BY, Rahman M, Loo LWM, Chan OTM, Horio D, Morita S, Bryant-Greenwood G
J Cancer Res Clin Oncol 2021 Jan;147(1):183-194. Epub 2020 Sep 29 doi: 10.1007/s00432-020-03401-9. PMID: 32995956Free PMC Article
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Clinical prediction guides

Hernandez BY, Rahman M, Loo LWM, Chan OTM, Horio D, Morita S, Bryant-Greenwood G
J Cancer Res Clin Oncol 2021 Jan;147(1):183-194. Epub 2020 Sep 29 doi: 10.1007/s00432-020-03401-9. PMID: 32995956Free PMC Article
Sun F, Zhang JX, Yang CY, Gao GQ, Zhu WB, Han B, Zhang LL, Wan YY, Ye XP, Ma YR, Zhang MM, Yang L, Zhang QY, Liu W, Guo CC, Chen G, Zhao SX, Song KY, Song HD
Eur J Endocrinol 2018 Jun;178(6):623-633. Epub 2018 Apr 12 doi: 10.1530/EJE-17-1017. PMID: 29650690Free PMC Article
Vigone MC, Di Frenna M, Guizzardi F, Gelmini G, de Filippis T, Mora S, Caiulo S, Sonnino M, Bonomi M, Persani L, Weber G
Clin Endocrinol (Oxf) 2017 Nov;87(5):587-596. Epub 2017 Jul 6 doi: 10.1111/cen.13387. PMID: 28561265
van Gucht ALM, Moran C, Meima ME, Visser WE, Chatterjee K, Visser TJ, Peeters RP
Curr Top Dev Biol 2017;125:337-355. Epub 2017 Mar 21 doi: 10.1016/bs.ctdb.2017.02.001. PMID: 28527577
García M, González de Buitrago J, Jiménez-Rosés M, Pardo L, Hinkle PM, Moreno JC
J Clin Endocrinol Metab 2017 Jul 1;102(7):2433-2442. doi: 10.1210/jc.2016-3977. PMID: 28419241Free PMC Article

Recent systematic reviews

Da DZ, Wang Y, Wang M, Long Z, Wang Q, Liu J
Inquiry 2021 Jan-Dec;58:469580211067943. doi: 10.1177/00469580211067943. PMID: 34919466Free PMC Article
Chiesa AE, Tellechea ML
Front Endocrinol (Lausanne) 2021;12:643307. Epub 2021 Aug 18 doi: 10.3389/fendo.2021.643307. PMID: 34484109Free PMC Article
Huang CJ, Jap TS
J Chin Med Assoc 2015 Mar;78(3):145-53. Epub 2014 Nov 11 doi: 10.1016/j.jcma.2014.09.010. PMID: 25455162
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J Endocrinol Invest 2013 Sep;36(8):654-64. Epub 2013 May 22 doi: 10.3275/8973. PMID: 23698639

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