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Thyroid dyshormonogenesis 1(TDH1)

MedGen UID:
336422
Concept ID:
C1848805
Disease or Syndrome
Synonyms: HYPOTHYROIDISM, CONGENITAL, DUE TO DYSHORMONOGENESIS, 1; IODINE ACCUMULATION, TRANSPORT, OR TRAPPING DEFECT; TDH1; Thyroid Hormonogenesis Defect I; THYROID HORMONOGENESIS, GENETIC DEFECT IN, 1
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): SLC5A5 (19p13.11)
OMIM®: 274400

Definition

Approximately 10% of patients with congenital hypothyroidism harbor inborn errors of metabolism in one of the steps for thyroid hormone synthesis in thyrocytes (Vono-Toniolo et al., 2005). Dyshormonogenesis can be caused by recessive defects at any of the steps required for normal thyroid hormone synthesis. In untreated patients thyroid dyshormonogenesis is typically associated with goitrous enlargement of the thyroid secondary to long-term thyrotropin (TSH; see 188540) stimulation. Park and Chatterjee (2005) reviewed the genetics of primary congenital hypothyroidism, summarizing the different phenotypes associated with known genetic defects and proposing an algorithm for investigating the genetic basis of the disorder. Genetic Heterogeneity of Thyroid Dyshormonogenesis Other forms of thyroid hormone dysgenesis include TDH2A (274500), caused by mutation in the thyroid peroxidase gene (TPO; 606765) on 2p25; Pendred syndrome, a form of thyroid hormone dysgenesis associated with deafness (TDH2B; 274600) and caused by mutation in the SLC26A4 gene (605646) on 7q31; TDH3 (274700), caused by mutation in the thyroglobulin gene (TG; 188450) on 8q24; TDH4 (274800), caused by mutation in the iodotyrosine deiodinase gene (IYD; 612025) on 6q25; TDH5 (274900), caused by mutation in the DUOXA2 gene (612772) on 15q21; and TDH6 (607200), caused by mutation in the DUOX2 gene (606759) on 15q21. [from OMIM]

Additional description

From GHR
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.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.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.  https://ghr.nlm.nih.gov/condition/congenital-hypothyroidism

Clinical features

Goiter
MedGen UID:
42270
Concept ID:
C0018021
Finding
An enlargement of the thyroid gland.
Hypothyroidism
MedGen UID:
6991
Concept ID:
C0020676
Disease or Syndrome
Your thyroid is a butterfly-shaped gland in your neck, just above your collarbone. It is one of your endocrine glands, which make hormones. Thyroid hormones control the rate of many activities in your body. These include how fast you burn calories and how fast your heart beats. All of these activities are your body's metabolism. If your thyroid gland is not active enough, it does not make enough thyroid hormone to meet your body's needs. This condition is hypothyroidism. Hypothyroidism is more common in women, people with other thyroid problems, and those over 60 years old. Hashimoto's disease, an autoimmune disorder, is the most common cause. Other causes include thyroid nodules, thyroiditis, congenital hypothyroidism, surgical removal of part or all of the thyroid, radiation treatment of the thyroid, and some medicines. The symptoms can vary from person to person. They may include. -Fatigue. -Weight gain. -A puffy face. -Cold intolerance. -Joint and muscle pain. -Constipation. -Dry skin. -Dry, thinning hair. -Decreased sweating. -Heavy or irregular menstrual periods and fertility problems. -Depression. -Slowed heart rate. To diagnose hypothyroidism, your doctor will look at your symptoms and blood tests. Treatment is with synthetic thyroid hormone, taken every day. NIH: National Institute of Diabetes and Digestive and Kidney Diseases.
Growth delay
MedGen UID:
765377
Concept ID:
C3552463
Finding
A deficiency or slowing down of growth pre- and postnatally.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Constipation means that a person has three or fewer bowel movements in a week. The stool can be hard and dry. Sometimes it is painful to pass. At one time or another, almost everyone gets constipated. In most cases, it lasts a short time and is not serious. . There are many things you can do to prevent constipation. They include - Eating more fruits, vegetables and grains, which are high in fiber. - Drinking plenty of water and other liquids. - Getting enough exercise. - Taking time to have a bowel movement when you need to. - Using laxatives only if your doctor says you should. - Asking your doctor if medicines you take may cause constipation. . It's not important that you have a bowel movement every day. If your bowel habits change, however, check with your doctor. . NIH: National Institute of Diabetes and Digestive and Kidney Diseases.
Umbilical hernia
MedGen UID:
9232
Concept ID:
C0019322
Anatomical Abnormality
Protrusion of abdominal contents through a defect in the abdominal wall musculature around the umbilicus. Skin and subcutaneous tissue overlie the defect.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterestedness, listlessness, and indifference, resulting in difficulty performing simple tasks or concentrating.
Intellectual functioning disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. This has multiple potential etiologies, including genetic defects and perinatal insults. Intelligence quotient (IQ) scores are commonly used to determine whether an individual has an intellectual disability. IQ scores between 70 and 79 are in the borderline range. Scores below 67 are in the disabiled range. (from Joynt, Clinical Neurology, 1992, Ch55, p28)
Macroglossia
MedGen UID:
44236
Concept ID:
C0024421
Disease or Syndrome
Increased length and width of the tongue.
Macroglossia
MedGen UID:
44236
Concept ID:
C0024421
Disease or Syndrome
Increased length and width of the tongue.
Umbilical hernia
MedGen UID:
9232
Concept ID:
C0019322
Anatomical Abnormality
Protrusion of abdominal contents through a defect in the abdominal wall musculature around the umbilicus. Skin and subcutaneous tissue overlie the defect.
Xerosis
MedGen UID:
75479
Concept ID:
C0259817
Disease or Syndrome
Skin characterized by the lack of natural or normal moisture.

Recent clinical studies

Etiology

Um Sap SN, Koki P, Dongmo FN, De Djob L, Tedga A, Awa HM, Chelo D, Boula A
J Pediatr Endocrinol Metab 2015 Sep;28(9-10):1173-7. doi: 10.1515/jpem-2014-0497. PMID: 26030782
Lee CC, Harun F, Jalaludin MY, Heh CH, Othman R, Junit SM
BMJ Open 2015 Jan 5;5(1):e006121. doi: 10.1136/bmjopen-2014-006121. PMID: 25564141Free PMC Article
Stoppa-Vaucher S, Van Vliet G, Deladoëy J
Thyroid 2011 Jan;21(1):13-8. Epub 2010 Nov 8 doi: 10.1089/thy.2010.0205. PMID: 21054242Free PMC Article
Ramos HE, Nesi-França S, Boldarine VT, Pereira RM, Chiamolera MI, Camacho CP, Graf H, de Lacerda L, Carvalho GA, Maciel RM
Thyroid 2009 Jan;19(1):61-8. doi: 10.1089/thy.2008.0116. PMID: 18976153
Moreno JC, Visser TJ
Endocr Dev 2007;10:99-117. doi: 10.1159/0000106822. PMID: 17684392

Diagnosis

Um Sap SN, Koki P, Dongmo FN, De Djob L, Tedga A, Awa HM, Chelo D, Boula A
J Pediatr Endocrinol Metab 2015 Sep;28(9-10):1173-7. doi: 10.1515/jpem-2014-0497. PMID: 26030782
Lee CC, Harun F, Jalaludin MY, Heh CH, Othman R, Junit SM
BMJ Open 2015 Jan 5;5(1):e006121. doi: 10.1136/bmjopen-2014-006121. PMID: 25564141Free PMC Article
Kumorowicz-Czoch M, Tylek-Lemanska D, Starzyk J
J Pediatr Endocrinol Metab 2011;24(3-4):141-5. PMID: 21648281
Raymond J, LaFranchi SH
Curr Opin Endocrinol Diabetes Obes 2010 Feb;17(1):1-7. doi: 10.1097/MED.0b013e328333b0b2. PMID: 19901830
Ramos HE, Nesi-França S, Boldarine VT, Pereira RM, Chiamolera MI, Camacho CP, Graf H, de Lacerda L, Carvalho GA, Maciel RM
Thyroid 2009 Jan;19(1):61-8. doi: 10.1089/thy.2008.0116. PMID: 18976153

Therapy

Krude H, Kühnen P, Biebermann H
Best Pract Res Clin Endocrinol Metab 2015 Jun;29(3):399-413. Epub 2015 Apr 26 doi: 10.1016/j.beem.2015.04.004. PMID: 26051299
Nair PS, Sobhakumar S, Kailas L
Indian Pediatr 2010 Sep;47(9):757-60. Epub 2010 Jan 15 PMID: 20308767
Raymond J, LaFranchi SH
Curr Opin Endocrinol Diabetes Obes 2010 Feb;17(1):1-7. doi: 10.1097/MED.0b013e328333b0b2. PMID: 19901830
Turkkahraman D, Alper OM, Aydin F, Yildiz A, Pehlivanoglu S, Luleci G, Akcurin S, Bircan I
J Pediatr Endocrinol Metab 2009 Sep;22(9):845-51. PMID: 19960894
Pfarr N, Musholt TJ, Musholt PB, Brzezinska R, Pohlenz J
Clin Endocrinol (Oxf) 2006 May;64(5):514-8. doi: 10.1111/j.1365-2265.2006.02500.x. PMID: 16649969

Prognosis

Lee CC, Harun F, Jalaludin MY, Heh CH, Othman R, Junit SM
BMJ Open 2015 Jan 5;5(1):e006121. doi: 10.1136/bmjopen-2014-006121. PMID: 25564141Free PMC Article
Bekhit OE, Yousef RM
PLoS One 2013;8(6):e68048. Epub 2013 Jun 28 doi: 10.1371/journal.pone.0068048. PMID: 23840807Free PMC Article
Grasberger H, Refetoff S
Curr Opin Pediatr 2011 Aug;23(4):421-8. doi: 10.1097/MOP.0b013e32834726a4. PMID: 21543982Free PMC Article
Raymond J, LaFranchi SH
Curr Opin Endocrinol Diabetes Obes 2010 Feb;17(1):1-7. doi: 10.1097/MED.0b013e328333b0b2. PMID: 19901830
Moreno JC, Visser TJ
Endocr Dev 2007;10:99-117. doi: 10.1159/0000106822. PMID: 17684392

Clinical prediction guides

Lee CC, Harun F, Jalaludin MY, Heh CH, Othman R, Junit SM
BMJ Open 2015 Jan 5;5(1):e006121. doi: 10.1136/bmjopen-2014-006121. PMID: 25564141Free PMC Article
Ramos HE, Carré A, Chevrier L, Szinnai G, Tron E, Cerqueira TL, Léger J, Cabrol S, Puel O, Queinnec C, De Roux N, Guillot L, Castanet M, Polak M
Eur J Endocrinol 2014 Oct;171(4):499-507. doi: 10.1530/EJE-13-1006. PMID: 25214233
Grasberger H, Refetoff S
Curr Opin Pediatr 2011 Aug;23(4):421-8. doi: 10.1097/MOP.0b013e32834726a4. PMID: 21543982Free PMC Article
Stoppa-Vaucher S, Van Vliet G, Deladoëy J
Thyroid 2011 Jan;21(1):13-8. Epub 2010 Nov 8 doi: 10.1089/thy.2010.0205. PMID: 21054242Free PMC Article
Moreno JC, Visser TJ
Endocr Dev 2007;10:99-117. doi: 10.1159/0000106822. PMID: 17684392

Recent systematic reviews

Perry R, Heinrichs C, Bourdoux P, Khoury K, Szöts F, Dussault JH, Vassart G, Van Vliet G
J Clin Endocrinol Metab 2002 Sep;87(9):4072-7. doi: 10.1210/jc.2001-011995. PMID: 12213848

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