Congenital hypothyroidism and genetics
Congenital hypothyroidism is a condition present at birth where the thyroid gland fails to produce adequate hormones necessary for growth, brain development, and metabolism. If untreated, it can lead to severe complications, including intellectual disabilities and abnormal growth patterns. The condition can be sporadic, occurring in families without prior history, but about 15-20% of cases are inherited due to mutations in specific genes. Key genes associated with inherited congenital hypothyroidism include PAX8 and TSHR, which affect thyroid gland development, as well as TG, TPO, TSHB, DUOX2, and SLC5A5, which impact hormone production. Symptoms often emerge gradually and may include a puffy face, poor feeding, and short stature. Early diagnosis through newborn screening and prompt treatment with hormone replacement therapy, typically with levothyroxine, is essential for preventing long-term damage. Although prevention is limited, certain maternal health precautions during pregnancy can reduce risk factors associated with the condition.
Congenital hypothyroidism and genetics
ALSO KNOWN AS: Cretinism
DEFINITION The thyroid is a gland in the lower neck. It makes hormones that regulate growth, brain development, and metabolism. Hypothyroidism is a low or absent production of these hormones. Congenital means the condition is present since birth. If this condition is not treated it can cause damage to the brain; this can lead to intellectual disability and abnormal growth.
Risk Factors
Risk factors for congenital hypothyroidism may include medication during pregnancy, such as radioactive iodine therapy; having maternal autoimmune disease; having too much iodine during pregnancy; and an inborn error of metabolism. Some babies are born early (before forty weeks). This may cause a temporary shortage in the thyroid hormones.
Etiology and Genetics
Most cases of congenital hypothyroidism are sporadic, meaning that they occur in families with no history of the disorder and there is no identifiable genetic basis for the condition. About 15–20 percent of cases, however, are inherited, and at least seven different genes have been identified in which mutations can occur that will lead to expression of the disease. These genes can cause loss of thyroid function either by adversely affecting the growth and development of the thyroid gland itself or by disrupting the production of thyroid hormones in an otherwise normal appearing gland.
The PAX8 gene, found on the long arm of chromosome 2 at position 2q12–q14, encodes a that is essential for the proper formation of thyroxine-producing follicular cells. The TSHR gene (at position 14q31) specifies the thyroid-stimulating hormone receptor protein. Mutations in either of these genes affect thyroid gland development, and they are inherited in an autosomal dominant fashion, meaning that a single copy of the mutation is sufficient to cause full expression of the condition. An affected individual has a 50 percent chance of transmitting the mutation to each of his or her children.
Most cases of inherited congenital hypothyroidism, however, result from mutations in any one of five genes that reduce or eliminate the production of specific thyroid hormones. These genes are TG, TPO, TSHB, DUOX2, and SLC5A5, and they are found on chromosomes 8, 3, 1, 15 and 19, respectively. The inheritance pattern for mutations in each of these genes is autosomal recessive, meaning that both copies of the gene must be deficient in order for the individual to be afflicted. Typically, an affected child is born to two unaffected parents, both of whom are carriers of the recessive mutant allele. The probable outcomes for children whose parents are both carriers are 75 percent unaffected and 25 percent affected. If one parent has congenital hypothyroidism of this type and the other is a carrier, there is a 50 percent probability that each child will be affected. According to the Endocrine Society, about 1 in every 2,000 to 4,000 children were born with congenital hypothyroidism as of 2022.
Symptoms
Symptoms or signs take time to develop. The symptoms of congenital hypothyroidism may include a puffy face, coarse facial features, a dull look, a thick protruding tongue, poor feeding, choking episodes, constipation or reduced stooling, prolonged jaundice, short stature, and a swollen and protuberant belly button. Other symptoms may include decreased activity, sleeping a lot, rarely crying or a hoarse cry, dry and brittle hair, a low hairline, poor muscle tone, cool and pale skin, goiter (enlarged thyroid), birth defects (such as a heart valve abnormality), poor weight gain due to poor appetite, poor growth, difficult breathing, slow pulse, low temperature, and swollen hands, feet, and genitals.
Screening and Diagnosis
At birth, most infants are screened for this condition. Tests may include a measurement of free (unbound) thyroxine (T4) levels in the blood, a measurement of thyroid stimulating hormone (TSH) in the blood, and a thyroid scan (technetium). Nuclear imaging (scintigraphy) may help determine the cause of congenital hypothyroidism, which can guide treatment and prognosis.
Treatment and Therapy
The outcome is best if the condition is caught early. It is important to start treatment before the brain and nervous system are fully developed. If treatment is given early, it can prevent damage; left untreated, the condition can lead to intellectual disability and growth retardation.
Hormone replacement therapy is often done with the hormone thyroxine, given in the form of either levothyroxine, Levothroid, Levoxyl, or Synthroid. These tablets should be given at least thirty minutes before a meal or feeding.
Once medication starts, the levels of thyroid hormones are checked often, which will help to keep the values within normal range. If values are kept within a normal range, there are no side effects or complications.
Prevention and Outcomes
Most cases of congenital hypothyroidism cannot be prevented. A mother can do some things during her pregnancy to reduce the risk. She should not have radioactive iodine treatment or use iodine as an antiseptic. Mothers should also consume enough, but not too much, iodine.
Bibliography
Bongers-Schokking, J. J., et al. “Influence of Timing and Dose of Thyroid Hormone Replacement on Development in Infants with Congenital Hypothyroidism.” Journal of Pediatrics 136.3 (2000): 292–297. Print.
Castanet, M., M. Polak, and J. Léger. “Familial Forms of Thyroid Dysgenesis.” Endocrine Development 10 (2007): 15–28. Print.
"Congenital Hypothyroidism." Endocrine Society, 24 Jan. 2022, www.endocrine.org/patient-engagement/endocrine-library/congenital-hypothyroidism. Accessed 5 Sept. 2024.
"Congenital Hypothyroidism." Medline Plus. 1 Sept. 2015, medlineplus.gov/genetics/condition/congenital-hypothyroidism/. Accessed 5 Sept. 2024.
Grüters, A., H. Krude, and H. Biebermann. “Molecular Genetic Defects in Congenital Hypothyroidism.” European Journal of Endocrinology 151.Supp. 3 (2004): U39–44. Print.
LaFranchi, S. H., and J. Austin. “How Should We Be Treating Children with Congenital Hypothyroidism?” Journal of Pediatric Endocrinology and Metabolism 20.5 (2007): 559–578. Print.
Rose, S. R., et al. “Update of Newborn Screening and Therapy for Congenital Hypothyroidism.”Pediatrics 117.6 (2006): 2290–2303. Print.
Scheinberg, Dianne. "Congenital Hypothyroidism." Health Library. EBSCO, 13 Jan. 2014. Web. 21 July 2014.