Congenital hypothyroidism (Congenital hypothyroidism) - Genes DUOX2, DUOXA2, IYD, NKX2-5, PAX8, SLC5A5, SLC26A4, TG, THRA, TPO, TRHR, TSHB and TSHR
Congenital hypothyroidism (CH) is a congenital disease that affects infants as a result of a partial or complete loss of function of the thyroid. Thyroid hormones that contain iodine, which play an important role in the regulation of growth, development and metabolism of the brain. 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, abnormally localized, or very small in size. These cases are classified as thyroid dysgenesis. In other cases, there is a normal thyroid or larger, but the production of thyroid hormone decreases or does not occur. These cases are classified as dyshormonogenesis thyroid. Less frequently, the reduction or absence of thyroid hormone production is due to a deterioration of the stimulation of the production process, which is usually done by the pituitary. These cases are classified as central hypothyroidism.
Signs and symptoms of congenital hypothyroidism are due to a deficiency of thyroid hormones. Affected infants may not show characteristics of the disease, although some affected are less active and sleep more than usual. In addition, they may have difficulty feeding and constipation. If left untreated, congenital hypothyroidism can lead to mental retardation and slow growth. In the United States and many other countries, all newborns are examined for congenital hypothyroidism. If treatment begins in the first month after birth, newborns generally develop normally.
Congenital hypothyroidism can also occur as part of syndromes that affect other organs and tissues in the body. These forms of the disease are described as syndromic. Some common forms of hypothyroidism include Pendred syndrome, syndrome Bamforth-Lazarus and brain-lung-thyroid syndrome.
Congenital hypothyroidism can be due to a variety of factors, of which only some are genetic. The most common reason is lack of iodine in the diet of the mother and the affected child, which is essential for the production of thyroid hormones. Genetic causes account for about 15 to 20 percent of cases of congenital hypothyroidism. The reason the most common type of congenital hypothyroidism, thyroid dysgenesis, is unknown. Two of the genes involved in the thyroid dysgenesis are PAX8 gene (Paired box 8) and TSHR gene (thyroid stimulating hormone receptor). These genes play a role in the proper growth and development of the thyroid gland. Mutations in these genes inhibit or disrupt the normal development of the thyroid gland prior to birth. Dyshormonogenesis cases of thyroid are due to mutations in one of several genes involved in the production of thyroid hormones. These genes include DUOX2 (dual oxidase 2), SLC5A5 (solute carrier family 5 member 5), TG (thyroglobulin) and TPO (thyroid peroxidise). Mutations in genes DUOX2, SLC5A5, TG and TPO inhibit or reduce the production of thyroid hormones despite the thyroid gland is present. Mutations in the TSHB gene (thyroid stimulating hormone beta) inhibit thyroid hormone synthesis by affecting stimulating hormone production. Changes in this gene are the leading cause of central hypothyroidism.
The DUOX2 (dual oxidase 2) gene, located on the long arm of chromosome 15 (15q15.3), encoding the oxidase enzyme dual-2. This enzyme is found in the thyroid, salivary glands, the digestive tract and respiratory tract into the pharynx and lungs. Oxidase enzyme dual-2 helps to generate hydrogen peroxide, which is required for one of the final steps in the production of thyroid hormones. They have identified several genetic mutations in the gene responsible for congenital hypothyroidism DUOX2. Most of these mutations result in an abnormally small version of the dual-2 oxidase enzyme. The remaining mutations change amino acids used in the formation of the enzyme, which probably alter its structure. All mutations in the gene DUOX2 limit the ability of the enzyme to generate hydrogen peroxide. Without sufficient hydrogen peroxide, production of thyroid hormone is interrupted. In some cases, the thyroid gland enlarges in an attempt to compensate for the reduced production of thyroid hormone. Each cell in the body has two copies of the gene DUOX2. If both copies of the gene having a mutation, the cells in the thyroid gland produce very little hydrogen peroxide. As a result, the thyroid hormone levels are extremely low, causing severe congenital hypothyroidism. If only one copy of the gene is mutated DUOX2, it occurs a little hydrogen peroxide. As a result, the thyroid hormone levels are reduced slightly, causing mild congenital hypothyroidism. Sometimes, mild hypothyroidism is transient, and thyroid hormone concentrations that are low in childhood, increase with age.
The PAX8 (Paired box 8) gene, located on the long arm of chromosome 2 (2q13), it belongs to a gene family that plays a critical role in the formation of tissues and organs during embryonic development. PAX gene family is also important to maintain the normal function of certain cells after birth. To perform these functions, the PAX genes encode proteins that bind to specific areas of DNA. By joining DNA regions critical, these proteins help control gene expression. It is believed that during embryonic development active protein genes involved in the formation of kidney and thyroid gland. After birth, the protein regulates several genes involved in the production of thyroid hormones. They have identified at least 15 mutations in the gene PAX8. Some mutations cause congenital hypothyroidism, while others slightly reduce thyroid hormone levels or have no detectable effect. Most mutations change amino acids used in the formation of the protein. Other mutations alter protein production, which results in an abnormally small version. Almost all gene mutations prevent the protein from binding to DNA effectively. A mutation alters the interactions between the protein and other transcription factors. As a result, the protein can not perform its function in regulating the activity of certain genes. Mutations in the gene PAX8 disrupt normal growth or survival of thyroid cells during embryonic development. As a result, the thyroid gland is reduced in size and may be unable to produce normal amounts of thyroid hormones.
The SLC5A5 gene (solute carrier family 5 member 5), located on the short arm of chromosome 19 (19p13.11), encoding the protein cotransportadora sodium-iodide or NIS. In certain tissues, this protein facilitates iodide uptake. NIS protein supports a very efficient system which ensures that the dietary iodine accumulates in the thyroid gland to produce thyroid hormones. Besides the thyroid gland, the NIS protein is found in breast tissue during lactation, ovaries, salivary glands, parietal cells, lacrimal gland, and brain choroid plexus. During lactation, NIS protein carries iodide into breast milk to supply breastfed infants with this critical component of thyroid hormones. They have identified several mutations in the SLC5A5 gene in people with congenital hypothyroidism. About half of these mutations eliminate the SLC5A5 gene part and disrupt protein synthesis, which results in an abnormally small and non - functional protein. The remaining mutations change amino acids used to encode the NIS protein. Some amino acid substitutions prevent the protein is positioned in the cell membrane, deactivating iodide transport. Other amino acid substitutions do not affect the location of the membrane protein but change the three - dimensional shape of the protein, disrupting its function. As a result, the thyroid gland can not accumulate iodide efficiently, thereby decreasing the production of thyroid hormones.
The TG (thyroglobulin) gene, located on the long arm of chromosome 8 (8q24), encoding thyroglobulin protein found only in the thyroid gland. Thyroglobulin combines with iodine and decomposing modified to release thyroid hormones. Thyroglobulin also serves as a storage protein for iodine. Mutations in this gene removed a small gene segment or change one of the DNA nucleotides. As a result, the amount of protein available for the production of thyroid hormone is altered. In most affected individuals, the thyroid gland is enlarged in an attempt to compensate for the reduced production of hormones.
The TPO (thyroid peroxidise) gene located on the short arm of chromosome 2 (2p25), encoding the thyroid peroxidase enzyme, which plays a central role in the function of the thyroid gland, helping the chemical reaction that adds iodine protein thyroglobulin, a critical step in the generation of thyroid hormones. Have identified more than 30 mutations of TPO gene deleted, added or changed base pairs in the gene. Some mutations result in an abnormally small thyroid peroxidase which is degraded before it can be inserted into the cell membrane. Other mutations change the shape of the enzyme preventing it from working properly within the cell membrane. No functional thyroid peroxidase, iodine absorbed by the thyroid gland is not added to the thyroglobulin. As a result, the production of thyroid hormones is reduced or does not occur.
The TSHB (Thyroid stimulating hormone beta) gene, located on the short arm of chromosome 1 (1p13), encodes a protein subunit of thyroid stimulating hormone (TSH). This hormone consists of alpha and beta subunits. The TSHB gene encodes the beta subunit of thyroid stimulating hormone. The alpha and beta subunits are linked together to produce the active form of the hormone. A particular segment of the beta subunit is around the alpha subunit to form functional hormone. They have identified at least 10 TSHB gene mutations that alter the size or shape of the beta subunit of thyroid stimulating hormone. Other mutations change amino acids used in the formation of the subunit. As a result, the production of thyroid hormone is not stimulated. Moreover, the thyroid gland is reduced in size because their growth is not encouraged.
The TSHR gene (thyroid stimulating hormone receptor), located on the long arm of chromosome 14 (14q31), encoding a receptor that acts as a binding site for thyroid stimulating hormone (TSH). This receptor spans the membrane of follicular cells in the thyroid gland. Stimulating thyroid hormone binds to the extracellular portion of the receptor, activating a series of reactions that control development of the thyroid gland and functions. They have identified several mutations in the TSHR gene. These mutations change amino acids used to form the receptor stimulating thyroid hormone. Some of these mutations prevent the membrane receptor entire receiver is properly positioned, and in some cases persists within the cell. As a result, the receiver can not interact properly with the thyroid stimulating hormone. Other mutations affect the receptor's ability to bind to thyroid stimulating hormone, although the receiver is correctly position the membrane. Without proper receptor functioning, the production of thyroid hormone is not stimulated. Damaged receivers can also disrupt thyroid development, and as a result, the gland is smaller than normal.
Mutations in other genes have not been well characterized also cause congenital hypothyroidism. These genes include the gene DUOXA2 (dual oxidase maturation factor 2), located on the long arm of chromosome 15 (15q15.1); the IYD (iodotyrosine deiodinase) gene, located on the long arm of chromosome 6 (6q25.1); the gene NKX2-5 (NK2 homeobox 5), located on the long arm of chromosome 5 (5q34); SLC26A4 (solute carrier family 26 member 4), located on the long arm of chromosome 7 (7q31); THRA (Thyroid hormone receptor, alpha), located on the long arm of chromosome 17 (17q11.2); and TRHR gene (thyrotropin releasing hormone receptor), located on the short arm of chromosome 1 (1p13).
Most cases are sporadic congenital hypothyroidism, which means that occur in people with no history of disease in your family. Studies indicate that only 2 to 5 percent of cases are hereditary. When the disease is hereditary, many cases are inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease. Some inherited cases (those with a mutation in the gene or certain mutations PAX8 TSHR and DUOX2 gene) have a pattern of autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the disease. Other cases are due to new mutations in the gene that occur during the formation of reproductive cells or early embryonic development. These cases occur in people with no history of disease in your family.
Tests performed in IVAMI: in IVAMI perform detection of mutations associated with congenital hypothyroidism, by complete PCR amplification of the exons of DUOX2, DUOXA2, IYD, NKX2-5, PAX8, SLC5A5, SLC26A4, TG, THRA genes, TPO , TRHR, TSHB and TSHR, respectively, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).