Brain-lung-thyroid syndrome - Gen NKX2-1  

The brain-lung-thyroid syndrome is a group of disorders that affect the brain, lung and thyroid gland. This syndrome historically included problems with the three bodies, although designation now encompasses a combination of brain, lung and thyroid problems. About 50 percent of affected persons have problems with the three bodies, about 30 percent have brain disorders and thyroid and about 10 percent have brain and lung problems. The brain is only affected in 10 to 20 percent of people with the syndrome. These cases are sometimes called benign hereditary chorea isolated.

Almost all people with brain-lung-thyroid syndrome have brain abnormalities related to movement. Benign hereditary chorea is the most common feature of the syndrome. This feature is associated with chorea (on face, trunk and limbs), athetosis and other movement problems. Individuals with brain-lung-thyroid syndrome may have other abnormalities such as ataxia and dystonia. Movement problems usually begin about one year of age, but can manifest in early childhood or later, and are often preceded by hypotonia. Movement problems usually remain stable and can improve over time. Some affected people also have learning difficulties and intellectual disabilities.

Thyroid problems are the next most common feature of brain-lung-thyroid syndrome. Many people affected suffer from congenital hypothyroidism or compensated or subclinical hypothyroidism. Although a deficiency of thyroid hormones can lead to mental retardation and other neurological problems, it is not clear whether these problems in individuals with brain-lung-thyroid syndrome are due to hypothyroidism or brain abnormalities associated with the syndrome.

Some affected infants have respiratory distress syndrome, which causes extreme difficulty breathing and may endanger life. Other affected people develop pulmonary fibrosis or interstitial lung disease. In addition, affected individuals may suffer recurrent lung infections, which can endanger life. People with brain-lung-thyroid syndrome have an increased risk of developing lung cancer compared to the general population.

This process is due to mutations in the gene NKX2-1 (NK2 homeobox 1), located on the long arm of chromosome 14 (14q13.3), which encodes the protein homeobox Nkx-2.1. The homeobox proteins direct the formation of body structures in early embryonic development. This protein is particularly involved in the development and function of brain, lung and thyroid, acting as a transcription factor. In the brain, the homeobox protein 2.1 Nkx-regulates genes that play a role in the development and migration of interneurons, to its proper location. In the lungs, the homeobox protein Nkx-2.1 regulates the development of lung structures and expression of genes surfactants, which encode the synthesis of surfactant proteins. Along with certain fats, these proteins form surfactant lining the lung tissue and eases breathing. In the thyroid gland, homeobox protein Nkx-2.1 regulates genes that are critical in the production of thyroid hormones.

They have been described at least 100 mutations in the gene NKX2-1 in persons with brain-lung-thyroid syndrome. Many of the identified mutations result in an abnormally short homeobox protein Nkx-2.1 can not function properly. Other mutations replace amino acids in protein, which impairs their ability to bind DNA, or remove the entire gene NKX2-1. Homeobox protein deficiency Nkx-2.1 functional alters the expression of genes important for the normal development and functioning of the brain, lung and thyroid gland. Accordingly, coding surfactant proteins is reduced, causing difficulty in breathing; Expression of genes involved in the production of thyroid hormones is impaired, which explains hypothyroidism; and brain development deteriorates, probably due to the formation or inappropriate migration of interneurons, which may underlie motion abnormalities features brain-lung-thyroid syndrome.

This process is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the alteration. In some cases, an affected person inherits the mutation from an affected parent. Other cases are due to new mutations in the gene and occur in people with no history of disease in your family.

Tests performed in IVAMI: in IVAMI perform detection of mutations associated with cerebro-lung-thyroid complete by PCR amplification of the exons of the gene NKX2-1, 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).