Neurofibromatosis type 1 (von Recklinghausen disease, peripheral neurofibromatosis) (Neurofibromatosis type 1, von Recklinghausen Disease, Peripheral Neurofibromatosis) - NF1 Gene

Neurofibromatosis type 1 (von Recklinghausen disease or neurofibromatosis peripheral) is a genetic disease characterized by changes in pigmentation and tumor development along the nerves in the skin, brain and other body parts.

Signs and symptoms of this disease vary widely among affected individuals. Clinically, patients develop skin pigmentation, called spots "coffee with milk" because it is an area of skin darker than the surrounding. These spots increase in size and number as the individual grows. Along with this cutaneous manifestation, those affected develop neurofibromas, a non - cancerous benign tumors located in the same skin, or underlying it. Childhood Lisch nodules may appear on the ocular iris (iris hamartomas) that do not interfere with vision. Some patients develop optic nerve tumors (gliomas optical), which may or may not reduce vision. Other signs and symptoms that can be found are: hypertension, short stature, macrocephaly, scoliosis, learning difficulties and hyperactivity attention deficit disorder (ADHD). Some affected develop cancerous malignancies, sheaths near the spinal cord, or other brain tumors and hematologic malignancies (leukemias) peripheral nerves. These features are present in 90% of patients during puberty. Other manifestations which can develop less frequently are malignant neurofibrosarcomas, pheochromocytoma, or syndromes such as multiple endocrine neoplasia type 2 (MEN2), disease von Hippel-Lindau or paraganglioma (PGL) type 1 (PGL1) and type 4 (PGL4).

This disease (NF1), is different from neurofibromatosis type 2 (NF2) (central neurofibromatosis), which corresponds to a different genetic alteration caused by mutations in the gene encoding myelin (chromosome 23q12), characterized by the development bilateral acoustic neuromas or meningiomas, skin lesions accompanied by few or few neurofibromas.

Neurofibromatosis type 1 is due to mutations in the NF1 gene, located on the long arm of chromosome 17 (17q11.2). This gene spans 350 kb along with 60 exons encoding 2867 amino acids, of which the most common transcript gives rise to a protein of 2818 amino acids called neurofibromin. Neurofibromin is produced in many cells, including cells that surround nerves (oligodendrocytes and Schwann cells), intended to form the myelin sheaths that cover, isolate and protect nerve cells. Neurofibromin is a tumor suppressor protein, that reduces growth and rapid and uncontrolled cell division, avoiding the excessive cell growth. For this, the neufibromina exerts a negative regulation by removing the proto-oncogene "Ras", whose function is to stimulate growth and cell division.

There are more than 1000 mutations in the gene NF1 responsible for neurofibromatosis type 1 mutation in both copies of the gene NF1 Schwann cells leads to development of noncancerous tumors (neurofibromas). In some rare cases, inactivation of a copy of the NF1 gene increases the risk of developing juvenile myelomonocytic leukemia in children under two years. The mutations described in the NF1 gene may correspond to long or short deletions, insertions long or short, or specific missense mutations (nonsense) or loss of consciousness (missense). In 80% of cases these mutational changes result in a truncated by a premature termination of translation protein. Altered protein loses its normal activating function "Ras GTPase" which is designed to convert the active compound of protoconcogén "Ras" (Ras-GTP) in its inactive (Ras-GDP). When neurofibromin is altered, it can not inactivate the "Ras-GTP" and cell proliferation occurs mediated protooncogene "Ras". Therefore, tumors such as neurofibromas develop along nerves. It is unknown how the gene mutation leads to other events, such as changes in skin pigmentation or learning difficulty.

Neurofibromatosis type 1 is considered to have an autosomal dominant inheritance. People with this disease are born with a mutated copy of the NF1 gene in each cell. In about half of the cases, the altered gene is inherited from an affected parent. The remaining cases are due to new mutations in the NF1 gene and occur in people with no history of disease in your family. Unlike most other common autosomal dominant disorders in which an altered gene in each cell copy is sufficient to express the disease, the two copies of the NF1 gene must be altered to trigger tumor formation in neurofibromatosis type 1. a mutation in the second copy of the NF1 gene occurs during the life of a person in specialized cells around the nerves. Almost all people who are born with NF1 mutation, acquired a second mutation in many cells and develop tumors characteristic of neurofibromatosis type 1.

Tests in IVAMI: in IVAMI perform detection of mutations associated with neurofibromatosis type 1, by complete PCR amplification of the exons of the NF1 gene, and subsequent sequencing. To more than 1,000 different mutations along these exons have been described and existing mutations have been published in each exon to reduce costs, we propose to carry out genetic studies in five stages. These stages have established according to the frequency with which mutations have been described in each exon, as agreed with the client, so you can stop or continue the genetic study when the client indicates. In the first step in 9 exons described between 10 and 16 mutations (exons 4-b, 7, 13, 16, 22, 26, 27A, 29 and 37) would be considered; in the second stage, 11 exons in the described between 6 and 9 mutations (exons 6, 9, 10-a, 10-b, 11, 12, 20, 23, 23-II, 28 and 42) would be considered ; in the third stage, in 9 exons described 4 or 5 mutations (exons 5, 8, 10-c, 15, 18, 21, 31, 34 and 36) would be considered; in the fourth stage, 20 exons in the described 1 to 3 mutations (exons 1, 2, 3, 4-a, 4-c, 14, 17, 19-a, 19-b, 24, would be considered 25, 27-b, 30, 32, 33, 35, 38, 39, 43, 44, 45, 46, 47 and 48); and in the fifth stage, the remaining exons (9br, 23-a, 40, 41, 48-a, and 49) will be studied. Note: This selection was based on the publication of Fahsold, R., et al. Am J Hum Genet 2000, 66: 790-818.

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).