Noonan with multiple lentigines syndrome ...; LEOPARD syndrome; Myocardial lentigines (Noonan syndrome with multiple lentigines) - Genes PTPN11, RAF1, BRAF and MAP2K1
Noonan syndrome multiple lentigines, also known as LEOPARD syndrome or miocardiopática lengitinosis, is a multisystem disorder characterized by facial, skin and heart abnormalities. Its name is an acronym of the main manifestations associated with it : lentiginosis, abnormal ECG, ocular hypertelorism, pulmonary stenosis, abnormal genital, growth retardation and deafness ( "L engitines, E CG abnormalities conduction, O cular hypertelorism , P ulmonic stenosis, A BNORMAL genitalia, R etardation of growth, sensorineural eafness D ").
The most common among heart defects is hypertrophic cardiomyopathy, which affects about 80% of people with Noonan syndrome with multiple lentigines, followed by pulmonary stenosis (20%). Other common features may include spots called "latte", abnormal chest as pectus excavatum or pectus keel, cryptorchidism and hypospadias in males, ovaries underdeveloped or delayed puberty in women, hypotonia, intellectual disability mild and stunting. In addition to these demonstrations, people with Noonan syndrome with multiple lentigines may have a characteristic facial appearance. Ocular hypertelorism addition, affected individuals may have ptosis, thick lips and low - set ears.
The incidence of this anomaly is unknown, but is believed to be underdiagnosed, especially milder and / or absence of lentiginosis cases. Many of the signs and symptoms of Noonan syndrome with multiple lentigines are also produced in a similar process called Noonan syndrome. Although it may be difficult to distinguish the two syndromes in early childhood, the characteristics of both differ later in life. Noonan syndrome multiple lentigines is one of a group of related disorders collectively known as rasopathy. All these entities have similar signs and symptoms and are due to changes in the same cell signaling pathway. Besides Noonan multiple lentigines, the rasopathy include Noonan syndrome, the skin cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type 1 syndrome Legius.
This may be due to mutations in PTPN11 (protein tyrosine phosphatase, non-receptor type 11), RAF1 (Raf-1 proto-oncogene, serine / threonine kinase), BRAF (B-Raf proto-oncogene, serine / threonine genes kinase) and MAP2K1 (mitogen-activated protein kinase kinase 1). Approximately 85% of affected individuals have mutations in the PTPN11 gene. Another 10% of affected individuals have mutations in the gene RAF1. Mutations in BRAF and MAP2K1 genes, have been described in a few individuals, so mutations in these associated with the development of this syndrome is considered rare genes. A small proportion of affected individuals have a mutation identified in any of these genes. In these people, the cause of the disease is unknown.
The PTPN11, RAF1, MAP2K1 and BRAF genes encode proteins that are involved in important signaling pathways necessary for the proper formation of various types of tissues during development. These proteins also play a role in regulating cell division, cell migration and cell differentiation.
The PTPN11 (protein tyrosine phosphatase, non-receptor type 11), located on the long arm of chromosome 12 (12q24), encodes a tyrosine phosphatase 2 Src homology (SHP2) containing two domains of Src homology-2 ( N-SH2-SH2 C), and a phosphatase catalytic domain. Protein tyrosine phosphatase family are known to be signaling molecules that regulate many cellular processes such as growth and cell differentiation, mitotic cycle and oncogenic transformation processes. SHP2 helps regulate the activation of the signaling pathway RAS / MAPK. Indeed SHP2 is a key component of many signal transduction pathways that control development processes protein, including the formation of cardiac semilunar valves and hematopoietic cell differentiation. They have identified at least 11 mutations in the PTPN11 gene associated Noonan multiple lentigines. Most of these mutations change the amino acids in protein SHP2. A common mutation replaces the amino acid tyrosine by the amino acid cysteine at position 279 (Y279C or Tyr279Cys). Another mutation replaces the amino acid threonine by methionine at amino acid position 468 in the protein SHP2 (Thr468Met or T468M). It is believed that all known alterations in the PTPN11 gene associated with the syndrome alter the normal function of the protein. This decreased function of protein SHP2 alters activation of the signaling pathway RAS / MAPK. This poor regulation can lead to various features of the syndrome. Although the PTPN11 gene is an oncogene, it seems that a reduction in the function of this protein increases the risk of cancer in people affected.
The gene RAF1 (Raf-1 proto-oncogene, serine / threonine kinase), located on the short arm of chromosome 3 (3p25), is an oncogene that encodes a protein that is part of the signaling pathway RAS / MAPK. They have identified at least 2 mutations in the gene RAF1 in people with Noonan syndrome with multiple lentigines. These mutations change the amino acids in protein RAF1. A mutation replaces the amino acid serine by amino acid leucine at position 257 in the RAF1 (Ser257Leu or S257L) protein. The other mutation replaces the amino acid leucine for valine at amino acid position 613 in the RAF1 (Leu613Val or L613V) protein. It is believed that these changes abnormally activated the RAF1 protein, which interrupts the regulation of the signaling pathway RAS / MAPK, which controls cell functions such as growth and division. This poor regulation can lead to the various features of Noonan syndrome multiple lentigines.
BRAF (B-Raf proto-oncogene, serine / threonine kinase), located on the long arm of chromosome 7 (7q34), encodes a protein that helps transmit chemical signals from outside the cell to the cell nucleus. This protein is part of a signaling pathway known as the RAS / MAPK pathway, which controls several important cellular functions. Specifically, the RAS / MAPK pathway regulates growth and proliferation, differentiation, migration and apoptosis. Chemical signaling through this pathway is essential for normal development before birth. The BRAF gene belongs to a class of genes known as oncogenes, meaning that a mutation in them has the potential to cause normal cells to become cancerous. Mutations identified so far in the BRAF gene associated Noonan multiple lentigines (at least 2), individual amino acids change in BRAF. A mutation replaces the amino acid threonine by the amino acid proline at position 241 in BRAF (Thr241Pro or T241P). The other mutation replaces the amino acid leucine for phenylalanine at amino acid position 245 in BRAF (Leu245Phe or L245F). It is believed that these genetic changes abnormally activated BRAF, which interrupts the regulation of the signaling pathway RAS / MAPK controlling cell functions such as growth and division. This poor regulation can lead to various features of the syndrome.
Finally, the gene MAP2K1 (mitogen-activated protein kinase kinase 1), located on the long arm of chromosome 15 (15q22.1-q22.33), encodes the synthesis of a protein known as protein kinase MEK1. This protein is part of the signaling pathway RAS / MAPK. MEK1 protein kinase appears to be essential for normal development before birth and survival after birth. At least one mutation in the MAP2K1 gene has been identified in affected individuals. This mutation replaces the amino acid glutamic acid for the amino acid glycine at position 102 in the kinase MEK1 (Glu102Gly or E102G) protein. This change is likely to cause an increase in activation of the signaling pathway RAS / MAPK in cells throughout the body. The increase in signaling interferes with the normal development of many organs and tissues, resulting in the characteristic features of this syndrome.
Noonan syndrome multiple lentigines is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the disease. 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 in IVAMI: in IVAMI perform detection of mutations associated with Noonan syndrome multiple lentigines, by complete PCR amplification of the exons of PTPN11, RAF1, MAP2K1 and BRAF genes, respectively, and subsequent sequencing. We recommend starting the study by exons of PTPN11 gene responsible for most cases of the syndrome, with the possible reduction of time and cost involved in most cases. If not found the mutation in this gene, it offers the possibility to complete the study by amplifying and sequencing the remaining genes.
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).