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Leopard syndrome
Leopard syndrome is a rare autosomal dominant,[1] multisystem disease caused by a mutation in the protein tyrosine phosphatase, non-receptor type 11 gene (PTPN11). The disease is a complex of features, mostly involving the skin, skeletal and cardiovascular systems, they may or may not be present in all patients. The nature of how the mutation causes each of the condition's symptoms is not well known, however research is ongoing. Related to Noonan syndrome, Leopard syndrome is caused by a different missense mutation of the same gene. Leopard syndrome may also be called multiple lentigines syndrome, cardiomyopathic lentiginosis, Gorlin's syndrome II, Capute-Rimoin-Konigsmark-Esterly-Richardson syndrome, or Moynahan syndrome. Noonan syndrome is fairly common, affecting 1:1000 to 1:2500 live births, Neurofibromatosis 1 (once thought to be related to Leopard syndrome) is also common affecting 1 in 3500 individuals, however no epidemiologic data exists for Leopard syndrome.[2] Additional recommended knowledge
DiagnosisThe name of the condition is a mnemonic, originally coined in 1969,[3] as the condition is characterized by some of the following seven conditions, the first letters of which spell leopard, along with the characteristic "freckling" of the skin, caused by the lentigines that is reminiscent of the large cat.
The presence of all of these hallmarks is not needed for a diagnosis. A clinical diagnosis is considered made when, with lentigines present there are 2 other symptoms observed, such as ECG abnormalities and ocular hypertelorism, or without lentigines, 3 of the above conditions are present, with a first-degree relative (i.e. parent, child, sibling) with a clinical diagnosis. There is a genetic test for this disease. In a study of 10 infants with clinical indications of Leopard syndrome prior to their first birthday, 8 (80%) patients were confirmed to have the suspected mutation. An additional patient, with the suspected mutation was subsequently found to have NF1, following evaluation of the mother.[4] There are 5 identified allelic variants responsible for Leopard syndrome. Y279C, T468M, A461T, G464A, and Q510P which seems to be a unique familial mutation, in that all other variants are caused by transition errors, rather than transversion. HistoryZeisler and Becker first described a syndrome with multiple lentigines, hypertelorism, pectus carinatum (protruding breastbone) and prognathism (protrusion of lower jaw) in 1936.[5] Sporadic descriptions were added through the years. In 1962, cardiac abnormalities and short stature were first associated with the condition.[6] In 1966, three familial cases were added, a mother, her son and daughter.[7] Another case of mother to two separate children, with different paternity of the two children, was added in 1968.[8] It was believed as late as 2002[9] that Leopard syndrome was related to Neurofibromatosis 1, also known as von Recklinghausen syndrome. In fact, since both ICD9 and ICD10 lack a specific diagnosis code for Leopard syndrome, the diagnosis code for NF1 is still sometimes used for diagnostic purposes, although it has been shown that the gene is not linked to the NF1 locus.[10] EpidemiologyVarious literature describes it as being "rare"[11] or "extremely rare".[12] There is no epidemiologic data available, regarding how many in the world population suffer from the syndrome, however there are slightly over 100 cases described in medical literature. Additional symptoms
Unfortunately, due to the rarity of the syndrome itself, it is hard to determine whether certain additional diseases are actually a threat of the syndrome. With a base population of possibly less than one thousand individuals, one or two outlying cases can skew the statistical population very quickly. Prognosis and treatmentIn itself, Leopard syndrome is not a life threatening diagnosis, most people diagnosed with the condition live normal lives. Obstructive cardiomyopathy and other pathologic findings involving the cardiovascular system may be a cause of death in those whose cardiac deformities are profound. It is suggested that, once diagnosed, individuals be routinely followed by a cardiologist, endocrinologist, dermatologist, and other appropriate specialties as symptoms present. Prevention and managementIt is recommended that those with the syndrome who are capable of having children seek genetic counseling prior to deciding to have children. As the syndrome presents frequently as a forme fruste (incomplete, or unusual form) variant, an examination of all family members must be undertaken.[15] As an autosomal dominant trait there is a fifty percent chance with each child, that they will also be born with the syndrome. This does not take into account the possibility of the gene mutating, on its own, in a child of a Leopard syndrome patient who does not inherit the gene from the affected parent. Since the syndrome has a variable penetrance and expression, one generation may have a mild expression of the syndrome, while the next may be profoundly affected. Once a decision to have children is made, and the couple conceives, the fetus is monitored during the pregnancy for cardiac evaluation. If a gross cardiac malformation is found, parents receive counseling on continuing with the pregnancy. Other management is routine care as symptoms present:
Molecular mechanicsIn the two predominant mutations of Leopard syndrome (Y279C and T468M) the mutations cause a loss of catalytic activity of the SHP2 (a variant name for PTPN11) protein, which is a previously unrecognized behavior for this class of mutations.[17] This interferes with growth factor and related signalling. While further research confirms this mechanism,[18][19] additional research is needed to determine how this relates to all of the observed effects of Leopard syndrome. See alsoReferences
Categories: Genetic disorders | Syndromes |
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This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Leopard_syndrome". A list of authors is available in Wikipedia. |