Leopard syndrome overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2]
Overview
Leopard syndrome is a rare autosomal dominant[1] multisystemic disease caused by a mutation in the protein tyrosine phosphatase non-receptor type 11 gene. 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 affect these systems 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 (1:1000 to 1:2500 live births), and neurofibromatosis 1 (which was once thought to be related to Leopard syndrome) is also common (1:3500), but however no epidemiologic data exists for Leopard syndrome.[2]
Historical Perspective
It was first described by Zeisler and Becker with multiple lentigines, hypertelorism, pectus carinatum (protruding breastbone) and prognathism (protrusion of lower jaw) in 1936.[3] In 1962, cardiac abnormalities and short stature were first associated with the condition.[3] In 1966, three familial cases were added.[4] In 1968 another case of mother to two separate children, with different paternity of the two children, was added.[5] It was believed as late as 2002[6] that Leopard syndrome was related to neurofibromatosis type I (Von Recklinghausen syndrome).
Pathophysiology
In the two predominant mutations of Leopard syndrome, the mutations cause a loss of catalytic activity of the SHP2 protein(the gene product of the PTPN11 gene), which is a previously unrecognized behavior for this class of mutations.[7] This interferes with growth factor and related signalling. While further research confirms this mechanism,[8][9] additional research is needed to determine how this relates to all of the observed effects of Leopard syndrome.
Causes
Molecular studies have shown that Leopard syndrome is caused by different missense mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located at chromosome 12q22-qter.[10] Mutations cause a loss of catalytic activity of the SHP2 protein (the gene product of the PTPN11 gene), which is a previously unrecognized behavior for this class of mutations.[11] This interferes with growth factor and related signalling.
Epidemiology and Demographics
Leopaed syndrome is a rare condition, but the exact birth prevalence is unknown. Approximately 200 patients have been reported.[12] However, Leopard syndrome is likely underdiagnosed or misdiagnosed as many of its features are mild and the correct diagnosis might be missed in the absence of lentiginosis.
Natural History, Complications and Prognosis
In 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 should be routinely followed by a cardiologist, endocrinologist, dermatologist, and other appropriate specialties as symptoms present.
History and Symptoms
Leopard syndrome affects many areas in the body. The characteristic feature associated with the condition is brown skin spots called lentigines. Patients are showing a wide spectrum of features include multiple lentigines, facial dysmorphisms, cardiac anomalies, electrocardiographic (EKG) conduction abnormalities, retardation of growth, abnormal genitalia and sensorineural deafness.[13]
Laboratory Findings
Hormonal abnormalities may be revealed in some patients with endocrine system involvement. laboratory studies should include molecular analysis of the PTPN11 and RAF1 genes.[14]
Imaging Studies
Different imaging studies like X-rays, CT scanning, and Echocardiography have been used to detect abnormalities of LEOPARD syndrome.
Medical Therapy
Medical management depend on the symptoms present. Drug therapy for cardiac abnormalities,endocrine, and dermatological issues is recommended.
Surgical Therapy
Different procedures may be necessary in cases with severe outflow tract obstruction[15], patients with cryptorchidism, genitourinary, or severe skeletal deformity.
Primary Prevention
Genetic counseling should be offered before deciding to have children, careful examination of all family members as the syndrome usually present with incomplete form.
Secondary Prevention
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.
References
- ↑ Coppin BD, Temple IK (1997). "Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis)". J. Med. Genet. 34 (7): 582–6. PMID 9222968.
- ↑ Tullu MS, Muranjan MN, Kantharia VC; et al. (2000). "Neurofibromatosis-Noonan syndrome or LEOPARD Syndrome? A clinical dilemma". J Postgrad Med. 46 (2): 98–100. PMID 11013475.
- ↑ 3.0 3.1 Zeisler, Erwin P. (1936). "GENERALIZED LENTIGO<subtitle>ITS RELATION TO SYSTEMIC NONELEVATED NEVI</subtitle>". Archives of Dermatology. 33 (1): 109. doi:10.1001/archderm.1936.01470070112010. ISSN 0003-987X.
- ↑ Walther RJ, Polansky BJ, Grotis IA (1966). "Electrocardiographic abnormalities in a family with generalized lentigo". N. Engl. J. Med. 275 (22): 1220–5. PMID 5921856.
- ↑ Matthews NL (1968). "Lentigo and electrocardiographic changes". N. Engl. J. Med. 278 (14): 780–1. PMID 5638719.
- ↑ National Library of Medicine MeSH: C05.660.207.525
- ↑ Tartaglia M, Martinelli S, Stella L; et al. (2006). "Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease". Am. J. Hum. Genet. 78 (2): 279–90. doi:10.1086/499925. PMID 16358218.
- ↑ Hanna N, Montagner A, Lee WH; et al. (2006). "Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1". FEBS Lett. 580 (10): 2477–82. doi:10.1016/j.febslet.2006.03.088. PMID 16638574.
- ↑ Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG (2006). "PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects". J. Biol. Chem. 281 (10): 6785–92. doi:10.1074/jbc.M513068200. PMID 16377799.
- ↑ Digilio MC, Sarkozy A, de Zorzi A, Pacileo G, Limongelli G, Mingarelli R; et al. (2006). "LEOPARD syndrome: clinical diagnosis in the first year of life". Am J Med Genet A. 140 (7): 740–6. doi:10.1002/ajmg.a.31156. PMID 16523510.
- ↑ Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E, Cordeddu V; et al. (2006). "Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease". Am J Hum Genet. 78 (2): 279–90. doi:10.1086/499925. PMC 1380235. PMID 16358218.
- ↑ Voron DA, Hatfield HH, Kalkhoff RK (1976). "Multiple lentigines syndrome. Case report and review of the literature". Am J Med. 60 (3): 447–56. PMID 1258892.
- ↑ Gorlin RJ, Anderson RC, Blaw M (1969). "Multiple lentigenes syndrome". Am J Dis Child. 117 (6): 652–62. PMID 5771505.
- ↑ Digilio MC, Sarkozy A, de Zorzi A; et al. (2006). "LEOPARD syndrome: clinical diagnosis in the first year of life". Am. J. Med. Genet. A. 140 (7): 740–6. doi:10.1002/ajmg.a.31156. PMID 16523510.
- ↑ Limongelli G, Pacileo G, Marino B, Digilio MC, Sarkozy A, Elliott P; et al. (2007). "Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome". Am J Cardiol. 100 (4): 736–41. doi:10.1016/j.amjcard.2007.03.093. PMID 17697839.