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] 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 (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] 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.[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. Not less than 200 patients have been reported and two reviews published.[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 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 (ECG) conduction abnormalities, retardation of growth, abnormal genitalia and sensorineural deafness.[13]
Laboratory Findings
Diagnosis of Leopard syndrome is sometimes difficult because of the overlap with Noonan syndrome and neurofibromatosis 1. In these patients, the presence of the disease can be confirmed with a mutation-based diagnosis, laboratory studies should include molecular analysis of the PTPN11 and RAF1 genes. 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.[14] There are 5 identified allelic variants responsible for Leopard syndrome. Which seems to be a unique familial mutation, in that all other variants are caused by transition errors, rather than transversion.
Imaging Studies
- CT scanning or MRI - Brain atrophy may be revealed
- Skeletal radiography - Detection of skeletal malformation and bone age assessment.
- Echocardiography - Indicated for visualization of structural heart abnormalities.
- Electrocardiography - Excludes conduction abnormalities.
- Ultrasonography or Urographic examination - For assessment of the genitourinary system.
- Audiography or Auditory evoked potentials - For detection of sensorineural deafness.
Medical Therapy
Medical management is routine care as symptoms present. For those with endocrine issues (low levels of thyrotopin [a pituitary hormone responsible for regulating thyroid hormones], follicle stimulating hormone) drug therapy is recommended. Retinoids decrease abnormal hyperproliferative keratinocytes and may reduce potential for malignant degeneration. So an alternative treatment with tretinoin or hydroquinone creams may help. Hydroquinone lightens hyperpigmented skin through inhibiting enzymatic oxidation of tyrosine and suppressing other melanocyte metabolic processes which will inhibit melanogenesis. Drug therapies for those with cardiac abnormalities, as those abnormalities become severe enough to warrant the use of these therapies, EKG's are mandatory prior to any surgical interventions, due to possible arrhythmia. patients with ventricular hypertrophy may follow familial Hypertrophic cardiomyopathy algorithms.[15] Genitourinary, musculoskeletal, neurological and orthodontic anomalies should be monitored and treated as for Noonan syndrome.[16]
Surgical Therapy
For those who are disturbed by the appearance of lentigines, Cryosurgery may be beneficial. Due to the large number of lentigines this may prove time consuming. In case of cardiac anomalies at diagnosis, a periodic assessment should be performed as recommended by the cardiologist. Mild pulmonary valve stenosis has a good prognosis, while severe valvular dysplasia may recommend valvulotomy or valvulectomy.[17]
Primary Prevention
It is recommended that those with the syndrome who are capable of having children seek genetic counseling before 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.[18] 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.
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.; Calabrò, R.; Marino, B.; Dallapiccola, B. (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. Unknown parameter
|month=ignored (help) - ↑ Tartaglia, M.; Martinelli, S.; Stella, L.; Bocchinfuso, G.; Flex, E.; Cordeddu, V.; Zampino, G.; Burgt, Iv.; Palleschi, A. (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. Unknown parameter
|month=ignored (help) - ↑ 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. Unknown parameter
|month=ignored (help) - ↑ Gorlin, RJ.; Anderson, RC.; Blaw, M. (1969). "Multiple lentigenes syndrome". Am J Dis Child. 117 (6): 652–62. PMID 5771505. Unknown parameter
|month=ignored (help) - ↑ 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.
- ↑ Elliott, P.; McKenna, WJ. (2004). "Hypertrophic cardiomyopathy". Lancet. 363 (9424): 1881–91. doi:10.1016/S0140-6736(04)16358-7. PMID 15183628. Unknown parameter
|month=ignored (help) - ↑ van der Burgt, I. (2007). "Noonan syndrome". Orphanet J Rare Dis. 2: 4. doi:10.1186/1750-1172-2-4. PMID 17222357.
- ↑ Limongelli, G.; Pacileo, G.; Marino, B.; Digilio, MC.; Sarkozy, A.; Elliott, P.; Versacci, P.; Calabro, P.; De Zorzi, A. (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. Unknown parameter
|month=ignored (help) - ↑ Józwiak S, Schwartz RA, Janniger CK (1996). "LEOPARD syndrome (cardiocutaneous lentiginosis syndrome)". Cutis. 57 (4): 208–14. PMID 8727768.