Leopard syndrome is a rare [[autosomal dominant]],<ref>{{cite journal |author=Coppin BD, Temple IK |title=Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis) |journal=J. Med. Genet. |volume=34 |issue=7 |pages=582–6 |year=1997 |pmid=9222968 |doi=}}</ref> 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 type I|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.<ref>{{cite journal |author=Tullu MS, Muranjan MN, Kantharia VC, ''et al'' |title=Neurofibromatosis-Noonan syndrome or LEOPARD Syndrome? A clinical dilemma |journal=J Postgrad Med |volume=46 |issue=2 |pages=98–100 |year=2000 |pmid=11013475 |url=http://www.jpgmonline.com/article.asp?issn=0022-3859;year=2000;volume=46;issue=2;spage=98;epage=100}}</ref>
LEOPARD syndrome is a rare [[autosomal dominant]],<ref>{{cite journal |author=Coppin BD, Temple IK |title=Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis) |journal=J. Med. Genet. |volume=34 |issue=7 |pages=582–6 |year=1997 |pmid=9222968 |doi=}}</ref> caused by a [[mutation]] in the [[PTPN11|protein tyrosine phosphatase non-receptor type 11 gene]]. Many systems can be involved, mostly involving the skin, skeletal and cardiovascular systems, but in other cases they are absent. The word LEOPARD is an acronym for the major features of this disorder, including multiple '''L'''entigines, '''E'''KG abnormalities, '''O'''cular hypertelorism, '''P'''ulmonic stenosis, '''A'''bnormal genitalia, '''R'''etardation of growth, and sensorineural '''D'''eafness
==Historical Perspective==
==Historical Perspective==
It was first described by Zeisler and Becker with multiple [[lentigo|lentigines]], [[hypertelorism]], [[pectus carinatum]] (protruding breastbone) and [[prognathism]] (protrusion of lower jaw) in 1936.<ref name="Zeisler1936">{{cite journal|last1=Zeisler|first1=Erwin P.|title=GENERALIZED LENTIGO<subtitle>ITS RELATION TO SYSTEMIC NONELEVATED NEVI</subtitle>|journal=Archives of Dermatology|volume=33|issue=1|year=1936|pages=109|issn=0003-987X|doi=10.1001/archderm.1936.01470070112010}}</ref>
It was first described by Zeisler and Becker with multiple [[lentigo|lentigines]], [[hypertelorism]], [[pectus carinatum]] (protruding breastbone) and [[prognathism]] (protrusion of lower jaw) in 1936.<ref name="Zeisler1936">{{cite journal|last1=Zeisler|first1=Erwin P.|title=GENERALIZED LENTIGO<subtitle>ITS RELATION TO SYSTEMIC NONELEVATED NEVI</subtitle>|journal=Archives of Dermatology|volume=33|issue=1|year=1936|pages=109|issn=0003-987X|doi=10.1001/archderm.1936.01470070112010}}</ref>
In 1962, cardiac abnormalities and short stature were first associated with the condition.<ref name="Zeisler1936">{{cite journal|last1=Zeisler|first1=Erwin P.|title=GENERALIZED LENTIGO<subtitle>ITS RELATION TO SYSTEMIC NONELEVATED NEVI</subtitle>|journal=Archives of Dermatology|volume=33|issue=1|year=1936|pages=109|issn=0003-987X|doi=10.1001/archderm.1936.01470070112010}}</ref>
In 1962, cardiac abnormalities and short stature were first associated with the condition.<ref name="Zeisler1936">{{cite journal|last1=Zeisler|first1=Erwin P.|title=GENERALIZED LENTIGO<subtitle>ITS RELATION TO SYSTEMIC NONELEVATED NEVI</subtitle>|journal=Archives of Dermatology|volume=33|issue=1|year=1936|pages=109|issn=0003-987X|doi=10.1001/archderm.1936.01470070112010}}</ref>
In 1966, three familial cases were added.<ref>{{cite journal |author=Walther RJ, Polansky BJ, Grotis IA |title=Electrocardiographic abnormalities in a family with generalized lentigo |journal=N. Engl. J. Med. |volume=275 |issue=22 |pages=1220–5 |year=1966 |pmid=5921856 |doi=}}</ref> In 1968 another case of mother to two separate children, with different paternity of the two children, was added.<ref>{{cite journal |author=Matthews NL |title=Lentigo and electrocardiographic changes |journal=N. Engl. J. Med. |volume=278 |issue=14 |pages=780–1 |year=1968 |pmid=5638719 |doi=}}</ref>
It was believed as late as 2002<ref>[http://www.nlm.nih.gov/cgi/mesh/2006/MB_cgi?mode=&term=LEOPARD+Syndrome&field=entry National Library of Medicine MeSH: C05.660.207.525]</ref> that Leopard syndrome was related to [[neurofibromatosis type I]] (von Recklinghausen syndrome).
==Pathophysiology==
==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.<ref>{{cite journal |author=Tartaglia M, Martinelli S, Stella L, ''et al'' |title=Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease |journal=Am. J. Hum. Genet. |volume=78 |issue=2 |pages=279–90 |year=2006 |pmid=16358218 |doi=10.1086/499925}}</ref> This interferes with growth factor and related signalling. While further research confirms this mechanism,<ref>{{cite journal |author=Hanna N, Montagner A, Lee WH, ''et al'' |title=Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1 |journal=FEBS Lett. |volume=580 |issue=10 |pages=2477–82 |year=2006 |pmid=16638574 |doi=10.1016/j.febslet.2006.03.088}}</ref><ref>{{cite journal |author=Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG |title=PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects |journal=J. Biol. Chem. |volume=281 |issue=10 |pages=6785–92 |year=2006 |pmid=16377799 |doi=10.1074/jbc.M513068200|url=http://www.jbc.org/cgi/content/full/281/10/6785}}</ref> additional research is needed to determine how this relates to all of the observed effects of Leopard syndrome.
LEOPARD syndrome is most commonly caused by [[missense mutation]]s in the [[PTPN11]] gene. It has also been associated with other gene mutations such as [[c-Raf|RAF1]] and [[BRAF]].
==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.<ref name="Digilio-2006">{{Cite journal | last1 = Digilio | first1 = MC. | last2 = Sarkozy | first2 = A. | last3 = de Zorzi | first3 = A. | last4 = Pacileo | first4 = G. | last5 = Limongelli | first5 = G. | last6 = Mingarelli | first6 = R. | last7 = Calabrò | first7 = R. | last8 = Marino | first8 = B. | last9 = Dallapiccola | first9 = B. | title = LEOPARD syndrome: clinical diagnosis in the first year of life. | journal = Am J Med Genet A | volume = 140 | issue = 7 | pages = 740-6 | month = Apr | year = 2006 | doi = 10.1002/ajmg.a.31156 | PMID = 16523510 }}</ref>
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.<ref name="Tartaglia-2006">{{Cite journal | last1 = Tartaglia | first1 = M. | last2 = Martinelli | first2 = S. | last3 = Stella | first3 = L. | last4 = Bocchinfuso | first4 = G. | last5 = Flex | first5 = E. | last6 = Cordeddu | first6 = V. | last7 = Zampino | first7 = G. | last8 = Burgt | first8 = Iv. | last9 = Palleschi | first9 = A. | title = Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. | journal = Am J Hum Genet | volume = 78 | issue = 2 | pages = 279-90 | month = Feb | year = 2006 | doi = 10.1086/499925 | PMID = 16358218 }}</ref> This interferes with growth factor and related signalling.
==Epidemiology and Demographics==
==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.<ref name="Voron-1976">{{Cite journal | last1 = Voron | first1 = DA. | last2 = Hatfield | first2 = HH. | last3 = Kalkhoff | first3 = RK. | title = Multiple lentigines syndrome. Case report and review of the literature. | journal = Am J Med | volume = 60 | issue = 3 | pages = 447-56 | month = Mar | year = 1976 | doi = | PMID = 1258892 }}</ref>
Leopaed syndrome is a rare condition, but the exact birth prevalence is unknown. Approximately 200 patients have been reported.<ref name="pmid1258892">{{cite journal| author=Voron DA, Hatfield HH, Kalkhoff RK| title=Multiple lentigines syndrome. Case report and review of the literature. | journal=Am J Med | year= 1976 | volume= 60 | issue= 3 | pages= 447-56 | pmid=1258892 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1258892 }} </ref> 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]].
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==
==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.
In general, males are more affected than females. LEOPARD syndrome is not a life threatening diagnosis, 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==
==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.<ref name="Gorlin-1969">{{Cite journal | last1 = Gorlin | first1 = RJ. | last2 = Anderson | first2 = RC. | last3 = Blaw | first3 = M. | title = Multiple lentigenes syndrome. | journal = Am J Dis Child | volume = 117 | issue = 6 | pages = 652-62 | month = Jun | year = 1969 | doi = | PMID = 5771505 }}</ref>
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, [[Failure to thrive|retardation of growth]], abnormal genitalia and [[Sensorineural hearing loss|sensorineural deafness]].<ref name="pmid5771505">{{cite journal| author=Gorlin RJ, Anderson RC, Blaw M| title=Multiple lentigenes syndrome. | journal=Am J Dis Child | year= 1969 | volume= 117 | issue= 6 | pages= 652-62 | pmid=5771505 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5771505 }} </ref>
===Laboratory Findings===
===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 [[c-Raf|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 [[Neurofibromatosis type I|NF1]], following evaluation of the mother.<ref>{{cite journal |author=Digilio MC, Sarkozy A, de Zorzi A, ''et al'' |title=LEOPARD syndrome: clinical diagnosis in the first year of life |journal=Am. J. Med. Genet. A |volume=140 |issue=7 |pages=740–6 |year=2006 |pmid=16523510 |doi=10.1002/ajmg.a.31156}}</ref>
Hormonal abnormalities may be revealed in some patients with endocrine system involvement. laboratory studies should include molecular analysis of the [[PTPN11]] and [[c-Raf|RAF1]] genes.<ref>{{cite journal |author=Digilio MC, Sarkozy A, de Zorzi A, ''et al'' |title=LEOPARD syndrome: clinical diagnosis in the first year of life |journal=Am. J. Med. Genet. A |volume=140 |issue=7 |pages=740–6 |year=2006 |pmid=16523510 |doi=10.1002/ajmg.a.31156}}</ref>
There are 5 identified [[alleles|allelic]] [[Genetic diversity|variant]]s 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===
===Imaging Studies===
*[[CT scanning]] or [[MRI]] - Brain atrophy may be revealed
Different imaging studies like [[X-rays]], [[CT scanning]], and [[Echocardiography]] have been used to detect abnormalities of LEOPARD syndrome.
*[[X-rays|Skeletal radiography]] - Detection of skeletal malformation and bone age assessment.
*[[Echocardiography]] - Indicated for visualization of structural heart abnormalities.
*[[Ultrasonography]] or [[Urographic examination]] - For assessment of the genitourinary system.
*[[Audiogram|Audiography]] or [[Brainstem auditory evoked potentials|Auditory evoked potentials]] - For detection of sensorineural deafness.
==Medical Therapy==
==Medical Therapy==
Medical management is routine care as symptoms present. For those with endocrine issues (low levels of [[thyroid stimulating hormone|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, [[electrocardiograph|EKG's]] are mandatory prior to any surgical interventions, due to possible [[arrhythmia]]. patients with ventricular hypertrophy may follow familial [[Hypertrophic cardiomyopathy]] algorithms.<ref name="Elliott-2004">{{Cite journal | last1 = Elliott | first1 = P. | last2 = McKenna | first2 = WJ. | title = Hypertrophic cardiomyopathy. | journal = Lancet | volume = 363 | issue = 9424 | pages = 1881-91 | month = Jun | year = 2004 | doi =10.1016/S0140-6736(04)16358-7 | PMID = 15183628 }}</ref> Genitourinary, musculoskeletal, neurological and orthodontic anomalies should be monitored and treated as for [[Noonan syndrome]].<ref name="van der Burgt-2007">{{Cite journal | last1 = van der Burgt | first1 = I. | title = Noonan syndrome. | journal = Orphanet J Rare Dis | volume = 2 | issue = | pages = 4 | month = | year = 2007 | doi = 10.1186/1750-1172-2-4 | PMID = 17222357 }}</ref>
Medical management depend on the symptoms present. Drug therapy for cardiac abnormalities,endocrine, and dermatological issues is recommended.
==Surgical Therapy==
==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.<ref name="Limongelli-2007">{{Cite journal | last1 = Limongelli | first1 = G. | last2 = Pacileo | first2 = G. | last3 = Marino | first3 = B. | last4 = Digilio | first4 = MC. | last5 = Sarkozy | first5 = A. | last6 = Elliott | first6 = P. | last7 = Versacci | first7 = P. | last8 = Calabro | first8 = P. | last9 = De Zorzi | first9 = A. | title = Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome. | journal = Am J Cardiol | volume = 100 | issue = 4 | pages = 736-41 | month = Aug | year = 2007 | doi = 10.1016/j.amjcard.2007.03.093 | PMID = 17697839 }}</ref>
Different procedures may be necessary in cases with severe outflow tract obstruction<ref name="pmid17697839">{{cite journal| author=Limongelli G, Pacileo G, Marino B, Digilio MC, Sarkozy A, Elliott P et al.| title=Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome. | journal=Am J Cardiol | year= 2007 | volume= 100 | issue= 4 | pages= 736-41 | pmid=17697839 | doi=10.1016/j.amjcard.2007.03.093 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17697839 }} </ref>, patients with [[cryptorchidism]], genitourinary, or severe skeletal deformity.
==Primary Prevention==
==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.<ref name="pmid8727768">{{cite journal| author=Józwiak S, Schwartz RA, Janniger CK| title=LEOPARD syndrome (cardiocutaneous lentiginosis syndrome). | journal=Cutis | year= 1996 | volume= 57 | issue= 4 | pages= 208-14 | pmid=8727768 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8727768 }} </ref> 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.
Genetic counseling should be offered before deciding to have children, careful examination of all family members as the syndrome usually present with incomplete form.
LEOPARD syndrome is a rare autosomal dominant,[1] caused by a mutation in the protein tyrosine phosphatase non-receptor type 11 gene. Many systems can be involved, mostly involving the skin, skeletal and cardiovascular systems, but in other cases they are absent. The word LEOPARD is an acronym for the major features of this disorder, including multiple Lentigines, EKG abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, and sensorineural Deafness
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.[2]
In 1962, cardiac abnormalities and short stature were first associated with the condition.[2]
Pathophysiology
LEOPARD syndrome is most commonly caused by missense mutations in the PTPN11 gene. It has also been associated with other gene mutations such as RAF1 and BRAF.
Epidemiology and Demographics
Leopaed syndrome is a rare condition, but the exact birth prevalence is unknown. Approximately 200 patients have been reported.[3] 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 general, males are more affected than females. LEOPARD syndrome is not a life threatening diagnosis, cardiomyopathy and other pathologic findings involving the cardiovascular system may be a cause of death in those whose cardiac deformities are profound.
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.[4]
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.[5]
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[6], 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. PMID9222968.
↑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. PMID16523510.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)