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| {{Infobox_Disease | | | __NOTOC__ |
| Name = LEOPARD syndrome |
| | {{Leopard syndrome}} |
| Image = Leopardsyn3.jpg|
| | {{CMG}}; {{AE}} {{MM}} |
| Caption = 21 month old, third generation patient, confirmed by genetic tests as [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176876&a=176876_AllelicVariant0005 Y279C], exhibiting ocular hyperteliorism, cephalofacial similarity.|
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| DiseasesDB = 7387 |
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| ICD10 = |
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| ICD9 = |
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| ICDO = |
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| OMIM = 151100 |
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| MedlinePlus = |
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| eMedicineSubj = derm |
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| eMedicineTopic = 627 |
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| MeshName = LEOPARD+Syndrome |
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| MeshNumber = C05.660.207.525 |
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| }} | |
| {{SI}} | |
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| {{CMG}} | | {{SK}} Capute-Rimoin-Konigsmark-Esterly-Richardson syndrome; cardiocutaneous syndrome; cardiomyopathic lentiginosis; Gorlin syndrome II; lentiginosis profusa syndrome; Moynahan syndrome; multiple lentigines syndrome; progressive cardiomyopathic lentiginosis |
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| ==Overview== | | ==[[Leopard syndrome overview|Overview]]== |
| 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>
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| ==Signs and symptoms== | | ==[[Leopard syndrome historical perspective|Historical Perspective]]== |
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| The name of the condition is a [[mnemonic]], originally coined in 1969,<ref>{{cite journal |author=Gorlin RJ, Anderson RC, Blaw M |title=Multiple lentigenes syndrome |journal=Am. J. Dis. Child. |volume=117 |issue=6 |pages=652–62 |year=1969 |pmid=5771505 |doi=}}</ref> 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 [[lentigo|lentigines]] that is reminiscent of the large cat.
| | ==[[Leopard syndrome pathophysiology|Pathophysiology]]== |
| * [[lentigo|Lentigines]] - Reddish-brown to dark brown [[macules]] (surface skin [[lesion]]) generally occurring in a high number (10,000+) over a large portion of the skin, at times higher than 80% coverage. These can even appear inside the mouth ([[Buccal mucosa]]), or on the surface of the eye ([[sclera]]l). These have irregular borders and range in size from 1 [[Millimetre|mm]] in diameter to [[café-au-lait spot]]'s, several [[Centimetre|cm]]'s in diameter. Also, some areas of [[vitiligo]]-like [[hypopigmentation]] may be observed.
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| * Electrocardiographic conduction abnormalities: Generally observed on an [[electrocardiograph]] as a [[bundle branch block]].
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| * [[Ocular hypertelorism]]: Wideset eyes, which lead to a similar facial resemblance between patients. Facial abnormalities are the second highest occurring symptom after the [[lentigo|lentigines]]. Abnormalities also include: broad nasal root, [[prognathism]] (protruding lower jaw), or low-set, possibly rotated ears.
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| * [[Pulmonary stenosis]]: Narrowing of the [[pulmonary artery]] as it exits the [[heart]]. Other cardiac abnormalities may be present, including [[aortic stenosis]], or [[mitral valve prolapse]].
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| * [[Abnormal]] [[genitalia]]: (usually [[cryptorchidism]] (retention of [[testicles]] in body) or [[monorchism]] (single testicle). In female patients, this presents as missing or single ovaries, much harder by nature to detect. Ultrasound imaging is performed at regular intervals, from the age of 1 year, to determine if ovaries are present.
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| * [[Failure to thrive|Retarded growth]]: Slow, or stunted growth. Most newborns with this syndrome are of normal birth weight and length, but will often slow within the first year.
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| * [[Deafness]]: [[Sensorineural hearing loss|Sensorineural]] (nerve deafness).
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| The presence of all of these [[hallmarks]] is not needed for a diagnosis. A clinical [[diagnosis]] is considered made when, with [[lentigo|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.<ref>{{cite journal |author=Voron DA, Hatfield HH, Kalkhoff RK |title=Multiple lentigines syndrome. Case report and review of the literature |journal=Am. J. Med. |volume=60 |issue=3 |pages=447–56 |year=1976 |pmid=1258892 |doi=}}</ref>
| | ==[[Leopard syndrome differential diagnosis|Differentiating Leopard syndrome from other Diseases]]== |
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| *additional dermatologic abnormalities (axillary freckling, localized [[hypopigmentation]], interdigital webbing, hyperelastic skin)
| | ==[[Leopard syndrome epidemiology and demographics|Epidemiology and Demographics]]== |
| *Mild mental retardation is observed in about 30% of those affected with the syndrome
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| *[[Nystagmus]] (involuntary eye movements), [[seizures]], or [[hyposmia]] (reduced ability to smell) has been documented in a few patients
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| *In 2004, a patient was reported with recurrent upper extremity [[aneurysms]] that required surgical repairs.<ref>{{cite journal |author=Yagubyan M, Panneton JM, Lindor NM, Conti E, Sarkozy A, Pizzuti A |title=LEOPARD syndrome: a new polyaneurysm association and an update on the molecular genetics of the disease |journal=J. Vasc. Surg. |volume=39 |issue=4 |pages=897–900 |year=2004 |month=April |pmid=15071461 |doi=10.1016/j.jvs.2003.11.030 |url=}}</ref>
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| *In 2006, a LEOPARD syndrome patient was reported with [[leukemia|acute myelogenous leukemia]].<ref>{{cite journal |author=Uçar C, Calýskan U, Martini S, Heinritz W |title=Acute myelomonocytic leukemia in a boy with LEOPARD syndrome (PTPN11 gene mutation positive) |journal=J. Pediatr. Hematol. Oncol. |volume=28 |issue=3 |pages=123–5 |year=2006 |month=March |pmid=16679933 |doi=10.1097/01.mph.0000199590.21797.0b |url=}}</ref>
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| 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.
| | ==[[Leopard syndrome natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
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| <gallery>
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| Image:Leopardsyn1a.jpg|Three-quarter facial view, first generation patient showing slight prognathism and [[low set ears]].
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| Image:Leopardsyn2.jpg|Thirty seven year old, second generation patient, exhibiting hypertelorism, broad nasal root, slight ptosis
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| Image:Leopardsyn2e.jpg|Hand of thirty seven year old patient showing interdigital webbing
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| Image:Leopardsyn2f.jpg|Thirty seven year old patient demonstrating hyperelasticity
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| Image:Autosomal Dominant Pedigree Chart.svg|LEOPARD syndrome is inherited in an [[autosomal dominant]] fashion, although it can also arise due to spontaneous mutation.
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| Image:Leopardsyn3.jpg|21 month old, third generation patient, confirmed by genetic tests as [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176876&a=176876_AllelicVariant0005 Y279C], exhibiting ocular hyperteliorism, cephalofacial similarity.
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| Image:Leopardsyn2b.jpg|Torso of thirty seven year old, second generation patient, exhibiting lentiginosis.
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| </gallery>
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| ==Diagnosis== | | ==Diagnosis== |
| The presence of the disease can be confirmed with a genetic test. 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>
| | [[Leopard syndrome history and symptoms| History and Symptoms]] | [[Leopard syndrome laboratory findings|Laboratory Findings]] | [[Leopard syndrome imaging findings|Imaging Findings]] |
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| There are 5 identified [[alleles|allelic]] [[Genetic diversity|variant]]s responsible for LEOPARD syndrome. [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176876&a=176876_AllelicVariant0005 Y279C], [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176876&a=176876_AllelicVariant0006 T468M], [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176876&a=176876_AllelicVariant0020 A461T], [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176876&a=176876_AllelicVariant0021 G464A], and [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176876&a=176876_AllelicVariant0022 Q510P] which seems to be a unique familial mutation, in that all other variants are caused by transition errors, rather than [[transversion]].
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| ==Pathophysiology==
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| In the two predominant mutations of LEOPARD syndrome ([http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176876&a=176876_AllelicVariant0005 Y279C] and [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176876&a=176876_AllelicVariant0006 T468M]) 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.
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| ==Prognosis and treatment==
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| 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.
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| It is suggested that, once diagnosed, individuals be routinely followed by a cardiologist, endocrinologist, dermatologist, and other appropriate specialties as symptoms present.
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| 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=Emedicine>{{cite web |author=Sergiusz Jozwiak, MD, PhD|url=http://www.emedicine.com/DERM/topic627.htm |title=eMedicine - LEOPARD Syndrome |accessdate=2008-01-20 |format= |work=}}</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.
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| 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.
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| Other management is routine care as symptoms present:<ref name=Emedicine/>
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| # 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.
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| # 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. An alternative treatment with tretinoin or hydroquinone creams may help.
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| # Drug therapies for those with cardiac abnormalities, as those abnormalities become severe enough to warrant the use of these therapies. [[electrocardiograph|ECG's]] are mandatory prior to any surgical interventions, due to possible [[arrythmia]].
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| ==Epidemiology==
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| Various literature describes it as being "rare"<ref name=Emedicine/> or "extremely rare".<ref>{{cite web |url=http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=LEOPARD%20Syndrome |title=NORD - National Organization for Rare Disorders, Inc. |accessdate=2008-01-20 |format= |work=}}</ref> 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.
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| ==History==
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| Zeisler and Becker first described a syndrome with multiple [[lentigo|lentigines]], [[hypertelorism]], [[pectus carinatum]] (protruding breastbone) and [[prognathism]] (protrusion of lower jaw) in 1936.<ref>{{cite journal|author=Zeisler EP, Becker SW|title=Generalized lentigo: its relation to systemic nonelevated nevi|journal=Arch Dermatol Syphilol|year=1936|volume=33|pages=109–125}}</ref> Sporadic descriptions were added through the years. In 1962, cardiac abnormalities and short stature were first associated with the condition.<ref>{{cite journal|author=Moynahan EJ|title=Multiple symmetrical moles, with psychic and somatic infantilism and genital hypoplasia: first male case of a new syndrome|journal=Proc Roy Soc Med|volume= 55|pages=959–960|year=1962 }} {{PMC|1896920}} <!--not indexed on Pubmed--></ref> In 1966, three familial cases were added, a mother, her son and daughter.<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> Another case of mother to two separate children, with different paternity of the two children, was added in 1968.<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>
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| 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). In fact, since both [[ICD9]] and [[ICD10]] lack a specific diagnosis code for LEOPARD syndrome, the diagnosis code for [[Neurofibromatosis type I|NF1]] is still sometimes used for diagnostic purposes, although it has been shown that the gene is not linked to the [[Neurofibromatosis type I|NF1]] locus.<ref>{{cite journal |author=Ahlbom BE, Dahl N, Zetterqvist P, Annerén G |title=Noonan syndrome with café-au-lait spots and multiple lentigines syndrome are not linked to the neurofibromatosis type 1 locus |journal=Clin. Genet. |volume=48 |issue=2 |pages=85–9 |year=1995 |pmid=7586657 |doi=}}</ref>
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| ==See also==
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| * [[Noonan syndrome]]
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| * [[Neurofibromatosis]]
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| ==References==
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| {{reflist|2}}
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| ==External links==
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| * {{GeneTests|LEOPARD}}
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| * {{WhoNamedIt|synd|2212}}
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| * {{DermAtlas|981603547}}
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| * [http://www.dermnetnz.org/systemic/leopard.html Dermnetnz]
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| * [http://www.dermis.net/dermisroot/en/37635/diagnose.htm DermIS]
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| * [http://www.hgfound.org Human Growth Foundation]
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| * [http://www.magicfoundation.org MAGIC Foundation for Children's Growth]
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| | ==Treatment== |
| | [[Leopard syndrome medical therapy|Medical Therapy]] | [[Leopard syndrome surgery|Surgery]] | [[Leopard syndrome primary prevention|Primary Prevention]] | [[Leopard syndrome secondary prevention|Secondary Prevention]] |
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| | ==Case Studies== |
| | [[Leopard syndrome case study one|Case#1]] |
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| [[Category:Genetic disorders]] | | [[Category:Genetic disorders]] |
| [[Category:Syndromes]] | | [[Category:Syndromes]] |
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| [[de:LEOPARD-Syndrom]]
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| [[fr:Syndrome LEOPARD]]
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| [[pl:Zespół LEOPARD]]
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| {{WH}} | | {{WH}} |
| {{WS}} | | {{WS}} |
| {{jb1}}
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