Name = LEOPARD syndrome
DiseasesDB = 7387
OMIM = 151100
eMedicineSubj = derm
eMedicineTopic = 627
MeshName = LEOPARD+Syndrome
MeshNumber = C05.660.207.525
LEOPARD syndrome is a rare
autosomal dominant, [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=] multisystem disease caused by a mutationin 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 mutationof 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 syndromeis 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. [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]
igns and symptoms
The name of the condition is a
mnemonic, originally coined in 1969, [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=] 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.
* 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), or on the surface of the eye ( scleral). These have irregular borders and range in size from 1 mm in diameter to café-au-lait spot's, several cm's in diameter. Also, some areas of vitiligo-like hypopigmentationmay be observed.
Electrocardiographicconduction abnormalities: Generally observed on an electrocardiographas a bundle branch block.
Ocular hypertelorism: Wideset eyes, which lead to a similar facial resemblance between patients. Facial abnormalities are the second highest occurring symptom after the lentigines. Abnormalities also include: broad nasal root, prognathism(protruding lower jaw), or low-set, possibly rotated, ears.
Pulmonary stenosis: Narrowing of the pulmonary arteryas it exits the heart. Other cardiac abnormalities may be present, including aortic stenosis, or mitral valve prolapse.
Abnormal genitalia: (usually cryptorchidism(retention of testiclesin 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.
* 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.
Deafness: Sensorineural (nerve deafness).
The presence of all of these
hallmarksis not needed for a diagnosis. A clinical diagnosisis 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. [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=]
*additional dermatologic abnormalities (axillary freckling, localized
hypopigmentation, interdigital webbing, hyperelastic skin)
*Mild mental retardation is observed in about 30% of those affected with the syndrome
Nystagmus(involuntary eye movements), seizures, or hyposmia(reduced ability to smell) has been documented in a few patients
*In 2004, a patient was reported with recurrent upper extremity
aneurysmsthat required surgical repairs. [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=Apr |pmid=15071461 |doi=10.1016/j.jvs.2003.11.030 |url=]
*In 2006, a LEOPARD syndrome patient was reported with acute myelogenous leukemia. [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=Mar |pmid=16679933 |doi=10.1097/01.mph.0000199590.21797.0b |url=]
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.
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 NF1, following evaluation of the mother. [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]
There are 5 identified allelic variants 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
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 activityof the SHP2 protein(the gene product of the " PTPN11" gene), which is a previously unrecognized behavior for this class of mutations. [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] This interferes with growth factor and related signalling. While further research confirms this mechanism, [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] [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] additional research is needed to determine how this relates to all of the observed effects of LEOPARD syndrome.
Prognosis and treatment
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.
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.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=] 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:
# For those with endocrine issues (low levels of thyrotopin [a pituitary hormone responsible for regulating thyroid hormones] ,
follicle stimulating hormone) drug therapy is recommended.
# 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.
# Drug therapies for those with cardiac abnormalities, as those abnormalities become severe enough to warrant the use of these therapies. ECG's are mandatory prior to any surgical interventions, due to possible
Various literature describes it as being "rare" or "extremely rare". [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=] 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.
Zeisler and Becker first described a syndrome with multiple lentigines,
hypertelorism, pectus carinatum(protruding breastbone) and prognathism(protrusion of lower jaw) in 1936. [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] Sporadic descriptions were added through the years. In 1962, cardiac abnormalities and short stature were first associated with the condition. [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 ] In 1966, three familial cases were added, a mother, her son and daughter. [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=] Another case of mother to two separate children, with different paternity of the two children, was added in 1968. [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=]
It was believed as late as 2002 [ [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] ] that LEOPARD syndrome was related to
neurofibromatosis type I(von Recklinghausen syndrome). In fact, since both ICD9and ICD10lack 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. [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=]
* [http://www.dermnetnz.org/systemic/leopard.html Dermnetnz]
* [http://www.dermis.net/dermisroot/en/37635/diagnose.htm DermIS]
* [http://www.hgfound.org Human Growth Foundation]
* [http://www.magicfoundation.org MAGIC Foundation for Children's Growth]
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