LEOPARD Syndrome

LEOPARD Syndrome (LS) is an autosomal dominant disorder causing skin, facial, and cardiac anomalies. 

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LEOPARD Syndrome (LS) is an autosomal dominant disorder causing skin, facial, and cardiac anomalies. 

LEOPARD is an acronym for the main features of the disorder: multiple Lentigines, ECG conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, and sensorineural Deafness. Other LS findings can include skeletal abnormalities, intellectual disability, acute myelogenous leukemia and neuroblastoma.

Mutations in two genes cause LEOPARD Syndrome: the PTPN11 gene, which accounts for 90% of cases, and RAF1 (exons 7, 12, 14, and 17), which accounts for another 3%. The Ambry Test: LEOPARD Syndrome includes concurrent sequencing of the full PTPN11 gene and the relevant exons of RAF1 for mutation detection in 93% of cases.

Noonan Syndrome is also caused by PTPN11 and RAF1 mutations. Please see our separate Noonan Syndrome Test listing for Noonan Syndrome testing information.

Disease Name 
LEOPARD Syndrome
Disease Information 

LEOPARD syndrome (LS) is a rare, autosomal dominant disorder with high penetrance and variable expressivity characterized by skin, facial, and cardiac anomalies. LEOPARD is an acronym for the main features of the disorder: multiple Lentigines, ECG conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, and sensorineural Deafness.1,2,3,4,5,6 Lentigines are dispersed flat black-brown macules, which mostly appear on the face, neck and upper trunk. Typically, they do not appear until 4-5 years of age and increase in number until puberty.4 Café au lait spots are also seen.5 Facial features of LS include inverted triangular-shaped face, down-slanting palpebral fissures, low-set posterior rotated ears with thickened helices, and hypertelorism. The neck can also be short with excess nuchal skin.5 Birth weight is usually normal in patients with LS, but post-natal growth retardation may result in short stature.5 Sensorineural deafness is seen in approximately 20% of patients.4 Hypertrophic cardiomyopathy, if present, is the only life threatening condition identified in LS patients. Adults with LS do not tend to require special medical care and have a normal life span.8 LS is caused by mutations in one of two genes, PTPN11 which accounts for 90% of cases, and RAF1 (exons 7, 12, 14, and 17), which accounts for another 3%.3 Other findings of LS include skeletal abnormalities, like broad chest and pectus carinatum/excavatum in 75% of newborns,5 and mild learning difficulties to mental retardation (seen in approximately 30% of patients).1 LS has also been associated with acute myelogenous leukemia and neoroblastoma in some patients.

Testing Benefits & Indication 

Diagnosis of Leopard syndrome (LS) can be difficult due to its variable expressivity and genetic overlap with Noonan syndrome. Molecular genetic testing can be a useful tool for diagnosis confirmation of LS.8 Parental testing should be considered when a mutation has been identified in a patient to determine if mutation is de novo or inherited and for accurate risk assessment. Prenatal diagnosis is available for families with a known disease-causing mutation.

Test Description 

The Ambry Test: LEOPARD Syndrome is a full gene sequence analysis performed by PCR-based double-stranded automated sequencing in the sense and antisense directions for exons 1-15 of the PTPN11 gene and exons 7,12, 14, and 17 of the RAF1 gene, plus at least 20 bases into the 5’ and 3’ ends of all the introns. Specific mutation analysis for individual PTPN11 and RAF1 mutations known to be in the family is also available.

Mutation Detection Rate 

Mutations in PTPN11 and RAF1 account for 93% of LS.3 The Ambry Test: LEOPARD Syndrome can detect approximately 99% of known mutations.

Specimen Requirements 

Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Blood Spot: Call for availability
Saliva: Collect 2 ml into Oragene™ DNA Self-Collection container. Store and ship at room temperature.
DNA: Minimum DNA Amount of 5μg of DNA at a concentration of ~100ng/μl in 50μl TE (10mM Tris-Cl pH 8.0, 1mM EDTA); preferred 20μg. Store frozen and ship on ice or dry ice.  
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case.

Billing Codes 
Test Code Technique
2280 PTPN11 Gene Sequence Analysis

 

Turnaround Time 
Technique Days
PTPN11 Gene Sequence Analysis 10-21

 

Genes 
References 

1. Sarkozy A, Conti E, Digilo MC et al. Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J Med Genet. 2004;41: e68. [PMID: 15121796]

2. Sommerville J & Bonham-Carter RE. The heart in lentiginosis. Br Heart J. 1972;34:58-66. [PMID: 4258224]

3. Pandit B, Sarkozy A, Pennacchio LA et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007;39:1007-1012. [PMID: 17603483]

4. Coppin BD & Temple IK. Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis). J Med Genet. 1997;34:582-586. [PMID: 9222968]

5. Digilio MC, Sarkozy A, de Zorzi A et al. LEOPARD syndrome: clinical diagnosis in the first year of life. Am J Med Genet A. 2006;140:740-746. [PMID: 16523510]

6. Limongelli G, Pacileo G, Marino B et al. Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome. Am J Cardiol. 2007;100:736-741. [PMID: 17697839]

7. Keren B et al. PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience. J Med Genet. 2004;41:e117. [PMID: 15520399]

8. Merks JH et al. High incidence of malformation syndromes in a series of 1,073 children with cancer. Am J Med Genet. 2005;134:132-143. [PMID: 15712196]

9. Sarkozy A, Digilio MC, Dallapiccola B. Leopard syndrome. Orphanet J Rare Dis. 2008;3:13. [PMID: 18505544]