LEOPARD Syndrome

LEOPARD syndrome is a rare inherited condition with symptoms involving the skin, face, and heart.  Because these can be variable and overlap with other inherited conditions, genetic testing can confirm the diagnosis and identify family members that may be at risk.


LEOPARD syndrome is a rare inherited condition with symptoms involving the skin, face, and heart.  Because these can be variable and overlap with other inherited conditions, genetic testing can confirm the diagnosis and identify family members that may be at risk.

Ambry offers testing for the most common genetic causes of LEOPARD syndrome in order to allow people to make informed decisions about their healthcare and medical management.

Disease Name 
LEOPARD Syndrome
Disease Information 

LEOPARD syndrome (LS) is a rare inherited disorder, and the exact incidence is not known.1 LS is passed through families in an autosomal dominant pattern.1 This disorder has high penetrance but variable expressivity.2 LEOPARD is an acronym for the main features of the disorder: multiple Lentigines (pigmented spots on the skin), ECG conduction abnormalities, Ocular hypertelorism (widely-spaced eyes), Pulmonic stenosis (narrowing of the pulmonary artery), Abnormal genitalia, Retardation of growth, and sensorineural Deafness.1,2

Lentigines are dispersed flat black-brown macules that 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.3  Café-au-lait spots are also common.4  Facial characteristics of LS often include an inverted triangular appearance to the face, down-slanting eyes, low-set posteriorly rotated ears with thickened helices, and hypertelorism. The neck can also be shorter, with excess nuchal skin.4  Birth weight is usually normal in patients with LS, but postnatal growth retardation may result in short stature.4,5  Sensorineural deafness is seen in approximately 20% of patients.3  Hypertrophic cardiomyopathy (HCM), if present, is a life threatening condition identified in LS patients.6  Other findings of LS include skeletal abnormalities, like a broad chest and pectus carinatum/excavatum in 75% of newborns,and developmental delay to varying degrees (seen in approximately 30% of patients).7 LS has also been associated with acute myelogenous leukemia and neuroblastoma in some patients.

LS is caused by mutations in one of three genes, PTPN11 (accounts for 90% of cases) and RAF1 (exons 7, 12, 14, and 17 accounts for another 3-5%) and BRAF (accounting for less than 5% of cases).3,5,8  Diagnosis of LS can be difficult due to its variable expressivity and significant clinical overlap with Noonan syndrome. Molecular genetic testing can be a useful tool for diagnosis confirmation/clarification of LS, establishing prognosis, allowing adequate follow-up, and identifying at-risk family members.2

Testing Benefits & Indication 

Genetic testing for LS is can establish an accurate diagnosis, which allows for medical screening/treatment and at-risk family members to be identified.  It may be considered for:

  • Confirming a clinical diagnosis of LS
  • A person with a congenital heart defect and any characteristic finding associated with LS
  • Testing a parent of a child with a known mutation
  • Other at-risk family members, including prenatal testing for a known familial mutation
Test Description 

Ambry’s LEOPARD syndrome testing provides gene sequencing of the two genes implicated in close to 95% of cases.  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 Site Analysis for PTPN11 and RAF1 mutations known to be in the family is also available.

Mutation Detection Rate 

Mutations in PTPN11 and RAF1 account for 93-95% of LS (clinical sensitivity).3,5,8  Ambry’s LEOPARD gene sequencing test detects approximately 99% of known mutations in these genes (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Turnaround Time 
TEST CODE Technique Days                       
8460 LEOPARD Syndrome  (PTPN11, RAF1 exons 7, 12, 14, and 17)          10-28


  1. Orphanet.  http://www.orpha.net//consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=500.  Updated 2008.  Accessed 2015.
  2. Santoro C, et al.  LEOPARD syndrome: clinical dilemmas in differential diagnosis of RASopathies.  BMC Med Genet. 2014 Apr 26;15:44.  [PMID: 24767283]
  3. Coppin BD and Temple IK. Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis). J Med Genet. 1997;34:582-586. [PMID: 9222968]
  4. Digilio MC, et al. LEOPARD syndrome: clinical diagnosis in the first year of life. Am J Med Genet A. 2006;140:740-746. [PMID: 16523510]
  5. Gelb B and Tartaglia M.  LEOPARD Syndrome.  Initial positing 2007, updated 2010.  GeneReviews. 2014. Pagon RA, Adam MP, Ardiner HH et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2014. 
  6. Onesti MG et al.  An uncommon association between skin lesions and LEOPARD syndrome affected an old patient. Case report.  Ann Ital Chir. 2011 Jan-Feb;82(1):79-82. [PMID: 21657161]
  7. 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]
  8. Lauriol, J and Kontaridis, MI.  PTPN11-associated mutations in the heart: has LEOPARD changed its RASpots? Trends Cardiovasc Med. 2011 May;21(4):97-104 [PMID: 22681964]