Trait Document

LEOPARD syndrome is a genetic condition, and the acronym stands for the common features seen in this syndrome: Lentigines (i.e., brown-black spots on the skin similar to freckles), ECG conduction abnormalities (i.e., problems with the electrical activity of the heart), Ocular hypertelorism (i.e., widely spaced eyes), Pulmonic stenosis (i.e., a heart defect where there is narrowing of the artery that carries blood from the heart to the lungs), Abnormal genitalia (e.g., undescended testicles in males), Retardation of growth (i.e., short stature), and sensorineural Deafness (i.e., hearing loss due to damage to the inner ear). There is great deal of variation in the clinical features observed among individuals with LEOPARD syndrome, even within the same family. Lentigines typically first appear in early childhood and can rapidly increase in number (i.e. to the thousands) by puberty. Skeletal problems and hypertrophic cardiomyopathy (i.e., a heart condition where the heart becomes thicker, making it more difficult for it to pump blood to the rest of the body) are commonly seen in this condition. A minority of individuals with LEOPARD syndrome have learning disabilities and/or mild intellectual disability.

LEOPARD syndrome can be diagnosed either by meeting certain clinical criteria or by genetic testing for a change or mutation in one of three genes: PTPN11, RAF1 or BRAF. These genes are involved in a complex signaling pathway called the “RAS-MAPK pathway” which is important for the proper formation of many different types of tissue during human development. A mutation in any one of these genes disrupts this signaling pathway.

Management and surveillance of individuals with LEOPARD syndrome often includes regular physical exams, eye exams, hearing evaluations, kidney ultrasounds, and ultrasounds of the heart. Educational services are also recommended for individuals with learning disabilities/intellectual disability.

LEOPARD syndrome is inherited in an autosomal dominant pattern. This means inheriting one mutation is enough for an individual to be affected and show signs of LEOPARD syndrome. The mutation can be inherited from an affected parent or it can occur brand new (de novo) in an affected child.

The risk to family members depends on whether or not the individual with LEOPARD syndrome has a parent affected with LEOPARD syndrome. If a parent also has LEOPARD syndrome, the risk of having a child with LEOPARD syndrome is 50% with each pregnancy. If a parent does not have LEOPARD syndrome, the risk of future pregnancies being affected is very low.

Certain types of mutations in the PTPN11 gene cause LEOPARD syndrome, while other types of mutations in the same gene cause a different genetic syndrome called Noonan syndrome (see trait profile). While both conditions share similar features, individuals with Noonan syndrome typically do not have multiple lentigines.