Multiple lentigines syndrome

Multiple lentigines syndrome (formerly called LEOPARD syndrome) is a condition that affects many areas of the body. The characteristic features associated with the condition include brown skin spots called lentigines that are similar to freckles, abnormalities in the electrical signals that control the heartbeat, widely spaced eyes (ocular hypertelorism), a narrowing of the artery from the heart to the lungs (pulmonary stenosis), abnormalities of the genitalia, short stature, and hearing loss. These features vary, however, even among affected individuals in the same family. Not all individuals affected with multiple lentigines syndrome have all the characteristic features of this condition.

The lentigines seen in multiple lentigines syndrome typically first appear in mid-childhood, mostly on the face, neck, and upper body. Affected individuals may have thousands of brown skin spots by the time they reach puberty. Unlike freckles, the appearance of lentigines has nothing to do with sun exposure. In addition to lentigines, people with this condition may have lighter brown skin spots called café-au-lait spots. Café-au-lait spots tend to develop before the lentigines, appearing within the first year of life in most affected people.

Abnormal electrical signaling in the heart can be a sign of other heart problems. Of the people with multiple lentigines syndrome who have heart problems, about 80 percent have hypertrophic cardiomyopathy, which is a thickening of the heart muscle that forces the heart to work harder to pump blood. The hypertrophic cardiomyopathy in affected individuals most often affects the lower left chamber of the heart (the left ventricle). Up to 20 percent of people with multiple lentigines syndrome who have heart problems have pulmonary stenosis.

People with multiple lentigines syndrome can have a distinctive facial appearance. In addition to ocular hypertelorism, affected individuals may have droopy eyelids (ptosis), thick lips, and low-set ears.

Abnormalities of the genitalia occur most often in males with multiple lentigines syndrome. The most common abnormality in affected males is undescended testes (cryptorchidism). Other males may have a urethra that opens on the underside of the penis (hypospadias). Males with multiple lentigines syndrome may have a reduced ability to have biological children (decreased fertility). Females with multiple lentigines syndrome may have poorly developed ovaries and delayed puberty.

At birth, people with multiple lentigines syndrome are typically of normal weight and height, but in some, growth slows over time. This slow growth results in short stature in 50 to 75 percent of people with multiple lentigines syndrome.

Approximately 20 percent of individuals with multiple lentigines syndrome develop hearing loss. This hearing loss is caused by abnormalities in the inner ear (sensorineural deafness) and can be present from birth or develop later in life.

Other signs and symptoms of multiple lentigines syndrome include learning disorders, mild developmental delay, a sunken or protruding chest, and extra folds of skin on the back of the neck.

Many of the signs and symptoms of multiple lentigines syndrome also occur in a similar disorder called Noonan syndrome. It can be difficult to tell the two disorders apart in early childhood. However, the features of the two disorders differ later in life.

Read more about Noonan syndrome.

Multiple lentigines syndrome is thought to be a rare condition; approximately 200 cases have been reported worldwide.

Mutations in the PTPN11, RAF1, or BRAF genes cause multiple lentigines syndrome. Approximately 90 percent of individuals with multiple lentigines syndrome have mutations in the PTPN11 gene. RAF1 and BRAF gene mutations are responsible for a total of about 10 percent of cases. A small proportion of people with multiple lentigines syndrome do not have an identified mutation in any of these three genes. In these individuals, the cause of the condition is unknown.

The PTPN11, RAF1, and BRAF genes all provide instructions for making proteins that are involved in important signaling pathways needed for the proper formation of several types of tissue during development. These proteins also play roles in the regulation of cell division, cell movement (migration), and cell differentiation (the process by which cells mature to carry out specific functions).

Mutations in the PTPN11, RAF1, or BRAF genes lead to the production of a protein that functions abnormally. This abnormal functioning impairs the protein's ability to respond to cell signals. A disruption in the regulation of systems that control cell growth and division leads to the characteristic features of multiple lentigines syndrome.

Read more about the BRAF, PTPN11, and RAF1 genes.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.