Noonan syndrome with multiple lentigines

Noonan Syndrome with Multiple Lentigines (NSML), formerly known as LEOPARD syndrome, is a rare genetic disorder characterized by distinctive facial features, heart defects, developmental delays, and multiple lentigines. NSML is part of a group of disorders known as RASopathies, which are caused by mutations in genes that are part of the RAS/MAPK pathway, crucial for cell division, growth, and differentiation.

Characteristics

NSML is characterized by multiple lentigines, which are flat, black-brown skin lesions that are similar to freckles. These lentigines typically increase in number with age, starting in childhood and peaking during adolescence. Other common features include:

• Cardiac anomalies: Most notably, hypertrophic cardiomyopathy, which is a condition where the heart muscle becomes abnormally thick.
• Facial features: Individuals with NSML often have distinctive facial features such as widely spaced eyes (hypertelorism), drooping eyelids (ptosis), and low-set ears.
• Skeletal abnormalities: Such as chest deformities (pectus excavatum or pectus carinatum) and scoliosis.
• Growth and developmental delays: Short stature and developmental delays are common, though intelligence ranges from normal to mild intellectual disability.
• Hearing loss: Sensorineural hearing loss can occur in some individuals.

Genetics

NSML is caused by mutations in the PTPN11, RAF1, or BRAF genes. These genes encode proteins that are part of the RAS/MAPK pathway, which is involved in cell growth and division. Mutations in these genes lead to uncontrolled cell growth, which contributes to the development of the features of NSML. The condition is inherited in an autosomal dominant pattern, meaning a mutation in just one of the two copies of the gene is sufficient to cause the disorder.

Diagnosis

Diagnosis of NSML is based on clinical evaluation and the identification of characteristic features. Genetic testing can confirm the diagnosis by identifying a mutation in one of the associated genes. Prenatal testing is available for families with a known mutation.

Management

Management of NSML requires a multidisciplinary approach. Treatment is symptomatic and supportive, focusing on the management of heart defects, hearing loss, and developmental delays. Regular monitoring by a cardiologist is essential due to the risk of hypertrophic cardiomyopathy. Early intervention programs for developmental delays and educational support are beneficial for affected individuals.

Prognosis

The prognosis for individuals with NSML varies depending on the severity of the symptoms. Heart defects, particularly hypertrophic cardiomyopathy, can be life-threatening and are a major determinant of prognosis. With appropriate management, however, many individuals with NSML lead normal or near-normal lives.

See Also

• RASopathy
• Hypertrophic cardiomyopathy
• Genetic testing
• Autosomal dominant inheritance