SNP Shot: Genomic Insights

Noonan syndrome with multiple lentigines, previously known as LEOPARD syndrome, is a disorder affecting numerous bodily systems. As the name implies, it shares similarities with Noonan syndrome, making early differentiation challenging. However, their characteristics diverge as individuals age. Distinctive features include lentigines (small, brown, freckle-like spots), heart defects, widely spaced eyes (ocular hypertelorism), a sunken or protruding chest (pectus excavatum or carinatum), and short stature. The severity of these features varies, even among family members. It's important to note that not every individual with Noonan syndrome with multiple lentigines exhibits all of these characteristics.

Lentigines typically emerge in mid-childhood, primarily on the face, neck, and upper body. By puberty, affected individuals may have thousands of these small, dark brown spots. Unlike freckles, lentigines are unrelated to sun exposure. Alongside lentigines, lighter brown spots called café-au-lait spots may also appear, often preceding the lentigines and developing within the first year of life.

Among those with Noonan syndrome with multiple lentigines who experience heart defects, approximately 80% have hypertrophic cardiomyopathy, a condition characterized by a thickening of the heart muscle that increases the heart's workload. This usually affects the left ventricle. Up to 20% of affected individuals with heart problems may have pulmonary stenosis, a narrowing of the artery connecting the heart to the lungs.

Individuals with Noonan syndrome with multiple lentigines often have a characteristic facial appearance. Beyond ocular hypertelorism, they may exhibit droopy eyelids (ptosis), thick lips, and low-set ears. Additionally, chest abnormalities are common, manifesting as either pectus excavatum or pectus carinatum.

At birth, individuals with Noonan syndrome with multiple lentigines usually have normal weight and height. However, some experience slowed growth over time, leading to shorter-than-average stature, although this is only significant in less than half of the affected individuals.

Other signs and symptoms include hearing loss due to inner ear abnormalities (sensorineural deafness), mild intellectual disability, and extra skin folds on the back of the neck. Affected males frequently have genital abnormalities such as undescended testes (cryptorchidism) and hypospadias (urethral opening on the underside of the penis), which can impair fertility. Females may have poorly developed ovaries and delayed puberty.

Noonan syndrome with multiple lentigines is categorized as a RASopathy, a group of related conditions with similar signs and symptoms caused by alterations in the same cell signaling pathway. Other RASopathies include Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type 1, and Legius syndrome.

Inheritance:

Noonan syndrome with multiple lentigines follows an autosomal dominant inheritance pattern. This means that having only one copy of the altered gene in each cell is sufficient to cause the condition. Some people inherit the gene alteration from a parent who also has the condition, while others develop it due to a new gene variant with no family history of the disorder.