What is Noonan syndrome?
Noonan syndrome is a common autosomal dominant disorder associated with mutations in the RAS/MAPK pathway, and is one of a group of conditions collectively known as RASopathies.
Noonan syndrome is characterised by:
- Distinctive facial appearance
- Short stature
- Chest deformity
- Congenital heart disease.
Noonan syndrome is also known as:
- Familial Turner syndrome
- Female pseudo-Turner syndrome
- Male Turner syndrome
- Noonan-Ehmke syndrome
- Pseudo-Ullrich Turner syndrome
- Turner-like syndrome
- Turner phenotype with normal karyotype
- Ullrich-Noonan syndrome.
*Image sourced from Wikipedia
What causes Noonan syndrome?
Noonan syndrome is caused by mutations in genes associated with the RAS/MAPK cell-signalling pathway, which is required for normal cell division, proliferation, differentiation and migration. These mutations lead to loss of regulation of cell growth and division.
Mutations in the PTPN11 gene are implicated in > 50% of cases. Gene mutations in SOS1 are implicated in 10–15% and mutations in RAF1 and RIT1 account for approximately 5% each. A number of other genes account for the rest.
The genetic cause behind Noonan syndrome is unknown in up to 20% of cases.
What are the clinical features of Noonan syndrome?
Noonan syndrome affects males and females in all races. 50–70% of people with Noonan syndrome are of short stature. Weight and length at birth are usual normal, but growth slows over time. This is thought to be associated with abnormal levels of growth hormone.
Noonan syndrome presents with distinctive facial features, such as:
- Deep philtrum (groove between the nose and mouth)
- Hypertelorism (widely spaced eyes)
- Low-set ears rotated backward
- High arched palate
- Poor teeth alignment
- Micrognathia (small lower jaw).
Other clinical manifestations of Noonan syndrome include:
- Webbed neck
- Short neck/low posterior hair line
- Pectus excavatum (sunken sternum) or pectus carinatum (protruding sternum)
- Scoliosis – abnormal lateral curvature of the spine
- Bleeding disorders
- Hypogonadism – impaired gonad function that can lead to insufficient production of sex hormones.
Congenital heart disease is common in most cases of Noonan syndrome, with the most common defect being pulmonary valve stenosis.
Cutaneous symptoms of Noonan Syndrome are varied and literature on the topic is limited. Documented cutaneous effects of Noonan syndrome include:
- Pigmented melanocytic naevi (moles)
- Abnormal dermatoglyphics (fingerprints) – increased numbers of whorls on the fingertips secondary to peripheral lymphoedema
- Stasis dermatitis – common inflammatory dermatosis of the lower limbs, due to venous pooling
- Plantar hyperkeratosis – thickening of the skin on the soles of the feet (keratoderma).
Noonan syndrome with multiple lentigines, formerly known as LEOPARD syndrome, is similar to Noonan syndrome. It has characteristic cutaneous features, including:
- Café au lait macules — flat light brown macules, caused by collection of pigment-producing melanocytes in the epidermis
- Lentigines — pigmented flat or slightly raised lesion with well defined border. Unlike freckles, these spots are not affected by sun exposure.
What are the complications of Noonan syndrome?
Hypertrophic cardiomyopathy is common in those with critical congenital pulmonary valve stenosis.
Individuals with Noonan syndrome have an eight-fold increased risk of developing haematological malignancies, the most common being leukaemia.