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The incidence of NS is estimated to be between 1:1000 and 1:2500 live births.

The main facial features of NS are hypertelorism with down-slanting palpebral fissures, ptosis and low-set posteriorly rotated ears with a thickened helix. The cardiovascular defects most commonly associated with this condition are pulmonary stenosis and hypertrophic cardiomyopathy. Other associated features are webbed neck, chest deformity, mild intellectual deficit, cryptorchidism, poor feeding in infancy, bleeding tendency and lymphatic dysplasia.

In approximately 50% of cases, the disease is caused by missense mutations in the PTPN11 gene (12q24.1), resulting in a gain of function of the non-receptor protein tyrosine phosphatase SHP-2 protein. Recently, mutations in other genes from the RAS MAPK pathway (KRAS, SOS1, and RAF1) have been identified in a small portion of patients with NS.

Mutation analysis can be carried out on blood samples and should be recommended for any subject with a suspected diagnosis of NS. However, the diagnosis cannot be excluded on a molecular basis, as the sensitivity of combined screening of all known genes allows confirmation in less than 75% of patients.

The differential diagnosis should include Turner syndrome, cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type 1 (NF1) and LEOPARD syndrome (see these terms).

Prenatal DNA testing can be carried out on chorionic villus and amniotic fluid samples if the mutation has already been identified in a family member, but the complexity of the analysis makes diagnosis on an index case technically challenging during the short period of time available during pregnancy. Preimplantation genetic diagnosis may also be a possibility. NS should be considered in all foetuses with polyhydramnios, pleural effusions, oedema and increased nuchal fluid with a normal karyotype.

The syndrome is transmitted as an autosomal dominant trait.

Management should address feeding problems in early childhood, and include evaluations of cardiac function and assessments of growth and motor development. Physiotherapy and speech therapy should be offered if indicated. A complete eye examination and hearing evaluation should be performed during the first few years of schooling. Preoperative coagulation studies are indicated.

With special care and counselling, the majority of children with NS will grow up and function normally in the adult world. Signs and symptoms lessen with age and most adults with NS do not require special medical care.