88  Noonan Syndrome

88.1 Definition

Noonan syndrome (NS) is a genetic disorder in which multiple organ systems are affected and is typically characterised by distinct facial features, short stature, congenital heart disease and neurodevelopment abnormalities.

88.2 Genetics

NS occurs sporadically or in an autosomal dominant manner, the latter being the most common mode of transmission. In either case, males and females are affected equally. In familial cases, the mother is usually the transmitting parent because a considerable proportion of affected males have problems with fertility. Several mutations in the genes involved in the renin-angiotensin system (RAS)–mitogen-activated protein kinase (MAPK) pathway have been implicated. Such mutations are currently detected in approximately 70% of cases. Mutations in the PTPN11 gene on chromosome 12q24.1 are by far the commonest. There is a correlation between specific gene mutations and the clinical manifestations of the syndrome. Autosomal recessive forms of the disorder have also been identified.

88.3 Clinical features

The clinical manifestations depend on the affected gene and the stage of life at which the patient is presenting. Suggestive findings on prenatal ultrasound scans include lymphatic system anomalies such as increased nuchal translucency, cystic hygroma and fetal ascites. Other supportive findings include polyhydramnios, short femur length, renal and cardiac defects (particularly pulmonary valve dysplasia) in the fetus. At birth, most affected neonates appear unremarkable. Birth weight and head circumference are usually within the normal range. A cardiac murmur may be detected on routine newborn examination. Male neonates may have cryptorchidism. The affected infant may present with feeding difficulties requiring ongoing nasogastric feeding or gastrostomy, which can impair growth. Talipes equinovarus may be present in 5% of patients. The characteristic facial features of NS become more apparent in early childhood and include a triangular-shaped face, hypertelorism, blue-green irises, down-slanting palpebral fissures, epicanthal folds, ptosis, low-set ears with thickened posteriorly rotated auricles, high nasal bridge and upturned nose, short webbed neck and micrognathia. Short stature is present in 85% of cases. Cutaneous features in childhood include lymphedema affecting the lower limbs and genitals, follicular keratosis of the face and extensor surfaces, multiple lentigines and café au lait spots. Musculoskeletal features include a shield chest, cubitus valgus, pectus carinatum or excavatum, scoliosis, and joint laxity. Affected children are usually hypotonic with delayed motor and speech development. Expressive language skills are more affected. A careful family history is important with emphasis on the presence of congenital heart disease, short stature or unusual facies among first-degree relatives.

88.4 Associations

Congenital heart disease is present in almost 80% of patients with NS. The main cardiac lesion is a dysplastic or stenotic pulmonic valve. Other associated cardiac defects include hypertrophic cardiomyopathy (30%), atrial septal defect, ventricular septal defects, tetralogy of Fallot, and coarctation of the aorta. Most patients have more than one cardiac defect. Renal anomalies such as ectopic kidneys are present in 10% of cases. Fifty per cent of affected males have cryptorchidism with hypoplastic testes. There is an increased risk of the development of certain cancers because of gene mutations affecting the RAS-MAPK pathway, an important cell signalling pathway. These include neuroblastoma, acute lymphoblastic leukaemia, low-grade glioma, rhabdomyosarcoma, juvenile myelomonocytic leukaemia and myeloproliferative disorders. There are associated autoimmune diseases such as systemic lupus erythematosus and autoimmune thyroiditis. Seizure disorders, unexplained peripheral neuropathy and intellectual disabilities have been documented in association with NS.

88.5 Investigations

Amniocentesis for the fetal karyotype can be done if prenatal USG findings are suggestive. A normal karyotype rules out Turner syndrome which is a close differential. Genetic studies to identify the specific gene mutation are important to help confirm the diagnosis and determine prognosis. Other investigations are conducted based on the affected organ systems. These include echocardiography and electrocardiography for cardiac defects, coagulation screen with full hematologic workup for associated bleeding and neoplastic disorders, renal ultrasonographic examination for genitourinary problems and brain and spine MRI if neurologic symptoms are present.

88.6 Treatment

Treatment is focused on the presenting symptoms and the affected organ systems. A multidisciplinary team made up of paediatricians, geneticists, cardiologists, haematologists, ophthalmologists, neurologists, urologists, endocrinologists, audiologists, physical therapists, speech therapists, occupational therapists, clinical psychologists, and social workers is needed to manage the various complications associated with NS. Growth hormone therapy can be given to affected children with growth impairment to accelerate growth to a near-normal adult height.

88.7 Complications

These include delayed or absent puberty, neurodevelopment and behavioural problems such as autism spectrum disorders, attention deficit hyperactivity disorder and seizure disorders. Other complications are bleeding diathesis most commonly from factors XI and XII deficiency and platelet disorders. Ophthalmologic complications include strabismus, amblyopia, refractive errors, posterior embryotoxon, optic nerve hypoplasia and nystagmus. Progressive hearing loss (sensorineural, conductive, or mixed loss) and recurrent otitis media are known to occur. Orthopaedic complications include joint contractures, fusion of the cervical spine and scoliosis.

88.8 Notes on counselling

Parents need to be counselled regarding recurrence risk with each pregnancy in familial cases and prenatal diagnosis offered. Families of affected children need to be informed that although there is no definitive cure for NS, the various associations and complications can be managed very well by a multidisciplinary team to ensure the child has an excellent quality of life. Affected children with mild or no learning difficulties do not require special education but can integrate well into mainstream schools. Families of affected children should be linked to support groups. Patients with bleeding disorders must be advised against the use of aspirin and aspirin-containing products or other medications that may interfere with coagulation or platelet function.