Noonan Syndrome

Etiology

Noonan syndrome is a pleomorphic autosomal dominant inherited disease. Thus, parents with Noonan syndrome have a 50% chance of passing the mutation on to their children. Noonan syndrome has been associated with advanced paternal age. Noonan Syndrome can also occur via de novo mutation or sporadic mutation. The mutated genes are involved in the RAS/MAPK cell signaling pathway. Please refer to the pathology section for more information on the RAS/MAPK pathway.[1][2]

Epidemiology

Noonan syndrome occurs in approximately 1 in 1000 to 2500. Since the inheritance pattern is autosomal dominant, it affects both females and males equally. Males may display cryptorchidism, thus making the diagnosis at a younger age. Noonan syndrome occurs across all ethnic groups equally.[1][2]

Pathophysiology

The RAS/MAPK pathway mutation in Noonan syndrome classifies Noonan syndrome as RASopathy. RASopathies are genetic syndromes that involve germline mutations in the Ras/mitogen-activated protein kinase (MAPK) pathway. These syndromes include cardiofaciocutaneous syndrome, Costello syndrome, Neurofibromatosis type 1 (NF1), and LEOPARD syndrome. The Ras/MAPK pathway is needed for cell division, proliferation, differentiation, and migration. It is vital for healthy development. The most common mutation in Noonan syndrome occurs in the PTPN11 gene. A smaller portion of mutations occurs in SOS1, RAF1, and RIT1. Mutations in PTPN11 can be inherited, autosomal dominant, or occur de novo through sporadic mutation. The mutations involved in Noonan syndrome are considered a gain of function mutation, causing inappropriate prolongation of the RAS/MAPK signaling. The prolongation of the RAS/MAPK pathway gives way to the pleomorphic characteristics found in Noonan syndrome.[1][2]

History and Physical

Noonan syndrome has phenotypical heterogeneous manifestations, which change with age. The most consistent features are widely set eyes, low-set ears, short stature, and pulmonic stenosis. Diagnostic criteria have been developed to aid in the diagnosis of Noonan syndrome. Please refer to the attached table for the criteria. One of the more common features prenatally is increased nuchal translucency in utero. However, increased nuchal translucency is associated with other conditions, such as Down syndrome. Other manifestations include polyhydramnios from renal anomalies, congenital heart diseases, mild limb shortening, and fetal macrosomia. As noted before, the vague symptoms present in the prenatal period can elude to various other conditions. Therefore, the index of suspicion for Noonan Syndrome must be relatively high. If karyotyping is done, it reveals a normal karyotype, ruling out trisomies. Noonan syndrome should be considered in all fetuses with increased nuchal translucency, polyhydramnios, and cardiac abnormalities with a normal karyotype.

For many with Noonan syndrome, there are no clinical manifestations at birth. Macrosomia and macrocephaly may be present. Cryptorchidism may be present in males. Males have an increased risk of infertility, even if without a previous diagnosis of cryptorchidism. Most females are not at risk for infertility. The most common congenital heart defects are pulmonic stenosis and hypertrophic cardiomyopathy; depending on the severity, it may or may not be detected in a routine physical. The infant may experience feeding difficulties and failure to thrive, hearing loss, and strabismus. Noonan syndrome is associated with intellectual and developmental delays. Patients may display delayed speech or motor milestones, deafness, and short stature.

Distinct facial characteristics are formed in early childhood and change as people age. Features include hypertelorism, low-set ears, blue irises, ptosis, mild neck webbing, high forehead, down-slanting palpebral fissures, and epicanthic folds. In adulthood, facial features show signs of premature aging, and lengthening the jaw gives the face a triangular shape. Lymphatic dysplasia is common and can lead to early generalized lymphoedema in the extremities and abdomen. A fetal examination may show a cystic hygroma, a fluid-filled sac caused by a blockage in the lymphatic system. Patients may experience easy bruising or bleeding due to coagulopathy. The most common etiology is due to factor XI deficiency. Skeletal abnormalities are also common, such as pectus carinatum or pectus excavatum.[3][4][5]

Evaluation

Noonan syndrome remains a clinical diagnosis. Molecular genetic testing can be done to confirm the diagnosis. Upon diagnosis of Noonan syndrome, various organ systems should be evaluated (see Image. Diagnostic Criteria for Noonan Syndrome). Along with a complete physical and neurological exam, the following should be considered:[3][4][5]

• Cardiac evaluation, including echocardiography and electrocardiograph
• Ophthalmologic evaluation
• Audiologic evaluation
• Renal ultrasound
• Coagulation profile for coagulopathies
• Development assessment.
• Imaging of chest and back for skeletal abnormalities

Treatment / Management

There is no cure for Noonan syndrome as it is a genetically inherited disease. Management of Noonan syndrome is targeted toward symptomatic improvement and supportive care. Interprofessional care is often needed; multiple organ systems are to be addressed. Hearing tests and ophthalmic exams are appropriate throughout childhood. In males with cryptorchidism, orchiopexy should be performed when the child is around 1 year old if the testes have not descended to reduce the risk of development of testicular cancer in adulthood. For congenital heart defects, an echo and ECG should be obtained. Even in patients without a diagnosis of cardiac defects, a cardiac evaluation is needed every 5 years. Short stature can be evaluated for the treatment of growth hormone. Appropriate supportive measures can be used to target lymphedema.[5][6]

Differential Diagnosis

The differential diagnosis for Noonan syndrome is broad. Many other chromosomal abnormalities can cause a similar constellation of symptoms of congenital heart defect, short stature, and developmental delay.

• Turner syndrome
  • Noonan syndrome has been referred to as “pseudo-Turner syndrome” due to the similarities between Turner and Noonan syndromes. Both syndromes display a webbed neck and short stature. However, only females are affected by Turner syndrome (45, X0), as the X chromosome is affected. Both males and females are affected by Noonan syndrome, and the karyotype is normal.

Noonan syndrome is considered a RASopathy since the genetic mutations affect the RAS/MAPK pathway. Other RASopathies exhibit similar features to those in Noonan syndrome. These conditions include:

• Cardiofasciocutaneous syndrome
• Costello syndrome
• Neurofibromatosis 1
• Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome)

Prognosis

The prognosis in those with Noonan Syndrome depends on their phenotype's severity. The severity of the heart defect is linked to the mortality and morbidity of patients. Many patients have an average lifespan and minimal morbidity.[5]

Complications

Complications of the disease include developmental delay with cognitive deficits that limit functionality and require aggressive support services for the affected patient. Physical complications may be due to severe cardiac abnormalities, such as valvular stenosis and hypertrophic cardiomyopathy, requiring ongoing medical care. Some patients have bleeding disorders with frequent medical care for the management of bleeding diatheses.[7][8]