Noonan syndrome

Noonan syndrome (NS) is a genetically and phenotypically heterogeneous non-aneuploidic congenital RASopathy. Affected individuals can bear some clinical features similar to that of Turner syndrome. 

Epidemiology

The estimated incidence is at ~1 in 1000-2500 ¹⁰. As individuals have normal number of chromosomes, both males and females can be affected.  

Clinical presentation

An immense number of clinical features have been described which can be present at varying degrees. These include:

• craniofacial

  • telecanthus, hypertelorism

  • low-set ears, rotated ears +/- thickened helix

  • epicanthus

  • facial asymmetry

  • intellectual disability

  • microgenia

  • low neck hairline

• cervicothoracic

  • pterigium colli: webbed neck

  • winged scapulae

  • pectus excavatum

  • pectus carinatum

• cardiopulmonary

  • pulmonary stenosis (with dysplastic pulmonary valve): most common cardiac anomaly ³

  • hypertrophic cardiomyopathy ^3,4: thought to affect ~20% of individuals ³

  • patent ductus arteriosus (PDA)

• vascular

  • congenital lymphovascular abnormalities

    • cystic hygroma

    • lymphedema ⁵

    • lymphangiectasia(e) ²

• generalized musculoskeletal

  • short stature

  • hypotonia

  • delayed sternal ossification ⁷

• renal anomalies

  • dilated renal pelvices ^6,9

Pathology

Genetics

The inheritance is autosomal dominant although a significant proportion of cases are sporadic ⁸. Many genes have been implicated, the most common being the PTPN11 gene which encodes for SHP2, which results in an inability to inactivate SHP2 causing increased signaling of the Ras/MAPK pathway. However, other genes that may be less commonly implicated include SOS1, KRAS, RAF1, NRAS, and SHOC2 ¹⁰. Because of its effect in amplifying the Ras/MAPK pathway, it is considered to be a RASopathy ¹⁰.

Radiographic features

Ultrasound

Early 1^st trimester ultrasound may show nuchal edema or a cystic hygroma similar to that of Turner syndrome. With subsequent scanning, some of the above individual clinical features may be present sonographically.

History and etymology

It is named after Jacqueline A Noonan (1928-fl 2019), an American pediatric cardiologist ¹¹.