WHAT IS IT?

Noonan syndrome is an autosomal dominant disorder that is multi-systemic and occurs and affects approximately 1 in 1,000 to 2,500 people.  In the past, it was also referred to, incorrectly, as ‘Male Turner Syndrome, ‘Female Pseudo-Turner Syndrome’ and ‘Turner Phenotype with Normal Karyotype’. Noonan syndrome is a distinct disorder that can affect both males and females.

Prenatal Detection and Management

Large NT  but normal karyotype (both standard karyotype and microarray will be normal)

• NT ≥ 3 mm in the first trimester and normal karyotype may confer approximately 10% risk for Noonan syndrome
  • Consider molecular testing (gene sequencing)  for Noonan syndrome even without additional ultrasound findings as detailed anatomy scan may be limited in the first trimester
• Associated prenatal sonographic anomalies that should raise suspicion:
  • Polyhydramnios
  • hydrops fetalis
  • renal anomalies
  • distended jugular lymphatic sacs
  • hydrothorax
  • cardiac anomalies
  • cystic hygroma
  • ascites
• A larger NT is especially concerning, as median measurement is approximately 8 mm
• Pathogenic variants associated with Noonan syndrome are too small to be detected with microarray
  • Gene sequencing of DNA derived from CVS or amniocentesis necessary

KEY CLINICAL FINDINGS:

Growth

• Postnatal short stature (50 to 70%)
• Failure to thrive in infancy

Facial features

• Deep, prominent philtrum
• Wide spaced eyes (usually blue or green)

Head & neck

• High arched palate and poor tooth alignment
• Micrognathia
• Low-set ears
• Short neck
• Cystic Hygroma and/or Excess neck skin
• NT and nuchal fold may both be increased

Cardiovascular – may have critical congenital heart disease

• Pulmonic stenosis (20-50%)
• Hypertrophic Cardiomyopathy (20-30%)
• Atrial septal defects
• Ventricular septal defects
• Patent ductus arteriosus
• Aortic coarctation
• Lymphatic disorders

Chest

• Pectus carinatum
• Pectus excavatum
• Shield chest

Genitourinary

• Males: Delayed puberty and undescended testes (cryptorchidism) are common leading to infertility
• Females: May have delayed puberty and fertility issues but uncommon

Neurologic

• Intellectual abilities may be mildly lowered
• Speech Delay
• Learning disabilities (25%)
• Visual abnormalities
• Deafness

Bleeding disorders

• Von Willebrand disease
• Thrombocytopenia
• Coagulopathies (factors V, VIII, XI, XII, protein C)
• Platelet dysfunction

Neoplasia

• May have eight-fold risk for malignancies, such as leukemia

KEY POINTS:

Genetics

• Noonan syndrome is one of the RASopathies
• RAS/MAPK pathway critical for cell division, proliferation, differentiation and migration
• Pathogenic variants lead to gain of function – proteins remain inappropriately ‘turned on’
• Autosomal dominant inheritance pattern
• A pathogenic variant will be found in one of the parents in 30 – 75% of cases, with the remainder resulting from a spontaneous de novo mutation in the following genes:
  • PTPN11 gene (50%)
  • SOS1 (10 to 15 %)
  • RAF1 (5%)
  • RIT1 (5%)
  • KRAS (< 5%)
  • NRAS (limited reports)
  • BRAF (<2%)
  • MAP2K1 (<2%)
  • Unknown
• Recurrence risk is 50% if a parent is found to have the variant
• Recurrence risk is <1% if de novo mutation is present

Learn More – Primary Sources:

Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings

GeneReviews: Noonan Syndrome

Noonan Syndrome – Genetics Home Reference

Testing for Noonan Syndrome after Increased Nuchal Translucency

Locate a genetic counselor or genetics services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC

Locate a Maternal Fetal Medicine Specialist:

SMFM

Related ObG Topics:

How Common is Noonan Syndrome When the NT is Large but Chromosomes Appear Normal?

SMFM Guidance – The Role of Prenatal Ultrasound and NIPT 

Cystic Hygroma: Definition, Genetics and Prognosis

Nuchal Translucency – First Trimester Measurement

Is There Value to an Early Anatomy Scan with an Enlarged NT?