Large NT but Normal Karyotype? Noonan Syndrome Basics

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