II. Epidemiology

  1. Autosomal Dominant in 40% of cases (Sporadic in 60% of cases)
  2. Incidence
    1. Severe Phenotype: 1 in 1000 to 2500
    2. Mild Phenotype: 1 in 100

III. Pathophysiology

  1. Genetic mutation affecting RAS/Mitogen-Activated Protein Kinase (MAPK)
    1. Protein Tyrosine phosphatase non-receptor type 11 gene mutation (PTPN11) is causative in 50% of cases
    2. Affects cell cycle

IV. Signs: Prenatal (Ultrasound and lab)

  1. Increased Nuchal Translucency
  2. Polyhydramnios
  3. Hydrothorax
  4. Abnormal maternal Triple Screen

V. Signs: Newborn

  1. Head large in contrast to a small face
  2. Tall forehead and narrow temples
  3. Wide-spaced eyes (Hypertelorism)
  4. Palpebral fissure (at canthus) slants downward
  5. Epicanthal folds
  6. Wide, depressed nose with upturned bulbous tip
  7. Small chin
  8. Short neck and increased nuchal skin
  9. Ears rotated back
  10. Dorsal hand and foot edema

VI. Signs: Infant

  1. Wispy Hair
  2. Eyes prominent with Droopy Eyelids
  3. Wide, depressed nose with upturned bulbous tip
  4. Philtrum deeply grooved resulting in an upper lip with cupid's bow shape

VII. Signs: Child or Teen

  1. Curly, wool-like hair
  2. Wide forehead
  3. Small chin
  4. Webbed Neck
  5. Wide-spaced nipples
  6. Pectus Excavatum or pectus carnitum (inferior Sternum depressed)
  7. Cubitus valgus (Forearm laterally deviated)
  8. Head in shape of an inverted triangle

VIII. Signs: Adult

  1. High anterior hairline
  2. Head in shape of an inverted triangle
  3. Nasolabial folds prominent
  4. Prominent skin Wrinkles

IX. Associated Conditions

  1. Congenital Heart Disease
    1. Pulmonic Stenosis
    2. Hypertrophic Cardiomyopathy
  2. Hematologic disorders
    1. Bleeding Disorders (Platelet or Clotting Factor disorder)
    2. Leukemia or myeloproliferative disorder
    3. Lymphedema
  3. Growth disorder
    1. Failure to Thrive (and feeding difficulties)
    2. Short Stature (in 50-70% of cases)
      1. Final adult height in males: 63-66 in
      2. Final adult height in females: 59-61 in
  4. Genitourinary
    1. Delayed Puberty
    2. Male Infertility
    3. Cryptorchidism
    4. Renal malformation (e.g. duplex collecting system, solitary Kidney)
  5. Musculoskeletal
    1. Chest deformity (Pectus Excavatum or Pectus carnitum)
    2. Scoliosis
    3. Talipes Equinovarus
    4. Cubitus valgus
  6. Neurologic
    1. Normal intelligence in most patients
    2. Developmental Delay, Learning Disorders and speech disorders may occur
  7. Eye Disorders: Visual deficit
    1. Strabsimus
    2. Nystagmus
    3. Cataracts
  8. Ear Disorders
    1. Sensorineural Hearing Loss
    2. Deafness
  9. Skin Disorders
    1. Dystrophic Nails
    2. Prominent finger pad and toe pads
    3. Elastic skin
    4. Numerous Lentigines

X. Differential Diagnosis

  1. Turner Syndrome
    1. Similar phenotypic features, but Noonan Syndrome has a normal karyotype and occurs in both males and females
  2. Cardio-facio-cutaneous syndrome
  3. Costello Syndrome
  4. LEOPARD Syndrome
    1. Acronym: Lentigines, EKG abnormalities, ocular Hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, Deafness
  5. Neurofibromatosis 1
  6. Watson Syndrome

XI. Diagnosis: Two or more positive criteria consistent with Noonan Syndrome

  1. Characteristic facial features (see signs above)
  2. Developmental Delay
  3. Delayed Puberty or Infertility
  4. Short Stature (<10% and especially if <3%)
  5. Pectus Excavatum or pectus carnitum
  6. Cryptorchidism (Undescended Testes)
  7. First degree relative diagnosed with Noonan Syndrome (or with suggestive features)
  8. Congenital Heart Disease
    1. Especially Pulmonic Stenosis, Hypertrophic Cardiomyopathy or EKG abnormalities)

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