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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Ontology: Noonan Syndrome (C0028326)

Definition (MSH) A genetically heterogeneous, multifaceted disorder characterized by short stature, webbed neck, ptosis, skeletal malformations, hypertelorism, hormonal imbalance, CRYPTORCHIDISM, multiple cardiac abnormalities (most commonly including PULMONARY VALVE STENOSIS), and some degree of INTELLECTUAL DISABILITY. The phenotype bears similarities to that of TURNER SYNDROME that occurs only in females and has its basis in a 45, X karyotype abnormality. Noonan syndrome occurs in both males and females with a normal karyotype (46,XX and 46,XY). Mutations in a several genes (PTPN11, KRAS, SOS1, NF1 and RAF1) have been associated the the NS phenotype. Mutations in PTPN11 are the most common. LEOPARD SYNDROME, a disorder that has clinical features overlapping those of Noonan Syndrome, is also due to mutations in PTPN11. In addition, there is overlap with the syndrome called neurofibromatosis-Noonan syndrome due to mutations in NF1.
Definition (NCI) Noonan syndrome caused by mutations in the PTPN11 gene.
Definition (NCI) A genetic syndrome caused by mutations in the PTPN11 gene (over 50% of the cases) or less frequently mutations in the SOS1, RAF1, or KRAS genes. It is characterized by short stature, webbed neck, hypertelorism, low-set ears, deafness, and thrombocytopenia or abnormal platelet function.
Concepts Disease or Syndrome (T047) , Congenital Abnormality (T019)
MSH D009634
ICD10 Q87.1
SnomedCT 205684007, 88327006, 205794007, 205824006
English Noonan Syndrome, Turner's phenotype, karyo norm, TURNER PHENOTYPE WITH NORMAL KARYOTYPE, NOONAN SYNDROME 1, NOONAN SYNDROME, NS1, Noonan's syndrome (diagnosis), Syndrome, Noonan, Turner phenotype, karyotype normal, Noonan Syndrome [Disease/Finding], males syndrome turners, noonans syndrome, familial syndrome turners, noonan's syndrome, noonan syndrome, male turner syndrome, Turner Phenotype with Normal Karyotype, Noonan Syndrome 1, Noonan-Ehmke Syndrome, Syndrome, Ullrich-Noonan, Turner Like Syndrome, Noonan Ehmke Syndrome, Ullrich Noonan Syndrome, Syndrome, Pseudo-Ullrich-Turner, Turner's Phenotype, Karyotype Normal, Turner-Like Syndrome, Familial Turner Syndrome, Turner Syndrome, Familial, Syndrome, Noonan-Ehmke, Syndrome, Familial Turner, Pseudo-Ullrich-Turner Syndrome, Pseudo Ullrich Turner Syndrome, Syndrome, Turner-Like, Ullrich-Noonan Syndrome, Noonan syndrome (disorder), Ullrich-Turner syndrome, Noonan's Syndrome, Noonan's syndrome, Turner's phenotype, karyotype normal, Noonan's syndrome (disorder), Turner's phenotype, karyotype normal (disorder), Noonan, Noonan syndrome, Noonan-Ehmke syndrome, Turner-like syndrome
Swedish Noonans syndrom
Japanese ヌーナンショウコウグン, 男性Turner症候群, ターナー症候群-男性, メイルターナー症候群, ヌーナン症候群, 男性ターナー症候群, Noonan症候群, Turner症候群-男性
Czech Noonanové syndrom
Finnish Noonanin oireyhtymä
Russian TERNERA SINDROM MUZHSKOI, NUNAN SINDROM, UIL'RIKHA SINDROM MUZHSKOI, НУНАН СИНДРОМ, ТЕРНЕРА СИНДРОМ МУЖСКОЙ, УИЛЬРИХА СИНДРОМ МУЖСКОЙ
Polish Zespół Turnera mężczyzn, Zespół Noonan
Hungarian Noonan-syndroma
Norwegian Noonans syndrom, Noonan-syndrom
Spanish síndrome de Ullrich - Turner, síndrome tipo Turner, síndrome de Noonan - Ehmke, fenotipo de Turner, cariotipo normal (trastorno), fenotipo de Turner, cariotipo normal, síndrome de Noonan (trastorno), síndrome de Noonan, Síndrome de Noonan
French Syndrome de Noonan de type 1, Phénotype de Turner avec caryotype normal, Syndrome de Noonan
Dutch syndroom van Noonan, Noonan-syndroom, Syndroom, Noonan-
German Noonan Syndrom, Noonan-Syndrom
Italian Sindrome di Noonan
Portuguese Síndrome de Noonan