Noonan syndrome (NS) is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. Facial features include widely spaced eyes, light-colored eyes, low-set ears, a short neck, and a small lower jaw. Heart problems may include pulmonary valve stenosis. The breast bone may be either protruding or be sunken, while the spine may be abnormally curved. Intelligence is often normal. Complications of NS may include leukemia.
|Other names||Male Turner syndrome, Noonan-Ehmke syndrome, Turner-like syndrome, Ullrich-Noonan syndrome|
|A 12-year-old girl with Noonan syndrome. Typical webbed neck. Double structural curve with rib deformity.|
|Specialty||Medical genetics, pediatrics|
|Symptoms||Mildly unusual facial features, short height, congenital heart disease, bleeding problems, skeletal malformations|
|Usual onset||Present at birth|
|Types||Type 1 to 6|
|Causes||Genetic mutation (autosomal dominant)|
|Diagnostic method||Suspected based on symptoms, confirmed with genetic testing|
|Differential diagnosis||Cardiofaciocutaneous syndrome, Turner syndrome, Costello syndrome, neurofibromatosis type 1|
|Treatment||Based on the symptoms|
|Prognosis||Depends on the severity of heart problems|
|Frequency||1 in 100 (1 in 2,000 severe disease)|
A number of genetic mutations can result in Noonan syndrome. The condition may be inherited from a person's parents or occur as a new mutation during early development. It is autosomal dominant. Noonan syndrome is a type of RASopathy, the underlying mechanism for which involves a problem with a cell signaling pathway. The diagnosis may be suspected based on symptoms, medical imaging, and blood tests. Confirmation may occur with genetic testing.
No cure is known. Treatment is based on symptoms and the underlying problems. Special help in school may be required. Growth hormone during childhood can increase a person's final height. Long-term outcomes typically depend on the severity of heart problems.
An estimated one in 100 people are mildly affected, while about one in 2000 have a more severe form of the disease. Males appear to be affected more often than females. The condition was first described in 1883 and was named after Jacqueline Noonan, who described further cases in 1963.
- 1 Signs and symptoms
- 2 Causes
- 3 Diagnosis
- 4 Management
- 5 Prognosis
- 6 History
- 7 References
- 8 External links
Signs and symptomsEdit
Up to 85% of people with NS have one of these heart defects:
- Pulmonary valvular stenosis (50–60%)
- Septal defects: atrial (10–25%) or ventricular (5–20%)
- Hypertrophic cardiomyopathy (12–35%)
Restrictive lung function has been reported in some people.
- Failure to thrive from infancy to puberty (75%)
- Decreased appetite
- Digestive problems
- Frequent or forceful vomiting
- Swallowing difficulties
- Intestinal malrotation
- Need for a feeding tube
- Low gut motility
- Gastroparesis (delayed gastric emptying)
- Cryptorchidism (undescended testicles)
- Bleeding disorders
- Easy bruising
- Amegakaryocytic thrombocytopenia (low platelet count)
- Blood clotting disorders
- Von Willebrand disease
- Prolonged activated partial thromboplastin time
- Partial deficiency of factor VIII:C
- Partial deficiency of factor XI:C
- Partial deficiency of factor XII:C
- Platelet dysfunction
- Combined coagulation defects
- Imbalance of plasminogen activator inhibitor type-1 (PAI-1) and tissue plasminogen activator (t-PA) activity
- Joint pain or muscle pain, especially in adults, which can vary in severity
- Undifferentiated connective-tissue disorders
- Prominence of breast bone (pectus carinatum)
- Depression of breast bone (pectus excavatum)
- Joint contractures (tightness)
- Joint hypermobility (looseness)
- Winging of the scapula
- Hypotonia (low muscle tone)
- Hypermobility syndrome
- Lordosis (increased hollow in the back) due to poor stomach muscle tone
- Arnold-Chiari malformation (type 1), which can lead to hydrocephalus, has been noted in some people.
For short stature, growth hormone is sometimes combined with IGF-1 (or as an alternative, IGF-1 as a stand-alone) can be used to achieve an increased height/final height quicker.
- Excess skin on the back of the neck
- Low hairline at the nape of the neck
- High hairline at the front of the head
- Large head
- Triangular face shape
- Broad forehead
- Short neck, webbed neck
- Hypertelorism (widely set eyes) (95%)
- Epicanthal folds (extra fold of skin at the inner corner of the eye)
- Ptosis (drooping of the eyelids)
- Proptosis (bulging eyes)
- Refractive visual errors
- Strabismus (inward or outward turning of the eyes)
- Nystagmus (jerking movement of the eyes)
- Small, upturned nose
Ears and hearingEdit
- Low-set ears (in over 90%)
- Backward-rotated ears (over 90%)
- Thick helix (outer rim) of ear (over 90%)
- Incomplete folding of ears
- Chronic otitis media (ear infections)
- Hearing loss
Mouth and speechEdit
- Deeply grooved philtrum (top lip line) (over 90%)
- Micrognathia (undersized lower jaw)
- High arched palate
- Dental problems
- Articulation difficulties
- Poor tongue control
- Bluntly ended fingers
- Extra padding on fingers and toes
- Edema of the back of hands and tops of feet
- Cubitus valgus (Wide carrying angle of the elbows)
Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with autosomal dominant inheritance and variable expression. Mutations in the Ras/mitogen activated protein kinase signaling pathways are known to be responsible for about 70% of NS cases.
Persons with NS have up to a 50% chance of transmitting it to their offspring. The fact that an affected parent is not always identified for children with NS suggests several possibilities:
- Manifestations could be so subtle as to go unrecognized (variable expressivity)
- NS is heterogeneous, comprising more than one similar condition of differing causes, and some of these may not be inherited.
- A high proportion of cases may represent new, sporadic mutations.
|Type||Online Mendelian Inheritance in Man database||Gene||Year found||Locus||% of cases||Description||Refs.|
|NS1||PTPN11||2001||12q24.1||50%||The PTPN11 gene encodes the protein tyrosine phosphatase SHP-2. This protein is a component of several intracellular signal transduction pathways involved in embryonic development that modulate cell division, differentiation, and migration, including one mediated by the epidermal growth factor receptor, which is important in the formation of the semilunar heart valves.
Duplication of the chromosome region containing PTPN11 can also result in NS.
|NS2||Unknown; autosomal recessive|||
|NS4||SOS1||2006||2p21||10%||Activating mutations in SOS1 can give rise to NS. SHP-2 and SOS1 positively regulate the Ras/MAP kinase pathway, suggesting that its dysregulation mediates NS development.|||
NS can be confirmed genetically by the presence of any of the known mutations listed above. However, despite identification of 14 causative genes, the absence of a known mutation will not exclude the diagnosis, as more, as-yet-undiscovered genes can cause NS. Thus, the diagnosis of NS is still based on clinical features. In other words, it is made when a physician feels that a person has enough of the features to warrant the label. The principal values of making a genetic diagnosis are that it guides additional medical and developmental evaluations, it excludes other possible explanations for the features, and it allows more accurate recurrence risk estimates. With more genotype-phenotype correlation studies being performed, a positive genetic diagnosis will help the clinician to be aware of possible anomalies specific to that certain gene mutation. For example, an increase in hypertrophic cardiomyopathy is seen in people with a mutation of KRAS and an increased risk of juvenile myelomonocytic leukemia exists for a mutation of PTPN11. In the future, studies may lead to a targeted management of NS symptoms that depends on what genetic mutation a person has.
First-trimester ultrasound of Noonan syndrome may reveal nuchal edema or cystic hygroma similar to Turner syndrome. Follow-up scans may show clinical features as described above. A study shows this disease is also associated with hepatosplenomegaly and with kidney anomalies including malrotation and a solitary kidney. A rare case of choledochal cysts is also reported.
- Turner syndrome, a different disorder often confused with NS because of several physical features that they share
- Fetal alcohol syndrome, another disorder sometimes confused with NS because of some common facial features and intellectual disability
- Other RASopathies, particularly:
- Costello syndrome
- Legius syndrome
- Noonan Syndrome with multiple lentigines, as known as LEOPARD syndrome, a related disorder caused by mutations in PTPN11 that are catalytically inactivating.
- Cardiofaciocutaneous syndrome, a related disorder which also affects genes encoding elements of the Ras/MAP kinase pathway.
- Neuropsychological testing is recommended to find strengths and challenges to tailor support needed for school and career.
- Educational customization such as an individualized education program plan is sometimes needed for school-aged children.
- Speech therapy if speech and articulation issues present
- Physical therapy and occupational therapy for gross- and fine-motor delays
- Hypotonia and motor difficulties often impact handwriting. Accommodations for lessening handwriting demands will improve performance and save long-term hand function.
- A few people with Noonan syndrome have been reported to develop malignant hyperthermia, but NS is not associated with MH. Only King-Denborough syndrome and central core disease are associated with MH. King-Denborough syndrome has been linked to a mutation on chromosome 19 located near the gene that encodes the ryanodine receptor, whereas NS is associated with a mutation on chromosome 12.
A 2007 study followed 112 individuals for a mean of 12 years (mean age 25.3, range 12–71). No one died during follow-up, but several required medical interventions. The mean final heights were 167 and 153 cm for men and women, respectively, which is about 2 standard deviations below normal.
Jacqueline Noonan was practicing as a pediatric cardiologist at the University of Iowa when she noticed that children with a rare type of heart defect, valvular pulmonary stenosis, often had a characteristic physical appearance, with short stature, webbed neck, wide spaced eyes, and low-set ears. Both boys and girls were affected. These characteristics were sometimes seen running in families, but were not associated with gross chromosomal abnormalities. She studied 833 people with noonan syndrome at the congenital heart disease clinic, looking for other congenital abnormalities, and in 1963 presented a paper: "Associated non-cardiac malformations in children with congenital heart disease". This described 9 children who in addition to congenital heart disease had characteristic facial features, chest deformities and short stature.
Dr. John Opitz, a former student of Dr. Noonan's, first began to call the condition "Noonan syndrome" when he saw children who looked like those whom Dr. Noonan had described. Dr. Noonan produced a paper entitled "Hypertelorism with Turner Phenotype" in 1968, and in 1971 at the Symposium of Cardiovascular defects, the name 'Noonan syndrome' became officially recognized.
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