Noonan syndrome: Difference between revisions
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Revision as of 02:31, 12 August 2013
| Noonan syndrome | |
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| A 12-year-old girl with Noonan syndrome. Note the typical webbed neck and the severe scoliosis. | |
| ICD-10 | Q87.1 |
| ICD-9 | 759.89 |
| OMIM | 163950 |
| DiseasesDB | 29094 |
| MedlinePlus | 001656 |
| MeSH | D009634 |
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Noonan syndrome Microchapters |
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Diagnosis |
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Treatment |
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Case Studies |
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Noonan syndrome On the Web |
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American Roentgen Ray Society Images of Noonan syndrome |
For patient information, click here.
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Scott Williams; Ayokunle Olubaniyi, M.B,B.S [2]
Synonyms and keywords: Female pseudo-Turner syndrome; female pseudo-Turner’s syndrome; male Turner syndrome; male Turner’s syndrome; Noonan’s syndrome; Turner phenotype with normal karyotype; Turner’s phenotype with normal karyotype
Overview
Noonan Syndrome (NS) is a relatively common congenital genetic condition which affects both males and females. It used to be referred to as the male version of Turner's syndrome[1]; however, the genetic causes of Noonan syndrome and Turner syndrome are distinct. The principal features include congenital heart malformation, short stature, learning problems, indentation of the chest, impaired blood clotting, and a characteristic configuration of facial features. The syndrome is named after Dr Jacqueline Noonan.
It is believed that between approximately 1 in 1,000 and 1 in 2,500 children worldwide are born with NS. It is one of the most common genetic syndromes associated with congenital heart disease, similar in frequency to Down syndrome. However, the range and severity of features can vary greatly in patients with NS. Therefore, the syndrome is not always identified at an early age.
Historical Perspective
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. Even though these characteristics were sometimes seen running in families, chromosomes appeared grossly normal. She studied 833 patients at the congenital heart disease clinic, looking for other congenital abnormalities, and in 1962 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 faces, chest deformities and short stature. Both males and females were found to be similarly affected, and the chromosomes were apparently normal.
Dr John Opitz, a former student of Dr Noonan, first began to call the condition "Noonan Syndrome" when he saw children who looked like those whom Dr Noonan had described. Dr Noonan later produced a paper entitled "Hypertelorism with Turner Phenotype", and in 1971 at the Symposium of Cardiovascular defects, the name 'Noonan Syndrome' became officially recognized.
Pathophysiology
Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with autosomal dominant inheritance and variable expression. A person with NS has up to a 50% chance of transmitting it to a child. The fact that an affected parent is not always identified for children with NS suggests several possibilities:
- a parent could carry the gene without being affected (incomplete penetrance)
- manifestations are variably expressed and could be so subtle as to go unrecognized (variable expressivity)
- a high proportion of cases represent new, sporadic mutations or
- Noonan syndrome is heterogeneous, comprising more than one similar condition of differing cause, some not inherited.
In most of the families with multiple affected members, NS maps to chromosome 12q24.1. In 2001, it was reported that approximately half of a group of patients with Noonan syndrome carried a mutation of the PTPN11 gene at that location, which encodes protein tyrosine phosphatase SHP-2.[2] The SHP2 protein is a component of several intracellular signal transduction pathways involved in embryonic development that modulate cell division, differentiation, and migration, including that mediated by the epidermal growth factor receptor. The latter pathway is important in the formation of the cardiac semilunar valves. It has recently been shown that activating mutations in SOS1 also give rise to NS.[3] Shp2 and SOS1 both have roles as positive regulators of the Ras/MAP kinase pathway suggesting that dysregulation of this pathway may play a major role in the genesis of this syndrome.[4] Additional mutations in KRAS [5] and RAF1[6] genes have been reported to cause Noonan syndrome in a smaller percentage of individuals with the syndrome. Chromosomal abnormalities, such as a duplication of chromosome region 12q24 encompassing gene PTPN11 can result in an apparent Noonan syndrome[7].
Manifestations by organ system
The most prevalent (common) signs are highlighted in bold with frequency listed in parentheses.
Cardiac
2/3 of patients have a heart defect
- Pulmonary Valvular Stenosis —(50%)
- Septal defects: atrial —(10%) or ventricular —(less common)
- Heart murmur
- Cardiomyopathy
Gastrointestinal System
- Failure to thrive as an infant
- Decreased appetite
- Digestive problems
- Frequent or forceful vomiting
- Swallowing difficulties
Genito-Urinary System
- Cryptorchidism (undescended testicles) — (almost all males)
Lymphatic System
- Posterior cervical Hygroma (webbed neck)
- Lymphedema (build-up of body fluid due to poor functioning of the lymphatic system)
Developmental
- Clumsiness
- Poor coordination
- Motor delay
- Mental retardation —(1/3 of patients have mild MR)
- Learning disabilities
- Speech and language delays
Musculoskeletal
- Some patients with Noonan Syndrome suffer from severe joint pain or muscle pain often with no identifiable cause
Hematologic
- 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
- Combined Coagulation deficiencies
Neurological
- Arnold Chiari Malformation (Type 1) has been noted in some patients with Noonan Syndrome
Diagnosis
Despite identification of four causative genes, the diagnosis of Noonan syndrome is still based on clinical features. In other words, it is made when a physician feels that a patient has enough of the features to warrant the label indicating association. The patient can be tested for mutations in the PTPN11, SOS1, or KRAS genes, however absence of a mutation will not exclude the diagnosis as there are more as yet undiscovered genes that cause NS. The principal values of making such a 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.
Physical Examination
STATURE/POSTURE
- Short stature
- Cervical (neck) spine fusion
- Scoliosis
- Prominence of breast bone (pectus carinatum)
- Depression of breast bone (pectus excavatum)
- Joint contractures or tightness
- Joint hyperextensibility or looseness
- Growth retardation
- Winging of the scapula
- Hypotonia (low muscle tone)
HEAD
- Excess skin on the back of the neck
- Low hairline at the nape of the neck
- Large head
- Triangular face shape
- Broad forehead
- Short neck, webbed neck, posterior cervical
- Curly hair
EYES
- Widely set eyes (hypertelorism) —(95%)
- Drooping of the eyelids (ptosis (eyelid))
- Epicanthal folds (extra fold of skin at the inner corner of the eye)
- Proptosis (bulging eyes)
- Refractive visual errors
- Inward or outward turning of the eyes (strabismus)
- Nystagmus - jerking movement of the eyes
NOSE
- Small, upturned nose
EARS/HEARING
- Low set ears —(over 90%)
- Backward rotated ears —(over 90%)
- Thick helix of ear (outer rim) —(over 90%)
- Incomplete folding of ears
- Chronic Otitis media (ear infections)
MOUTH/SPEECH
- Deeply grooved philtrum (top lip line) —(over 90%)
- Micrognathia (undersized lower jaw)
- High Arched palate
- Dental problems
- Articulation Difficulties
- Poor tongue control
LIMBS/EXTREMITIES
- Bluntly ended fingers
- Extra padding on fingers and toes
- Edema of the back of hands and tops of feet
- Cubitus valgus (elbow deformity: with abnormal turning-in)
SKIN
- Lymphedema (swelling of the extremities)
- Keloids (scar hypertrophy)
- Hyperkeratosis - overdevelopment of outer skin layer
- Pigmented nevi (birthmark)
References
- ↑ Curcić-Stojković O, Nikolić L, Obradović D, Krstić A, Radić A (1978). "[Noonan's syndrome. (Male Turner's syndrome, Turner-like syndrome)]". Med Pregl. 31 (7–8): 299–303. PMID 692497.
- ↑ Tartaglia M, Mehler EL, Goldberg R; et al. (2001). "Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome". Nat. Genet. 29 (4): 465–8. doi:10.1038/ng772. PMID 11704759.
- ↑ Roberts AE, Araki T, Swanson KD; et al. (2007). "Germline gain-of-function mutations in SOS1 cause Noonan syndrome". Nat. Genet. 39 (1): 70–4. doi:10.1038/ng1926. PMID 17143285.
- ↑ Bentires-Alj M, Kontaridis MI, Neel BG (2006). "Stops along the RAS pathway in human genetic disease". Nat. Med. 12 (3): 283–5. doi:10.1038/nm0306-283. PMID 16520774.
- ↑ Schubbert S, Zenker M, Rowe SL; et al. (2006). "Germline KRAS mutations cause Noonan syndrome". Nat. Genet. 38 (3): 331–6. doi:10.1038/ng1748. PMID 16474405.
- ↑ Razzaque MA, Nishizawa T, Komoike Y; et al. (2007). "Germline gain-of-function mutations in RAF1 cause Noonan syndrome". Nat. Genet. 39 (8): 1013–7. doi:10.1038/ng2078. PMID 17603482.
- ↑ Shchelochkov OA et al, Am J Med Genet A, 2008 Apr 15;146A(8):1042-8
External links
Template:Phakomatoses and other congenital malformations not elsewhere classified