Noonan syndrome

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Noonan syndrome
Classification and external resources
Noonan syndrome.PNG
A 12-year-old girl with Noonan syndrome. Typical webbed neck. Double structural curve with rib deformity.
ICD-10 Q87.1
ICD-9 759.89
OMIM 163950 605275 609942 610733 611553
DiseasesDB 29094
MedlinePlus 001656
eMedicine article/947504
Patient UK Noonan syndrome
MeSH D009634
GeneReviews

Noonan syndrome (NS) is a relatively common autosomal dominant congenital disorder that affects both males and females equally.[1]:550 It used to be referred to as the male version of Turner's syndrome[2] (and is still sometimes described in this way);[3] however, the genetic causes of Noonan syndrome and Turner syndrome are distinct. The principal features include congenital heart defect (typically pulmonary valve stenosis; also ASD and hypertrophic cardiomyopathy), short stature, learning problems, pectus excavatum, impaired blood clotting, and a characteristic configuration of facial features including a webbed neck and a flat nose bridge. The syndrome is named after Dr. Jacqueline Noonan. It is a RASopathy, being caused by a disorder of RAS-MAPK pathway signaling.

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.

Characteristics[edit]

Often called a "hidden" condition, NS may show no signs obvious to the casual onlooker, but the problems may be many and complex. The most prevalent (common) signs are highlighted in bold, with frequency listed in parentheses.

By organ system[edit]

Anesthesia risk[edit]

  • Individuals with NS are not at elevated risk for malignant hyperthermia when receiving general anesthesia.[4]
  • Some individuals with NS have been reported to develop respiratory depression from narcotics given during and after surgery, which has sometimes required cardiac resuscitation. Impaired anesthetic clearance in the 24–48 hours after surgery has also been reported.

Heart[edit]

Up to ~85% of people with NS have one of the following heart defects:

  • Pulmonary valvular stenosis (50–60%)
  • Septal defects: atrial (10–25%) or ventricular (5–20%)
  • Heart murmur
  • Hypertrophic cardiomyopathy (12–35%)

Lungs[edit]

  • Restrictive lung function has been reported in some patients

Gastrointestinal system[edit]

Genito-urinary system[edit]

Lymphatic system[edit]

Developmental[edit]

  • Intellectual disability, usually mild; Jaqueline Noonan has stated that she met a pharmacist in his 60's who diagnosed himself.[5]
  • Clumsiness
  • Motor development delay
  • Learning disabilities
  • Speech-language pathology
  • Autism, pervasive developmental disorder (uncommon)
  • Frequent illnesses, pain, headaches and fatigue that can affect school attendance are possible
  • Neuropsychological testing is recommended to find strengths and challenges to tailor support needed for school, career.
  • Individualized education plan (IEP) or a 504 plan is sometimes needed for school-aged children.
  • Speech therapy for speech and articulation issues, physical therapy and occupational therapy for gross and fine motor delays are needed.

Hematologic[edit]

Musculoskeletal[edit]

Neurological[edit]

By physical appearance[edit]

Stature and posture[edit]

Head[edit]

  • 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
  • Curly hair

Eyes[edit]

Nose[edit]

  • Small, upturned nose

Ears and hearing[edit]

  • 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 and speech[edit]

  • Deeply grooved philtrum (top lip line) (over 90%)
  • Micrognathia (undersized lower jaw)
  • High arched palate
  • Dental problems
  • Articulation difficulties
  • Poor tongue control

Limbs/extremities[edit]

  • 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[edit]

Causes[edit]

NS may be inherited in an autosomal dominant pattern with variable expression.

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 ~70% of NS cases.[7]

A person with NS has 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:

  1. manifestations could be so subtle as to go unrecognized (variable expressivity)
  2. NS is heterogeneous, comprising more than one similar condition of differing causes, some not inherited, or
  3. a high proportion of cases represent new, sporadic mutations.
Type Online Mendelian Inheritance in Man database Gene Description
NS1 163950 PTPN11 In most families with multiple affected members, NS maps to chromosome 12 q24.1. Approximately half of a group of patients with NS carried a mutation of the PTPN11 gene at that location, which encodes protein tyrosine phosphatase SHP-2.[8] 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 half-moon shaped heart valves.
Duplication of chromosome region 12q24 encompassing gene PTPN11 can also result in an apparent NS.[9]
NS2 605275 unknown (autosomal recessive)[10]
NS3 609942 KRAS Mutations in KRAS genes can cause NS in a smaller percentage of individuals, as reported 2006.[11]
NS4 610733 SOS1 Activating mutations in SOS1 can give rise to NS, as reported 2006.[12] SHP-2 and SOS1 positively regulate the Ras/MAP kinase pathway, suggesting that its dysregulation plays a role in NS development.[13]
NS5 611553 RAF1 Mutations in RAF1genes can cause NS in a smaller percentage of individuals, as reported in 2007.[14]

A condition known as "neurofibromatosis-Noonan syndrome" is associated with neurofibromin.[15]

Diagnosis[edit]

Despite identification of fourteen 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 following genes are known to cause NS. Four genes currently associated with the majority of cases (with the percentage of cases in brackets): PTPN11 (50%), RAF1 (3–17%), SOS1 (10%), KRAS (<5%). Heterozygous mutations in NRAS, HRAS, BRAF, SHOC2, MAP2K1, MAP2K2, and CBL have also been associated with a smaller percentage of NS and related phenotypes.[16]

An 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 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, there is an increase in hypotrophic cardiomyopathy in patients with a mutation on the KRAS gene, and an increased risk of Juvenile myelomonocytic leukemia for a mutation of the PTPN11 gene. In the future, further studies may lead to a targeted management of Noonan Syndrome symptoms, depending on what genetic mutation a patient has.

History[edit]

The oldest known case of Noonan syndrome, described in 1883 by Kobylinski

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 produced a paper entitled "Hypertelorism with Turner Phenotype" in 1968,[17] and in 1971 at the Symposium of Cardiovascular defects, the name 'Noonan Syndrome' became officially recognized.

See also[edit]

References[edit]

  1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. ISBN 0-7216-2921-0. 
  2. ^ 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. 
  3. ^ "Noonan syndrome" at Dorland's Medical Dictionary
  4. ^ "Does Noonan Syndrome Increase Malignant Hyperthermia Susceptibility?". Malignant Hyperthermia Association of the United States. Retrieved 24 October 2014. 
  5. ^ Charity Nebbe (27 February 2014). "Noonan Syndrome with guest Dr Jaqueline Noonan". Iowa Public Radio, Talk of Iowa. Retrieved 27 February 2014. 
  6. ^ Reinker, Kent; Stevenson DA; Tsung A (July–August 2011). "Orthopaedic conditions in Ras/MAPK related disorders.". Journal of Pediatric Orthopeadics 31 (5). doi:10.1097/BPO.0b013e318220396e. PMID 21654472. 
  7. ^ Razzaque MA, Komoike Y, Nishizawa T, et al. (March 2012). "Characterization of a novel KRAS mutation identified in Noonan syndrome". Am. J. Med. Genet. A 158A (3): 524–32. doi:10.1002/ajmg.a.34419. PMID 22302539. 
  8. ^ 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. 
  9. ^ Shchelochkov OA, Patel A, Weissenberger GM, et al. (April 2008). "Duplication of chromosome band 12q24.11q24.23 results in apparent Noonan syndrome". Am. J. Med. Genet. A 146A (8): 1042–8. doi:10.1002/ajmg.a.32215. PMID 18348260. 
  10. ^ Van Der Burgt, I.; Brunner, H. (2000). "Genetic heterogeneity in Noonan syndrome: Evidence for an autosomal recessive form". American Journal of Medical Genetics 94 (1): 46–51. doi:10.1002/1096-8628(20000904)94:1<46::AID-AJMG10>3.0.CO;2-I. PMID 10982482.  edit
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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. 
  14. ^ 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. 
  15. ^ De Luca, A.; Bottillo, I.; Sarkozy, A.; Carta, C.; Neri, C.; Bellacchio, E.; Schirinzi, A.; Conti, E.; Zampino, G.; Battaglia, A.; Majore, S.; Rinaldi, M. M.; Carella, M.; Marino, B.; Pizzuti, A.; Digilio, M. C.; Tartaglia, M.; Dallapiccola, B. (2005). "NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome". American Journal of Human Genetics 77 (6): 1092–1101. doi:10.1086/498454. PMC 1285166. PMID 16380919.  edit
  16. ^ http://www.mayomedicallaboratories.com/interpretive-guide/?alpha=N&unit_code=61851
  17. ^ Noonan, JA (1968). "Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease". Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. Noonan JA. Am J Dis Child. Oct; 116 (4): 373–80. PMID 4386970. 
  18. ^ CDC. (2004). Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis. Can be downloaded at http://www.cdc.gov/fas/faspub.htm.

External links[edit]