Noonan Syndrome – Definition
Noonan syndrome (OMIM #163950) is an autosomal-dominant, hereditary developmental disorder with a distinct phenotype (see the clinical features) and a slightly increased risk of cancer.
Synonym:
NS
Genes:
PTPN11 (50%), SOS1 (13%), RAF1 (5%), RIT1 (5%), rarer: KRAS, NRAS, BRAF, MAP2K1, RRAS, RASA2, A2ML1, SOS2, LZTR1, CBL, SHOC2, PPP1CB
Gene products:
SHP2, SOS1, RAF1, RIT1, KRAS, NRAS, BRAF, MAP2K1, RRAS, RASA2, A2ML1, SOS2, LZTR1, CBL, SHOC2, PPP1CB
Function:
RAS signaling pathway
Pattern of inheritance:
Autosomal dominant
Prevalence:
1:2.000
Genotype-phenotype correlation:
Specific pathogenic variants in PTPN11 (e.g. codon 61 or T73I) or KRAS (T58I): risk of a myeloproliferative disorder
Specific pathogenic variants in SHOC2 (S2G) or PPP1CB (P49R): Noonan syndrome-like disease with loose anagen hair (NSLAH)
Specific pathogenic variants in PTPN11 (T468M and Y279C): Noonan syndrome with multiple lentigines (NSML)
Pathogenic variants in CBL: CBL syndrome (CBLS)
Penetrance:
Nearly 100% (relates to the syndrome and not to the development of neoplasia)
Noonan Syndrome – Diagnosis
The diagnosis is confirmed clinically; in many cases, it is possible to prove the existence of a pathogenic RAS signaling pathway variant in one of the above-mentioned genes.
Differential Diagnoses
- Costello syndrome
- CFC syndrome
- Neurofibromatosis type 1
- Legius syndrome
Clinical Presentation
Noonan syndrome is associated with various changes, including striking facies with low-lying ears that are rotated towards the back, hypertelorism, ocular ptosis, a broad neck, and a low hairline. In addition, there may also be proportionate dwarfism, congenital heart defects (particularly pulmonary stenosis, hypertrophic cardiomyopathy), thoracic deformity, skin and hair changes, vision problems, cryptorchidism, learning disabilities, and a bleeding tendency.
The risk of cancer in children with NS is around 8 times higher. The cancer spectrum lists the following types of cancer (excerpt): Gliomas, such as dysembryoplastic neuroepithelial tumors, acute lymphoblastic leukemia, neuroblastoma, rhabdomyosarcoma
Specific mutations in PTPN11 (especially, but not exclusively, codon 61 or T73I) or KRAS (T58I) are associated with an increased risk of polyclonal, often transient myeloproliferative disorders during the first few months of life. These myeloproliferative disorders sometimes progress aggressively, and therapy is indicated.
Besides the changes typical of Noonan syndrome, darkly pigmented skin and ectodermal abnormalities can also be identified in people with NSLAH.
People suffering from NSML exhibit a Noonan syndrome phenotype and multiple lentigines, often accompanied by hypertrophic cardiomyopathy and a hearing impairment.
Noonan syndrome-like CBLS has a variable phenotype characterized by vasculitis, mild changes reminiscent of Noonan syndrome, and a high risk of juvenile myelomonocytic leukemia (JMML).
Specific Features of Treatment
In children suffering from a myeloproliferative disorder with Noonan syndrome or from JMML with CBL syndrome, the treatment approach should be discussed with the EWOG MDS Study. At present, treatment is only indicated for symptoms due to myeloproliferative disorders or JMML. It is possible for the symptoms to spontaneously regress. Occasionally, the progression may be aggressive.
Diagnosis of Noonan Syndrome- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis of Noonan Syndrome - What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection in Your Patients
According to the latest AACR guidelines, the following screening tests are recommended for patients with Noonan syndrome, CBL syndrome and NSML:
Myeloproliferative diseases
- Clinical examination with special attention to hepatosplenomegaly and clinical signs of leukaemia from birth or diagnosis
- every 3 months during the first year of life
- Then at each well-child visit up to the age of 5 years
- as needed for clinical signs
- No regular blood tests in asymptomatic/healthy children (previously recommended for PTPN11 and KRAS)
- Complete blood cound in case of symptoms or hepatosplenomegaly
- Consult myeloproliferative disease experts if blood count is abnormal
Brain tumours
No early detection if no clinical symptoms occur.
Additionally for Noonan syndrome with multiple lentigines
- Dermatological examination annually from birth
