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.

Key Data

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Synonym NS
Genes PTPN11 (50%), SOS1 (13%), RAF1 (5%), RIT1 (5%), seltener: 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
Heredity Autosomal dominant
Prevalence 1:2.000
Genotype-phenotype correlation Specific mutations in PTPN11 (e.g. codon 61 or T73I) or KRAS (T58I): risk of a myeloproliferative disorder
Specific mutations in SHOC2 (S2G) or PPP1CB (P49R): Noonan syndrome-like disease with loose anagen hair (NSLAH)
Specific mutations in PTPN11 (T468M and Y279C): Noonan syndrome with multiple lentigines (NSML)
Mutations in CBL: CBL syndrome (CBLS)
Penetrance Nearly 100% (relates to the syndrome and not to the development of neoplasia)
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Diagnosis

Diagnosis

The diagnosis is confirmed clinically; in many cases, it is possible to prove the existence of an RAS signaling pathway mutation in one of the above-mentioned genes.

Differential Diagnoses

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).

Therapeutic Considerations

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.

Surveillance Recommendations

Surveillance Recommendations

In general, no cancer screening measures are indicated, since the risk of cancer is only slightly increased. In children with CFC syndrome and in children with mutations in PTPN11 and KRAS associated with myeloproliferative disorders, the following may be worth considering:

  • 0 to 5 years: a physical examination paying particular attention to the size of the spleen and the blood count, making comparisons every 3-6 months

  • In addition, examinations to check for other non-hemato-oncological complications may also be useful (e.g. vasculitis with CBL syndrome).