Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Noonan Syndrome (NS) [Q87.1]

OMIM numbers: 163950, 176876 (PTPN11), 609942, 190070 (KRAS), 610733, 182530 (SOS1), 611553, 164760 (RAF1), 613224, 164790 (NRAS), 613706, 164757 (BRAF), 615355, 609591 (RIT1), 601589 (RASA2) 176872 (MAP2K1/MEK1), 165360 (CBL)

Dr. rer. biol. hum. S. Chahrokh-Zadeh, Dr. rer. nat. Karin Mayer

Scientific Background

The Noonan syndrome is an autosomal dominant disease occurring with a frequency of 1 in 1,000-2,500 live births. Signs and symptoms are variable and range from facial dysmorphia (broad forehead, hypertelorism, low ears, outward-sloping eyelid axis), proportionate short stature, pterygium colli, breast deformations, cryptorchidism, intellectual disability, mild tendency to bleed as well as cardiac defect, usually in the form of a pulmonary stenosis or hypertrophic cardiomyopathy. The PTPN11 gene, which encodes a cytoplasmic protein tyrosine phosphatase (SHP-2) is the gene mainly affected in Noonan syndrome. Mutations in the PTPN11 gene which almost exclusively lead to amino acid substitutions are the molecular cause in approximately 50% of all Noonan patients examined so far.

So far, mutations have been identified in seven other genes of the RAS/ERK/MAP kinase signal transduction in the Noonan syndrome. In up to 15% of all Noonan patients who did not have a mutation in the PTPN11 gene, mutations were detected in the SOS1 (Son of Sevenless) gene. The clinical phenotype of patients with SOS1 mutations exhibits the typical characteristics of the Noonan syndrome. However, growth and mental development are normal and cardiac defects are less severe.

Mutations in the RAF1 gene were found in approx. 8% of all Noonan patients. Almost all patients with RAF1 mutations have hypertrophic cardiomyopathy.

In about 5% of patients mutations in the recently discovered RIT1 gene can be found.

Furthermore, mutations were found in the KRAS gene in approximately 3% of all Noonan patients. Most of these mutations lead to severe phenotypes.

Mutations in the genes MEK1 and BRAF, however, are less frequently found. These genes are more frequently affected in patients with cardio-facial-cutaneous (CFC) syndrome. MEK1 mutations have so far been found in less than 4% of all examined patients with Noonan syndrome. The frequency of mutations in the BRAF gene in Noonan syndrome is estimated to be 2%. The described patients display neonatal growth impairment, mild cognitive deficits and muscular hypotonia. With a frequency of 1%, mutations in the NRAS as well as the CBL gene are even rarer.

Mutations of the above-mentioned genes and the genes MEK2, SHOC2, HRAS and NF1 are found in patients with diseases similar to the Noonan syndrome such as cardio-facial-cutaneous (CFC), LEOPARD, Noonan syndrome with juvenile myelomonocytic leukemia (JMML), neurofibromatosis-Noonan syndrome, among others.

In approximately 25% of all patients with Noonan syndrome, no mutation can be found in any of the eight above-mentioned genes.