Dr. rer. biol. hum. S. Chahrokh-Zadeh, Dr. rer. nat. Karin Mayer
Noonan syndrome is an autosomal dominant inherited disease occurring with a frequency of 1 in 1,000-2,500 live births. Symptoms are variable and range from facial dysmorphia (broad forehead, hypertelorism, low ears and outward-sloping eyelid axis), proportionate short stature, pterygium colli, breast deformations, cryptorchidism, intellectual disability, a slight tendency to bleed as well as cardiac defects, usually in the form of pulmonary stenosis or hypertrophic cardiomyopathy. The gene mainly affected in Noonan syndrome is the PTPN11 gene, which encodes a cytoplasmic protein tyrosine phosphatase (SHP-2). Pathogenic variants in the PTPN11 gene that lead almost exclusively to amino acid substitutions are the molecular cause in approximately 50% of all Noonan patients examined so far.
Pathogenic variants have so far been identified in several other genes of the RAS-ERK-MAP-kinase signal transduction pathway in Noonan syndrome. In up to 15% of Noonan patients where no PTPN11 gene mutation was detected, mutations were detected in the SOS1 (son of sevenless) gene. Mutations in the RAF1 gene are found in approximately 8% of Noonan patients; almost all patients with RAF1 mutations have hypertrophic cardiomyopathy. Further genes include RIT1 (approximately 5% of patients) and KRAS (approximately 3% of patients); pathogenic variants in these genes lead predominantly to severe phenotypes.
Pathogenic variants in the genes MAP2K1, MAP2K2 and BRAF are rarely identified in Noonan syndrome; these genes are more frequently altered in patients with cardio-facial-cutaneous (CFC) syndrome. The frequency of pathogenic BRAF variants in Noonan syndrome is estimated to be 2%. Patients have neonatal growth retardation, mild cognitive deficiency and muscle hypotonia. With a frequency of 1%, mutations in the NRAS and CBL genes are even rarer. Further genes described in connection with Noonan syndrome include RASA2, PPP1CB (Noonan syndrome-like disorder with loose anagen hair) and MRAS.
Variants of the above-mentioned genes and the genes MAP2K2, SHOC2, HRAS and NF1 are also found in patients with the Noonan syndrome-like diseases such as cardiofaciocutaneous syndrome (CFC), LEOPARD syndrome, Noonan syndrome with juvenile myelomonocytic leukemia (JMML) and neurofibromatosis-Noonan syndrome. Pathogenic variants in the NF1 gene have also been identified in Noonan syndrome patients who do not fulfil the classic criteria of classical neurofibromatosis.
In approximately 25% of all Noonan syndrome patients, no causal mutation can be found in any of the currently known genes.
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