NOONAN SYNDROME AND THE RASOPATHIES
Noonan syndrome is characterized by cardiac defects, short stature, cryptorchidism, and characteristic facial features (ptosis, hypertelorism, a low hairline, and neck webbing). The most common cardiac defects seen (85–90
% overall) are pulmonary stenosis, hypertrophic cardiomyopathy, and VSD. 65 % may have a clotting defect. It affects approximately 1 in 2.5,000 people and was originally thought to be a variant of Turner’s syndrome because neck webbing and short stature were features of both. However, the karyotype is normal in Noonan syndrome (NS), and it is inherited as an autosomal dominant trait. Mutations in PTPN11 are found in about half of patients with this condition, and the gene product, SHP2, is a component of the mitogen- activated protein kinase (MAPK) signaling pathway. More recently, germline gain-of-function mutations in other genes involved in the same Ras/MPK pathway have been found in a proportion of cases, e.g., SHOC2, KRAS, SOS1, NRAS, BRAF, and RAF1 (Pandit et al. 2006). Autosomal recessive Noonan syndrome may be caused by mutations in the SHOC2 gene.
LEOPARD syndrome (LS), so called because of its clinical features of lentigines, ECG anomalies, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, growth retardation, and deafness, is caused by gain-of-function mutations in PTPN11 and therefore considered as a variant of Noonan syndrome (Tartaglia et al. 2006).
Germline mutations in other genes involved in the Ras/MPK pathway have been identified in children with related disorders, e.g., cardio-facio- cutaneous syndrome (CFC) and Costello syndrome.
Preliminary studies have suggested that there is an increased risk of cancer in patients with Noonan syndrome with germline PTPN11 mutations in older age groups, but this has not been confirmed. The main risk is for juvenile myelomonocytic leukemia. One mutation, threonine to isoleucine at position 73 in SHP-2 (Thr73Ile), has been found in several NS patients suffering from JMML (Jongmans et al. 2011; Tartaglia et al. 2003).
CFC presents with cardiac defects, characteristic coarse facial features, hyperkeratotic skin lesions and nevi, sparse curly hair, sparse eyebrows, and severe developmental delay and is associated with germline mutations in BRAF, KRAS, BRAF, MEK1, or MEK2 (Roberts et al. 2006), and Costello syndrome is characterized by cardiac defects, short stature, coarse facial features, and a significant increased risk of cancer, due to germline mutations in HRAS (Kerr et al. 2006).
It is thought that increased MAPK signal transduction results in cancer susceptibility; a germline HRAS mutation which encodes a p.G12V amino acid change with very high transforming potential causes severe neonatal lethal Costello syndrome. Most cases of Costello syndrome are due to a less strongly activating mutation p.G12S, which results in a 15 % lifetime risk of Tumours. There is another recurrent mutation, p.G13C, which results in a milder phenotype. The lifetime risk of cancer in Costello syndrome is estimated to be 15 %, 60 % of these being rhabdomyosarcoma, which tend to occur in childhood, and others commonly being neuroblastoma and bladder cancer. The bladder cancer may occur as early as the second decade of life.
The risk of rhabdomyosarcoma in Costello syndrome is similar to that in Beckwith–Wiedemann syndrome, which may justify screening. Based on the recommendations for screening BWS patients, it has been suggested that children with Costello syndrome be offered screening by ultrasound examination of the abdomen and pelvis 3–6 monthly until 10 years of age for rhabdomyosarcoma and abdominal neuroblastoma, urine catecholamine metabolite analysis 6–12 monthly until 5 years of age for neuroblastoma, and annual urinalysis for hematuria for bladder carcinoma after 10 years of age (Gripp et al. 2002).
Noonan, CFC, and Costello syndromes, together with neurofibromatosis type 1 and Noonan syndrome with multiple lentigines (LEOPARD syndrome), caused by germline mutations in the genes in the Ras/MAPK pathway, are becoming known as the RASopathies, and a RASopathy patient/family support group has been proposed, but the patient groups remain separate as the issues are all rather different for the different conditions.