Noonan Syndrome

Noonan Syndrome (NS) is characterised by short stature, typical facial dysmorphology and congenital heart defects. The incidence of NS is estimated to be between 1:1000 and 1:2500 live births. The main facial features of NS are hypertelorism with down-slanting palpebral fissures, ptosis and low-set posteriorly rotated ears with a thickened helix. The cardiovascular defects most commonly associated with this condition are pulmonary stenosis and hypertrophic cardiomyopathy. Other associated features are webbed neck, chest deformity, mild intellectual deficit, cryptorchidism, poor feeding in infancy, bleeding tendency and lymphatic dysplasias. The syndrome is transmitted as an autosomal dominant trait. In approximately 50% of cases, the disease is caused by missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the non-receptor protein tyrosine phosphatase SHP-2 protein. Recently, mutations in the KRAS gene have been identified in a small proportion of patients with NS. A DNA test for mutation analysis can be carried out on blood, chorionic villi and amniotic fluid samples. NS should be considered in all foetuses with polyhydramnion, pleural effusions, oedema and increased nuchal fluid with a normal karyotype. With special care and counselling, the majority of children with NS will grow up and function normally in the adult world. Management should address feeding problems in early childhood, evaluation of cardiac function and assessment of growth and motor development. Physiotherapy and/or speech therapy should be offered if indicated. A complete eye examination and hearing evaluation should be performed during the first few years of schooling. Preoperative coagulation studies are indicated. Signs and symptoms lessen with age and most adults with NS do not require special medical care.

The RASopathies are a group of disorders caused by a germline mutation in one of the genes encoding a component of the RAS/MAPK pathway. These disorders, including neurofibromatosis type 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome and Legius syndrome, among others, have overlapping clinical features due to RAS/MAPK dysfunction. Although several of the RASopathies are very rare, collectively, these disorders are relatively common. In this Review, we discuss the pathogenesis of the RASopathy-associated genetic variants and the knowledge gained about RAS/MAPK signaling that resulted from studying RASopathies. We also describe the cell and animal models of the RASopathies and explore emerging RASopathy genes. Preclinical and clinical experiences with targeted agents as therapeutics for RASopathies are also discussed. Finally, we review how the recently developed drugs targeting RAS/MAPK-driven malignancies, such as inhibitors of RAS activation, direct RAS inhibitors and RAS/MAPK pathway inhibitors, might be leveraged for patients with RASopathies.

Noonan syndrome (NS) is among the most common nonchromosomal disorders affecting development and growth. NS is caused by aberrant RAS-MAPK signaling and is genetically heterogeneous, which explains, in part, the marked clinical variability documented for this Mendelian trait. Recently, we and others identified SOS1 as a major gene underlying NS. Here, we explored further the spectrum of SOS1 mutations and their associated phenotypic features. Mutation scanning of the entire SOS1 coding sequence allowed the identification of 33 different variants deemed to be of pathological significance, including 16 novel missense changes and in-frame indels. Various mutation clusters destabilizing or altering orientation of regions of the protein predicted to contribute structurally to the maintenance of autoinhibition were identified. Two previously unappreciated clusters predicted to enhance SOS1's recruitment to the plasma membrane, thus promoting a spatial reorientation of domains contributing to inhibition, were also recognized. Genotype-phenotype analysis confirmed our previous observations, establishing a high frequency of ectodermal anomalies and a low prevalence of cognitive impairment and reduced growth. Finally, mutation analysis performed on cohorts of individuals with nonsyndromic pulmonic stenosis, atrial septal defects, and ventricular septal defects excluded a major contribution of germline SOS1 lesions to the isolated occurrence of these cardiac anomalies.

The variety of genes associated with Noonan syndrome spectrum disorders (NSSD) is expanding, and real-life experience with its management is increasing; however, phenotypic differences among genotypes remain poorly defined. We aimed to assess clinical characteristics and response to growth hormone (GH) therapy in a genetically confirmed, single-country multicentre NSSD cohort. We included 101 patients with NSSD (56 males) from six centres: 76 with (likely) pathogenic PTPN11 variants, 7 with SOS1 variants, and 18 with other gene variations. All completed at least one year of GH therapy; 23 reached final height. Parental heights were below average (fathers: - 0.33 SDS [- 1.19; 0.39], p < 0.01; mothers: - 0.68 SDS [- 1.47; 0.12], p < 0.001; medians [IQR]). SOS1-NS patients were born earlier (gestational week 36 [31; 37]) compared to PTPN11-NS. Birth length (- 1.23 SDS [- 1.74; - 0.57]) was more reduced than weight (- 0.29 SDS [- 1.10; 0.54]; p < 0.0001); PTPN11-NS/SOS1-NS had the lowest birth weights (p < 0.05). GH was started at 6.4 years (3.8; 9.5), with baseline height-SDS - 2.92 (- 3.64; - 2.47). Median annual height-SDS increments were similar across genotypes: 0.61 (year 1; n = 101), 0.28 (year 2; n = 92), 0.21 (year 3; n = 77), 0.07 (year 4; n = 63), and 0.09 (year 5; n = 41), leading to height-SDS - 1.97 (- 2.81; - 1.42) after 5 years. Menarche occurred at age 15.7 (13.8; 17.2) years (n = 13), and final height-SDS (available in 23 patients) reached - 1.68 (- 2.65; - 0.41). Conclusions Growth restriction in NSSD begins prenatally, especially in PTPN11-NS and SOS1-NS. GH therapy was associated with improved height SDS, with the largest height gains observed before puberty. Earlier treatment initiation may therefore be beneficial for growth outcomes. What is Known: • Noonan syndrome spectrum disorders (NSSD) are genetically heterogeneous, with pathogenic variants in the PTPN11 and SOS1 genes being most prevalent. Phenotypic differences among genotypes remain poorly defined. • Short stature is a key NSSD feature. Growth hormone (GH) therapy is beneficial, but prior studies lacked genetic justification or had limited sample sizes. What is New: • We analysed perinatal data and real-life GH outcomes in 101 genetically confirmed NSSD cases. • SOS1-NS was linked to prematurity. Birth length was more reduced than weight across genotypes; PTPN11/SOS1 cases had the lowest birth weights. GH therapy was associated with an increase in height SDS from - 2.92 to - 1.97 (median) following 5 years, and to - 1.68 in those with final height.