Pediatric Dimensions Review Article ISSN: 2397-950X Novel insights in Noonan syndrome Giulia Dodi and Francesco Chiarelli* Department of Paediatrics, University of Chieti, Italy Abstract Noonan syndrome is an inherited developmental disorder, classically identified by typical appearance, short stature, and cardiologic impairment. Nowadays it is recognized as part of RASopathies, i.e. a group of genetic disorders affecting the RAS-MAPK pathway. Diagnosis and clinical management of Noonan syndrome are challenging for the general paediatrician and children do require thorough multidisciplinary assessments throughout growth. Particularly, they must be referred to both paediatric endocrinologists and paediatric cardiologists. Prompt diagnosis is possible and genetic counselling for affected families is essential. This paper reviews clinical features and current treatment guidelines of Noonan syndrome in order to allow general paediatricians to better care children and adolescents with Noonan syndrome and to ensure a proper multidisciplinary approach. Introduction to 1 case per 2500 live births [1,4]. It is the most common cause of congenital heart disease after trisomy 21. Noonan syndrome (MIM 163950) (NS) is a genetic developmental disorder, historically identified by typical physical appearance Pathogenesis associated to short stature and congenital heart defects. Jaqueline NS is a genetic pathology due to sporadic or inherited mutations, Noonan, a paediatric cardiologist, was the first to characterize the with normal karyotype; most cases are transmitted in an autosomal syndrome: she identified nine children with remarkably similar faces, dominant manner and for these reasons males and females are equally short stature, significant chest deformities and pulmonary stenosis. affected. As similar autosomal dominant disorders, a significant Initially, NS was mixed up with Turner syndrome; the fact that males percentage of cases result from de novo mutations. NS is characterized could be affected and reports of normal karyotypes helped to separate by incomplete penetrance: parents can be affected by mild forms. these two entities. In 1994, Noonan syndrome was mapped to 12q24.1 In addition, it seems that the mother is more often the transmitting and genetic heterogeneity was documented. In 2001 Tartaglia and parent: it depends on normal pubertal development in affected females, colleagues identified the first gene (PTPN11) associated to NS [1]. while affected males usually present cryptorchidism [5]. As mentioned, To date, pathogenetic mutations have been demonstrated in several pathogenetic mutations are part of RAS MAPK signal transduction genes across RAS-MAPK signal transduction pathway (mitogen- pathway. In addition to PTPN11, that accounts for approximatively activated protein kinase), that is an important regulator of cell growth, 50% of mutations, pathogenetic mutations have been demonstrated in differentiation and senescence [2]. Gradually, other syndromes related SOS1, RAF1, KRAS, NRAS, SHOC2, CBL, BRAF, SOS2, RIT1, RRAS, to NS have been described: NS with multiple lentigo or LEOPARD RASA2, SPRY1, LZTR1, MAP3K8, MYST4, and A2ML1 [2]. PTPN11, syndrome (MIM 151100), Noonan-like syndrome with loose anagen SOS1, RAF1 and RIT1 cover 93% of reported mutations. However, hair (MIM 607721), Costello syndrome (MIM 218040), cardio-facio- in 20-30% of all patients with NS, genetic mutations have not been cutaneous syndrome (MIM 115150), type I neurofibromatosis (MIM identified [6]. PTPN11 (protein tyrosine phosphatase non-receptor 162200), and Legius syndrome (MIM 611431) [2,3]. Currently, NS and type 11) gene encodes for SHP-2, a tyrosine phosphatase, that is related disorders are collectively named RASopathies, i.e. a group of involved in several developmental processes such as limb development, diseases related by constitutional dysregulation of the RAS signalling semilunar valvulogenesis, haemopoietic cell differentiation and pathway and phenotype resembling NS [3]. Cardiac involvement, mesodermal patterning and is widely expressed in several tissues such impaired growth, intellectual disabilities, predisposition to cancer and as heart, muscles and brain [7]. PTPN11 mutations result in a gain ectodermal, muscle and skeletal defects are variably represented. An of function of SHP-2. There are no phenotypic features exclusive to extensive description of all RASopathies goes beyond the intent of this a specific genotype, anyway genotype-phenotype correlations may be paper: we will provide a general overview of NS as a paradigm for this useful since there are significant differences in the risk of various NS group of pathologies. In fact, the aim of this paper is to summarize the manifestations based on the causative gene (Table 1). For instance, general characteristics of NS with special attention to cardiac disease NS type 1 (MIM 163950), due to PTPN11 mutations, is characterized and GH therapy; people with NS and other RASopathies require prompt diagnosis and multidisciplinary interventions at different stages of their lives. *Correspondence to: Francesco Chiarelli, Department of Paediatrics, University Epidemiology of Chieti, Chieti, Italy, Tel: +39 0871 358015; Fax: + 39 0871 574538; E-mail: [email protected] With a cumulative incidence of about 1 per 1000 live births, RASopathies represent one of the largest groups of developmental Key words: general paediatrician, Noonan syndrome, short stature disorders [2]. The incidence of NS is estimated to be 1 case per 1000 Received: April 10, 2020; Accepted: April 24, 2020; Published: April 29, 2020 Pediatr Dimensions, 2020 doi: 10.15761/PD.1000203 Volume 5: 1-6 Dodi G (2020) Novel insights in Noonan syndrome Table 1. Genotype phenotype correlations in Noonan Syndrome. 15%. Less common spinal abnormalities include kyphosis, spina bifida, Phenotype Gene Location Inheritance vertebral and rib abnormalities and genu valgum. Talipes equinovarus, NS1 PTPN11 12q24.13 AD radioulnar synostosis, cervical spine fusion and joint contractures were NS2 LZTR1 22q11.21 AR reported, too [12]. NS3 KRAS 12p12.1 AD NS4 SOS1 2p22.1 AD Short stature NS5 RAF1 3p25.2 AD A cardinal feature of NS, which can lead to diagnosis, is postnatal NS6 NRAS 1p13.2 AD proportionate short stature, reported in 80% of patients. In fact, prenatal NS7 BRAF 7q34 AD growth is classically normal, with birth weight and body length in the NS8 RIT1 1q22 AD normal range. NS patients could present feeding difficulties, justifying NS9 SOS2 14q21.3 AD enteral nutrition in one-fifth of infants. This period of failure to thrive NS10 LZTR1 22q11.21 AD is self-limited [9]. Postnatal growth failure may appear from the first NS12 MRAS 3q22.3 AD year of life. The mean height follows the lower limit of the normal NS13 RRAS2 11p15.2 AD population (third percentile or -2 standard deviation score SDS) until *PTPN11 Protein Tyrosine Phosphatase Non-Receptor Type 11, LZTR1 Leucine Zipper the age of puberty, after which it declines further as a result of delayed like Transcription Regulator 1, KRAS KRAS Proto-Oncogene, GTPase, SOS1 SOS Ras/Rac Guanine Nucleotide Exchange Factor 1, RAF1 Raf-1 Proto-Oncogene, Serine/ puberty and attenuated pubertal growth spurts. Since bone maturity is Threonine Kinase, NRAS, BRAF B-Raf Proto-Oncogene, Serine/Threonine Kinase, RIT1 usually delayed, prolonged growth into the 20s is possible. Anyway, the Ras Like Without CAAX 1, SOS2 SOS Ras/Rho Guanine Nucleotide Exchange Factor 2, final adult height is around -2SDS in both sexes; it is estimated 161-167 MRAS Muscle RAS Oncogene Homolog, RRAS2 RAS Related 2. [8]. cm in males and 150-155 cm in females [13]. Specific growth charts are by frequent pulmonary stenosis and atrial septal abnormality, shorter available and should be used in growth assessment of these patients stature, lower insulin growth factor-1 (IGF1) levels, more bleeding [12]. To date, the primary cause of short stature in NS is unclear. For diathesis and juvenile myelomonocytic leukaemia. Whereas, in NS type instance, insulin like growth factor 1 (IGF-1) concentrations are as low 3 (MIM 609942), due to KRAS mutations, hypertrophic cardiomyopathy or low-normal in patients with PTPN11 mutations [14-16]. Anyway, and naevi, lentigo, and café au lait spots are typical [2,8]. the role of growth hormone in these children is still under study and is being disputed. Clinical presentation Neuropsychological development NS is a clinically heterogeneous disorder with multiple congenital malformations; it includes dysmorphic facial features, short stature, Early developmental milestones may be delayed in NS infants, partly congenital heart diseases and parenchymal abnormalities and due to joint hyperextensibility and hypotonia, frequently described in comorbidities. The diagnosis of NS is historically based on clinical these children. First words average age is around 15 months; this delay findings using the scoring system by van der Burgt (1997). Anyway, the may be related to articulation deficiency, that is relatively common, distinctive phenotypic triad is made up by facial features, short stature hearing loss, or perceptual motor disabilities. During school-age about and cardiopathies [9,10]. 50% of children present coordination disorders [17,18]. Individuals with NS have mildly lowered intellectual abilities, with IQ scores below Physical appearance 70 in 6%-23% of patients. Around a quarter of children affected by NS have learning disabilities and some of them require special education Facial and musculoskeletal