174:5 C Cessans, V Ehlinger and Growth patterns of Noonan 174:5 641–650 Clinical Study others syndrome Growth patterns of patients with Noonan syndrome: correlation with age and genotype Catie Cessans1,*, Virginie Ehlinger2,*, Catherine Arnaud2,3, Armelle Yart4, Yline Capri5, Pascal Barat6, Benoit Cammas6, Didier Lacombe7, Régis Coutant8, Albert David9, Sabine Baron10, Jacques Weill11, Bruno Leheup12, Marc Nicolino13, Jean-Pierre Salles1,14, Alain Verloes5, Maithé Tauber1,14, Hélène Cavé5 and Thomas Edouard1,14 1Endocrine, Bone Diseases, and Genetics Unit, Children’s Hospital, Toulouse University Hospital, Toulouse, France, 2UMR 1027 INSERM, University of Toulouse Paul Sabatier, Toulouse, France, 3Clinical Epidemiology Unit, Toulouse University Hospital, Toulouse, France, 4INSERM UMR 1048, Institute of Cardiovascular and Metabolic Diseases (I2MC), University of Toulouse Paul Sabatier, Toulouse, France, 5Departments of Genetics, Robert-Debré University Hospital, APHP, Paris, France, 6Pediatric Endocrinology Department, Clinical investigation Centre (CIC 1401), Bordeaux University Hospital, Bordeaux, France, 7Genetics Department, Bordeaux University Hospital, EA4576, Bordeaux, France, 8Pediatric Endocrinology Department, Angers University Hospital, Angers, France, 9 10 Genetics Department, Nantes University Hospital, Nantes, France, Pediatric Endocrine Unit, Nantes University Correspondence 11 12 Hospital, Nantes, France, Pediatric Endocrine Unit, Lille University Hospital, Lille, France, Pediatric and should be addressed 13 Genetics Unit, Nancy University Hospital, Vandoeuvre, France, Pediatric Endocrinology Department, to T Edouard 14 Lyon University Pediatric Hospital, INSERM U.1060/UCBL/HCL, France, INSERM UMR 1043, Centre of Email Pathophysiology of Toulouse Purpan (CPTP), University of Toulouse Paul Sabatier, Toulouse, France [email protected] *(C Cessans and V Ehlinger contributed equally to this work.) Abstract Background: Growth patterns of patients with Noonan syndrome (NS) were established before the involved genes were identified. Objective: The goal of this study was to compare growth parameters according to genotype in patients with NS. Subjects and methods: The study population included 420 patients (176 females and 244 males) harboring mutations in European Journal European of Endocrinology the PTPN11, SOS1, RAF1, or KRAS genes. NS-associated PTPN11 mutations (NS-PTPN11) and NS with multiple lentigines- associated PTPN11 mutations (NSML-PTPN11) were distinguished. Birth measures and height and body mass index (BMI) measures at 2, 5, 10 years, and adulthood were compared with the general population and between genotypes. Results: Patients with NS were shorter at birth (mean birth length standard deviation score (SDS): –1.0 ± 1.4; P < 0.001) and throughout childhood than the healthy population, with height SDS being –2.1 ± 1.3 at 2 years, and –2.1 ± 1.2 at 5 and 10 years and adulthood (P < 0.001). At birth, patients with NS-PTPN11 were significantly shorter and thinner than patients with NSML-PTPN11, SOS1, or KRAS. Growth retardation was significantly less severe and less frequent at 2 years in patients with NSML-PTPN11 and SOS1 than in patients with NS-PTPN11 (P < 0.001 and P = 0.002 respectively). Patients with NS had lower BMI at 10 years (P < 0.001). No difference between genotypes was demonstrated. Conclusion: Determining the growth patterns of patients with NS according to genotype should better inform clinicians about the natural course of growth in NS so that they can optimize the follow-up and management of these patients. European Journal of Endocrinology (2016) 174, 641–650 Introduction Noonan syndrome (NS; Mendelian inheritance in man features, heart defects (i.e. pulmonary valve stenosis and (MIM) #163950) is a relatively frequent (estimated hypertrophic cardiomyopathy), developmental delay, prevalence of 1 in 1000 – 2500 live births) autosomal and short stature (1). These distinctive traits are shared, dominant disorder characterized by facial dysmorphic with variable severity, by NS-related diseases, namely NS www.eje-online.org © 2016 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-15-0922 PrintedinGreat Britain Downloaded from Bioscientifica.com at 09/28/2021 04:48:29AM via free access 10.1530/EJE-15-0922 Clinical Study C Cessans, V Ehlinger and Growth patterns of Noonan 174:5 642 others syndrome with multiple lentigines (NSML; MIM #151100), NS with symptoms of NS that lead to the diagnosis (12). Specific loose anagen hair (MIM #607721), cardiofaciocutaneous growth charts were established more than 25 years ago syndrome (MIM #115150), Costello syndrome (MIM (13, 14) before the genes involved in NS were identi- 218040), and neurofibromatosis type I (MIM #162200). fied. The discovery of these genes made it possible to In the past decade, mutations in several genes encoding look for genotype–phenotype correlations in growth components of the RAS/MAPK signaling pathway patterns. However, to our knowledge, only one study were discovered to be involved in NS and NS-related investigated the growth characteristics according to diseases, and this group of disorders is now termed the genotype in 127 patients with NS and 10 patients with RASopathies (2). They are one of the largest groups of NS-related diseases, with interesting preliminary results multiple congenital anomaly diseases known. (15). In this study, growth parameters (height, weight, The classical form of NS is principally associated and body mass index (BMI)) were converted to age-spe- with heterozygous missense mutations in four genes: cific and sex-specific standard deviations on the basis of PTPN11, SOS1, RAF1, and KRAS genes, accounting for children’s growth standards, and then cumulated before 50, 10, 10, and <2%, respectively, of the NS cases (1). searching for differences between genotypes. As a result, A dozen genes have been found to be implicated in NS, variations according to age and genotype could not be but genetic screening remains negative in about 30% of investigated. patients with NS. In this study, we aimed to describe the growth char- NSML, previously referred as LEOPARD syndrome acteristics (i.e. measurements at birth, height, and BMI) (acronym for multiple Lentigines, Electrocardiographic of patients with NS and NSML according to their age and conduction abnormalities, Ocular hypertelorism, Pulmo- genotype, and evaluate whether mutations in the differ- nary stenosis, Abnormal genitalia, Retardation of growth, ent genes involved in NS and NSML may have differential sensorineural Deafness), is closely related to NS. Indeed, impact in growth. To achieve this goal, we took advan- because lentigines appear with age, these two syndromes tage of a French national database and present the growth might be difficult to differentiate in early life. NSML is parameters at different ages according to their genotype allelic with NS, being mainly caused by PTPN11 (12q24.13) in 420 patients with NS or NSML harboring mutations in mutations (>80% of patients) and more rarely by RAF1 the PTPN11, SOS1, RAF1, or KRAS genes. (3p25.2) mutations (3, 4). So far, more than 60 mutations in PTPN11 have been associated with NS, which mainly affect the interaction between the SH2 and the protein Subjects and methods European Journal European of Endocrinology tyrosine phosphatase (PTP) domains, and about 20 muta- Patient population tions, all targeting specific residues within the PTP domain, have been linked to NSML (5). The PTPN11 gene encodes The majority of French patients with NS and NS-related Shp2, a widely expressed nonreceptor PTP that plays key disorders are referred for molecular testing to the roles in organism development and homeostasis by con- Department of Genetics of Robert-Debré Hospital (Paris, trolling major growth factors/hormone-triggered signal- France). The clinical data are recorded by the clinicians ing pathways, notably the RAS/MAPK pathway (6). From on standard datasheets. The data include, among other a biochemical point of view, it has been shown that NS- features, the gestational age and measurements at birth causing mutations induce hyperactivation of the phospha- (weight, length, and head circumference), and the height tase (gain-of-function mutation), while NSML-associated and weight at the time of consultation, at 2, 5, 10 years of mutations result in reduced Shp2 catalytic activity (inac- age, and in adulthood. Treatment with growth hormone tivating mutation) (7, 8). How NS-Shp2 and NSML-Shp2 (GH) is also recorded. mutants can result in related syndromes while displaying The study was approved by the Paris-Bichat-Claude opposite biochemical effects is still a matter of debate (9). Bernard Institutional Review Board (n°2003/15) and Interestingly, a differential impact of these mutants on the informed consent was obtained from legal guardians for phosphatidylinositol 3-kinase (PI3K)/Akt signaling path- genetic analyses and for building up the database. way has been causally linked to the development of hyper- Inclusion criteria for our study were a diagnosis of trophic cardiomyopathy, which is preferentially found in NS or NSML between 2002 and 2012, caused by germline patients with NSML (10, 11). mutations in one of the following genes: PTPN11, Proportionate short stature, reported in more than SOS1, RAF1, or KRAS. Two types of PTPN11 mutations 70% of affected patients, is one of the main clinical were distinguished: NS-associated PTPN11 mutations www.eje-online.org Downloaded