Abstract background noonan syndrome ns is an autosomal dominant disorder that. In several studies ptpn11 is one of the genes with a significant number of pathogenic variants in nsaffected patients. The spectrum of genetic variants and phenotypic features of. Noonan syndrome ns is a relatively common inborn disorder that affects 1 in 1,000 to 1 in 2,500 live births 0. Series of affected individuals heterozygous for mutations in different disease genes are. Clinical expressions of ns are highly variable and include short stature, distinctive craniofacial dysmorphism, cardiovascular abnormalities, and developmental delay. Noonan syndrome ns is a common, clinically and genetically heterogeneous condition characterized by distinctive facial features, short stature, chest deformity, congenital heart disease, and other comorbidities.
Cancer risk in patients with noonan syndrome carrying a ptpn11 mutation. Noonan syndrome ns is a relatively common genetic syndrome with variable features including short stature, congenital heart disease, distinctive facial characteristics, skeletal anomalies, and varying degrees of developmental delay. Noonan syndrome is a condition that is characterized by mildly unusual facial characteristics, short stature, heart defects, bleeding problems, skeletal malformations, and many other signs and symptoms. Noonan syndrome may be inherited in up to 75 per cent of cases.
In the past decade, progress has been made in elucidating the pathogenesis of this disorder using a positional cloning approach. Molecular and clinical analysis of raf1 in noonan syndrome and related disorders. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, characteristic facies, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Pdf noonan syndrome ns is a common autosomal dominant multisystem disorder, caused by mutations in more than 10 genes in the. Therefore single gene testing can be elected for this gene with reflex to a larger panel. Noonan syndrome ns is characterized by short stature, congenital heart defect, and developmental delay of variable degree. Noonan syndrome ns is a common autosomal dominantrecessive disorder. Noonan syndrome symptoms, diagnosis and treatment bmj. Noonan syndrome is a genetic disorder that causes abnormal development of. Conversely, lossoffunction mutations have also been identified, which. We analyzed ptpn11 and kras genes by bidirectional sequencing in 95 probands with ns and 29 with noonanlike syndromes, including previously reported patients already screened for ptpn11 gene mutations. Noonan syndrome ns is characterised by short stature, typical facial dysmorphology and congenital heart defects.
Facial features include widely spaced eyes, lightcolored eyes, lowset ears, a short neck, and a small lower jaw. Mutations that cause noonan syndrome alter genes encoding proteins with roles in the rasmapk pathway, leading to pathway dysregulation. Noonan syndrome and clinically related disorders ncbi nih. Noonan syndrome is a genetic multisystem disorder characterised by distinctive facial features, developmental delay, learning difficulties, short stature, congenital heart disease, renal anomalies, lymphatic malformations, and bleeding difficulties. It is clinically and genetically heterogeneous condition characterized by cardiovascular abnormalities, distinctive facial features, chest deformity, short stature, and other comorbidities.
Neuropsychological functioning in individuals with noonan. Clinical and molecular profiles article pdf available in frontiers in genetics 10333 april 2019 with 67 reads how we measure reads. Noonan syndrome genetic and rare diseases information. That gene encodes shp2, a protein tyrosine kinase that plays diverse roles in signal transduction including signaling via the. It is characterised by a pattern of typical facial dysmorphism and malformations including congenital cardiac defects, short stature, abnormal chest shape, broad or webbed neck, and a variable learning disability. Autosomal recessive noonan syndrome associated with. Background noonan syndrome is an autosomal dominant, multisystemic disorder caused by dysregulation of the rasmitogen activated protein kinase mapk pathway. The rasopathies are a group of medical genetic syndromes that. Activating mutations of rras2 are a rare cause of noonan. Pdf noonan syndrome is a common autosomal dominant disorder characterized by short stature, congenital heart disease and facial dysmorphia with an. Most affected individuals have characteristic facial. Noonan syndrome ns, omim 163950 is the eponymous name for the disorder described by the pediatric cardiologist jacqueline noonan more than 40 years ago noonan, 1968.
A variety of cardiac defects may be present, including pulmonary stenosis, patent ductus arteriosus, hypertrophic cardiomyopathy, and coarctation of the aorta. Noonan syndrome ns1, omim 163950 is a common autosomal dominant disorder characterized by short stature, congenital heart disease, facial dysmorphia and other features such as cryptorchidism, bleeding diathesis, skeletal malformations and mild cognitive delays with variable expressivity. Noonan syndrome ns is one of the more common genetic conditions. Noonan syndrome is now known to be a genetically heterogeneous disorder with nearly one half of cases caused by gainoffunction. Noonan syndrome ns, an autosomal dominant developmental genetic disorder, is caused by germline mutations in genes associated with the ras mitogenactivated protein kinase mapk pathway. To characterize the molecular genetics of autosomal recessive noonan syndrome. Families underwent phenotyping for features of noonan syndrome in children and their parents.
She based the description of this putatively novel syndrome on observations made in 9 patients with pulmonic stenosis, a distinctive dysmorphic facial appearance with hypertelorism, ptosis and lowset ears, webbed. Heart problems may include pulmonary valve stenosis. Noonan syndrome ns, the most common entity among the rasopath. Therefore, clinically diagnosed ns individuals are initially tested for. N2 noonan syndrome ns is a genetically heterogeneous disorder that can result from mutations in the ptpn11, sos1, kras, raf1 and mek1 genes, which encode transducers participating in the rasmap kinase mapk signaling pathway. The incidence of ns is estimated as 1 in 1,000 to 1 in 2,500 births, so it is still a relatively rare condition. Noonan syndrome is a common autosomal dominant disorder characterized by short stature, congenital heart disease and facial dysmorphia with an incidence. The lymphatic phenotype in noonan and cardiofaciocutaneous. This is a pdf file of an unedited manuscript that has. The cause of noonan syndrome in 15 to 20 percent of people with this disorder is. Most of the genes mutated in patients with noonan syndrome cause dysregulated rasmapk signaling 57. The clinical manifestations of noonan syndrome are extremely heterogeneous, and this heterogeneity can be at least partially ascribed to the individual gene and the type of mutation involved. Molecular genetic testing used in noonan syndrome ns.
Characteristics and interventions provides an indepth analysis on this disorder that pediatric endocrinologists and primary care clinicians can use to make sure they provide affected patients with an updated model of care and appropriate treatment. Clinical and molecular characterization of children with noonan syndrome and other rasopathies in argentina a. Ptpn11 and kras gene analysis in patients with noonan and. About onethird of affected children have mild intellectual disability. The main facial features of ns are hypertelorism with downslanting palpebral fissures, ptosis and lowset posteriorly rotated ears with a thickened helix. Noonan syndrome is part of a spectrum of disorders with overlapping phenotypes that include craniofacial features 1 and cardiovascular abnormalities 2,3 and overlaps with cardiofaciocutaneous and costello syndromes 4. Genes shown to be mutated in these disorders include ptpn11.
Unveiling the molecular basis of the noonan syndrome. Molecular and phenotypic spectrum of noonan syndrome in. Molecular and clinical studies in 107 noonan syndrome. Mutations in other genes each account for a small number of cases. Noonan syndrome ns is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. Advances in the molecular genetics of noonan syndrome and phenotypegenotype correlations. Heterozygous, pathogenic variants in 11 known genes account for approximately 80% of cases. See more ideas about noonan syndrome, 7th grade science and genetics. Noonan syndrome ns is a developmental disorder characterized by facial dysmorphia, short stature, cardiac defects, and skeletal malformations.
The cause of noonan syndrome in 15 to 20 percent of people with this disorder is unknown. The severity of ns is the same in males and females. Noonan syndrome is a common genetic disorder that causes multiple congenital abnormalities and a large number of potential health conditions. We recently demonstrated that mutations in ptpn11, the gene encoding the nonreceptortype protein tyrosine phosphatase shp2 src homology region 2domain phosphatase2, cause ns, accounting for. Because of the difficulty in establishing a diagnosis of ns, the. Sos1 gene mutations cause an additional 10 to 15 percent, and raf1 and rit1 genes each account for about 5 percent of cases.
Noonan syndrome orphanet journal of rare diseases full. Noonan syndrome ns is a genetic disorder caused by the hyperactivation of the. Improved molecular detection of mosaicism in beckwith. Mutations in multiple genes can cause noonan syndrome.
Advances in the molecular genetics of noonan syndrome and. The prevalence of this disorder is estimated to be 12500 live births. In noonan syndrome ns, four genes of this pathway ptpn11, sos1, raf1, and kras are responsible for roughly 70% of the cases. Noonan syndrome is a genetic condition that usually includes heart anomalies and. Important progress in understanding the molecular basis of this and other related conditions was made in 2001 when germline mutations in the ptpn11 gene. Gene mutations identified in individuals with the ns phenotype are involved in the rasmapk mitogenactivated protein kinase signal transduction pathway and currently explain. Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Noonan syndrome is one of the most common syndromes with an estimated prevalence of 1 in 1,000 to 1 in 2,500 live births. Noonan syndrome is a genetic multisystem disorder characterised by distinctive facial features, developmental delay, learning difficulties, short stature, congenital heart disease, renal anomalies. Noonan syndrome is inherited in an autosomal dominant manner. The identification of novel genes associated with noonan syndrome has become increasingly challenging, since they might. Noonan syndrome turner 2014 journal of paediatrics. Heterozygous pathogenic mutations in ptpn11, kras, sos1, raf1, shoc2, nras, cbl, braf, and map2k1 account for approximately 75%80% of all noonan syndrome cases.
Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism undescended testes, bleeding problems, and eye differences. Approximately 50% of individuals with noonan syndrome have a pathogenic missense point mutation in the ptpn11 gene. Clinical expressions of ns are highly variable and include short stature, distinctive craniofacial dysmorphism, cardiovascular abnormalities, and developmental. The rasopathies are a group of genetic syndromes caused by upregulated ras signaling. Additionally known associated genes include rit1, ppp1cb, sos2, and ltrz1. Clinical and molecular characterization of children with. See also ns3 609942, caused by mutation in the kras gene 190070. Individuals with noonan syndrome ns have facial dysmorphology, which may include hypertelorism, downward slanting eyes, epicanthal folds, and lowset and posteriorly rotated ears. Noonan syndrome ns is a common autosomal dominant multisystem disorder, caused by mutations in more than 10 genes in the rasmapk signaling pathway. Noonan syndrome is inherited in an autosomal dominant pattern tartaglia et al. Pathogenetics of the rasopathies noonan syndrome awareness. Noonan syndrome is a relatively common, genetically heterogeneous mendelian trait with a pleiomorphic phenotype. Ns and noonan syndrome with multiple lentigines nsml, mim 151100 are the result of a gainoffunction mutation in ptpn11 52. Noonan syndrome is caused by a gainoffunction mechanism.
Noonan syndrome is a common autosomal dominant condition, readily recognisable in childhood. Noonan syndrome is a genetic condition that typically includes heart abnormalities and characteristic facial features. Noonan syndrome is an autosomal dominant dysmorphic syndrome characterized primarily by dysmorphic facial features, cardiac abnormalities, and short stature, among other features summary by shah et al. Clinical features, diagnosis and management guidelines. Noonan syndrome amy e roberts, judith e allanson, marco tartaglia, bruce d gelb noonan syndrome is a genetic multisystem disorder characterised by distinctive facial features, developmental delay, learning di. Rare variants in sos2 and lztr1 are associated with noonan. Cas9 genome editing in zebrafish, we successfully modeled the ventricular hypertrophy seen in noonan syndrome. Noonan syndrome ns is a relatively common, autosomaldominant inherited disorder that is predominantly characterised by short stature, subtle facial dysmorphisms, chest deformity, congenital heart disease, and variable degrees of developmental delay. The book examines recent advances in understanding and treating short stature in noonan syndrome, along with the latest progress.
Molecular biology laboratory, department of genetics. Ns is caused by gene mutations in a cellular signaling pathway that is essential for typical growth and development. The rasopathies, which include noonan syndrome ns and cardiofaciocutaneous syndrome cfc, are autosomal dominant disorders with genetic heterogeneity associated with germline mutations of genes. Molecular genetics of noonan syndrome italian ministry. Noonan syndrome is characterized by facial features, short stature, congenital heart defect, and developmental delay. Mutations in the ptpn11 gene cause about half of all cases. Noonan syndrome ns is a relatively common, autosomaldominant, inherited disorder that is predominantly characterized by short stature, subtle facial dysmorphisms, chest deformity, congenital heart disease, and variable degrees of developmental delay. Differential mutation frequencies are observed across populations. Signaling through ras and the mapk cascade controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes noonan syndrome ns, a developmental disorder whose major features include a. Activating mras mutations cause noonan syndrome associated.
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