| Written | 2005-06 | Marco Tartaglia, Bruce D Gelb |
| Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanitö, Rome, Italy |
| Identity |
| Other names | Male Turner syndrome |
| Pseudo-Turner syndrome | |
| Atlas_Id | 10085 |
| Genes implicated in | BRAF KRAS NRAS PTPN11 RAF1 RIT1 SOS1 |
| Inheritance | Noonan syndrome is an autosomal dominant disorder. Rare cases with parental consanguinity have been described, but it is not clear that these represent true instances of autosomal recessive inheritance. Like many autosomal dominant disorders, a significant, but not precisely determined, percentage of cases represent de novo mutagenesis. The prevalence of Noonan syndrome has not been determined accurately to date. Most authors cite the figure of 1 in 1,000-2,500 live births. However, that estimate was not based on a population study. Fetal loss occurs for Noonan syndrome so disease incidence is higher than prevalence, but no estimate of the magnitude of this discrepancy is available. |
| Clinics |
| Phenotype and clinics | Noonan syndrome is a clinically variable developmental disorder defined by short stature, facial dysmorphism and a wide spectrum of congenital heart defects. The distinctive facial features consist of a broad forehead, hypertelorism, down-slanting palpebral fissures, ptosis, high-arched palate and low-set, posteriorly rotated ears. Cardiovascular abnormalities, primarily pulmonic stenosis and hypertrophic cardiomyopathy, are present in up to 85% of affected individuals. Additional relatively frequent features are multiple skeletal defects (spine and chest), webbed neck, mental retardation, cryptorchidism and bleeding diathesis. |
 | |
| Neoplastic risk | Children with Noonan syndrome are predisposed to malignancies, juvenile myelomonocytic leukemia (JMML) most commonly. JMML, formerly termed juvenile chronic myeloid leukemia or chronic myelomonocytic leukemia, is a myeloproliferative/myelodysplastic disorder of childhood characterized by excessive proliferation of immature and mature myelomonocytic cells that originate from a pluripotent stem cell. In childhood, JMML accounts for approximately 30% of cases of myelodysplastic and myeloproliferative syndromes and 2% of leukemias. It typically presents in infancy and early childhood, and is often lethal. Recent studies have provided strong evidence that hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF), due to a selective inability to down-regulate the RAS/MAPK cascade, plays a central role in the clonal cell growth characteristic of JMML. In approximately 15-30% of JMML cases, the pathological activation of the RAS/MAPK cascade results from oncogenic NRAS or KRAS2 mutations that specifically affect GTP hydrolysis, leading to the accumulation of RAS in the GTP-bound active conformation. JMML has been reported in children with neurofibromatosis type 1 (NF1), an autosomal dominant disorder resulting from germline loss-of-function mutations of the NF1 tumor suppressor gene. In children with NF1 and JMML, the proliferative advantage of the leukemic cells results from a second hit, the somatic loss or inactivation of the normal NF1 allele. Since the NF1 gene product, neurofibromin, is a negative modulator of RAS function, this loss is associated with RAS hyperactivity. Remarkably, deregulated RAS function appears to be restricted to GM-CSF signaling in hematopoietic cells. More recently, somatic activating mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase (PTP) SHP-2, have been documented in approximately 35% of cases with JMML. Mutations in the PTPN11, RAS and NF1 genes are largely mutually exclusive in JMML, and their combined prevalence accounts for approximately 85% of cases. Acute lymphoblastic leukemia and solid tumors, particularly neuroblastoma and rhabdomyosarcoma, have also been documented with a relatively higher prevalence respect to the general population. |
| Evolution | In children with Noonan syndrome JMML may regress without treatment or follow an aggressive clinical course. By contrast, cases of JMML that arise in children without Noonan syndrome have a poor prognosis without hematopoietic stem cell transplantation. |
| Other findings |
| Note | A significant percentage of Noonan syndrome cases arise from de novo PTPN11 mutations. Among fourteen informative families, each consisting of an affected individual heterozygous for a PTPN11 mutation and unaffected parents, the paternal origin of mutation has been demonstrated in all cases. Consistent with this finding, advanced paternal age was noted among fathers of sporadic Noonan syndrome cases, compared with fathers of the reference population. Moreover, when a parent is affected with Noonan syndrome and harbors a PTPN11 mutation, a sex-ratio bias is operative for offspring who inherit the defect. This bias favors males by a factor of 2:1. The available data point to this bias being attributable to sex-specific developmental effects of PTPN11 mutations that favor survival of affected male embryos compared to female ones. |
| Genes involved and Proteins |
| Gene Name | PTPN11 (Protein tyrosine phosphatase, non-receptor type, 11) |
| Alias | SHP-2, SH-PTP2 (Src homology 2 domain-containing protein tyrosine phosphatase, 2) PTP2C (Protein tyrosine phosphatase 2C) BPTP3 |
| Location | 12q24.1 centromere - FLJ34154 - RPL6 - PTPN11 - RPH3A - OAS1 - telomere |
| DNA/RNA | |
 | |
| Description | The PTPN11 gene counts 16 exons. Exon 1 contains the 5'-UTR and the translation initiation ATG, and a few additional codons. Exon 15 contains the stop codon and exon 16 contains a major portion of the 3'-UTR. Other features of the PTPN11 gene, such as the promoter region and enhancer elements have not been delineated. |
| Transcription | A 7.0-kb transcript is detected in several tissues (heart, brain, lung, liver, skeletal muscle, kidney, and pancreas) with highest steady-state levels in heart and skeletal muscle. The predominant human PTPN11 mRNA contains an open reading frame of 1,779 bases, resulting in a predicted protein of 593 amino acid residues. |
| Pseudogene | A number of speudogenes, sharing more than 92% nucleotide identity with PTPN11 cDNA (including the untranslated regions), have been documented in the human genome. All the pseudogenes harbour frameshift mutations and multiple stop codons. Three of the five pseudogenes are likely to be expressed but with distinct tissue distribution and expression level. |
| Protein | |
 | |
| Description | SHP-2 is a member of a small subfamily of cytoplasmic Src homology 2 (SH2) domain-containing protein tyrosine phosphatases. The amino-terminal SH2 (N-SH2 and C-SH2) domains selectively bind to short amino acid motifs containing a phosphotyrosyl residue and promote SHP-2 association with cell surface receptors, cell adhesion molecules and scaffolding adapters. Crystallographic data indicate that the N-SH2 domain also interacts with the PTP domain using a separate site. As these subdomains show negative cooperativity, the N-SH2 domain functions as an intramolecular switch controlling SHP-2 catalytic activation. Specifically, the N-SH2 domain interacts with the PTP domain basally, blocking the catalytic site. Binding of the N-SH2 phosphopeptide-binding site to the phosphotyrosyl ligand promotes a conformational change of the domain that weakens the auto-inhibiting intramolecular interaction, making the catalytic site available to substrate, thereby activating the phosphatase. |
| Expression | Widely expressed in both embryonic and adult tissues. |
| Localisation | Cytoplasmic. It binds to activated cell surface receptors, cell adhesion molecules and scaffolding adapters. Phosphorylation of two tyrosine residues at the C-terminus by activated tyrosine kinase receptors creates binding sites for other SH2 domain-containing signal transducers. |
| Function | SHP-2 functions as a intracellular signal transducer. It positively modulates signal flow in most circumstances, but can also function as negative regulator depending upon its binding partner and interactions with downstream signaling networks. SHP-2 positively controls the activation of the RAS/MAPK cascade induced by several growth factors, and negatively regulates JAK/STAT signaling. In most cases, SHP-2's function in intracellular signaling appears to be immediately proximal to activated receptors and upstream to RAS. The mechanisms of SHP-2's action and its physiological substrates are still poorly defined. However, both membrane translocation and PTPase activity are required for SHP-2 function. SHP-2 is required during development. Embryos nullizygous for Shp-2 have defects in gastrulation and mesodermal patterning resulting in severe abnormalities in axial and paraxial mesodermal structures. Shp-2 function is also required for development of terminal and skeletal structures, semilunar valvulogenesis in the heart, and hematopoiesis. |
| Homology | PTPN6 (protein tyrosine phosphatase, non-receptor type, 6) previously known as SHP1 or SHP-1 (Src homology 2 domain-containing protein tyrosine phosphatase, 1). |
| Mutations | |
| Note | Studies reported PTPN11 mutation detection rates ranging between 33% to 60%. Differences in inclusion criteria stringency and recruiting strategies are likely to responsible for such variable mutation detection rate. It should also be emphasized that the mutation prevalence detected in any Noonan syndrome cohort is sensitive to its composition in terms of relative abundance of sporadic and familial cases, as PTPN11 mutations appear to be more prevalent among families transmitting the trait compared to sporadic cases. With those issues stipulated, the contribution of PTPN11 mutations to the etiology of Noonan syndrome appears to be approximately 50%. A statistically significant association with pulmonary valve stenosis and lower incidence of hypertrophic cardiomyopathy was found among the group with PTPN11 mutations. Overall, a large percentage of PTPN11 mutation-negative individuals tended to exhibit fewer or mild clinical features of NS, even though approximately half of the Noonan syndrome patients without a PTPN11 mutation appeared clinically indistinguishable from typical PTPN11 mutation-positive patients. |
| Germinal | The vast majority of mutations affect residues residing at or close to the interface between the N-SH2 and PTP domains. Increasing evidence supports that a number of Noonan syndrome-causative mutations promote SHP-2 gain-of-function by destabilizing the catalytically inactive conformation of the protein, and prolong signal flux through the RAS/MAPK pathway in a ligand-dependent manner. Selection: 124A>G (T42A), 182A>G (D61G), 184T>G (Y62D), 188A>G (Y63C), 214G>T (A72S), 215C>G (A72G), 218C>T (T73I), 228G>T,C (E76D), 236A>G (N79R), 317A>C (D106A), 922A>G (N308D). Two specific missense mutations (836A>G, Y279C; 1403C>T, T468M) have been identified to recur in LEOPARD syndrome, a developmental disorder closely related to Noonan syndrome. A mouse model bearing the NS-causative Asp61Gly mutation in the Ptpn11 gene has been recently generated and characterized. The Ptpn11D61G/D61G genotype is embryonic lethal. At day E13.5, these embryos are grossly edematous and hemorrhagic, and have diffuse liver necrosis. A number of severe cardiac defects are also observed. Heterozygous embryos exhibit cardiac defects, proportionate growth failure and perturbed craniofacial development. Hematologic anomalies include a mild myeloproliferative disease. Ptpn11D61G/+ embryonic fibroblasts are characterized by a three-fold increased Shp-2 activity and increased association of Shp-2 with Gab1 after stimulation with EGF. Cell culture and whole embryo studies reveal that increased RAS/MAPK signaling is variably present, appearing to be cell-context specific. |
| Somatic | Somatic activating mutations in PTPN11 have been documented in a heterogeneous group of hematologic malignancies and pre-leukemic disorders, and rarely in certain solid tumors. Selection: 181G>T (D61Y), 182A>T (D61V), 205G>A (E69K), 214G>A (A72T), 215C>T (A72V), 226G>A (E76K), 226G>C (E76Q), 227A>T (E76V), 227A>G (E76G), 227A>C (E76A), 1471C>T (P491S), 1472C>T (P491L), 1504T>C (S502P), 1504T>G (S502A), 1520C>A (T507K), 1528C>A (Q510K). |
| Bibliography |
| Noonan syndrome. |
| Allanson JE |
| Journal of medical genetics. 1987 ; 24 (1) : 9-13. |
| PMID 3543368 |
| Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. |
| Araki T, Mohi MG, Ismat FA, Bronson RT, Williams IR, Kutok JL, Yang W, Pao LI, Gilliland DG, Epstein JA, Neel BG |
| Nature medicine. 2004 ; 10 (8) : 849-857. |
| PMID 15273746 |
| Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. |
| Bentires-Alj M, Paez JG, David FS, Keilhack H, Halmos B, Naoki K, Maris JM, Richardson A, Bardelli A, Sugarbaker DJ, Richards WG, Du J, Girard L, Minna JD, Loh ML, Fisher DE, Velculescu VE, Vogelstein B, Meyerson M, Sellers WR, Neel BG |
| Cancer research. 2004 ; 64 (24) : 8816-8820. |
| PMID 15604238 |
| Cardiologic abnormalities in Noonan syndrome: phenotypic diagnosis and echocardiographic assessment of 118 patients. |
| Burch M, Sharland M, Shinebourne E, Smith G, Patton M, McKenna W |
| Journal of the American College of Cardiology. 1993 ; 22 (4) : 1189-1192. |
| PMID 8409059 |
| Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis. |
| Chen B, Bronson RT, Klaman LD, Hampton TG, Wang JF, Green PJ, Magnuson T, Douglas PS, Morgan JP, Neel BG |
| Nature genetics. 2000 ; 24 (3) : 296-299. |
| PMID 10700187 |
| Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. |
| Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, Pizzuti A, Dallapiccola B |
| American journal of human genetics. 2002 ; 71 (2) : 389-394. |
| PMID 12058348 |
| Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. |
| Fragale A, Tartaglia M, Wu J, Gelb BD |
| Human mutation. 2004 ; 23 (3) : 267-277. |
| PMID 14974085 |
| Crystal structure of the tyrosine phosphatase SHP-2. |
| Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, Shoelson SE |
| Cell. 1998 ; 92 (4) : 441-450. |
| PMID 9491886 |
| Mapping a gene for Noonan syndrome to the long arm of chromosome 12. |
| Jamieson CR, van der Burgt I, Brady AF, van Reen M, Elsawi MM, Hol F, Jeffery S, Patton MA, Mariman E |
| Nature genetics. 1994 ; 8 (4) : 357-360. |
| PMID 7894486 |
| Genotypic and phenotypic characterization of Noonan syndrome: new data and review of the literature. |
| Jongmans M, Sistermans EA, Rikken A, Nillesen WM, Tamminga R, Patton M, Maier EM, Tartaglia M, Noordam K, van der Burgt I |
| American journal of medical genetics. Part A. 2005 ; 134 (2) : 165-170. |
| PMID 15723289 |
| Phenotypic and genotypic characterisation of Noonan-like/multiple giant cell lesion syndrome. |
| Lee JS, Tartaglia M, Gelb BD, Fridrich K, Sachs S, Stratakis CA, Muenke M, Robey PG, Collins MT, Slavotinek A |
| Journal of medical genetics. 2005 ; 42 (2) : page e11. |
| PMID 15689434 |
| PTPN11 mutations in LEOPARD syndrome. |
| Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M, Fryns JP |
| Journal of medical genetics. 2002 ; 39 (8) : 571-574. |
| PMID 12161596 |
| PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group. |
| Loh ML, Reynolds MG, Vattikuti S, Gerbing RB, Alonzo TA, Carlson E, Cheng JW, Lee CM, Lange BJ, Children's Cancer Group, Meshinchi S |
| Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2004 ; 18 (11) : 1831-1834. |
| PMID 15385933 |
| Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. |
| Loh ML, Vattikuti S, Schubbert S, Reynolds MG, Carlson E, Lieuw KH, Cheng JW, Lee CM, Stokoe D, Bonifas JM, Curtiss NP, Gotlib J, Meshinchi S, Le Beau MM, Emanuel PD, Shannon KM |
| Blood. 2004 ; 103 (6) : 2325-2331. |
| PMID 14644997 |
| Congenital heart diseases in children with Noonan syndrome: An expanded cardiac spectrum with high prevalence of atrioventricular canal. |
| Marino B, Digilio MC, Toscano A, Giannotti A, Dallapiccola B |
| The Journal of pediatrics. 1999 ; 135 (6) : 703-706. |
| PMID 10586172 |
| The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. |
| Neel BG, Gu H, Pao L |
| Trends in biochemical sciences. 2003 ; 28 (6) : 284-293. |
| PMID 12826400 |
| Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. |
| Noonan JA |
| American journal of diseases of children (1960). 1968 ; 116 (4) : 373-380. |
| PMID 4386970 |
| The Ullrich-Noonan syndrome (Turner phenotype). |
| Nora JJ, Nora AH, Sinha AK, Spangler RD, Lubs HA |
| American journal of diseases of children (1960). 1974 ; 127 (1) : 48-55. |
| PMID 4809794 |
| Biased suppression of hematopoiesis and multiple developmental defects in chimeric mice containing Shp-2 mutant cells. |
| Qu CK, Yu WM, Azzarelli B, Cooper S, Broxmeyer HE, Feng GS |
| Molecular and cellular biology. 1998 ; 18 (10) : 6075-6082. |
| PMID 9742124 |
| The SH2 tyrosine phosphatase shp2 is required for mammalian limb development. |
| Saxton TM, Ciruna BG, Holmyard D, Kulkarni S, Harpal K, Rossant J, Pawson T |
| Nature genetics. 2000 ; 24 (4) : 420-423. |
| PMID 10742110 |
| Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2. |
| Saxton TM, Henkemeyer M, Gasca S, Shen R, Rossi DJ, Shalaby F, Feng GS, Pawson T |
| The EMBO journal. 1997 ; 16 (9) : 2352-2364. |
| PMID 9171349 |
| Somatic PTPN11 mutations in childhood acute myeloid leukaemia. |
| Tartaglia M, Martinelli S, Iavarone I, Cazzaniga G, Spinelli M, Giarin E, Petrangeli V, Carta C, Masetti R, Aricò M, Locatelli F, Basso G, Sorcini M, Pession A, Biondi A |
| British journal of haematology. 2005 ; 129 (3) : 333-339. |
| PMID 15842656 |
| Genotype-phenotype correlations in Noonan syndrome. |
| Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kress W, Tietze HU, Doerr HG, Hofbeck M, Singer H, Reis A, Rauch A |
| The Journal of pediatrics. 2004 ; 144 (3) : 368-374. |
| PMID 15001945 |
| Genetic heterogeneity in Noonan syndrome: evidence for an autosomal recessive form. |
| van Der Burgt I, Brunner H |
| American journal of medical genetics. 2000 ; 94 (1) : 46-51. |
| PMID 10982482 |
| Citation |
| This paper should be referenced as such : |
| Tartaglia, M ; Gelb, BD |
| Noonan syndrome |
| Atlas Genet Cytogenet Oncol Haematol. 2005;9(4):341-346. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Tumors/NoonanID10085.html |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year articles | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Fri Jun 30 11:24:31 CEST 2017 |
For comments and suggestions or contributions, please contact us