Noonan syndrome and related disorders: genetics and pathogenesis.

Noonan syndrome is a pleiomorphic autosomal dominant disorder with short stature, facial dysmorphia, webbed neck, and heart defects. In the past decade, progress has been made in elucidating the pathogenesis of this disorder using a positional cloning approach. Noonan syndrome is now known to be a genetically heterogeneous disorder with nearly one half of cases caused by gain-of-function mutations in PTPN11, the gene encoding the protein tyrosine phosphatase SHP-2. Similar germ line mutations cause two related genetic disorders, Noonan-like disorder with multiple giant cell lesion syndrome and LEOPARD syndrome, and somatic PTPN11 mutations can underlie certain pediatric hematopoietic malignancies, including juvenile myelomonocytic, acute lymphoblastic, and acute myelogenous leukemias. A mouse model of PTPN11-related Noonan syndrome was recently generated, providing a reagent for studying disease pathogenesis in greater depth as well as experimenting with novel therapeutic strategies.

[1]  G. Feng,et al.  Shp-2 Tyrosine Phosphatase Functions as a Negative Regulator of the Interferon-Stimulated Jak/STAT Pathway , 1999, Molecular and Cellular Biology.

[2]  M. Tartaglia,et al.  Exclusion of PTPN11 mutations in Costello syndrome: further evidence for distinct genetic etiologies for Noonan, cardio–facio–cutaneous and Costello syndromes , 2003, Clinical genetics.

[3]  I. Kaitila,et al.  A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia , 1995, Nature Genetics.

[4]  J. Krieger,et al.  Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation , 2004, American journal of medical genetics. Part A.

[5]  J. Noonan,et al.  Adult height in Noonan syndrome , 2003, American journal of medical genetics. Part A.

[6]  M. Loh,et al.  Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. , 2004, Blood.

[7]  J. Chen,et al.  Requirement of Shp-2 tyrosine phosphatase in lymphoid and hematopoietic cell development. , 2001, Blood.

[8]  D. Page,et al.  Detailed mapping, mutation analysis, and intragenic polymorphism identification in candidate Noonan syndrome genes MYL2,DCN, EPS8, andRPL6 , 2000, Journal of medical genetics.

[9]  T. Magnuson,et al.  Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis , 2000, Nature Genetics.

[10]  E. Zackai,et al.  Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome , 2002, Human Genetics.

[11]  G. Feng,et al.  Modulation of the Nuclear Factor κb Pathway by Shp-2 Tyrosine Phosphatase in Mediating the Induction of Interleukin (Il)-6 by IL-1 or Tumor Necrosis Factor , 2001, The Journal of experimental medicine.

[12]  B. Benacerraf,et al.  First trimester isolated fetal nuchal lucency: significance and outcome , 1997, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[13]  C. Ramachandran,et al.  The specificity of the N-terminal SH2 domain of SHP-2 is modified by a single point mutation. , 1998, Biochemistry.

[14]  M. Digilio,et al.  Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. , 2002, American journal of human genetics.

[15]  G. Feng,et al.  Identification of Shp-2 as a Stat5A Phosphatase* , 2003, The Journal of Biological Chemistry.

[16]  T. Pawson,et al.  The SH2 tyrosine phosphatase Shp2 is required for mammalian limb development , 2000, Nature Genetics.

[17]  M. Burch,et al.  A clinical study of Noonan syndrome. , 1992, Archives of disease in childhood.

[18]  K. Kosaki,et al.  Somatic PTPN11 mutation with a heterogeneous clonal origin in children with juvenile myelomonocytic leukemia , 2004, Leukemia.

[19]  Rivka L. Glaser,et al.  Dear old dad. , 2004, Science of aging knowledge environment : SAGE KE.

[20]  O. Ullrich,et al.  Über typische Kombinationsbilder multipler Abartungen , 1930, Zeitschrift für Kinderheilkunde.

[21]  H. Ropers,et al.  Spectrum of mutations in PTPN11 and genotype–phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome , 2003, European Journal of Human Genetics.

[22]  S. Orkin,et al.  A deletion mutation in the SH2-N domain of Shp-2 severely suppresses hematopoietic cell development , 1997, Molecular and cellular biology.

[23]  J. Kuriyan,et al.  Crystal structures of peptide complexes of the amino-terminal SH2 domain of the Syp tyrosine phosphatase. , 1994, Structure.

[24]  E. Nishida,et al.  Shp2, an SH2-containing Protein-tyrosine Phosphatase, Positively Regulates Receptor Tyrosine Kinase Signaling by Dephosphorylating and Inactivating the Inhibitor Sprouty* , 2004, Journal of Biological Chemistry.

[25]  B. Gelb,et al.  Phenotypic and genotypic characterisation of Noonan-like/multiple giant cell lesion syndrome , 2005, Journal of Medical Genetics.

[26]  C. E. Ford,et al.  A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner's syndrome). , 1959, Lancet.

[27]  T. Ogata,et al.  A 3‐bp deletion mutation of PTPN11 in an infant with severe Noonan syndrome including hydrops fetalis and juvenile myelomonocytic leukemia , 2004, American journal of medical genetics. Part A.

[28]  C. Desponts,et al.  Regulation of the Mitogen-activated Protein Kinase Signaling Pathway by SHP2* , 2002, The Journal of Biological Chemistry.

[29]  Michael A. Patton,et al.  Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome , 2001, Nature Genetics.

[30]  J. Licht,et al.  Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia , 2003, Nature Genetics.

[31]  Qiang Wang,et al.  The tyrosine phosphatase SHP-2 is required for mediating phosphatidylinositol 3-kinase/Akt activation by growth factors , 2001, Oncogene.

[32]  J. Boultwood,et al.  Mutations in PTPN11 are rare in adult myelodysplastic syndromes and acute myeloid leukemia , 2004, American journal of hematology.

[33]  E. Mariman,et al.  Clinical and molecular studies in a large Dutch family with Noonan syndrome. , 1994, American journal of medical genetics.

[34]  P. Taipale,et al.  Fetal nuchal translucency and normal chromosomes: a long‐term follow‐up study , 2001, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[35]  H. Broxmeyer,et al.  Biased Suppression of Hematopoiesis and Multiple Developmental Defects in Chimeric Mice Containing Shp-2 Mutant Cells , 1998, Molecular and Cellular Biology.

[36]  C. Moss,et al.  The cardio‐facio‐cutaneous syndrome: a manifestation of the Noonan syndrome? , 1994, The British journal of dermatology.

[37]  J. Noonan.  Noonan Syndrome , 1994, Clinical pediatrics.

[38]  B. Neel,et al.  Receptor-Specific Regulation of Phosphatidylinositol 3′-Kinase Activation by the Protein Tyrosine Phosphatase Shp2 , 2002, Molecular and Cellular Biology.

[39]  D. Wieczorek,et al.  Cardio‐facio‐cutaneous (CFC) syndrome — a distinct entity? Report of three patients demonstrating the diagnostic difficulties in delineation of CFC syndrome , 1997, Clinical genetics.

[40]  B. Neel,et al.  Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment. , 2004, Molecular cell.

[41]  A. Fryer,et al.  The cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome: are they the same? , 1991, American journal of medical genetics.

[42]  D. Seripa,et al.  Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes , 2003, Journal of medical genetics.

[43]  J. Krieger,et al.  Are Noonan syndrome and Noonan-like/multiple giant cell lesion syndrome distinct entities? , 2001, American journal of medical genetics.

[44]  A. Munnich,et al.  No evidence for linkage to the type 1 or type 2 neurofibromatosis loci in Noonan syndrome families. , 1993, American journal of medical genetics.

[45]  O. Ullrich.  Turner's syndrome and status bonnevie-ullrich; A synthesis of animal phenogenetics and clinical observations on a typical complex of developmental anomalies. , 1949, American journal of human genetics.

[46]  L. Chitty,et al.  Prenatal features of Noonan syndrome , 1999, Prenatal diagnosis.

[47]  B. Neel,et al.  Activated Mutants of SHP-2 Preferentially Induce Elongation of Xenopus Animal Caps , 2000, Molecular and Cellular Biology.

[48]  T. Ogata,et al.  Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome , 2004, American journal of medical genetics. Part A.

[49]  J. Fryns,et al.  PTPN11 mutation in a large family with Noonan syndrome and dizygous twinning , 2003, European Journal of Human Genetics.

[50]  D. Gilliland,et al.  Mouse model of Noonan syndrome reveals cell type– and gene dosage–dependent effects of Ptpn11 mutation , 2004, Nature Medicine.

[51]  B. Neel,et al.  The SH2-containing protein-tyrosine phosphatase SH-PTP2 is required upstream of MAP kinase for early xenopus development , 1995, Cell.

[52]  B. Dallapiccola,et al.  A novel PTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome , 2004, European Journal of Human Genetics.

[53]  B. Gelb,et al.  Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. , 2004, Blood.

[54]  S. Jeffery,et al.  Absence of linkage of Noonan syndrome to the neurofibromatosis type 1 locus. , 1992, Journal of medical genetics.

[55]  J. Opitz,et al.  Noonan syndrome: a review. , 1985, American journal of medical genetics.

[56]  M. Loh,et al.  Acquired PTPN11 mutations occur rarely in adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. , 2005, Leukemia research.

[57]  Jonathan A. Cooper,et al.  A new function for a phosphotyrosine phosphatase: linking GRB2-Sos to a receptor tyrosine kinase , 1994, Molecular and cellular biology.

[58]  Jie Wu,et al.  Noonan syndrome–associated SHP2/PTPN11 mutants cause EGF‐dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation , 2004, Human mutation.

[59]  T. Ogata,et al.  PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome. , 2002, The Journal of clinical endocrinology and metabolism.

[60]  M. Zollino,et al.  The Noonan-CFC controversy. , 1991, American journal of medical genetics.

[61]  T. Pawson,et al.  Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp‐2 , 1997, The EMBO journal.

[62]  E. Mariman,et al.  Mapping a gene for Noonan syndrome to the long arm of chromosome 12 , 1994, Nature Genetics.

[63]  B. Dallapiccola,et al.  Familial aggregation of genetically heterogeneous hypertrophic cardiomyopathy: a boy with LEOPARD syndrome due to PTPN11 mutation and his nonsyndromic father lacking PTPN11 mutations. , 2004, Birth defects research. Part A, Clinical and molecular teratology.

[64]  Steven A. Wall,et al.  Exclusive paternal origin of new mutations in Apert syndrome , 1996, Nature Genetics.

[65]  C. Walsh,et al.  Protein-tyrosine-phosphatase SHPTP2 couples platelet-derived growth factor receptor beta to Ras. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[66]  M. Digilio,et al.  Nonsyndromic Pulmonary Valve Stenosis and the PTPN11 Gene , 2003, American journal of medical genetics. Part A.

[67]  M. Patton,et al.  Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome. , 2004, American journal of human genetics.

[68]  Rivka L. Glaser,et al.  Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. , 2000, American journal of human genetics.

[69]  R. Gorlin,et al.  Noonan-like/multiple giant cell lesion syndrome. , 1991, American journal of medical genetics.

[70]  J. Reilly,et al.  Mutations in PTPN11 are uncommon in adult myelodysplastic syndromes and acute myeloid leukaemia , 2004, British journal of haematology.

[71]  M. Digilio,et al.  Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome , 2004, Journal of Medical Genetics.

[72]  H. Bolz,et al.  No mutation in the gene for Noonan syndrome, PTPN11, in 18 patients with Costello syndrome , 2003, American journal of medical genetics. Part A.

[73]  J. Opitz,et al.  The Noonan syndrome. , 1985, American journal of medical genetics.

[74]  H. Brunner,et al.  Genetic heterogeneity in Noonan syndrome: evidence for an autosomal recessive form. , 2000, American journal of medical genetics.

[75]  W. Kress,et al.  Genotype-phenotype correlations in Noonan syndrome. , 2004, The Journal of pediatrics.

[76]  B. Dallapiccola,et al.  A Novel PTPN11 mutation in LEOPARD syndrome , 2003, Human mutation.

[77]  B. Thilaganathan,et al.  Increased first trimester nuchal translucency: pregnancy and infant outcomes after routine screening for Down's syndrome in an unselected antenatal population. , 1999, The British journal of radiology.

[78]  Morag Park,et al.  Molecular Mechanism for the Shp-2 Tyrosine Phosphatase Function in Promoting Growth Factor Stimulation of Erk Activity , 2000, Molecular and Cellular Biology.

[79]  Judith G. Hall,et al.  Noonan syndrome: the changing phenotype. , 1985, American journal of medical genetics.

[80]  Y. Matsubara,et al.  Noonan syndrome with leukaemoid reaction and overproduction of catecholamines: a case report , 2003, European Journal of Pediatrics.

[81]  A. Munnich,et al.  Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. , 1998, American journal of human genetics.

[82]  Bruce D Gelb,et al.  PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. , 2002, American journal of human genetics.

[83]  J. Fryns,et al.  PTPN11 mutations in LEOPARD syndrome , 2002, Journal of medical genetics.

[84]  L. Farkas,et al.  A comprehensive scoring system for evaluating Noonan syndrome. , 1981, American journal of medical genetics.

[85]  S. Shoelson,et al.  Crystal Structure of the Tyrosine Phosphatase SHP-2 , 1998, Cell.

[86]  H. Kanegane,et al.  Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome. , 2004, The Journal of clinical endocrinology and metabolism.

[87]  C. Heldin,et al.  SHP-2 is involved in heterodimer specific loss of phosphorylation of Tyr771 in the PDGF β-receptor , 2002, Oncogene.

[88]  M. Loh,et al.  PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group , 2004, Leukemia.

[89]  J. Noonan.  Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. , 1968, American journal of diseases of children.

[90]  J. Opitz,et al.  PTPN11 mutations are not responsible for the Cardiofaciocutaneous (CFC) syndrome , 2003, European Journal of Human Genetics.

[91]  J. Fryns,et al.  Fine mapping of Noonan/cardio-facio cutaneous syndrome in a large family , 1998, European Journal of Human Genetics.

[92]  C. Maroun,et al.  The Tyrosine Phosphatase SHP-2 Is Required for Sustained Activation of Extracellular Signal-Regulated Kinase and Epithelial Morphogenesis Downstream from the Met Receptor Tyrosine Kinase , 2000, Molecular and Cellular Biology.

[93]  R. Gibbs,et al.  PTPN11 Mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13 , 2002, Human mutation.

[94]  Henry H. Turner,et al.  A SYNDROME OF INFANTILISM, CONGENITAL WEBBED NECK, AND CUBITUS VALGUS1 , 1938 .