Noonan Syndrome - Part Three
PTPN11
Normal allelic variants: Tartaglia et al (2001) identified the PTPN11 gene as causative of Noonan syndrome. The gene comprises 15 exons, with two tandemly arranged SRC-2 homology 2 (SH2) domains at the N terminus (N-SH2 and C-SH2), a single catalytic protein tyrosine phosphatase (PTP) domain, and a carbody tail with two TP sites and a proline-rich stretch. The SH2-PTP interaction maintains TP sites and a proline-rich stretch. The SH2-PTP interaction maintains the protein in an inactive state.
Pathologic allelic variants: Missense mutations in PTPN11 were identified in 50% of individuals examined. Ninety-five percent of mutations alter residues at or close to the SH2-PTP interacting surfaces, which are involved in switching between active and inactive conformations of the protein and cause catalytic activation and gain of function. Five percent of the mutations alter sensitivity to activation from binding partners. One 3-bp deletion has been described [Tartaglia et al 2002; Fragale et al 2004].
Normal gene product: PTPN11 encodes tyrosine-protein phosphatase non-receptor type II (SHP-2), a widely expressed extra-cellular protein. The protein is a key molecule in the cellular response to growth factors, hormones, cytokines and cell adhesion molecules. It is required in several intracellular signal transduction pathways that control diverse developmental processes (including cardiac semilunar valvulogenesis and blood cell progenitor commitment and differentiation) and has a role in modulating cellular proliferation, differentiation, migration, and apoptosis [Tartaglia et al 2002, Fragale et al 2004].
Abnormal gene product: Activation of tyrosine-protein phosphatase non-receptor type II stimulates epidermal growth factor-mediated RAS/ERK/MAPK activation, increasing cell proliferation [
Tartaglia et al 2002, Fragale et al 2004].
KRAS
Normal allelic variants: The gene has four exons spanning 45 kb. Alternative splicing results in two isoforms (4a and 4b) that differ at the C terminus. In 98% of transcripts, exon 4a is spliced out and only exon 4b is available for translation into protein. The effector or switch domains are part of exons 1 and 2, while binding to guanine nucleotide exchange factors occurs in exon 3.
Pathologic allelic variants: Somatic KRAS and NRAS mutations have been found in myeloid malignancies and other cancers. The association between abnormal Kras and Noonan syndrome is the first evidence of a role in embryonic development. These gain-of-function mutations confer similar biochemical and cellular phenotypes as Noonan syndrome-associated SHP-2 mutations.
Normal gene product: Ras proteins regulate cell fates by cycling between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound conformations. They are key regulators of the RAS-RAF-MEK-ERK pathway, which is important for proliferation, growth and death of cells.
Abnormal gene product: The abnormal K-Ras protein induces hypersensitivity of primary hematopoietic progenitor cells to growth factors and deregulates signal transduction in a cell lineage-specific manner. Strong gain-of-function KRAS mutations may be incompatible with life.
Resources
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.
National Library of Medicine Genetics Home Reference
Noonan syndrome
The Noonan Syndrome Support Group
PO Box 145 Upperco, MD 21155
Phone: 888-686-2224; 410-374-5245
Email: info@noonansyndrome.org
Human Growth Foundation
997 Glen Cove Avenue Suite 5
Glen Head NY 11545
Phone: 800-451-6434 Fax: 516-671-4055
Email: hgf1@hgfound.org
The MAGIC Foundation
6645 West North Avenue
Oak Park, IL 60302
Phone: 800-362-4423; 708-383-0808 Fax: 708-383-0899
Email: info@magicfoundation.org
References
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
Published Statements and Policies Regarding Genetic Testing
No specific guidelines regarding genetic testing for this disorder have been developed.Literature CitedAllanson J. Noonan syndrome. In: Cassidy SB, Allanson JE (eds) Management of Genetic Syndromes. Wiley-Liss, NY. 2005. (PubMed)
Allanson JE. Noonan syndrome. J Med Genet. 1987. 24:9-13. (PubMed)
Allanson JE, Hall JG, Hughes HE, Preus M, Witt RD. Noonan syndrome: the changing phenotype. Am J Med Genet. 1985. 21:507-14. (PubMed)
Allanson JE, Upadhyaya M, Watson GH, Partington M, MacKenzie A, Lahey D, MacLeod H, Sarfarazi M, Broadhead W, Harper PS, et al. Watson syndrome: is it a subtype of type 1 neurofibromatosis? J Med Genet. 1991. 28:752-6. (PubMed)
Aoki Y, Niihori H, Kurosawa K, Ohashi H, Tanaka Y, Filocamo M, Kato K, Suzuki Y, Kure S, Matsubara Y. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005. 37:1038-40. (PubMed)
Bentires-Alj M, Paez JG, David FS, Keilhack H, Halmos B, Naoki K, Maris JM, Richardson A, Bardelli A, Sugarbaker DJ, et al. Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res. 2004. 64:8816-20. (PubMed)
Binder G, Neuer K, Ranke MB, Wittekindt NE. PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome. J Clin Endocrinol Metab. 2005. 90:5377-81. (PubMed)
Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, Pizzuti A, Dallapiccola B. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet. 2002. 71:389-94. (PubMed)
Digilio MC, Marino B, Picchio F, Prandstraller D, Toscano A, Giannotti A, Dallapiccola B. Noonan syndrome and aortic coarctation. Am J Med Genet. 1998. 80:160-2. (PubMed)
Ferreira LV, Souza SA, Arnhold IJ, Mendonca BB, Jorge AA. PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) mutations and response to growth hormone therapy in children with Noonan syndrome. J Clin Endocrinol Metab. 2005. 90:5156-60. (PubMed)
Fragale A, Tartaglia M, Wu J, Gelb BD. Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Hum Mutat. 2004. 23:267-77. (PubMed)
Gandhi SV, Howarth ES, Krarup KC, Konje JC. Noonan syndrome presenting with transient cystic hygroma. J Obstet Gynaecol. 2004. 24:183-4. (PubMed)
George CD, Patton MA, el Sawi M, Sharland M, Adam EJ. Abdominal ultrasound in Noonan syndrome: a study of 44 patients. Pediatr Radiol. 1993. 23:316-8. (PubMed)
Holder-Espinasse M, Winter RM. Type I Arnold-Chiari malformation and Noonan syndrome. Clin Dysmorphol. 2003. 12: (PubMed)
Ion A, Tartaglia M, Song X, Kalidas K, van der Burgt I, Shaw AC, Ming JE, Zampino G, Zackai EH, Dean JC, et al. Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome. Hum Genet. 2002. 111:421-7. (PubMed)
Ishizawa A, Oho S, Dodo H, Katori T, Homma SI. Cardiovascular abnormalities in Noonan syndrome: the clinical findings and treatments. Acta Paediatr Jpn. 1996. 38:84-90. (PubMed) Jongmans M, Otten B, Noordam K, van der Burgt I. Genetics and variation in phenotype in Noonan syndrome. Horm Res 62 Suppl. 2004. 3:56-9. (PubMed)
Joo JG, Beke A, Toth-Pal E, Csaba A, Papp C. Successful pregnancy in a Noonan syndrome patient after 3 unsuccessful pregnancies from severe fetal hydrops: a case report. J Reprod Med. 2005. 50:373-6. (PubMed)
Kratz CP, Niemeyer CM, Castleberry RP, Cetin M, Bergstrasser E, Emanuel PD, Hasle H, Kardos G, Klein C, Kojima S, et al. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood. 2005. 106:2183-5. (PubMed)
Lee DA, Portnoy S, Hill P, Gillberg C, Patton MA. Psychological profile of children with Noonan syndrome. Dev Med Child Neurol. 2005. 47:35-8. (PubMed)
Lee NB, Kelly L, Sharland M. Ocular manifestations of Noonan syndrome. Eye 6 (Pt. 1992. 3):328-34. (PubMed)
Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M, Fryns JP. PTPN11 mutations in LEOPARD syndrome. J Med Genet. 2002. 39:571-4. (PubMed)
Menashe M, Arbel R, Raveh D, Achiron R, Yagel S. Poor prenatal detection rate of cardiac anomalies in Noonan syndrome. Ultrasound Obstet Gynecol. 2002. 19:51-5. (PubMed)
Mendez HM and Opitz JM. Noonan syndrome: a review. Am J Med Genet. 1985. 21:493-506. (PubMed)
Niihori T, Aoki Y, Ohashi H, Kurosawa K, Kondoh T, Ishikiriyama S, Kawame H, Kamasaki H, Yamanaka T, Takada F, et al. Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. J Hum Genet. 2005. 50:192-202. (PubMed)
Noonan JA. Cardiac findings in cardio-facio-cutaneous syndrome: similarities to Noonan and Costello syndromes. Proc Greenwood Gen Ctr . 2001. (PubMed)
Noonan JA, Raaijmakers R, Hall BD. Adult height in Noonan syndrome. Am J Med Genet A. 2003. 123:68-71. (PubMed)
Ogawa M, Moriya N, Ikeda H, Tanae A, Tanaka T, Ohyama K, Mori O, Yazawa T, Fujita K, Seino Y, et al. Clinical evaluation of recombinant human growth hormone in Noonan syndrome. Endocr J. 2004. 51:61-8. (PubMed) Patton MA. Noonan syndrome: a review. Growth, Genetics and Hormones. 1994. 10:1-3. (PubMed)
Pierini DO and Pierini AM. Keratosis pilaris atrophicans faciei (ulerythema ophryogenes): a cutaneous marker in the Noonan syndrome. Br J Dermatol. 1979. 100:409-16. (PubMed)
Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Santa Cruz M, McCormick F, Rauen KA. Germline Mutations in Genes within the MAPK Pathway Cause Cardio-facio-cutaneous Syndrome. Science. 2006. 311:1287-90. (PubMed)
Sarkozy A, Obregon MG, Conti E, Esposito G, Mingarelli R, Pizzuti A, Dallapiccola B. A novel PTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome. Eur J Hum Genet. 2004. 12:1069-72. (PubMed)
Schubbert S, Zenker M, Rowe SL, Boll S, Klein C, Bollag G, van der Burgt I, Musante L, Kalscheuer V, Wehner LE, et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006. 38:331-6. (PubMed)
Sharland M, Burch M, McKenna WM, Paton MA. A clinical study of Noonan syndrome. Arch Dis Child. 1992. 67:178-83. (PubMed)
Sharland M, Patton MA, Talbot S, Chitolie A, Bevan DH. Coagulation-factor deficiencies and abnormal bleeding in Noonan's syndrome. Lancet. 1992. 339:19-21. (PubMed)
Tartaglia M, Cordeddu V, Chang H, Shaw A, Kalidas K, Crosby A, Patton MA, Sorcini M, van der Burgt I, Jeffery S, et al. Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome. Am J Hum Genet. 2004. 75:492-7. (PubMed)
Tartaglia M, Cotter PD, Zampino G, Gelb BD, Rauen KA. Exclusion of PTPN11 mutations in Costello syndrome: further evidence for distinct genetic etiologies for Noonan, cardio-facio-cutaneous and Costello syndromes. Clin Genet. 2003. 63:423-6. (PubMed)
Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner HG, Bertola DR, Crosby A, Ion A, et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002. 70:1555-63. (PubMed)
Tartaglia M, Martinelli S, Cazzaniga G, Cordeddu V, Iavarone I, Spinelli M, Palmi C, Carta C, Pession A, Arico M, et al. Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Blood. 2004. 104:307-13. (PubMed)
Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E, Cordeddu V, Zampino G, Burgt I, Palleschi A, Petrucci TC, et al. Diversity and Functional Consequences of Germline and Somatic PTPN11 Mutations in Human Disease. Am J Hum Genet. 2006. 78:279-90. (PubMed)
Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001. 29:465-8. (PubMed)
Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht JD, Gelb BD. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003. 34:148-50. (PubMed)
Tofil NM, Winkler MK, Watts RG, Noonan J. The use of recombinant factor VIIa in a patient with Noonan syndrome and life-threatening bleeding. Pediatr Crit Care Med. 2005. 6:352-4. (PubMed)
Troger B, Kutsche K, Bolz H, Luttgen S, Gal A, Almassy Z, Caliebe A, Freisinger P, Hobbiebrunken E, Morlot M, et al. No mutation in the gene for Noonan syndrome, PTPN11, in 18 patients with Costello syndrome. Am J Med Genet. 2003. 121A:82-4. (PubMed)
van der Burgt I, Thoonen G, Roosenboom N, Assman-Hulsmans C, Gabreels F, Otten B, Brunner HG. Patterns of cognitive functioning in school-aged children with Noonan syndrome associated with variability in phenotypic expression. J Pediatr. 1999. 135:707-13. (PubMed)
Witt DR, Hoyme HE, Zonana J, Manchester DK, Fryns JP, Stevenson JG, Curry CJ, Hall JG. Lymphedema in Noonan syndrome: clues to pathogenesis and prenatal diagnosis and review of the literature. Am J Med Genet. 1987. 27:841-56. (PubMed)
Witt DR, Keena BA, Hall JG, Allanson JE. Growth curves for height in Noonan syndrome. Clin Genet. 1986. 30:150-3. (PubMed)
Witt DR, McGillivray BC, Allanson JE, Hughes HE, Hathaway WE, Zipursky A, Hall JG. Bleeding diathesis in Noonan syndrome: a common association. Am J Med Genet. 1988. 31:305-17. (PubMed)
Yoshida R, Miyata M, Nagai T, Yamazaki T, Ogata T. A 3-bp deletion mutation of PTPN11 in an infant with severe Noonan syndrome including hydrops fetalis and juvenile myelomonocytic leukemia. Am J Med Genet A. 2004. 128:63-6. (PubMed)
Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kress W, Tietze HU, Doerr HG, Hofbeck M, Singer H, et al. Genotype-phenotype correlations in Noonan syndrome. J Pediatr. 2004. 144:368-74. (PubMed)
Chapter Notes
Revision History
16 May 2006 (cd) Revision: KRAS testing clinically available
1 May 2006 (ja) Revision: mutations in KRAS cause Noonan syndrome
9 March 2006 (me) Comprehensive update posted to live Web site
17 December 2003 (me) Comprehensive update posted to live Web site
15 November 2001 (me) Review posted to live Web site
2 August 2001 (ja) Original submission
Original Complete Article
Normal allelic variants: Tartaglia et al (2001) identified the PTPN11 gene as causative of Noonan syndrome. The gene comprises 15 exons, with two tandemly arranged SRC-2 homology 2 (SH2) domains at the N terminus (N-SH2 and C-SH2), a single catalytic protein tyrosine phosphatase (PTP) domain, and a carbody tail with two TP sites and a proline-rich stretch. The SH2-PTP interaction maintains TP sites and a proline-rich stretch. The SH2-PTP interaction maintains the protein in an inactive state.
Pathologic allelic variants: Missense mutations in PTPN11 were identified in 50% of individuals examined. Ninety-five percent of mutations alter residues at or close to the SH2-PTP interacting surfaces, which are involved in switching between active and inactive conformations of the protein and cause catalytic activation and gain of function. Five percent of the mutations alter sensitivity to activation from binding partners. One 3-bp deletion has been described [Tartaglia et al 2002; Fragale et al 2004].
Normal gene product: PTPN11 encodes tyrosine-protein phosphatase non-receptor type II (SHP-2), a widely expressed extra-cellular protein. The protein is a key molecule in the cellular response to growth factors, hormones, cytokines and cell adhesion molecules. It is required in several intracellular signal transduction pathways that control diverse developmental processes (including cardiac semilunar valvulogenesis and blood cell progenitor commitment and differentiation) and has a role in modulating cellular proliferation, differentiation, migration, and apoptosis [Tartaglia et al 2002, Fragale et al 2004].
Abnormal gene product: Activation of tyrosine-protein phosphatase non-receptor type II stimulates epidermal growth factor-mediated RAS/ERK/MAPK activation, increasing cell proliferation [
Tartaglia et al 2002, Fragale et al 2004].
KRAS
Normal allelic variants: The gene has four exons spanning 45 kb. Alternative splicing results in two isoforms (4a and 4b) that differ at the C terminus. In 98% of transcripts, exon 4a is spliced out and only exon 4b is available for translation into protein. The effector or switch domains are part of exons 1 and 2, while binding to guanine nucleotide exchange factors occurs in exon 3.
Pathologic allelic variants: Somatic KRAS and NRAS mutations have been found in myeloid malignancies and other cancers. The association between abnormal Kras and Noonan syndrome is the first evidence of a role in embryonic development. These gain-of-function mutations confer similar biochemical and cellular phenotypes as Noonan syndrome-associated SHP-2 mutations.
Normal gene product: Ras proteins regulate cell fates by cycling between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound conformations. They are key regulators of the RAS-RAF-MEK-ERK pathway, which is important for proliferation, growth and death of cells.
Abnormal gene product: The abnormal K-Ras protein induces hypersensitivity of primary hematopoietic progenitor cells to growth factors and deregulates signal transduction in a cell lineage-specific manner. Strong gain-of-function KRAS mutations may be incompatible with life.
Resources
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.
National Library of Medicine Genetics Home Reference
Noonan syndrome
The Noonan Syndrome Support Group
PO Box 145 Upperco, MD 21155
Phone: 888-686-2224; 410-374-5245
Email: info@noonansyndrome.org
Human Growth Foundation
997 Glen Cove Avenue Suite 5
Glen Head NY 11545
Phone: 800-451-6434 Fax: 516-671-4055
Email: hgf1@hgfound.org
The MAGIC Foundation
6645 West North Avenue
Oak Park, IL 60302
Phone: 800-362-4423; 708-383-0808 Fax: 708-383-0899
Email: info@magicfoundation.org
References
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
Published Statements and Policies Regarding Genetic Testing
No specific guidelines regarding genetic testing for this disorder have been developed.Literature CitedAllanson J. Noonan syndrome. In: Cassidy SB, Allanson JE (eds) Management of Genetic Syndromes. Wiley-Liss, NY. 2005. (PubMed)
Allanson JE. Noonan syndrome. J Med Genet. 1987. 24:9-13. (PubMed)
Allanson JE, Hall JG, Hughes HE, Preus M, Witt RD. Noonan syndrome: the changing phenotype. Am J Med Genet. 1985. 21:507-14. (PubMed)
Allanson JE, Upadhyaya M, Watson GH, Partington M, MacKenzie A, Lahey D, MacLeod H, Sarfarazi M, Broadhead W, Harper PS, et al. Watson syndrome: is it a subtype of type 1 neurofibromatosis? J Med Genet. 1991. 28:752-6. (PubMed)
Aoki Y, Niihori H, Kurosawa K, Ohashi H, Tanaka Y, Filocamo M, Kato K, Suzuki Y, Kure S, Matsubara Y. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005. 37:1038-40. (PubMed)
Bentires-Alj M, Paez JG, David FS, Keilhack H, Halmos B, Naoki K, Maris JM, Richardson A, Bardelli A, Sugarbaker DJ, et al. Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res. 2004. 64:8816-20. (PubMed)
Binder G, Neuer K, Ranke MB, Wittekindt NE. PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome. J Clin Endocrinol Metab. 2005. 90:5377-81. (PubMed)
Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, Pizzuti A, Dallapiccola B. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet. 2002. 71:389-94. (PubMed)
Digilio MC, Marino B, Picchio F, Prandstraller D, Toscano A, Giannotti A, Dallapiccola B. Noonan syndrome and aortic coarctation. Am J Med Genet. 1998. 80:160-2. (PubMed)
Ferreira LV, Souza SA, Arnhold IJ, Mendonca BB, Jorge AA. PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) mutations and response to growth hormone therapy in children with Noonan syndrome. J Clin Endocrinol Metab. 2005. 90:5156-60. (PubMed)
Fragale A, Tartaglia M, Wu J, Gelb BD. Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Hum Mutat. 2004. 23:267-77. (PubMed)
Gandhi SV, Howarth ES, Krarup KC, Konje JC. Noonan syndrome presenting with transient cystic hygroma. J Obstet Gynaecol. 2004. 24:183-4. (PubMed)
George CD, Patton MA, el Sawi M, Sharland M, Adam EJ. Abdominal ultrasound in Noonan syndrome: a study of 44 patients. Pediatr Radiol. 1993. 23:316-8. (PubMed)
Holder-Espinasse M, Winter RM. Type I Arnold-Chiari malformation and Noonan syndrome. Clin Dysmorphol. 2003. 12: (PubMed)
Ion A, Tartaglia M, Song X, Kalidas K, van der Burgt I, Shaw AC, Ming JE, Zampino G, Zackai EH, Dean JC, et al. Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome. Hum Genet. 2002. 111:421-7. (PubMed)
Ishizawa A, Oho S, Dodo H, Katori T, Homma SI. Cardiovascular abnormalities in Noonan syndrome: the clinical findings and treatments. Acta Paediatr Jpn. 1996. 38:84-90. (PubMed) Jongmans M, Otten B, Noordam K, van der Burgt I. Genetics and variation in phenotype in Noonan syndrome. Horm Res 62 Suppl. 2004. 3:56-9. (PubMed)
Joo JG, Beke A, Toth-Pal E, Csaba A, Papp C. Successful pregnancy in a Noonan syndrome patient after 3 unsuccessful pregnancies from severe fetal hydrops: a case report. J Reprod Med. 2005. 50:373-6. (PubMed)
Kratz CP, Niemeyer CM, Castleberry RP, Cetin M, Bergstrasser E, Emanuel PD, Hasle H, Kardos G, Klein C, Kojima S, et al. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood. 2005. 106:2183-5. (PubMed)
Lee DA, Portnoy S, Hill P, Gillberg C, Patton MA. Psychological profile of children with Noonan syndrome. Dev Med Child Neurol. 2005. 47:35-8. (PubMed)
Lee NB, Kelly L, Sharland M. Ocular manifestations of Noonan syndrome. Eye 6 (Pt. 1992. 3):328-34. (PubMed)
Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M, Fryns JP. PTPN11 mutations in LEOPARD syndrome. J Med Genet. 2002. 39:571-4. (PubMed)
Menashe M, Arbel R, Raveh D, Achiron R, Yagel S. Poor prenatal detection rate of cardiac anomalies in Noonan syndrome. Ultrasound Obstet Gynecol. 2002. 19:51-5. (PubMed)
Mendez HM and Opitz JM. Noonan syndrome: a review. Am J Med Genet. 1985. 21:493-506. (PubMed)
Niihori T, Aoki Y, Ohashi H, Kurosawa K, Kondoh T, Ishikiriyama S, Kawame H, Kamasaki H, Yamanaka T, Takada F, et al. Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. J Hum Genet. 2005. 50:192-202. (PubMed)
Noonan JA. Cardiac findings in cardio-facio-cutaneous syndrome: similarities to Noonan and Costello syndromes. Proc Greenwood Gen Ctr . 2001. (PubMed)
Noonan JA, Raaijmakers R, Hall BD. Adult height in Noonan syndrome. Am J Med Genet A. 2003. 123:68-71. (PubMed)
Ogawa M, Moriya N, Ikeda H, Tanae A, Tanaka T, Ohyama K, Mori O, Yazawa T, Fujita K, Seino Y, et al. Clinical evaluation of recombinant human growth hormone in Noonan syndrome. Endocr J. 2004. 51:61-8. (PubMed) Patton MA. Noonan syndrome: a review. Growth, Genetics and Hormones. 1994. 10:1-3. (PubMed)
Pierini DO and Pierini AM. Keratosis pilaris atrophicans faciei (ulerythema ophryogenes): a cutaneous marker in the Noonan syndrome. Br J Dermatol. 1979. 100:409-16. (PubMed)
Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Santa Cruz M, McCormick F, Rauen KA. Germline Mutations in Genes within the MAPK Pathway Cause Cardio-facio-cutaneous Syndrome. Science. 2006. 311:1287-90. (PubMed)
Sarkozy A, Obregon MG, Conti E, Esposito G, Mingarelli R, Pizzuti A, Dallapiccola B. A novel PTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome. Eur J Hum Genet. 2004. 12:1069-72. (PubMed)
Schubbert S, Zenker M, Rowe SL, Boll S, Klein C, Bollag G, van der Burgt I, Musante L, Kalscheuer V, Wehner LE, et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006. 38:331-6. (PubMed)
Sharland M, Burch M, McKenna WM, Paton MA. A clinical study of Noonan syndrome. Arch Dis Child. 1992. 67:178-83. (PubMed)
Sharland M, Patton MA, Talbot S, Chitolie A, Bevan DH. Coagulation-factor deficiencies and abnormal bleeding in Noonan's syndrome. Lancet. 1992. 339:19-21. (PubMed)
Tartaglia M, Cordeddu V, Chang H, Shaw A, Kalidas K, Crosby A, Patton MA, Sorcini M, van der Burgt I, Jeffery S, et al. Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome. Am J Hum Genet. 2004. 75:492-7. (PubMed)
Tartaglia M, Cotter PD, Zampino G, Gelb BD, Rauen KA. Exclusion of PTPN11 mutations in Costello syndrome: further evidence for distinct genetic etiologies for Noonan, cardio-facio-cutaneous and Costello syndromes. Clin Genet. 2003. 63:423-6. (PubMed)
Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner HG, Bertola DR, Crosby A, Ion A, et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002. 70:1555-63. (PubMed)
Tartaglia M, Martinelli S, Cazzaniga G, Cordeddu V, Iavarone I, Spinelli M, Palmi C, Carta C, Pession A, Arico M, et al. Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Blood. 2004. 104:307-13. (PubMed)
Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E, Cordeddu V, Zampino G, Burgt I, Palleschi A, Petrucci TC, et al. Diversity and Functional Consequences of Germline and Somatic PTPN11 Mutations in Human Disease. Am J Hum Genet. 2006. 78:279-90. (PubMed)
Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001. 29:465-8. (PubMed)
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Chapter Notes
Revision History
16 May 2006 (cd) Revision: KRAS testing clinically available
1 May 2006 (ja) Revision: mutations in KRAS cause Noonan syndrome
9 March 2006 (me) Comprehensive update posted to live Web site
17 December 2003 (me) Comprehensive update posted to live Web site
15 November 2001 (me) Review posted to live Web site
2 August 2001 (ja) Original submission
Original Complete Article
posted by Pat O'Connor @ 4:29 AM
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