title: Noonan syndrome: relationships between genotype, growth, and growth factors.
abstract: BACKGROUND
  Half of the patients with Noonan syndrome (NS) carry mutation of the PTPN11 gene, which plays a role in many hormonal signaling pathways. The mechanism of stunted growth in NS is not clear.
  
  
  OBJECTIVE
  The objective of the study was to compare growth and hormonal growth factors before and during recombinant human GH therapy in patients with and without PTPN11 mutations (M+ and M-).
  
  
  METHODS
  This was a prospective multicenter study in 35 NS patients with growth retardation. Auxological data and growth before and during 2 yr of GH therapy are shown. GH, IGF-I, IGF binding protein (IGFBP)-3, and acid-labile subunit (ALS) levels were evaluated before and during therapy.
  
  
  RESULTS
  Molecular investigation of the PTPN11 coding sequence revealed 12 different heterozygous missense mutations in 20 of 35 (57%). Birth length was reduced [mean -1.2 sd score (SDS); six m+ and two m- were < -2 SDS] but not birth weight. M+ vs. M- patients were shorter at 6 yr (P = 0.04). In the prepubertal group (n = 25), GH therapy resulted in a catch-up height SDS, which was lower after 2 yr in M+ vs. M- patients (P < 0.03). The mean peak GH level (n = 35) was 15.4 +/- 6.5 ng/ml. Mean blood IGF-I concentration in 19 patients (11 m+, eight m-) was low (especially in M+) for age, sex, and puberty (-1.6 +/- 1.0 SDS) and was normalized after 1 yr of GH therapy (P < 0.001), without difference in M+ vs. M- patients. ALS levels (n = 10) were also very low. By contrast, the mean basal IGFBP-3 value (n = 19) was normal.
  
  
  CONCLUSIONS
  In NS patients with short stature, some neonates have birth length less than -2 SDS. Growth of M+ is reduced and responds less efficiently to GH than M- patients. The association of low IGF-I and ALS with normal IGFBP-3 levels could explain growth impairment of M+ children and could suggest a GH resistance by a late postreceptor signaling defect.
authors.affiliation: Department of Pediatrics, University Hospital, 49933 Angers, France. jmlimal@chu-angers.fr
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Limal
authors.forename: Béatrice
authors.initials: B
authors.lastname: Parfait
authors.forename: Sylvie
authors.initials: S
authors.lastname: Cabrol
authors.forename: Damien
authors.initials: D
authors.lastname: Bonnet
authors.forename: Bruno
authors.initials: B
authors.lastname: Leheup
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Michel
authors.initials: M
authors.lastname: Vidaud
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Bouc
mesh_terms: D000293:Adolescent; D000886:Anthropometry; D001724:Birth Weight / Q000502:physiology; D002352:Carrier Proteins / Q000097:blood; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006023:Glycoproteins / Q000097:blood; D006128:Growth / Q000502:physiology*; D006130:Growth Disorders / Q000235:genetics / Q000473:pathology; D013006:Growth Hormone / Q000627:therapeutic use; D006133:Growth Substances / Q000378:metabolism*; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D007231:Infant, Newborn; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D009634:Noonan Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D011446:Prospective Studies; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D011627:Puberty / Q000502:physiology; D013268:Stimulation, Chemical
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D006133:Growth Substances; D018972:Insulin-Like Growth Factor Binding Protein 3; D047908:Intracellular Signaling Peptides and Proteins; C075944:insulin-like growth factor binding protein, acid labile subunit; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases