This Article Full Text Full Text (PDF) All Versions of this Article: 91/1/300    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Limal, J.-M. Articles by Le Bouc, Y. Search for Related Content PubMed PubMed Citation Articles by Limal, J.-M. Articles by Le Bouc, Y. Related Collections Neuroendocrinology and Pituitary Pediatric Endocrinology

Noonan Syndrome: Relationships between Genotype, Growth, and Growth Factors

Department of Pediatrics (J.-M.L.), University Hospital, 49933 Angers, France; Molecular Genetics Laboratory (B.P., M.V.), Faculté de Pharmacie, 75006 Paris, France; Pediatric Endocrine Unit (S.C., Y.L.B.), Armand-Trousseau Hospital, 75012 Paris; Université Pierre et Marie Curie, 75005 Paris, France; Pediatric Cardiology Unit (D.B.) and Department of Genetics (S.L.), Necker-Enfants Malades Hospital, 75743 Paris, France; and Department of Pediatrics (B.L.), University Hospital, 54000 Nancy, France

Address all correspondence and requests for reprints to: J. M. Limal, Department of Pediatrics, University Hospital, 4 rue Larrey, 49933 Angers, France. E-mail: jmlimal{at}chu-angers.fr.

Context: 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–).

Setting, Design, and Patients: 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.

This article has been cited by other articles:

				C Noordam, P G M Peer, I Francois, J De Schepper, I van den Burgt, and B J Otten Long-term GH treatment improves adult height in children with Noonan syndrome with and without mutations in protein tyrosine phosphatase, non-receptor-type 11 Eur. J. Endocrinol., September 1, 2008; 159(3): 203 - 208. [Abstract] [Full Text] [PDF]

				A C Shaw, K Kalidas, A H Crosby, S Jeffery, and M A Patton The natural history of Noonan syndrome: a long-term follow-up study Arch. Dis. Child., February 1, 2007; 92(2): 128 - 132. [Abstract] [Full Text] [PDF]