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.
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 NSpatients 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 NSpatients 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: Audrey De Rocca Serra-Nédélec; Thomas Edouard; Karine Tréguer; Mylène Tajan; Toshiyuki Araki; Marie Dance; Marianne Mus; Alexandra Montagner; Maïté Tauber; Jean-Pierre Salles; Philippe Valet; Benjamin G Neel; Patrick Raynal; Armelle Yart Journal: Proc Natl Acad Sci U S A Date: 2012-02-27 Impact factor: 11.205
Authors: Helen L Storr; Sumana Chatterjee; Louise A Metherell; Corinne Foley; Ron G Rosenfeld; Philippe F Backeljauw; Andrew Dauber; Martin O Savage; Vivian Hwa Journal: Endocr Rev Date: 2019-04-01 Impact factor: 19.871
Authors: Judith E Allanson; Axel Bohring; Helmuth-Guenther Dörr; Andreas Dufke; Gabrielle Gillessen-Kaesbach; Denise Horn; Rainer König; Christian P Kratz; Kerstin Kutsche; Silke Pauli; Salmo Raskin; Anita Rauch; Anne Turner; Dagmar Wieczorek; Martin Zenker Journal: Am J Med Genet A Date: 2010-08 Impact factor: 2.802
Authors: S Walton-Betancourth; C E Martinelli; N K Thalange; M P Dyke; C L Acerini; S White; C Camacho-Hübner; M O Savage Journal: J Endocrinol Invest Date: 2007-05 Impact factor: 4.256