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Protein-Tyrosine Phosphatase, Nonreceptor Type 11 Mutation Analysis and Clinical Assessment in 45 Patients with Noonan Syndrome

Department of Pediatrics, Keio University School of Medicine (R.Y., T.H.), Tokyo 160-8582, Japan; Division of Endocrinology and Metabolism, Tokyo Metropolitan Kiyose Children’s Hospital (Y.H.), Kiyose 204-8567, Japan; Department of Pediatrics, Dokkyo University School of Medicine Koshigaya Hospital (T.N.), Koshigaya 343-8555, Japan; Department of Pediatrics, Nagasaki University School of Medicine (E.K.), Nagasaki 852-8501, Japan; Department of Pediatrics, Tokyo Dental College Ichikawa General Hospital (Y.T.), Ichikawa 252-8713, Japan; Department of Pediatrics, Toyama Medical and Pharmaceutical University (H.K.), Toyama 930-0194, Japan; Department of Pediatrics, Yamanashi University School of Medicine (K.O.), Kofu 409-3898, Japan; Department of Pediatrics, Tokyo Medical and Dental University School of Medicine (T.On.), Tokyo 113-8519, Japan; Hanew Endocrine Clinic (K.H), Sendai 980-0824, Japan; Divisions of Molecular Medicine (T.Ok.), Adolescent and Young Adult Medicine (R.H.), and Endocrinology and Metabolism (T.T.), National Center for Child Health and Development, Tokyo 154-8535, Japan; and Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development (R.Y., T.Og.), Tokyo 154-8567, Japan

Address all correspondence and requests for reprints to: Dr. Tsutomu Ogata, Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, 3-35-31 Taishido, Setagaya, Tokyo 154-8567, Japan. E-mail: tomogata{at}nch.go.jp.

We report on PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11) mutation analysis and clinical assessment in 45 patients with Noonan syndrome. Sequence analysis was performed for all of the coding exons 1–15 of PTPN11, revealing a novel 3-bp deletion mutation and 10 recurrent missense mutations in 18 patients. Clinical assessment showed that 1) the growth pattern was similar in mutation-positive and mutation-negative patients, with no significant difference in birth length [–0.6 ± 2.2 SD (n = 10) vs. –0.6 ± 1.4 SD (n = 21); P = 0.95], childhood height [–2.6 ± 1.1 SD (n = 14) vs. –2.1 ± 1.6 SD (n = 23); P = 0.28], or target height [–0.4 ± 0.9 SD (n = 14) vs. –0.2 ± 0.7 SD (n = 17); P = 0.52]; 2) pulmonary valve stenosis was more frequent in mutation-positive patients than in mutation-negative patients (10 of 18 vs. 6 of 27; P = 0.02), as was atrial septal defect (10 of 18 vs. 4 of 27; P = 0.005), whereas hypertrophic cardiomyopathy was present in five mutation-negative patients only; and 3) other features were grossly similar in the prevalence between mutation-positive and mutation-negative patients, but hematological abnormalities, such as bleeding diathesis and juvenile myelomonocytic leukemia, were exclusively present in mutation-positive patients (5 of 18 vs. 0 of 27; P = 0.007). The results suggest that PTPN11 mutations account for approximately 40% of Noonan syndrome patients, as has been reported previously. Furthermore, assessment of clinical features, in conjunction with data reported previously, implies that the type of cardiovascular lesions and the occurrence of hematological abnormalities are different in mutation-positive and mutation-negative patients, whereas the remaining findings are similar in the two groups of patients.

This work was supported by a grant for Child Health and Development from the Ministry of Health, Labor, and Welfare (14C-1) and a grant-in-aid from the Ministry of Education, Science, Sports, and Culture (15591150).

Abbreviations: ASD, Atrial septal defect; BL, birth length; BW, birth weight; CH, childhood (5–7 yr of age) height; HCM, hypertrophic cardiomyopathy; JMML, juvenile myelomonocytic leukemia; MI, mitral valve insufficiency; NS, Noonan syndrome; PS, pulmonary valve stenosis; PTP, protein-tyrosine phosphatase; PTPN11, protein-tyrosine phosphatase, nonreceptor type 11; SDS, SD score; SH2, Src homology 2; TH, target height.

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