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      Genotype-Phenotype Correlation in Patients Suspected of Having Sotos Syndrome

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          Background: Deletions and mutations in the NSD1 gene are the major cause of Sotos syndrome. We wanted to evaluate the genotype-phenotype correlation in patients suspected of having Sotos syndrome and determine the best discriminating parameters for the presence of a NSD1 gene alteration. Methods: Mutation and fluorescence in situ hybridization analysis was performed on blood samples of 59 patients who were clinically scored into 3 groups. Clinical data were compared between patients with and without NSD1 alterations. With logistic regression analysis the best combination of predictive variables was obtained. Results: In the groups of typical, dubious and atypical Sotos syndrome, 81, 36 and 0% of the patients, respectively, showed NSD1 gene alterations. Four deletions were detected. In 23 patients (2 families) 19 mutations were detected (1 splicing defect, 3 non-sense, 7 frameshift and 8 missense mutations). The best predictive parameters for a NSD1 gene alteration were frontal bossing, down-slanted palpebral fissures, pointed chin and overgrowth. Higher incidences of feeding problems and cardiac anomalies were found. The parameters, delayed development and advanced bone age, did not differ between the 2 subgroups. Conclusions: In our patients suspected of having Sotos syndrome, facial features and overgrowth were highly predictive of a NSD1 gene aberration, whereas developmental delay and advanced bone age were not.

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          Most cited references 12

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          Body index measurements in 1996-7 compared with 1980.

          To compare the distribution of body mass index (BMI) in a national representative study in The Netherlands in 1996-7 with that from a study in 1980. Cross sectional data on height, weight, and demographics of 14 500 boys and girls of Dutch origin, aged 0-21 years, were collected from 1996 to 1997. BMI references were derived using the LMS method. The 90th, 50th, and 10th BMI centiles of the 1980 study were used as baseline. Association of demographic variables with BMI-SDS was assessed by ANOVA. BMI age reference charts were constructed. From 3 years of age onwards 14-22% of the children exceeded the 90th centile of 1980, 52-60% the 50th centile, and 92-95% the 10th centile. BMI was related to region, educational level of parents (negatively) and family size (negatively). The -0.9, +1.1, and +2.3 SD lines in 1996-7 corresponded to the adult cut off points of 20, 25, and 30 kg/m(2) recommended by the World Health Organisation/European childhood obesity group. BMI age references have increased in the past 17 years. Therefore, strategies to prevent obesity in childhood should be a priority in child public health.
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            Haploinsufficiency of NSD1 causes Sotos syndrome.

            We isolated NSD1 from the 5q35 breakpoint in an individual with Sotos syndrome harboring a chromosomal translocation. We identified 1 nonsense, 3 frameshift and 20 submicroscopic deletion mutations of NSD1 among 42 individuals with sporadic cases of Sotos syndrome. The results indicate that haploinsufficiency of NSD1 is the major cause of Sotos syndrome.
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                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                October 2004
                21 October 2004
                : 62
                : 4
                : 197-207
                aDepartment of Pediatrics, bCenter for Human and Clinical Genetics, cDepartment of Endocrinology and Metabolic Diseases and dDepartment of Medical Statistics, Leiden University Medical Center, Leiden; eDepartment of Clinical Genetics, University Medical Center, Utrecht; fDepartment of Human Genetics, University Medical Center Nijmegen, Nijmegen; gDepartment of Clinical Genetics and hDepartment of Pediatrics, Academic Medical Center, Amsterdam; iDepartment of Clinical Genetics, Groningen Academic Hospital, Groningen; jDepartment of Clinical Genetics, Academic Hospital Maastricht and kResearch Institute Growth and Development, Maastricht University, Maastricht, The Netherlands, and lCenter for Child and Adolescent Health, Munich, Germany
                81063 Horm Res 2004;62:197–207
                © 2004 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 5, References: 18, Pages: 11
                Original Paper


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