Lonneke de Boer a , Sarina G. Kant b , Marcel Karperien a,c , Lotte van Beers b , Jennifer Tjon c , Geraldine R. Vink b , Dewy van Tol b , Hans Dauwerse b , Saskia le Cessie d , Frits A. Beemer e , Ineke van der Burgt f , Ben C.J. Hamel f , Raoul C. Hennekam g,h , Ursula Kuhnle l , Inge B. Mathijssen g , Hermine E. Veenstra-Knol i , Connie T. Schrander Stumpel j,k , Martijn H. Breuning b , Jan M. Wit a
21 October 2004
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.