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R Solomon-Zemler Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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L Basel-Vanagaite Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Raphael Recanati Genetic Institute, Rabin Medical Center – Beilinson Hospital, Petach Tikva, Israel
Felsenstein Medical Research Center, Petach Tikva, Israel
Pediatric Genetics, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel

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D Steier Day Hospitalization Department, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel

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S Yakar David B. Kriser Dental Center, Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York, USA

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E Mel Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel

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M Phillip Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel

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L Bazak Raphael Recanati Genetic Institute, Rabin Medical Center – Beilinson Hospital, Petach Tikva, Israel

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D Bercovich Tel-Hai College, Tel-Hai, Israel

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H Werner Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Shalom and VardaYoran Institute for Human Genome Research, Tel Aviv University, Tel Aviv, Israel

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L de Vries Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel

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Mutation in the insulin-like growth factor-1 receptor (IGF1R) gene is a rare cause for intrauterine and postnatal growth disorders. Patients identified with IGF1R mutations present with either normal or impaired glucose tolerance. None of the cases described so far showed hypoglycemia. We aimed to identify the genetic basis for small for gestational age, short stature and hypoglycemia over three generations in one family. The proband, a 9-year-old male, presented in infancy with recurrent hypoglycemic episodes, symmetric intrauterine growth retardation and postnatal growth retardation. Blood DNA samples from the patient, his parents, a maternal sister and maternal grandmother underwent Sanger sequencing of the IGF1R gene. Primary skin fibroblast cultures of the patient, his mother and age- and sex-matched control donors were used for gene expression and receptor functional analyses. We found a novel heterozygous mutation (c.94 + 1g > a, D1105E) affecting the splicing site of the IGF1R mRNA in the patient, his mother and his grandmother. Primary fibroblast cultures derived from the patient and his mother showed reduced proliferation and impaired activation of the IGF1R, evident by reduced IGF1R and AKT phosphorylation upon ligand binding. In conclusion, the newly identified heterozygous missense mutation in exon 1 of IGF1R (D1105E) results in impaired IGF1R function and is associated with small for gestational age, microcephaly and abnormal glucose metabolism. Further studies are required to understand the mechanisms by which this mutation leads to hypoglycemia.

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