ESPE Abstracts (2014) 82 FC4.1

Heterozygous IGF1R Mutations Represent a Frequent Finding in Patients with Pre- and/or Postnatal Proportional Undergrowth and Low, Normal or Supranormal IGF1

Angel Campos-Barrosa,b, Ana Gómez-Núñeza,b, Isabel González-Casadoc, Luis Salamanca-Fresnoc, Sixto García-Miñaura,b, Purificación Ros-Pérezd, Victoria Borrás-Péreze, Laura Audíf,g, Jordi Rosell-Andreoh, Diego de Sotto-Estebani, Beatriz García-Cuarteroj, Amparo González-Vergazj, Jaime Cruz-Rojok, Lucía Garzónk & Elena Gallego-Gómezk

aHospital Universitario La Paz, INGEMM, IdiPAZ, UAM, Madrid, Spain; bCIBERER (U753), ISCIII, Madrid, Spain; cHospital Universitario La Paz, Pediatric Endocrinology, Madrid, Spain; dHospital Universitario Puerta de Hierro-Majadahonda, Pediatric Endocrinology, Madrid, Spain; eHospital General de Granollers, Pediatric Endocrinology, Barcelona, Spain; fHospital Vall d’Hebrón, Pediatric Endocrinology, Barcelona, Spain; gVHIR, CIBERER (U712), ISCIII, Autonomous University, Barcelona, Spain; hDepartment of Genetics, Hospital Universitari Son Espases, Palma de Mallorca, Spain; iHospital Universitari Son Espases, Pediatric Endocrinology, Palma de Mallorca, Spain; jHospital Universitario Severo Ochoa, Pediatric Endocrinology, Madrid, Spain; kHospital Universitario 12 de Octubre, Pediatric Endocrinology, Madrid, Spain

Background: IGF1 resistance syndrome (IGF1RS) is characterized by intrauterine and postnatal growth deficit with normal or supranormal IGF1 levels. Additional features may include intellectual deficit, microcephaly and dysmorphisms. IGF1RS may be caused by genomic or genetic defects affecting the IGF1R locus (15q26.3).

Objective and hypotheses: To investigate the frequency of IGF1R mutations in a cohort of patients with pre- and/or postnatal proportional undergrowth.

Method: Subjects: 46 children born small for gestational age (SGA) and/or presenting with postnatal proportional undergrowth without known molecular defects in GHR, IGF1 and IGFALS. Molecular studies: Mutation screening of the coding sequences, intron/exon boundaries and regulatory regions of IGF1R by HRM and sequencing; deletions/duplications analysis of IGF1R coding regions by MLPA and chromosome 15q26.3 region by aCGH.

Results: 8/46 patients (17.4%) presented a heterozygous mutation in IGF1R. Two were de novo deletions of the 15.q26.2–26.3 region encompassing IGF1R. The remaining six patients presented five different mutations, four novel, all classified as probably pathogenic by bioinformatic prediction tools. Four were missense mutations affecting highly conserved residues and the fifth a frameshift duplication predicted to elongate and alter the protein C-terminal sequence.

Conclusion: Heterozygous IGF1R mutations represent a frequent finding (17.4%) in the patients born SGA and/or with postnatal proportional undergrowth examined. The clinical phenotypes of the individuals with IGF1R mutations are very variable. IUGR, microcephaly and psychomotor developmental delay, together with increased IGF1 levels, are the predominant findings, though not present in all patients. These results indicate that heterozygous IGF1R mutations cause a phenotypically variable IGF1 resistance syndrome associated with proportional undergrowth with a higher prevalence than initially predicted.