ESPE Abstracts (2014) 82 P-D-1-1-144

Genetics of Growth Failure in Small for Gestational Age Children

Romy Keppler, Natascha van der Werft-Grohmann, Karl Otfried Schwab & Ekkehart Lausch


Department of Pediatrics, Freiburg University Hospital, Freiburg, Germany


Background: Small for gestational age (SGA), defined as ≤−2.0 SDS birth length or weight, is a condition seen in up to 3% of all newborn. Most SGA children catch up height in postnatal life. In a significant number (~10%), however, height remains below the third centile. Recombinant GH therapy is indicated when growth failure continues to 4 years of age. The pathophysiological basis of SGA is complex: monogenic disorders and/or fetal programming by environmental factors like placental–fetal insufficiency all have the same clinical presentation and may act together. Importantly, no predictors are known for the efficacy of GH therapy. Preliminary evidence indicates that a significant fraction of SGA patients may carry genetic aberrations of the IGF hormone-receptor system.

Objective and hypotheses: In our study, we aimed for a detailed clinical, genetic, and molecular characterization of SGA children refractive to GH therapy. In a cohort of 62 selected SGA children, we screened for mutations in a gene panel of the GH/IGF1 axis to provide the molecular basis for future functional studies and therapeutic intervention.

Method: Clinical, biochemical, and molecular characterization of SGA patients by next generation sequencing (NGS) panel on a semiconductor-based platform and Sanger confirmation analysis.

Results: Our analysis included the genes CUL7, OBSL1, CCDC8, and FBXW8, which are associated with 3M syndrome. In seven of 62 SGA patients, recessive mutations in either of these disease genes were found, in one case presenting as compound digenic variants in CUL7 and OBSL1. None of the patients responded to GH therapy. CUL7 is a ubiquitin ligase of IRS1, a transducer of IGF1 receptor signalling.

Conclusion: Thus, 3M is a disorder of GH/IGF1 axis that has an unexpectedly high prevalence in non-GH responsive SGA children. Therefore, we performed functional characterization of IGF1 signalling in 3M syndrome as a step towards an adjusted therapy for these patients.

Article tools

My recent searches

No recent searches.