ESPE Abstracts

Introduction: Silver-Russell syndrome 5 (SRS5) is characterized by asymmetric intrauterine growth restriction (IUGR), poor postnatal growth, macrocephaly at birth and feeding difficulties. Other possible features include triangular shaped face, prominent forehead, hypertelorism, epicanthus, micrognathia, brachydactyly, clinodactyly of the 5th hand finger, and syndactyly of the 2nd and 3rd toe fingers. Pathogenic variants of the HMGA2 gene, on chromosome 12q14, which regulates the transcription of the growth factor IGF2, have been recently associated with this syndrome.

Aim: Herein we present a 2.5-year-old boy with growth delay, SRS-like phenotype, and a variant of uncertain significance in the HMGA2 gene, which hasn’t been described yet in the medical literature.

Material and Methods: A 2.5-year-old boy was referred due to growth delay. From the perinatal history he was born at gestational age of 37 weeks. His birth weight was 2260gr and birth length 46cm (IUGR). The family history was unremarkable. The clinical examination showed a triangular face, hypertelorism, micrognathia and long eyelashes. Rest examination was normal. Furthermore, his weight (8kg) and height (75cm) were from birth, below the third percentile. Cardiac examination, renal ultrasound, hormonal and basic laboratory tests including celiac disease antibodies were found to be unremarkable. His bone age was delayed by 7 months. In view of his clinical features, a genetic consult was requested.

Results: In view of normal Array Comparative Genomic Hybridization (aCGH) and negative result for epimutation at chromosome 11p15 and maternal uniparental disomy of chromosome 7, a Whole Exome Sequence (WES) was revealed the variant c.111+5G>A in the HMGA2 gene, which may cause a disruption in the splicing process and is being considered as a variant of uncertain significance (VUS). At last, our patient was commenced on replacement therapy with recombinant human growth hormone (HGH) with a good response.

Conclusion: SRS presents a large genetic heterogeneity. Genetic testing confirms the diagnosis in 60% of SRS cases. Except for the epimutation of the imprinting center region 1 (ICR1) on chromosome 11 or the maternal uniparental disomy of chromosome 7 (matUPD7), twenty-eight pathogenic variants in the HMGA2 gene, in patients with clinical SRS phenotype have been recently reported. Therefore, HMGA2 gene testing should be always checked in the SRS patients that are found negative for the typical 11p15 (epi)mutations and matUPD7, as well as be added to growth retardation disorder panels. To the best of our knowledge, the above-mentioned variant hasn’t been described yet in the medical literature.