ESPE Abstracts

Background: Genetic workup is negative in up to 40% of children presenting with clinical signs of Silver-Russell syndrome (SRS). HMGA2 variants causing SRS are rare, accounting for less than 1% of all reported cases.

Case description: A 1y,8m-old boy was referred to our endocrinology institute due to severe failure to thrive (HAZ=-4.6 SDS, WAZ=-4.8 SDS) and feeding difficulties requiring nutritional support via PEG. He was born at 36 weeks of gestation weighing 1770 g, to non-consanguineous parents of Jewish Iranian (M-148 cm) and Yemenite (F-158 cm) origin. Physical features suggestive of SRS included relative macrocephaly and typical facies. Workup for etiologies of short stature, including a GH stimulation test, was normal.

Genetic workup: The patient underwent prenatal genetic testing because of a maternal abnormality in the corpus callosum, which was later ruled out in our patient by MRI. Amniocentesis was performed during the 2nd trimester. Chromosomal Microarray Analysis and trio exome sequencing were interpreted as normal. Postnatal revision of the raw data according to the updated phenotype revealed a novel heterozygous pathogenic variant in the HMGA2 gene, inherited from the father: c.27dup (p.Gln10fs, NM_003483.6, hg19). This frameshift variant is classified as pathogenic as this is a null variant in a gene where loss of function is a known mechanism of disease; it has not been reported in the healthy population databases; and the patient's phenotype is highly specific and consistent with this genetic etiology.

Discussion: Pathogenic variants in the HMGA2 gene, de-novo or transmitted by either parent, are a very rare cause of SRS, also referred to as SRS type 5. The phenotype of these patients is similar to that of patients carrying 11p15.5 epigenetic defects, however, as this is a germline mutation, body asymmetry is not present. Using the LOVD and ClinVar databases, only 4 other frameshift likely pathogenic/pathogenic variants have been reported to date.

Conclusion: In patients with IUGR and postnatal growth failure, rare etiologies of Russell-Silver Syndrome, such as variants in the HMGA2 gene, must be considered, especially as the recurrence risk is 50% in inherited cases.