Case report:

Insulin-like growth factor 2 protein is crucial for fetal growth and is regulated by an IGF2 gene which is paternally expressed. Loss-of-function variants in IGF2 that were paternally transmitted have been associated with a phenotype resembling Silver-Russell syndrome (SRS), characterized by intrauterine growth restriction (IUGR), developmental issues, macrocephaly, and facial abnormalities. SRS diagnosis relies on clinical traits assessed by the NH-CSS*, with genetic abnormalities often involving chromosomes 7 or 11. The study described a paternally transmitted IGF2 variant that was found in an SRS-diagnosed boy and highlighted growth hormone (GH) therapy’s efficacy. 

The 2-year boy, referred for presumed SRS, exhibited typical SRS features and was born with severe IUGR*. Growth hormone therapy started at 3 years of age due to a significant height deficit. Genomic analysis, including SNP array and MLPA, ruled out chromosomal abnormalities. Using Geneyx Analysis, variants were annotated, and genes were prioritized based on the strength of gene-phenotype association.  

Figure 1 Results of sequence analysis of the proband, his father and grandmother.

Figure 2 Height and weight during GH treatment plotted on Italian growth chart for boys (18). TH, target height.

A heterozygous IGF2 variant c.[-6-2A>G] was identified and rated as likely pathogenic by The American College of Medical Genetics (ACMG). Segregation analysis via Sanger sequencing revealed that proband inherited the variant from his father who inherited the variant from his mother, resulting in asymptomatic carrier status for the patient’s father because of the maternal imprinting of IGF2. Growth hormone treatment showed positive growth results, increasing the patient’s growth rate from 5 cm/year to 8 cm/year initially. No adverse effects or health issues were noted during therapy. While serum protein levels were initially increased slightly, they later rose significantly and stayed raised throughout therapy.In summary, the study described a novel IGF2 c.[-6-2A>G] variant in a boy with SRS clinical attributes. Molecular analyses excluded chromosomal abnormalities and the variant was classified as likely pathogenic. Paternal inheritance of the variant was confirmed through segregation analysis. The patient responded positively to growth hormone therapy, with increased growth rates. Elevated serum protein levels correlated with growth hormone treatment duration. The study highlighted the value of targeted exome sequencing in identifying IGF2 mutations and emphasized early intervention benefits in genetic conditions. 

• ¹Pediatric Section, University Hospital Arcispedale Sant’Anna, University of Ferrara, Ferrara, Italy
• ²Endocrinology and Diabetology Unit, Pediatric University Department, Bambino Gesù Children’s Hospital, Rome, Italy
• ³Laboratory of Medical Genetics, Bambino Gesù Children’s Hospital, Rome, Italy
• ⁴Pediatric University Department, Bambino Gesù Children’s Hospital, Rome, Italy
• ⁵Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, Rome, Italy
• ⁶Research Area for Innovative Therapies in Endocrinopathies, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
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Glossary:

IUGR: Fetus with a weight below the 10th percentile for its gestational age.

NH-CSS: stands for Netchine-Harbison Clinical Scoring System. It is a diagnostic tool used to assess and diagnose Silver-Russell syndrome (SRS). 

Explore additional studies utilizing Geneyx Analysis for comprehensive clinical variant analysis.