Endocrine Abstracts

JOINT3700

Introduction: Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder characterized by short stature, a typical facial phenotype, and body asymmetry. Molecular genetic abnormalities, such as maternal uniparental disomy of chromosome 7 and hypomethylation of the 11p15 region, are commonly observed in SRS, approximately 40% of patients still lack a confirmed genetic diagnosis. Identifying the underlying molecular cause is essential for accurate diagnosis, effective treatment, and genetic counseling for affected families.

Materials and Methods: A 7-year-old girl was referred due to concerns of growth and weight delay. She was born from second pregnancy complicated by intrauterine growth restriction and delivered by cesarean section at 39 weeks. Birth weight 1820 g (SDS: -3.3), birth length 44 cm (SDS: -4.34), Apgar score 6/8. The family history was non-contributory: maternal height 168 cm, paternal height 170 cm, target height of 160.5 cm (SDS: 0.08). There were no reported comorbidities.

Results: At the time of evaluation, the girl had a proportional physique. Notable dysmorphic features included a wide protruding forehead, clinodactyly of the fifth finger, and abnormal dental development. Height 103.0 cm (SDS: -3.2), weight 13.8 kg, BMI SDS -1.9. Over the past 18 months, she had grown 6.5 cm. During examination, bone age was delayed by 1 year, and IGF-1 was measured at 103 ng/ml. No deficiency of other pituitary tropic hormones was detected. To investigate maternal uniparental disomy of chromosome 7, microsatellite analysis was performed on critical loci at 7q33-34 (D7S2202, D7S91824) and 7p12.1-12.3 (D7S2422, D7S2519). Additionally, multilocus methylation-sensitive PCR was used to assess allele-specific methylation in the 11p15 region, including the H19/IGF2 imprinting control region. The analyses excluded characteristic molecular genetic defects of SRS, including maternal uniparental disomy of chromosome 7 and hypomethylation of the 11p15 region. Given the negative results, the patient and her parents underwent whole-exome sequencing of peripheral blood lymphocyte DNA in a "trio" format. A previously undescribed heterozygous de novo variant was identified in the HMGA2 gene (NC_000012.2:g.65825359G>A, NM_003483.6: c.89G>A, p.(Gly30Asp)), associated with SRS type 5 (OMIM: 618908). Segregation analysis in the family confirmed the variant by Sanger sequencing.

Conclusion: The use of advanced genetic testing methods, including whole-genome and whole-exome sequencing, significantly improves diagnostic accuracy in patients with suspected SRS. The identification of a novel monogenic cause in this patient facilitated the initiation of somatotropic treatment and enabled comprehensive genetic counseling for the family.