Silver-Russell Syndrome and 12q14.3 microdeletion

Silver-Russell Syndrome (SRS) is a genetic disorder causing failure with prenatal and postnatal growth. Other common characteristics of SRS include a larger head at birth, protruding forehead in early life, body asymmetry and substantial feeding difficulties.

chromosome 12

SRS can be caused by different genetic mechanisms. The most common abnormalities are related to the epi-mutation of either the 11p15.5 region or chromosome 7. An epi-mutation is a mutation that does not affect the DNA sequence but results in a change in gene expression. However, in rare cases SRS may be caused by mutations of the HMGA2 gene or deletions, involving this gene. HMGA2 in particular regulates the transcription of the known fetal growth factor IGF2. Previous studies have confirmed that HMGA2 has shown to be essential in regulating cell growth and embryonic development.

The study follows a 3 year old male with a clinical diagnosis of SRS associated with a de novo heterozygous deletion of the long arm of the chromosome 12 (12q14.3) encompassing the HMGA2 gene. He was born at term but his weight was 2350 g (less than 3rd percentile), his length was 47 cm (2nd percentile), and his head circumference (HC) was 31 cm (less than 3rd percentile). At two years of age his weight and length remained at less than 3rd percentile, but his HC (47.3cm) had increased slightly to the tenth percentile. Using the Netchine–Harbison clinical scoring system (NH-CSS), which is the only scoring system for the diagnosis of SRS that was developed using prospective data, the 3yo boy received a score of 5 out of 6.

Review of all previously known patients with mutations of the HMGA2 gene or deletions of 12q14.3 involving this gene showed that all such patients were underweight and showed growth failure. However body asymmetry, another item of the NH-CSS, does not seem to be a typical feature of the 12q14.3 microdeletion syndrome, but it is reported in this 3yo male patient who has lower limbs asymmetry. Finally, the patient presents a moderate speech delay. The presence of neurodevelopmental disorders (language and/or motor delay, learning difficulties, intellectual disability, behavioral problems), seems to be a distinct and frequent feature of 12q14.3 microdeletion syndrome.

The authors suggest investigating the HMGA2 gene in all the patients with an evocative phenotype for SRS and negative genetic results for an epi-mutation of either the 11p15.5 region or chromosome 7.

Mercadante F. et al. “12q14.3 microdeletion involving HMGA2 gene cause a Silver-Russell syndrome-like phenotype: A case report and review of the literature”. Italian Journal of Pediatrics, 2020, v. 46:108.

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