12q14.3 microdeletion involving HMGA2 gene cause a Silver-Russell syndrome-like phenotype: a case report and review of the literature

Abstract

Background: Silver-Russell Syndrome (SRS) is a genetic disorder characterized by intrauterine and postnatal growth restriction and normal head circumference with consequent relative macrocephaly. Addictional findings are protruding forehead in early life, body asymmetry (of upper and lower limbs) and substantial feeding difficulties. Although several genetic mechanisms that cause the syndrome are known, more than 40% of patients with a SRSlike phenotype remain without an etiological diagnosis. In the last few years, different clinical reports have suggested that mutations or deletions of the HMGA2 gene can be responsible for a SRS-like phenotype in patients with negative results of the common diagnostic tests for this syndrome. Case presentation: We present a 3-year-old male patient with clinical diagnosis of Silver-Russell Syndrome (SRS) associated with a de novo heterozygous deletion of the long arm of the chromosome 12 (12q14.3) encompassing the HMGA2 gene. Conclusions: Our report confirms the etiological role of HMGA2 as a disease gene in the development of a SRS-like phenotype.

Case Report: Two New Cases of Chromosome 12q14 Deletions and Review of the Literature

“…Twenty-seven individuals (14 females, and 13 males) with overlapping deletions located within 12q13q15 have been previously reported with varying degrees of global developmental delay/intellectual disability, growth retardation and short stature as the main phenotype (Menten et al, 2007 ; Buysse et al, 2009 ; Mari et al, 2009 ; Spengler et al, 2010 ; Lynch et al, 2011 ; Alyaqoub et al, 2012 ; Bibb et al, 2012 ; Takenouchi et al, 2012 ; Fischetto et al, 2017 ; Heldt et al, 2018 ; Mercadante et al, 2020 ; Figure 3 , Supplementary Table 2 ).…”

“…Genes discussed in the main text or in the Supplemental Materials are indicated. Fischetto et al, 2017;Heldt et al, 2018;Mercadante et al, 2020; Figure 3, Supplementary Table 2).…”

“…It is unknown whether those cases later on developed this condition. Interestingly, the neurodevelopmental phenotypes associated with deletions of 12q14 cannot be explained by haploinsufficiency of either HMGA2 or LEMD3 alone, as individuals that only have gene specific alterations either showed normal development (Buysse et al, 2009;Leszinski et al, 2018;Hübner et al, 2020), or only mild delay (Mercadante et al, 2020). Psychomotor retardation is also rarely encountered in Silver-Russel syndrome.…”

“…The deletion encountered in individual 1 overlaps with 22 reported deletions which have been associated with a 12q14 microdeletion syndrome (Menten et al, 2007 ; Buysse et al, 2009 ; Mari et al, 2009 ; Spengler et al, 2010 ; Lynch et al, 2011 ; Alyaqoub et al, 2012 ; Bibb et al, 2012 ; Takenouchi et al, 2012 ; Nso-Roca et al, 2014 ; Mc Cormack et al, 2015 ; Fischetto et al, 2017 ; Heldt et al, 2018 ; Mercadante et al, 2020 ), and the boundaries largely overlap with seven of these previously published deletions (Menten et al, 2007 ; Buysse et al, 2009 ; Bibb et al, 2012 ; Takenouchi et al, 2012 ), with an SRO located in 12q14.3. Menten et al described three individuals, with a core phenotype of mild intellectual disability, low birth weight with failure to thrive in early infancy, proportionate short stature and osteopoikilosis (the latter is in combination with multiple subcutaneous nevi or nodules also known as Buschke-Ollendorf syndrome) (Hellemans et al, 2004 ).…”

“…In the 12q14 deletions discussed above HMGA2 was hypothesized to be causal for failure to thrive and short statures (Menten et al, 2007 ; Buysse et al, 2009 ; Bibb et al, 2012 ; Takenouchi et al, 2012 ). Mari et al ( 2009 ), Heldt et al ( 2018 ), and Mercadante et al ( 2020 ) described individuals with a clinical phenotype reminiscent to Silver-Russel syndrome, with deletions that included HMGA2 and a limited number of additional genes (Mari et al, 2009 ; Heldt et al, 2018 ; Mercadante et al, 2020 ). Smaller genetic alterations, solely affecting HMGA2 , including a 7bp deletion that affects splicing (De Crescenzo et al, 2015 ), a 7.3Kb deletion of exon 1 and 2 (Leszinski et al, 2018 ), other small deletions (Buysse et al, 2009 ), and missense and truncating variants have subsequently been found in Silver-Russel syndrome like cases (Abi Habib et al, 2018 ; Hübner et al, 2020 ), pinpointing HMGA2 as the causative gene.…”