Silver-Russell syndrome secondary to rare (epi)genotypes exhibits phenotypic heterogeneity challenging clinical diagnosis

We evaluated the suitability of SRS as an umbrella term for these (epi)genotypes by identifying key clinical features and assessing the validity of NH-CSS. An extensive literature search identified 22 IGF2, 18 HMGA2, 11 CDKN1C and 11 PLAG1 cases. Clinical phenotypes including the NH-CSS criteria were interrogated to assess (dis)similarity between the molecular subgroups of SRS. To understand the phenotypic differences in the six molecular subsets (11p15LOM, upd(7)mat, CDKN1C, IGF2, HMGA2 and PLAG1) we analysed both grouped and individual molecular causes. Grouped molecular cause analyses included comparisons between:
i) Common imprinted causes (11p15LOM and upd(7)mat)
ii) Imprinted monogenic causes (CDKN1C and IGF2) and
iii) Non-imprinted monogenic causes (HMGA2 and PLAG1)