ESPE Yearbook of Paediatric Endocrinology

Brief Summary: Two Japanese children with Silver Russell Syndrome (SRS) are reported, one with a de novo pathogenic frameshift sequence variant (Case 1) and the other with a 3.4 MB de novo microdeletion (Case 2) in HMGA2 (High Mobility Group AT-hook 2; OMIM *600,698). Both genetic findings meet the criteria established by the ACMG/AMP¹. Case 1 had 5 of 6 (no body asymmetry) and Case 2 had 4 of 6 (no prominent forehead or body asymmetry) of the Netchine-Harbison criteria for SRS. A literature review suggested that patients with HMGA2 mutations may have more severe features of SRS, compared to children with SRS due to PLAG1 mutations, IGF2 intragenic sequence variants or H19/IGF2:IG-DMR epimutations.

HMGA2 is a transcription factor gene on chromosome 12q14.3 that increases expression of both IGF2 and PLAG1. In turn, PLAG1 enhances IGF2 expression. HMGA2 plays a critical role in fetal growth, and common variants have been associated with child and adult height². When expressed in adult cells, HMGA2 is an oncoprotein and is highly expressed in various human cancers, serving as a prognostic marker³.

Their literature search revealed 24 patients with 21 different HMGA2 intragenic sequence variants/microdeletions and 23 patients with 18 different HMGA2 microdeletions ranging from 1.35 -10.12 Mb (group 1 and group 2 for comparisons, respectively). Group 1 tended to have more frequent SRS features, whereas cleft palate and micrognathia were more frequent in group 2 suggesting that disruption of multiple genes can attenuate the SRS phenotype. Intellectual disability is more frequent in group 2, and osteopoikilosis (hyperostotic areas near articulations) is exclusively seen in group 2.

The authors suggest a possible gene dosage effect of HMGA2 since most are heterozygous, whereas homozygous patients are more severely affected with short stature compared to their carrier parents. The microdeletion in their patient was paternally inherited and published cases were due to maternally inherited sequence variants or maternal familial microdeletions. Therefore, it is unlikely that defective imprinting of HMGA2 is involved. Indeed, HMGA2 is not an imprinted human locus according to the online database Geneimprint, nor imprinted in any reported mouse models⁴.

The SRS phenotype is similar but more severe in patients with HMGA2 sequence variants than those with PLAG1 sequence variants (N=11). This is likely due to a greater disruption of IGF2 expression. Both are less frequent causes of SRS than IGF2 intragenic sequence variants (N=14) and H19/IGF2:IG-DMR epimutations (N=226).

References: 1. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May; 17(5): 405–424. doi: 10.1038/gim.2015.30.2. Weedon MN, Lettre G, Freathy RM, Lindgren CM, Voight BF, Perry JR, Elliott KS, Hackett R, Guiducci C, Shields B, Zeggini E, Lango H, Lyssenko V, Timpson NJ, Burtt NP, Rayner NW, Saxena R, Ardlie K, Tobias JH, Ness AR, Ring SM, Palmer CN, Morris AD, Peltonen L, Salomaa V; Diabetes Genetics Initiative; Wellcome Trust Case Control Consortium; Davey Smith G, Groop LC, Hattersley AT, McCarthy MI, Hirschhorn JN, Frayling TM. A common variant of HMGA2 is associated with adult and childhood height in the general population. Nat Genet. 2007 Oct;39(10):1245-50. doi: 10.1038/ng2121.3. Zhang S, Mo Q, Wang X. Oncological role of HMGA2 (Review). Int J Oncol. 2019 Oct;55(4):775-788. doi: https://doi.org/10.3892/ijo.2019.4856.4. Geneimprint (http://www.geneimprint.com/ or http://www.geneimprint.org/), Copyright © 2024, Randy L. Jirtle, PhD.