Syndromic mental retardation with thrombocytopenia due to 21q22.11q22.12 deletion: Report of three patients

Abstract

During the last few years, an increasing number of microdeletion/microduplication syndromes have been delineated. This rapid evolution is mainly due to the availability of microarray technology as a routine diagnostic tool. Microdeletions of the 21q22.11q22.12 region encompassing the RUNX1 gene have been reported in nine patients presenting with syndromic thrombocytopenia and mental retardation. RUNX1 gene is responsible for an autosomal dominant platelet disorder with predisposition to acute myelogenous leukemia. We report on three novel patients with an overlapping "de novo" interstitial deletion involving the band 21q22 characterized by array-CGH. All our patients presented with severe developmental delay, dysmorphic features, behavioral problems, and thrombocytopenia. Comparing the clinical features of our patients with the overlapping ones already reported two potential phenotypes related to 21q22 microdeletion including RUNX1 were highlighted: thrombocytopenia with +/- mild dysmorphic features and syndromic thrombocytopenia with growth and developmental delay.

Fanconi anemia‐like presentation in an infant with constitutional deletion of 21q including the RUNX1 gene

“…With the availability of CMA analysis, more patients with subtle 21q deletions have been described, and a syndromic form of intellectual disability, growth delay, and thrombocytopenia has recently been described in subjects with a critical deletion interval spanning 21q22.11q22.12 including the RUNX1 gene [Hoyer et al, 2007;Beri-Dexheimer et al, 2008;Shinawi et al, 2008;Lyle et al, 2009;Katzaki et al, 2010;van der Crabben et al, 2010;Byrd et al, 2011;Thevenon et al, 2011]. Our patient appears to fit this phenotype and shares the findings of low birth weight, short stature, and microcephaly identified in several subjects.…”

“…With the availability of chromosomal microarray analysis (CMA), more patients have been identified, and fine mapping of several deletions has revealed the important finding of platelet abnormalities, especially thrombocytopenia, in a number of subjects, with increased risk of developing acute myelogenous leukemia (AML) [Shinawi et al, 2008;Katzaki et al, 2010;Lindstrand et al, 2010]. A syndromic appearance has been described in those with 21q22 microdeletions including the RUNX1 gene, with a combination of intellectual disability, dysmorphic features, and thrombocytopenia [Katzaki et al, 2010].…”

“…With the availability of chromosomal microarray analysis (CMA), more patients have been identified, and fine mapping of several deletions has revealed the important finding of platelet abnormalities, especially thrombocytopenia, in a number of subjects, with increased risk of developing acute myelogenous leukemia (AML) [Shinawi et al, 2008;Katzaki et al, 2010;Lindstrand et al, 2010]. A syndromic appearance has been described in those with 21q22 microdeletions including the RUNX1 gene, with a combination of intellectual disability, dysmorphic features, and thrombocytopenia [Katzaki et al, 2010]. The RUNX1 gene, also known as CBFA2 and AML1, has been implicated in this platelet phenotype, as individuals and families with point mutations and intragenic deletions of this gene are at risk for the dominant condition, Familial Platelet Disorder with Predisposition to AML (FPD/AML) [Arepally et al, 1998;Song et al, 1999;Michaud et al, 2002;Ganly et al, 2004;Osato, 2004;Kuo et al, 2009].…”

Familial myelodysplastic syndromes: a review of the literature

“…The clinical features of reported cases where descriptions of hematologic findings were available are summarized in Table 2. [28][29][30][31][32][33][34][35][36] All but one case 32 reported thrombocytopenia, with qualitative platelet defects described in 2 cases. 30,36 MDS/AML developed in 3 cases, with a median age of onset of six years (range 5-8 years).…”

“…38 Using bioinformatic analysis, Katzaki et al found that 4 out of 9 patients with overlapping deletions of 21q22 had a deletion of the miRNA miR-802. 34 However, 2 of the patients who developed MDS/AML were included in the analysis and both retained expression of miR-802. Therefore, the role of miRNAs in FPD/AML leukemogenesis is still not clear and further studies are required to clarify whether miR-802 influences the hematologic phenotype.…”