Monosomy 21q22.11‐q22.13 presenting as a Fanconi anemia phenotype

Abstract

We report on a 5-year-old Caucasian female with multiple anomalies whose deletion, 46,XX,del(21)(q22.11q22.13), was determined by a 105K oligonucleotide-based microarray. This case is a unique deletion that mimicked Fanconi anemia (combination of thrombocytopenia, thumb anomalies, congenital heart defects, borderline small head circumference, strabismus, hydronephrosis, and significant developmental delay) but testing for Fanconi anemia was negative, as was testing for a wide array of genetic/metabolic conditions. Microarray testing done at 5 months failed to demonstrate the interstitial deletion that was found on a newer generation microarray test performed after 3 years of age. When compared to other reported cases of partial monosomy 21q, the unique features of this case include: (1) cleft palate, although high palate is reported in other cases; (2) neonatal thrombocytopenia requiring platelet transfusion; (3) a platelet function defect, reported previously as platelet storage pool defect as part of a familial platelet disorder; and (4) an immune function defect. Similar to other reported patients with terminal 21q deletion, this child had significant developmental delay, and feeding and growth problems. This case also highlights the ability for newer technology microarrays to identify small interstitial deletions previously missed by an earlier version microarray. The advances in the microarray technologies are allowing us to better define new phenotypes and leading to the identification of a diagnosis for many patients who have been previously undiagnosed. Review of the genes involved in these novel deletions allows the caring physician to design surveillance strategies that are custom-designed for these unique patients.

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.…”

“…At least one report has implicated deletion of the ITSN1 gene as critical for the association with intellectual impairment [Beri-Dexheimer et al, 2008], and others have implicated DSCR1 (RCAN1), and CLIC6 [Shinawi et al, 2008], but deletion of genes such as OLIG1 and OLIG2 may also be important contributors to the cognitive phenotype [Pritchard et al, 2008], as recent studies suggest that dosage of these genes is critical and their triplication may account for the neurological phenotype in murine models of Down syndrome [Chakrabarti et al, 2010]. Of note, cardiac malformations have been described in a subset of patients with 21q22 deletions encompassing RUNX1, including one with tetalogy of Fallot [Lindstrand et al, 2010] like our patient, one with transposition of the great vessels [Shinawi et al, 2008], four with an atrial septal defect [Beri-Dexheimer et al, 2008;Katzaki et al, 2010;Byrd et al, 2011;Thevenon et al, 2011], and three with unclassified heart defects [Yao et al, 2006;Lyle et al, 2009]. Several subjects have demonstrated corpus callosum dysgenesis (not apparent in our patient), which in combination with thrombocytopenia, intellectual disability, and dysmorphic features, has been termed the Braddock-Carey syndrome [Braddock and Carey, 1994;Thevenon et al, 2011].…”

“…The platelet abnormalities in many subjects with partial or complete monosomy 21 have demonstrated thrombocytopenia [Abeliovich et al, 1979;Huret et al, 1995;Huret and Leonard, 1997], and recurrent deletion of RUNX1 has emerged in the available case reports of patients with del21q and thrombocytopenia, some of whom also demonstrate qualitative platelet function defects [Shinawi et al, 2008;Katzaki et al, 2010;Lindstrand et al, 2010;Byrd et al, 2011;Thevenon et al, 2011;van der Crabben et al, 2010]. RUNX1 encodes one component of a heterodimeric transcription factor essential for normal hematopoietic development [Okuda et al, 1996;Wang et al, 1996].…”

Familial myelodysplastic syndromes: a review of the literature

“…[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). This median age is much lower than that of traditional FPD/AML and suggests that other genes within the 21q22 locus may also be important in leukemogenesis.…”

Case Report: Interstitial Deletion 21q22.13-Q22.3 in a Male Patient with Developmental Delay, Holoprosencephaly, Dysmorphic Features, and Multiple Congenital Anomalies

“…This gene encodes a cell adhesion molecule and is expressed in the heart during cardiac development and was proposed as a candidate gene for Down syndrome and congenital heart disease (DS-CHD) [27]. Congenital heart defect in the form of (VSD) was observed in our patient, and in other reported cases, however they reported deleted segment in more proximal region between (30,02-37,55Mb) [12,28] and (34,796 and 35,363) [9] including genes CLIC6 and RUNX1. Lindstrand [9] suggested that a critical region of 0.5 Mb between 34,796 and 35,363 including CLIC6 and RUNX1 and another 2 genes is associated with congenital heart disease, however, this region has shown duplication in our patient which might indicate different mechanism in causing heart defect.…”