Xp21 contiguous gene deletion syndrome presenting as Duchenne muscular dystrophy and glycerol kinase deficiency associated with intellectual disability: case report and review literature

Abstract

The contiguous gene deletion syndromes (CGDS) are rare genomic disorders resulting from the deletion of large segments of DNA, manifested as the concurrence of apparently unrelated clinical features. A typical example of CGDS is Xp21 contiguous gene deletion syndrome that involves GK and its neigh-boring genes (usually DMD and NR0B1) and results in a complex phenotype, which is related to the size of deletion and involved genes. Development delay and intellectual disability are almost a constant feature of patients with CGDS. We report the case of a boy with Duchenne muscular dystrophy (DMD) and glycerol kinase deficiency (GKD) as part of the contiguous gene deletion syndrome Xp2.1, in association with intellectual disability (ID) in whom multiplex ligation-dependent probe amplification (MLPA) test first identified a hemizygous deletion involving the entire dystrophin gene. Subsequently, the array CGH study identified a maternally inherited hemizygous deletion of the Xp21.2-Xp21.1 region of approximately 3.7Mb that included both DMD and GK genes confirming the diagnosis of Xp21 CGDS. Moreover, we report a review of the cases published in the literature over the last 20 years, for which a better description of the genes involved in the syndrome was available. Intellectual disability does not appear as a constant feature of the syndrome, reiterating the concept that complex GKD syndrome results from small deletions that affect closely related but separate loci for DMD, GK and adrenal hypoplasia, rather than a single large deletion including all genes. This case highlights the importance of more in-depth genetic investigations in presence of apparently unrelated clinical findings, allowing an accurate diagnosis of contiguous gene deletion syndromes.

Keywords: CGDS; DMD; GKD; IL1RAPL1; NR0B1; Xp21 contiguous gene deletion syndrome.

Figure 1.

Array 4x180K CGH analysis. The values of the positive or negative Log2 ratio (Y-axis) for each probe in this specific chromosome range (Xaxis) are represented by blue and red dots. The red bar corresponds to the deletion of about 3.7 Mb (hg19:ChrX:30615032-34345109), detected with 261 probes in our proband and his carrier mother. The wide deleted region includes the GK and DMD genes. Array CGH profiles shows: the hemizygous deletion in the proband (A) and the heterozygous deletion in his carrier mother (B)

Figure 2.

Gene map of region Xp21 on human X chromosome. The black box corresponds to the Xp21 contiguous gene deletion syndrome region, which includes twenty-three genes. The deletion identified in our proband can be visualized in the red box, which involves a region of 3.7 Mb (chrX:30,623,289-34,345,080) and encompasses DMD and GK genes. OMIM genes are in bold.