Xq28 duplication presenting with intestinal and bladder dysfunction and a distinctive facial appearance

Abstract

Xq28 duplications encompassing MECP2 have been described in male patients with a severe neurodevelopmental disorder associated with hypotonia and spasticity, severe learning disability and recurrent pneumonia. We identified an Xq28 duplication in three families where several male patients had presented with intestinal pseudo-obstruction or bladder distension. The affected boys had similar dysmorphic facial appearances. Subsequently, we ascertained seven further families where the proband presented with similar features. We demonstrated duplications of the Xq28 region in five of these additional families. In addition to MECP2, these duplications encompassed several other genes already known to be associated with diseases including SLC6A8, L1CAM and Filamin A (FLNA). The two remaining families were shown to have intragenic duplications of FLNA only. We discuss which elements of the Xq28 duplication phenotype may be associated with the various genes in the duplication. We propose that duplication of FLNA may contribute to the bowel and bladder phenotype seen in these seven families.

Figure 1

Photograph of the proband from family 1 demonstrating extreme abdominal distension due to chronic intestinal pseudo-obstruction. This child also shows characteristic facial features with pinched nose and a prominent forehead.

Figure 2

Schematic representation of the Xq28 region to demonstrate the extent of the duplications in families 1–10. Families 1, 2, 3, 4, 5, 8 and 9 were analysed using MLPA with the PO15C and the PO49 kits. The regions covered by both of these are indicated at the top of the diagram in relation to the position of known genes within the Xq28 region. The MLPA results in the above families are shown, with filled blocks indicating the duplicated regions and open blocks indicating normal copy number. When repeated, the MLPA result in family 3 has suggested that some regions may be triplicated and others duplicated, and this is currently the subject of further investigation. Families 6, 7 and 10 were studied by array CGH using the Agilent 44B array at a resolution of approximately 100 Mb, and the extent of the duplications is shown in the lower part of the diagram. These varied in size, the largest being approximately 4 Mb (150.49–154.5), the intermediate 1.3 Mb (152–153.4) and the smallest 650 kb (152.5–153.13).

Figure 3

Composite of faces showing, from left to right, two siblings from family 1, one from family 2 and the proband from family 4. All demonstrate similar hypotonic facies, narrow nose, prominent forehead and deep-set eyes. The mouth and chin are relatively small and the skin is thin with visible veins.