AB168. Novel DYM compound heterozygous mutations in a Malaysian boy with Dyggve-Melchior-Clausen syndrome

Background: Dyggve-Melchior-Clausen (DMC) syndrome and Smith-McCort Dysplasia (SMC) are rare, progressive, autosomal recessive skeletal dysplasias caused by mutations in the Dymeclin (DYM) gene, mapped to chromosome 18q21.1. These are allelic disorders and share many features including short stature, a barrel-shaped chest, platyspondyly, abnormalities of the epiphyses and metaphyses, and a distinctive lacy appearance of the iliac crest. The distinguishing feature is that individuals with DMC have intellectual disabilities whereas SMC is associated with normal intelligence.

Case presentation: We present a 6-year-old Malaysian boy, the elder of two children born to a non-consanguineous Chinese couple. He was a term baby but was small and short for gestational age at birth. He initially presented to the paediatric endocrinologist for concerns of short stature and was subsequently referred prior to the age of three for suspicion of mucopolysaccharidosis (MPS) from his vertebral radiological findings. Clinical evaluation revealed that he had short stature, microcephaly and prominent pectus carinatum. He had normal early developmental milestones but on follow-up, it became obvious he had learning difficulties with expressive speech delay. His skeletal radiographs showed platyspondyly with a double hump and anterior breaking, broad ribs, widened metacarpals, abnormally shaped femoral heads and lacy crests of the iliac wings. Molecular testing of the DYM gene identified novel compound heterozygous mutations—a deletion c.242_249del8 in exon 4 was inherited from his father and a single nucleotide duplication c.1917dupT in exon 17 was inherited from his mother. Both these mutations cause a frameshift and result in aberrant mRNA processing. The parents are therefore heterozygous carriers. Our patient was initially thought to have Smith-McCort dysplasia SMC but his diagnosis had since been revised to DMC when it became evident he had speech delay and was faltering with his learning from the age of four. This diagnosis would also seem to be more in keeping with his genotypic change. A formal psychometric assessment was planned to evaluate his intelligence more objectively.

Conclusions: We wish to highlight the phenotypic and radiological features of this rare entity and the role of molecular testing. It is important to remember that certain other disorders especially Morquio A (MPS type IVA) may mimic this condition on vertebral radiological changes. Diagnosis confirmation with finding the DYM mutations not only allows for accurate genetic counselling and prenatal testing, but also directs one to be vigilant for potential life-threatening complications in this disorder like atlanto-axial instability.

Keywords: DYMeclin (DYM); skeletal dysplasia; 18q21.1; short stature