Proteoglycans is a component of extracellular matrix, forming a mesh around structural proteins including collagen and elastin, and providing elasticity to tissue structure. Proteoglycans is formed by the attachment of glycosaminoglycans to a core protein, a process that requires three enzymes: galactosyltransferase-1, galactosyltransferase-2 and glucoronosyltransferase-1, encoded by B4GALT7, B3GALT6 and B3GAT3 respectively. B3GALT6 mutations are associated with osteoporosis, but fractures have not previously been described in individuals with mutations in B4GALT7.
Male A presented at age 8 months with spontaneous rib fractures. He was born at term by elective caesarean section with no evidence of fractures at birth. Birth weight was 2.78 kg (−1.64 SDS). He developed severe gastrooesophageal reflux, faltering growth (length and weight −4.9 and −5.4 SDS respectively) and motor delay. His mother had multiple moderate impact fractures in childhood, but neither his father nor two half-siblings had fractured.
On examination, he was markedly hypotonic and unable to roll. He had little muscle bulk, but prominent subcutaneous fat. His sclerae were white. Other dysmorphic features included soft cleft palate, marked palgiocephaly and bilateral syndactyly of the second and third toes. A skeletal survey showed osteopenia, compression fractures of T12, L2 and L4 vertebrae and bilateral radioulnar synostosis. Novel compound heterozygous mutations in B4GALT7 (Cys214Tyr & 277dupC) were identified.
Prior to the genetic diagnosis, he commenced pamidronate at age 2.5 years due to increasing back pain requiring opioid analgesia and progression of vertebral collapse. After 1 year of treatment, improvement in pain and vertebral morphometry was evident. He has not sustained any long bone fractures.
Galactosyltransferase-1 deficiency is rare with only 26 previously reported cases. The phenotype is expanding, but common clinical features include short stature, hypermobility, and skeletal abnormalities including radioulnar synostosis. This is the first report of fractures in this disorder with multiple vertebral collapse fractures presenting prior to ambulation. Residual enzyme function varies by genotype, and it is postulated that these novel mutations might profoundly reduce galactosyltransferase-1 activity leading to the severe bone phenotype. This case highlights the need to consider defects of proteoglycans synthesis in individuals with fractures and short stature.
Disclosure: The authors declared no competing interests.
27 - 30 Jun 2015