Bone Fragility With Contractures, Arterial Rupture, And Deafness

A number sign (#) is used with this entry because the disorder is caused by mutation in the PLOD3 gene, which encodes lysyl hydroxylase-3 (603066).

Clinical Features

Salo et al. (2008) described a female proband with a novel connective tissue disorder secondary to lysyl hydroxylase-3 (LH3) deficiency. The patient was born to a nonconsanguineous couple of European descent. Pregnancy was complicated by intrauterine growth retardation. Craniofacial features included flat facial profile, simple, low-set ears, shallow orbits, short, upturned nose, and downturned corners of the mouth. Skeletal features included talipes equinovarus, progressive scoliosis, osteopenia, and several pathologic fractures. She was noted to have profound bilateral sensorineural deafness, myopia, and cataracts. Blistering occurred in her fingers and toes that healed without scarring. Her skin exhibited easy bruisability. In the second decade, spontaneous vascular ruptures occurred. A spontaneous cerebral arterial hemorrhage presented with hemiplegia, and a rupture of popliteal aneurysm presented with pain and swelling. A male sib was stillborn at 28 weeks' gestation. Intrauterine growth retardation complicated the pregnancy. Autopsy revealed a porencephalic cyst with dilation of the cerebral ventricles.

Biochemical Features

In their proband with a novel connective tissue disorder, Salo et al. (2008) analyzed urinary pyridinium collagen crosslinks and found absence of the disaccharide component of pyridinoline (Glc-Gal-PYD), which normally comprises approximately 15% of free pyridinoline crosslinks. The lack of glycosylated collagen crosslinks suggested a defect of an enzyme glycosylating hydroxylysine residue, for which the lysyl hydroxylase-3 gene was the prime candidate. The patient also had markedly reduced serum collagen glucosyltransferase (GGT) activity and decreased concentration of LH3 protein in lymphoblastoid cells.

Molecular Genetics

By analysis of LH3 cDNA in a patient with a connective tissue disorder and lysyl hydroxylase-3 deficiency, Salo et al. (2008) identified compound heterozygosity for 2 mutations: an asn223-to-ser (N223S) missense mutation (603066.0001) and a 1-bp deletion (2071delT; 603066.0002). The mutations occurred in conserved regions of the LH3 amino acid sequence responsible for GGT and lysyl hydroxylase activity.