Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. Osteogenesis imperfecta type VI is a severe autosomal recessive form of the disorder ... Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. Osteogenesis imperfecta type VI is a severe autosomal recessive form of the disorder (Glorieux et al., 2002; Becker et al., 2011).
Glorieux et al. (2002) described a novel form of OI, which they designated OI type VI, in 8 patients (6 males). None of the patients, all of whom had earlier been diagnosed with OI type IV (166220) (Ward ... Glorieux et al. (2002) described a novel form of OI, which they designated OI type VI, in 8 patients (6 males). None of the patients, all of whom had earlier been diagnosed with OI type IV (166220) (Ward et al., 2000), had documented fractures at birth. Fractures were first documented between ages 4 and 18 months. Type VI OI patients sustained more frequent fractures than patients with OI type IV, which led to long bone deformity in 7 of the patients. Ligamentous laxity was present in 4 of the patients. Sclerae were white or faintly blue and teeth were normal. Radiologic findings included long bone deformity, coxa vara, and protrusio acetabuli. The vertebrae were wedge-shaped or biconcave. All patients had vertebral compression fractures. Wormian bones of the skull were absent. Lumbar spine bone mineral density (aBMD) was low and similar to age-matched patients with OI type IV. Two brothers, born to consanguineous parents, were unusual in that they showed severe osteopenia, bulbous metaphyses, and severe limb deformity. Histology of iliac biopsy specimens revealed a distinctive 'fish-scale' pattern of the lamellae. Another distinctive feature was the presence of excessive osteoid. Glorieux et al. (2002) concluded that the hyperosteoidosis points toward a defect in mineralization. Levels of biochemical bone markers were generally within the reference range but serum alkaline phosphatase levels were elevated compared to the levels in patients with OI type IV. Becker et al. (2011) described 4 affected individuals from 3 unrelated consanguineous families with a severe form of OI, which the authors stated was compatible with OI type III in the Sillence classification (see 259420). No intrauterine fractures were reported, and birth length and weight were normal. Dentinogenesis imperfecta was not present, and the sclerae were grayish. All 4 individuals had fractures of long bones and severe vertebral compression fractures, with resulting deformities observed as early as the first year of life. Bone mineral density was severely reduced. All had short stature and were wheelchair bound.
Becker et al. (2011) applied next-generation sequencing and identification of homozygous regions to analyze the exome of a single male individual, the offspring of consanguineous parents, who had a severe form of OI. They identified a homozygous truncating ... Becker et al. (2011) applied next-generation sequencing and identification of homozygous regions to analyze the exome of a single male individual, the offspring of consanguineous parents, who had a severe form of OI. They identified a homozygous truncating mutation in the SERPINF1 gene (172860.0001), which was also found in his affected brother. Their parents and 2 unaffected sisters were heterozygous carriers. Becker et al. (2011) also identified homozygosity for different truncating SERPINF1 mutations in 2 unrelated Turkish patients with severe OI (172860.0002-172860.0003). Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion. In affected members of 3 Saudi families with OI, Shaheen et al. (2012) identified homozygous mutations in the SERPINF1 gene (172860.0004-172860.0006). All of those affected had early childhood onset of fractures, and affected individuals in 2 families had blue sclera. There was no apparent involvement of the teeth or other organs. All responded well to bisphosphonate therapy. - Exclusion Studies Glorieux et al. (2002) screened both type I collagen genes (COL1A1 and COL1A2) using cDNA and genomic DNA and detected no mutations in their patients.