Osteogenesis imperfecta is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI ... Osteogenesis imperfecta is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most forms of OI are autosomal dominant with mutations in one of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Glorieux et al. (2000) described a novel autosomal dominant form of OI, which they designated OI type V, in 7 patients. The disorder was similar to OI type IV but had distinctive clinical, histologic, and molecular characteristics. OI type V is characterized by calcification of the forearm interosseous membrane, radial head dislocation, a subphyseal metaphyseal radiodense line, and hyperplastic callus formation (summary by Cho et al., 2012).
Type V OI is moderately deforming and patients exhibit moderate to severe bone fragility of long bones and vertebral bodies. All type V patients (4 males and 3 females) described by Glorieux et al. (2000) had experienced fractures ... Type V OI is moderately deforming and patients exhibit moderate to severe bone fragility of long bones and vertebral bodies. All type V patients (4 males and 3 females) described by Glorieux et al. (2000) had experienced fractures in the first year of life and had a history of frequent fractures (3.2 +/- 2.3 fractures/year). None of the patients had blue sclerae or dentinogenesis imperfecta. Radiographically, the patients were characterized by 3 distinctive features: hyperplastic callus formation at fracture sites, calcification of the interosseous membrane between the radius and ulna, and the presence of a radioopaque metaphyseal band adjacent to the growth plates. Hyperplastic callus presents as a hard painful swelling over affected bone and was present in 4 patients. All 7 patients had limitation of pronation/supination in one or both forearms, which was associated with a radiologically apparent calcification of the interosseous membrane. Three patients had anterior dislocation of the radial head. One patient had an additional calcified interosseous membrane in the left lower leg. A radiodense metaphyseal band immediately adjacent to the growth plates was a constant feature in growing patients. The band was most clearly visible in the metaphyses of the distal femora, proximal tibias, and the distal radii. Other radiologic findings included flattened, wedge-shaped, or biconcave vertebrae and wormian bones of the skull. Lumbar spine bone mineral density was low and similar to age-matched patients with OI type IV. Histology of iliac biopsy specimens revealed that lamellae were arranged in an irregular mesh-like pattern distinct from normal lamellar organization. Levels of biochemical bone markers were generally within the reference range, but serum alkaline phosphatase and urinary collagen type I N-telopeptide excretion (NTx) increased during periods of active hyperplastic callus formation.
Cho et al. (2012) studied 19 Korean individuals with OI type V, including 13 affected individuals from 3 families and 6 simplex individuals. Cho et al. (2012) performed whole-exome sequencing in an affected simplex individual and 3 unaffected ... Cho et al. (2012) studied 19 Korean individuals with OI type V, including 13 affected individuals from 3 families and 6 simplex individuals. Cho et al. (2012) performed whole-exome sequencing in an affected simplex individual and 3 unaffected members of her family, and manually selected sequence variations (including those of the 5-prime and 3-prime UTRs and intron regions) unique to the proband. Among the variations located in the linked region of family 1, Cho et al. (2012) focused on a heterozygous change in the IFITM5 gene (c.-14C-T; 614757.0001). Sanger sequencing confirmed that this variation completely cosegregated with the disease in family 1. Furthermore, it was not found in 200 unrelated normal chromosomes from individuals with the same ethnic background. Cosegregation in the other 2 families (families 2 and 3) and de novo occurrence in the 5 other simplex individuals confirmed that this variation is a disease-causing mutation of OI type V. Semler et al. (2012) independently performed whole-exome sequencing in a female with OI type V and her unaffected parents and identified a heterozygous de novo mutation in the 5-prime UTR of IFITM5 (c.-14C-T). They subsequently identified the identical heterozygous de novo mutation in a second individual with OI type V by Sanger sequencing. Rauch et al. (2013) sequenced exon 1 of the IFITM5 gene in 42 patients with OI type V (ages, 2-67 years; 18 females) from 23 different families and identified the c.-14C-T mutation in all. Despite the presence of the same mutation, there was marked interindividual phenotypic variability. Indicators of disease severity varied widely: height z-scores in 38 patients ranged from -8.7 to -0.1, median -3.5; median final height was 147 cm in 15 men and 145 cm in 10 women; lumbar spine areal bone mineral density z-score in the absence of bisphosphonate treatment was between -7.7 and -0.7 in 29 men, median -5.3; scoliosis was present in 57% and vertebral compression fractures in 90% of all patients. Rauch et al. (2013) suggested that the IFITM5 mutation leads to a dysregulation of periosteal bone formation in addition to the bone formation deficit in trabecular bone. - Exclusion Studies Glorieux et al. (2000) screened the coding regions and exon/intron boundaries of both type I collagen genes (COL1A1 and COL1A2) in their patients and detected no mutations affecting glycine residues or splice sites.