Osteogenesis imperfecta is a connective tissue disorder characterized by bone fragility and low bone mass. OI type VII is an autosomal recessive form of severe or lethal OI (summary by Barnes et al., 2006).
Ward et al. (2002) reported the clinical, radiologic, and histologic features of 4 children (aged 3.9-8.6 years at last follow-up; all girls) and 4 adults (aged 28-33 years; 2 women) with a novel form of autosomal recessive OI. ... Ward et al. (2002) reported the clinical, radiologic, and histologic features of 4 children (aged 3.9-8.6 years at last follow-up; all girls) and 4 adults (aged 28-33 years; 2 women) with a novel form of autosomal recessive OI. All of the patients were identified in 2 generations of 3 interrelated families in the small First Nations community in northern Quebec. Multiple fractures were present at birth in all children. Recurrent fractures occurred in all patients but fracture frequency appeared to decrease after puberty. Sclerae were minimally bluish. Progressive deformities led to short stature and severe ambulatory restriction in 2 of the 4 adults. None of the patients had dentinogenesis imperfecta, hearing loss, or ligamentous laxity. Striking radiographic findings included rhizomelia and coxa vara in all affected patients. Histomorphometric analyses of the iliac crest revealed findings similar to OI type I (166200): decreased cortical width and trabecular number, increased bone turnover, and preservation of the birefringent pattern of lamellar bone. Barnes et al. (2006) identified 10 children who had lethal or severe osteogenesis imperfecta without primary collagen mutations but with excess posttranslational modification of type I collagen, indicative of delayed folding of the collagen helix. Three patients had a clinical presentation similar to that of infants with autosomal dominant perinatal lethal type II osteogenesis imperfecta (OI2; 166210), but with distinctive features. In patients with CRTAP deficiency owing to recessive mutation, the head circumference is small, the eyes show proptosis because of shallow orbits, and the sclerae are white or light blue; patients with type II osteogenesis imperfecta, caused by a structural collagen defect, have relative macrocephaly and dark blue sclerae. In recessive and dominant lethal osteogenesis imperfecta the bones are severely undermineralized and have multiple fractures prenatally, resulting in an abducted positioning of the legs. On radiography, the long bones in infants with CRTAP deficiency are characterized by a lack of diaphyseal modeling (undertubulation). In both type II and type VII, respiratory insufficiency causes early death.
In genomic DNA from an affected member of a large consanguineous Quebec family with OI type VII described by Ward et al. (2002), Morello et al. (2006) identified homozygosity for a mutation in the CRTAP gene (605497.0001). The ... In genomic DNA from an affected member of a large consanguineous Quebec family with OI type VII described by Ward et al. (2002), Morello et al. (2006) identified homozygosity for a mutation in the CRTAP gene (605497.0001). The CRTAP gene encodes cartilage-associated protein, which Morello et al. (2006) showed is required for prolyl 3-hydroxylation (see 610339) of fibrillar type I (see 120150) and II (see 120140) collagens. Morello et al. (2006) also studied a consanguineous family in which 4 pregnancies were affected with severe OI (short limbs and multiple fractures). The diagnosis of recurrent OI type II had been made based on the clinical features and the biochemical finding of type I collagen overmodification, but mutations in COL1A1 (120150) or COL1A2 (120160) could not be identified. Sequence analysis of CRTAP coding regions from DNA of 3 affected individuals detected a homozygous mutation (605497.0002). The parents were asymptomatic but carriers of the deletion. Biochemical and MS/MS analysis of collagen from cultured fibroblasts from the proband confirmed collagen overmodification and showed that the target proline was underhydroxylated. CRTAP protein could not be identified in fibroblasts from 1 affected individual. Real-time PCR performed on RNA extracted from cultured fibroblasts showed that they contained 10% of the amount seen in the OI type VII cells and about 1% of that seen in control cells. Barnes et al. (2006) investigated the CRTAP gene in patients with osteogenesis imperfecta without a primary collagen mutation. They found homozygous or compound heterozygous mutations in the CRTAP gene in 3 of the 10 patients (605497.0003-605497.0006). The affected infants had null mutations in both CRTAP alleles, low levels of CRTAP mRNA, a lack of CRTAP protein, and minimal prolyl 3-hydroxylation of type I collagen. Type I collagen had a normal primary structure but showed excess posttranslational modification of the alpha-chain helical region. Valli et al. (2012) reported a 7-year-old Egyptian boy with nonlethal OI type VII caused by a homozygous null mutation in the CRTAP gene (605497.0007). The mutation resulted in reduction of CRTAP transcript levels to approximately 10% of normal levels and undetectable CRTAP protein in fibroblasts. The abnormal posttranslational modification of the patient's type I collagen was typical for OI type VII, with alpha-1(I)pro986 3-hydroxylation reduced to 5% of normal, and full helical overmodification indicated by 40% hydroxylysine levels. By immunofluorescence of long-term cultures, Valli et al. (2012) also identified a severe deficiency (10-15% of control) of collagen deposited in extracellular matrix, with disorganization of the minimal fibrillar network. Quantitative pulse-chase experiments corroborated deficiency of matrix deposition, rather than increased matrix turnover. Valli et al. (2012) concluded that defects of extracellular matrix, as well as intracellular defects in collagen modification, contribute to the pathology of OI type VII. In affected members of 2 Saudi families with OI type VII, Shaheen et al. (2012) identified homozygous mutations in the CRTAP gene (605497.0004 and 605497.0008, respectively). The affected individuals displayed severe prenatal onset of fractures. The proband in 1 family died during the neonatal period. The proband in the other family had blue sclera and dentinogenesis imperfecta, with no hearing or other organ involvement; on bisphosphonate therapy, she had fewer fractures and bone density improvement.