Alternative titles; symbols
SNOMEDCT: 205497004; ORPHA: 216820, 666; DO: 0110340;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q21.3 | Osteogenesis imperfecta, type IV | 166220 | Autosomal dominant | 3 | COL1A2 | 120160 |
| 17q21.33 | Osteogenesis imperfecta, type IV | 166220 | Autosomal dominant | 3 | COL1A1 | 120150 |
A number sign (#) is used with this entry because osteogenesis imperfecta type IV (OI4) is caused by heterozygous mutation in the COL1A1 gene (120150) or the COL1A2 gene (120160).
Osteogenesis imperfecta (OI) is a connective tissue disorder that is caused by an abnormality of type I collagen in over 90% of cases. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes: 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 sclera (259420); and OI type IV, with normal sclerae. Levin et al. (1978) suggested that OI subtypes could be further divided into types A and B based on the absence or presence of dentinogenesis imperfecta.
On the basis of a study in Australia, Sillence et al. (1979) concluded that in addition to dominantly inherited osteogenesis imperfecta with blue sclerae (OI type I) there is a variety with normal sclerae. This agreed with the distinction made by Bauze et al. (1975) and Francis et al. (1975) between 'blue-eyed' and 'white-eyed' OI, and supported by a biochemical difference. Sillence et al. (1979) found only 2 families with the 'white-eyed' type as contrasted with the many 'blue-eyed' families. They suggested that the family reported by Holcomb (1931) fell into the 'blue-eyed' category. Neither blue sclerae nor deafness was noted in the families reported by Ekman (1788) or by Lobstein (1835).
Johnson et al. (2002) reported a 35-year-old woman and 2 of her children with what the authors termed a 'variant' of OI type IVB. The woman had shown shortening of the limbs with severe angular malformations of the femora at birth. From 3 months to 1 year, her legs were maintained in plaster casts, which slightly improved the bowing. After starting to walk, her lower limbs showed significant improvement that lasted throughout adulthood. She had pale blue sclerae, which can occur in up to 10% of cases of OI type IV, easy bruising, 3 broken bones in her lifetime, recent development of lumbar spondylolisthesis, and dentinogenesis imperfecta. A son and daughter were shown to be severely affected during gestation. Johnson et al. (2002) noted that the proband had originally been classified as having kyphomelic dysplasia (211350), but molecular analysis showed a mutation in the COL1A2 gene (120160.0050).
From the cultured skin fibroblasts in a patient with type IV OI, Wenstrup et al. (1986) found that 2 populations of type I procollagen molecules were synthesized. The total amount of type I procollagen and the ratio of alpha-1 to alpha-2 chains were normal. The difference was shown to be due to excessive posttranslational modification in the case of one molecule. It appeared, furthermore, that incorporation of an abnormal chain into the triple helix resulted in excessive modification of all three chains; whether the alpha-1 or the alpha-2 chain was the site of mutation was not identified. The change was thought to involve the COOH-propeptide of the molecule. The biochemical abnormality had been found previously only in perinatal lethal OI type II. In a large kindred in which linkage studies indicated abnormality of the alpha-2 chain of type 1 collagen, Wenstrup et al. (1986) found that fibroblasts from 2 affected persons synthesized 2 populations of alpha-2 chains: one normal population and one with a deletion of about 10 amino acids from the middle of the triple helical domain.
Byers et al. (2006) published practice guidelines for the genetic evaluation of suspected OI.
Prenatal Diagnosis
In a family with type IV OI genetically linked to the COL1A2 gene, Tsipouras et al. (1987) showed by linkage analysis that a fetus was unaffected, having inherited the normal COL1A2 allele from her affected parent.
De Vos et al. (2000) reported the achievement of healthy twins by preimplantation genetic diagnosis in a couple in which the male partner carried a G-to-A substitution in exon 19 of the COL1A2 gene which resulted in a gly247-to-ser (G247S) missense change.
Plotkin et al. (2000) studied 9 severely affected OI patients under 2 years of age (2.3 to 20.7 months at entry), 8 of whom had type III OI and 1 of whom had type IV OI, for a period of 12 months. Pamidronate was administered intravenously in cycles of 3 consecutive days. Patients received 4 to 8 cycles during the treatment period, with cumulative doses averaging 12.4 mg/kg. Clinical changes were evaluated regularly during treatment, and radiologic changes were assessed after 6 to 12 months of treatment. The control group consisted of 6 age-matched, severely affected OI patients who had not received pamidronate treatment. During treatment bone mineral density (BMD) increased between 86% and 227%. The deviation from normal, as indicated by the z-score, diminished from -6.5 +/- 2.1 to -3.0 +/- 2.1 (P less than 0.001). In the control group, the BMD z-score worsened significantly. Vertebral coronal area increased in all treated patients (11.4 +/- 3.4 to 14.9 +/- 1.8 cm2; P less than 0.001), but decreased in the untreated group (P less than 0.05). In the treated patients, fracture rate was lower than in control patients (2.6 +/- 2.5 vs 6.3 +/- 1.6 fractures/year; P less than 0.01). No adverse side effects were noted, apart from the well-known acute phase reaction during the first infusion cycle. The authors concluded that pamidronate treatment in severely affected OI patients under 3 years of age is safe, increases BMD, and decreases fracture rate.
Astrom and Soderhall (2002) performed a prospective observational study using disodium pamidronate (APD) in 28 children and adolescents (aged 0.6 to 18 years) with severe OI or a milder form of the disease, but with spinal compression fractures. All bone metabolism variables in serum (alkaline phosphatase, osteocalcin, procollagen-1 C-terminal peptide, collagen-1 teleopeptide) and urine (deoxypyridinoline) indicated that there was a decrease in bone turnover. All patients experienced beneficial effects, and the younger patients showed improvement in well-being, pain, and mobility without significant side effects. Vertebral remodeling was also seen. They concluded that APD seemed to be an efficient symptomatic treatment for children and adolescents with OI.
Rauch et al. (2002) compared parameters of iliac bone histomorphometry in 45 patients (23 girls, 22 boys) with OI type I, III, or IV before and after 2.4 +/- 0.6 years of treatment with cyclical intravenous pamidronate (age at the time of the first biopsy, 1.4 to 17.5 years). There was an increase in bone mass due to increases in cortical width and trabecular number. The bone surface-based indicators of cancellous bone remodeling, however, were decreased. There was no evidence of a mineralization defect in any of the patients.
Lindsay (2002) reviewed the mechanism, effects, risks, and benefits of bisphosphonate therapy in children with OI. He stated that the clinical course and attendant morbidity for many children with severe OI is clearly improved with its judicious use. Nevertheless, since bisphosphonates accumulate in the bone and residual levels are measurable after many years, the long-term safety of this approach was unknown. He recommended that until long-term safety data were available, pamidronate intervention be reserved for those for whom the benefits clearly outweighed the risks.
Rauch et al. (2003) evaluated the effect of intravenous therapy with pamidronate on bone and mineral metabolism in 165 patients with OI types I, III, and IV. All patients received intravenous pamidronate infusions on 3 successive days, administered at age-dependent intervals of 2 to 4 months. During the 3 days of the first infusion cycle, serum concentrations of ionized calcium dropped and serum PTH levels transiently almost doubled. Two to 4 months later, ionized calcium had returned to pretreatment levels. During 4 years of pamidronate therapy, ionized calcium levels remained stable, but PTH levels increased by about 30%. In conclusion, serum calcium levels can decrease considerably during and after pamidronate infusions, requiring close monitoring especially at the first infusion cycle. In long-term therapy, bone turnover is suppressed to levels lower than those in healthy children. The authors stated that the consequences of chronically low bone turnover in children with OI were unknown.
Zeitlin et al. (2003) analyzed longitudinal growth during cyclical intravenous pamidronate treatment in children and adolescents (ages 0.04 to 15.6 years at baseline) with moderate to severe forms of OI types I, III, and IV and found that 4 years of treatment led to a significant height gain.
Rauch et al. (2006) studied the effect of pamidronate discontinuation in pediatric patients with moderate to severe OI types I, III, and IV. In the controlled study, 12 pairs of patients were matched for age, OI severity, and duration of pamidronate treatment. Pamidronate was stopped in one patient of each pair; the other continued to receive treatment. In the observational study, 38 OI patients were examined (mean age, 13.8 years). The intervention was discontinuation of pamidronate treatment for 2 years. The results indicated that bone mass gains continue after treatment is stopped, but that lumbar spine aBMD increases less than in healthy subjects. The size of these effects is growth dependent.
In a cohort of 540 individuals with OI studied longitudinally, Bellur et al. (2016) conducted a study to address whether cesarean delivery has an effect on at-birth fracture rates and whether an antenatal diagnosis of OI influences the choice of delivery method. They compared self-reported at-birth fracture rates among individuals with OI types I (166200), III (259420), and IV. When accounting for other covariates, at-birth fracture rates did not differ based on whether delivery was vaginal or by cesarean section. Increased birth weight conferred conferred higher risk for fractures irrespective of the delivery method. In utero fracture, maternal history of OI, and breech presentation were strong predictors for choosing cesarean delivery. The authors recommended that cesarean delivery should not be performed for the sole purpose of fracture prevention in OI, but only for other maternal or fetal indications.
To study 10 families with mild OI, Tsipouras et al. (1985) used 3 RFLPs associated with the alpha-2(I) collagen gene (COL1A2) known to be on chromosome 7. The 4 families with type IV OI showed tight linkage: maximum lod = 3.91 at theta 0.0. The 6 OI type I families showed very low positive lod scores at high values of theta. Reporting on the same study, Falk et al. (1986) found linkage between type IV OI and RFLPs of the alpha-2(I) procollagen gene.
Kamoun-Goldrat et al. (2008) described a father and son from a consanguineous Algerian family who had typical features of OI type IV but an improving course of the disease: severe modification of the long bones with complete improvement during growth. Both had blue sclerae and the son had dentinogenesis imperfecta. The disorder did not segregate with the COL1A1 or COL1A2 genes, no mutations in the coding sequences of these genes were identified by DHLPC analysis and cDNA sequencing, and Northern blot analysis did not indicate quantitative or qualitative abnormalities in collagen I mRNAs. Sequencing showed no evidence of alterations in the CRTAP (605497) gene, and father and son were heterozygous for markers surrounding the LEPRE1 gene (610339). Kamoun-Goldrat et al. (2008) identified a region of high concordance of homozygosity between markers D11S4127 and D11S4094 on chromosome 11q23.3-q24.1 in the father and son.
In a child with OI type IV, Marini et al. (1989) identified a mutation in the COL1A1 gene (120150.0012). See also de Vries and de Wet (1986) and 120150.0003.
In a patient with OI type IV, Wenstrup et al. (1988) identified a mutation in the COL1A2 gene (120160.0004), which resulted in increased posttranslational modification along the triple-helical domain.
Astrom, E., Soderhall, S. Beneficial effect of long term intravenous bisphosphonate treatment of osteogenesis imperfecta. Arch. Dis. Child. 86: 356-364, 2002. [PubMed: 11970931] [Full Text: https://doi.org/10.1136/adc.86.5.356]
Bauze, R. J., Smith, R., Francis, M. J. O. A new look at osteogenesis imperfecta. J. Bone Joint Surg. Br. 57: 2-12, 1975. [PubMed: 1117018]
Bellur, S., Jain, M., Cuthbertson, D., Krakow, D., Shapiro, J. R., Steiner, R. D., Smith, P. A., Bober, M. B., Hart, T., Krischer, J., Mullins, M., Byers, P. H., Pepin, M., Durigova, M., Glorieux, F. H., Rauch, F., Sutton, V. R., Lee, B., Members of the BBD Consortium, Nagamani, S. C. Cesarean delivery is not associated with decreased at-birth fracture rates in osteogenesis imperfecta. Genet. Med. 18: 570-576, 2016. [PubMed: 26426884] [Full Text: https://doi.org/10.1038/gim.2015.131]
Byers, P. H., Krakow, D., Nunes, M. E., Pepin, M. Genetic evaluation of suspected osteogenesis imperfecta (OI). Genet. Med. 8: 383-388, 2006. [PubMed: 16778601] [Full Text: https://doi.org/10.1097/01.gim.0000223557.54670.aa]
De Vos, A., Sermon, K., Van de Velde, H., Joris, H., Vandervorst, M., Lissens, W., De Paepe, A., Liebaers, I., Van Steirteghem, A. Two pregnancies after preimplantation genetic diagnosis for osteogenesis imperfecta type I and type IV. Hum. Genet. 106: 605-613, 2000. [PubMed: 10942108] [Full Text: https://doi.org/10.1007/s004390000298]
de Vries, W. N., de Wet, W. J. The molecular defect in an autosomal dominant form of osteogenesis imperfecta: synthesis of type I procollagen containing cysteine in the triple-helical domain of pro-alpha-1(I) chains. J. Biol. Chem. 261: 9056-9064, 1986. [PubMed: 3722186]
Ekman, O. J. Descriptionem casus aliquot osteomalacia sistens. Uppsala: Dissertatio Medica. 1788.
Falk, C. T., Schwartz, R. C., Ramirez, F., Tsipouras, P. Use of molecular haplotypes specific for the human pro-alpha-2(I) collagen gene in linkage analysis of the mild autosomal dominant forms of osteogenesis imperfecta. Am. J. Hum. Genet. 38: 269-279, 1986. [PubMed: 3006479]
Francis, M. J. O., Bauze, R. J., Smith, R. Osteogenesis imperfecta: a new classification. Birth Defects Orig. Art. Ser. XI(6): 99-102, 1975. [PubMed: 1201359]
Holcomb, D. Y. A fragile-boned family: hereditary fragilitas ossium. J. Hered. 22: 105-115, 1931.
Johnson, M. T., Morrison, S., Heeger, S., Mooney, S., Byers, P. H., Robin, N. H. A variant of osteogenesis imperfecta type IV with resolving kyphomelia is caused by a novel COL1A2 mutation. J. Med. Genet. 39: 128-132, 2002. [PubMed: 11836364] [Full Text: https://doi.org/10.1136/jmg.39.2.128]
Kamoun-Goldrat, A., Pannier, S., Huber, C., Finidori, G., Munnich, A., Cormier-Daire, V., Le Merrer, M. A new osteogenesis imperfecta with improvement over time maps to 11q. Am. J. Med. Genet. 146A: 1807-1814, 2008. [PubMed: 18553516] [Full Text: https://doi.org/10.1002/ajmg.a.32379]
Levin, L. S., Salinas, C. F., Jorgenson, R. J. Classification of osteogenesis imperfecta by dental characteristics. (Letter) Lancet 311: 332-333, 1978. Note: Originally Volume I. [PubMed: 75372] [Full Text: https://doi.org/10.1016/s0140-6736(78)90108-3]
Lindsay, R. Modeling the benefits of pamidronate in children with osteogenesis imperfecta. J. Clin. Invest. 110: 1239-1241, 2002. [PubMed: 12417561] [Full Text: https://doi.org/10.1172/JCI17051]
Lobstein, J. G. C. F. M. Lehrbuch der pathologischen Anatomie. Stuttgart: Bd II (pub.) 1835. P. 179.
Marini, J. C., Grange, D. K., Gottesman, G. S., Lewis, M. B., Koeplin, D. A. Osteogenesis imperfecta type IV: detection of a point mutation in one alpha-1(I) collagen allele (COL1A1) by RNA/RNA hybrid analysis. J. Biol. Chem. 264: 11893-11900, 1989. [PubMed: 2745420]
Plotkin, H., Rauch, F., Bishop, N. J., Montpetit, K., Ruck-Gibis, J., Travers, R., Glorieux, F. H. Pamidronate treatment of severe osteogenesis imperfecta in children under 3 years of age. J. Clin. Endocr. Metab. 85: 1846-1850, 2000. [PubMed: 10843163] [Full Text: https://doi.org/10.1210/jcem.85.5.6584]
Rauch, F., Munns, C., Land, C., Glorieux, F. H. Pamidronate in children and adolescents with osteogenesis imperfecta: effect of treatment discontinuation. J. Clin. Endocr. Metab. 91: 1268-1274, 2006. [PubMed: 16434452] [Full Text: https://doi.org/10.1210/jc.2005-2413]
Rauch, F., Plotkin, H., Travers, R., Zeitlin, L., Glorieux, F. H. Osteogenesis imperfecta types I, III, and IV: effect of pamidronate therapy on bone and mineral metabolism. J. Clin. Endocr. Metab. 88: 986-992, 2003. [PubMed: 12629073] [Full Text: https://doi.org/10.1210/jc.2002-021371]
Rauch, F., Travers, R., Plotkin, H., Glorieux, F. H. The effects of intravenous pamidronate on the bone tissue of children and adolescents with osteogenesis imperfecta. J. Clin. Invest. 110: 1293-1299, 2002. [PubMed: 12417568] [Full Text: https://doi.org/10.1172/JCI15952]
Sillence, D. O., Senn, A., Danks, D. M. Genetic heterogeneity in osteogenesis imperfecta. J. Med. Genet. 16: 101-116, 1979. [PubMed: 458828] [Full Text: https://doi.org/10.1136/jmg.16.2.101]
Tsipouras, P., Sangiorgi, F. O., Chu, M.-L., Weil, D., Schwartz, R. C., Ramirez, F. DNA markers associated with the human procollagen genes. (Abstract) Cytogenet. Cell Genet. 40: 762-763, 1985.
Tsipouras, P., Schwartz, R. C., Goldberg, J. D., Berkowitz, R. L., Ramirez, F. Prenatal prediction of osteogenesis imperfecta (OI type IV): exclusion of inheritance using a collagen gene probe. J. Med. Genet. 24: 406-409, 1987. [PubMed: 2886666] [Full Text: https://doi.org/10.1136/jmg.24.7.406]
Wenstrup, R. J., Cohn, D. H., Cohen, T., Byers, P. H. Arginine for glycine substitution in the triple-helical domain of the products of one alpha-2(I) collagen allele (COL1A2) produces the osteogenesis imperfecta type IV phenotype. J. Biol. Chem. 263: 7734-7740, 1988. [PubMed: 2897363]
Wenstrup, R. J., Hunter, A. G. W., Byers, P. H. Osteogenesis imperfecta type IV: evidence of abnormal triple helical structure of type I collagen. Hum. Genet. 74: 47-53, 1986. [PubMed: 3759085] [Full Text: https://doi.org/10.1007/BF00278784]
Wenstrup, R. J., Tsipouras, P., Byers, P. H. Osteogenesis imperfecta type IV: biochemical confirmation of genetic linkage to the pro-alpha-2(1) gene of type I collagen. J. Clin. Invest. 78: 1449-1455, 1986. [PubMed: 3782466] [Full Text: https://doi.org/10.1172/JCI112735]
Zeitlin, L., Rauch, F., Plotkin, H., Glorieux, F. H. Height and weight development during four years of therapy with cyclical intravenous pamidronate in children and adolescents with osteogenesis imperfecta types I, III, and IV. Pediatrics 111: 1030-1036, 2003. [PubMed: 12728084] [Full Text: https://doi.org/10.1542/peds.111.5.1030]