Osteogenesis Imperfecta, Type Iii

A number sign (#) is used with this entry because osteogenesis type III (OI3) is caused by heterozygous mutation in one of the genes for type I collagen, COL1A1 (120150) or COL1A2 (120160).

Clinical Features

In Victoria, Australia, Sillence et al. (1979) found type III OI to be about one-eighth as frequent as dominantly inherited OI with blue sclerae. Scleral hue, which may be bluish at birth, usually normalizes with age. Patients reported in the literature with normal sclerae have shown progressive deformity of the limbs in childhood and of the spine in late childhood and adolescence. Dentinogenesis imperfecta is particularly striking, especially in the primary dentition. Sillence et al. (1979) observed 2 families with consanguineous parents. Some of the cases referenced in 166210 presumably represent this type.

Peltonen et al. (1980) studied procollagen synthesis by fibroblasts from a male patient who died at age 18 years after a fall from his wheelchair. He was born with multiple fractures. He had blue sclerae, but normal dentition. He developed severe kyphoscoliosis and multiple limb deformities. Whether this represented Sillence's type III OI or new mutation for Sillence's type I OI (166200) was not clear. When fibroblasts were incubated with tritiated-mannose, type I procollagen contained 2 to 3 times more labeled-mannose than that from normal fibroblasts, although type III procollagen produced simultaneously by the patient's fibroblasts was not abnormal. The type I collagen synthesized by the patient's fibroblasts was secreted into the medium abnormally slowly. The patient's procollagen formed insoluble aggregates with abnormal facility. The findings were interpreted as indicating an amino acid change, presumably in the COOH-terminal propeptide because this was the site of the mannose, which altered the protein's glycosylation. Unfortunately, it was not possible to study the collagen of the parents of this case; this might have permitted conclusions as to whether the patient was homozygous for an amino acid substitution or heterozygous.

Nicholls et al. (1979, 1984) described absence of alpha-2 chains in a child of a third-cousin marriage who they suggested had Sillence type III OI, although the sclerae were described as 'significantly blue.' Type I collagen consisted only of alpha-1 chains, i.e., was an alpha-1 trimer. The child had remarkably mild manifestations. The first recognized fracture, of the humerus, occurred at age 5 weeks. Following another break 2 weeks later, x-rays showed normal width of bones with signs of several earlier fractures. Nicholls et al. (1984) concluded that the child was homozygous for an abnormal pro-alpha-2(I) chain (120160) which does not associate with pro-alpha-1(I) chains and therefore is not incorporated into triple helical trimers of type I procollagen. In a child with type III OI, Pope et al. (1985) showed an abnormality of the alpha-2 chain of type I collagen, specifically a 4-bp deletion which led to frame shift at the carboxyl end of the protein. Because of this, the normal type I helix could not be assembled and the alpha-2 gene product was degraded intracellularly.

Tenni et al. (1988) reported a male infant with type III OI in whom biochemical analysis of the alpha-1(I) chains was consistent with a mutation towards the C-terminus of the triple helix or within the C-propeptide.

Byers et al. (2006) published practice guidelines for the genetic evaluation of suspected OI.

Heterogeneity

Among 345 pedigrees with OI, Sillence et al. (1986) found 7 that had autosomal recessive inheritance suggested by segregation pattern or parental consanguinity and answering to the other criteria of type III OI: normal sclerae and teeth, fractures or deformability present from birth. They described 'popcorn calcification' in the growth plates found radiographically in OI III, but not specific for this form of OI or indeed for any form of OI, being seen also in Strudwick spondylometaepiphyseal dysplasia (184250), Jansen metaphyseal dysplasia (156400), and parastremmatic dysplasia (168400). They concluded that OI III is probably heterogeneous.

Population Genetics

Beighton and Versfeld (1985) suggested that type III OI is relatively high in the black population of South Africa. The high frequency did not seem to be limited to one tribe. Whereas in Australian whites the ratio of OI I to OI III is about 7 to 1 (Sillence et al., 1979), in South African blacks it is about 1 to 6. The authors cited a report of a relatively high frequency of OI III in Nigeria. In Zimbabwe, Viljoen and Beighton (1987) identified 58 cases of OI in institutions for crippled persons; 42 of the patients had the rare OI type III. The Shona and the Ndebele, both major tribal groups, had a similar and relatively high gene frequency for this disorder. Both tribes were derived from common progenitors, but until 150 years earlier had been geographically separated for 2 millennia; they remain culturally and socially distinct. Viljoen and Beighton (1987) inferred that the mutation for OI III in Africa occurred at least 2000 years ago.

Molecular Genetics

Starman et al. (1989) reported a family in which the OI III phenotype was caused by a dominant mutation in the COL1A1 gene that resulted in substitution of cysteine for glycine at position 526 of the triple helix (120150.0005). This and other experience suggested to Starman et al. (1989) that a significant proportion of individuals with the OI III phenotype have a dominant mutation which, in some families, is inherited. Pruchno et al. (1991) found a heterozygous de novo mutation, gly154-to-arg, in 2 unrelated individuals with a progressive deforming variety of OI compatible with OI type III (see 120150.0030). Dominant inheritance of OI III was also supported by Cohen-Solal et al. (1991), who found biochemical evidence of heterozygosity. The parents were nonconsanguineous. Parental gonadal mosaicism was presumed. Molyneux et al. (1993) also presented molecular evidence of heterozygosity for a new dominant mutation in a child with progressive deforming OI. They concluded with the statement that 'in the majority of instances, the phenotype results from heterozygosity for mutations in one of the genes that encode chains of type I collagen.'

De Paepe et al. (1997) identified homozygosity for a gly751-to-ser mutation of the COL1A2 gene (120160.0039) in 2 sibs; the 2 parents, who were first cousins, and 2 other sibs were heterozygous and had manifestations consistent with type I OI (166200).

Cabral et al. (2001) reported a 13-year-old girl with severe type III OI in whom they identified heterozygosity for a gly76-to-glu substitution in the COL1A1 gene (120150.0065). The authors stated that this was the first delineation of a glutamic acid substitution in the alpha-1(I) chain causing nonlethal osteogenesis imperfecta.

Autosomal dominant inheritance of OI type III is represented by a family in which the affected member of the first generation had molecularly proven mosaicism for a heterozygous 562-bp deletion in the COL1A1 gene (120150.0054) (Cabral and Marini, 2004).

Genotype/Phenotype Correlations

Faqeih et al. (2009) reported 3 unrelated patients with OI type III, brachydactyly, and intracranial hemorrhage, 1 of whom was previously described by Cole and Lam (1996), who all had glycine mutations involving exon 49, in the most C-terminal part of the triple helical domain of COL1A2 (120160.0037, 120160.0054, and 120160.0055, respectively). Faqeih et al. (2009) suggested that mutations in this region of COL1A2 carry a high risk of abnormal limb development and intracranial bleeding.

Clinical Management

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 (166220), 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 cyclic 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 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 .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 areal bone mineral density (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, III, 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.

Gene Therapy

Chamberlain et al. (2004) used adeno-associated virus vectors to disrupt dominant-negative mutant COL1A1 (120150) collagen genes in mesenchymal stem cells, also known as marrow stromal cells, from individuals with severe OI, demonstrating successful gene targeting in adult human stem cells.