Osteogenesis imperfecta type I is a dominantly inherited, generalized connective tissue disorder characterized mainly by bone fragility and blue sclerae. In most cases, 'functional null' alleles of COL1A1 on chromosome 17 or COL1A2 on chromosome 7 lead to ... Osteogenesis imperfecta type I is a dominantly inherited, generalized connective tissue disorder characterized mainly by bone fragility and blue sclerae. In most cases, 'functional null' alleles of COL1A1 on chromosome 17 or COL1A2 on chromosome 7 lead to reduced amounts of normal collagen I.
Osteogenesis imperfecta (see Byers, 1993) is characterized chiefly by multiple bone fractures, usually resulting from minimal trauma. Affected individuals have blue sclerae, normal teeth, and normal or near-normal stature (for growth curves, see Vetter et al., 1992). Fractures ... Osteogenesis imperfecta (see Byers, 1993) is characterized chiefly by multiple bone fractures, usually resulting from minimal trauma. Affected individuals have blue sclerae, normal teeth, and normal or near-normal stature (for growth curves, see Vetter et al., 1992). Fractures are rare in the neonatal period; fracture tendency is constant from childhood to puberty, decreases thereafter, and often increases following menopause in women and after the sixth decade in men. Fractures heal rapidly with evidence of a good callus formation, and, with good orthopedic care, without deformity. Hearing loss of conductive or mixed type occurs in about 50% of families, beginning in the late teens and leading, gradually, to profound deafness, tinnitus, and vertigo by the end of the fourth to fifth decade. Additional clinical findings may be thin, easily bruised skin, moderate joint hypermobility and kyphoscoliosis, hernias, and arcus senilis. Mitral valve prolapse, aortic valvular insufficiency, and a slightly larger than normal aortic root diameter have been identified in some individuals (Hortop et al., 1986), but it is not clear that these disorders are significantly more frequent than in the general population. Radiologically, wormian bones are common but bone morphology is generally normal at birth, although mild osteopenia and femoral bowing may be present. Vertebral body morphology in the adult is normal initially, but often develops the classic 'cod-fish' appearance (Steinmann et al., 1991). - EYES Individuals with OI type I have distinctly blue sclerae which remain intensely blue throughout life, in contrast to the sclerae in OI type III and OI type IV which may also be blue at birth and during infancy. The intensity of the blue fades with time such that these individuals may have sclerae of normal hue by adolescence and adult life (Sillence et al., 1993). In a likely heterogeneous group of 16 patients with OI syndromes, Kaiser-Kupfer et al. (1981) found low ocular rigidity and small corneal diameter and globe length; no correlation was found between rigidity of the eyeball and blueness of the sclera. The central corneal thickness was found to be significantly lower in 53 patients with OI than that in 35 patients with otosclerosis and in 35 control subjects (Pedersen and Bramsen, 1984). Hartikka et al. (2004) found that patients with COL1A1 mutations more frequently had blue sclerae than those with COL1A2 mutations. In addition, patients with COL1A2 mutations tended to be shorter than those with COL1A1 mutations. - CARDIOVASCULAR The prevalence and severity of cardiovascular involvement in OI type I was determined in a prospective study of patients of all ages (Pyeritz and Levin, 1981). Mitral valve prolapse occurred in 18% (3 times the prevalence in unaffected relatives) and rarely progressed to mitral regurgitation. Mean aortic root diameter was slightly but significantly increased and was associated with aortic regurgitation in 1 to 2%. No patient had suffered a dissection. Later, Hortop et al. (1986) studied 109 persons with nonlethal OI from 66 families. They could demonstrate no definite increase in the frequency of mitral valve prolapse over that to be expected in any group of persons. Aortic root dilatation was found by echocardiogram to be present in 8 of 66 persons with OI syndrome; dilatation was mild and unrelated to age of the patient but was strikingly aggregated in families. Of 109 persons surveyed, valvular disease was evident clinically in only 4 persons (aortic regurgitation in 2, aortic stenosis in one, and mitral valve prolapse in one). Hortop et al. (1986) stated that aortic root dilatation was seen in each of the different OI syndromes but strikingly segregated within certain families. They concluded that the mild and apparently nonprogressive nature of this lesion in OI argues against the use of beta-adrenergic blockade in affected individuals in the absence of systemic arterial hypertension. Mayer et al. (1996) reported a 35-year-old woman with a mild form of OI1 who presented with spontaneous dissection of the right internal carotid artery and the right vertebral artery after scuba diving. She had no obvious head or neck trauma. Other than a history of easy bruising and bluish sclerae, she had no evidence of a connective tissue disorder. There had been no bone fractures or dental problems nor was there family history of vasculopathy. Genetic analysis identified a heterozygous mutation in the COL1A1 gene (G13A; 120150.0052). - EARS In likely heterogeneous groups of patients with OI, about half of affected individuals have hearing loss that begins during the second decade as a conductive loss; older individuals have sensorineural losses (Riedner et al., 1980; Pedersen, 1984). In only 1 major study was a majority of patients with sensorineural pattern observed (Shapiro et al., 1982). A female-to-male preponderance of 2:1 has been reported (Shea and Postma, 1982). Hearing loss is different from otosclerosis. Vertigo is frequently associated with otosclerosis in which the hearing loss clinically resembles that in OI. Vertigo is also common in basilar impression found in up to 25% of adult OI patients. To evaluate the cause, frequency, and characteristics of vertigo in OI, Kuurila et al. (2003) studied 42 patients by interview, clinical examination, and audiologic examination supplemented with electronystagmography (ENG) and lateral skull radiography. Audiometry showed hearing loss in 25 patients (59.5%). In 9 patients (21%), abnormal skull base anatomy was found in the forms of basilar impression, basilar invagination, or both. Vertigo, mostly of floating or rotational sensation of short duration, was reported by 22 patients (52.4%). Patients with hearing loss tended to have more vertigo than patients with normal hearing. Vertigo was not correlated with type of hearing loss or auditory brain stem response pathology. ENG was abnormal in 14 patients (33.3%). Kuurila et al. (2003) concluded that vertigo is common in patients with OI and that in most cases, it is secondary to inner ear pathology. Hartikka et al. (2004) reported a correlative analysis between types of mutation in the COL1A1 and COL1A2 genes and OI-associated hearing loss. A total of 54 Finnish OI patients with previously diagnosed hearing loss or age 35 or more years were analyzed for mutations in COL1A1 or COL1A2. Altogether 49 mutations were identified, of which 41 were novel. No correlation was found between the mutated gene or mutation type and hearing pattern. The authors interpreted this to mean that the basis of hearing loss in OI is complex, and that it is a result of multifactorial, still unknown genetic effects. - SKIN Using a suction-cup technique, Hansen and Jemec (2002) performed quantitative studies of skin mechanics (elasticity, distensibility, and hysteresis) in 10 patients with OI, 8 with type I and 2 with type III (259420), and 24 age-matched controls. Skin elasticity, distensibility, and hysteresis were significantly decreased in patients versus controls. OI type I patients had decreased distensibility and hysteresis but increased elasticity in comparison to the type III patients. The authors concluded that the skin of patients with OI is more stiff and less elastic than normal skin. These changes differ from age-related changes, which have been described as increased distensibility and viscosity (similar to hysteresis). - CRANIOFACIAL AND DENTAL To obtain baseline information on craniofacial development in OI patients who had not received bisphosphonate treatment, Waltimo-Siren et al. (2005) used lateral radiographs to analyze the size and form of the bony structures in heads of 59 consecutive patients with OI types I, III, or IV (Sillence classification). In OI type I they found linear measurements that were smaller than normal, indicating a general growth deficiency, but no remarkable craniofacial deformity. In OI types III and IV, the growth impairment was pronounced and the craniofacial form was altered as a result of differential growth deficiency and bending of the skeletal head structures. They found strong support both for an abnormally ventral position of the sella region due to bending of the cranial base and for a closing mandibular growth rotation. Vertical underdevelopment of the dentoalveolar structures and the condylar process were identified as the main reasons for the relative mandibular prognathism in OI. Waltimo-Siren et al. (2005) concluded that facial growth impairment would probably remain characteristic for many OI patients despite the widespread intervention with bisphosphonates and that orthodontic treatment should be further developed. - CLINICAL VARIABILITY The disorder may exhibit considerable interfamilial and intrafamilial variability in the number of fractures and degree of disability. Rowe et al. (1985) reported a spectrum of disease severity within a 5-generation family. Those most severely affected exhibited more severe short stature and a mild degree of scoliosis relative to those who were less severely affected. Most striking were identical twins, the offspring of a mildly affected mother. Twin B was born small for gestational age, had had 12 fractures and was 150 cm tall (third centile) at 11 years of age. Her twin was born appropriate for gestational age and had had only 2 fractures at age 8 and 9 secondary to strenuous exercise; her current height was 162 cm (50th centile). This family study suggested that the severity of the disease is roughly correlated with the reduction in collagen I synthesis. Willing et al. (1990) described 5 affected individuals of a 3-generation family with marked clinical variability. They wondered if there might be subtle biochemical differences between the family members with respect to the amount of the abnormal pro-alpha-1(I) chains produced or their intracellular fate, but no differences were observed. They noticed that the more severely affected family members had children with both mild and severe phenotypes, while the mildly affected individual had an offspring with a mild phenotype. This suggested to them that there might be some other, not identified, factor segregating independently in this family that acts to modulate the final phenotype. - CLASSIFICATION Using clinical, radiographic, and genetic criteria, Sillence et al. (1979) developed the classification currently in use into types I to IV: a dominant form with blue sclerae, type I; a dominant form with normal sclerae, type IV (166220); a perinatally lethal OI syndrome, type II (166210); and a progressively deforming form with normal sclerae, type III. The biochemical and linkage studies support the broad validity of the classification but confirm that it is incomplete. Although biochemical and genetic studies will provide the basis of the most rational classification, even such a detailed scheme probably will never predict correctly the evolution of OI in every affected individual, because of the still unexplained variability of expression seen in many families (Byers, 1993). Bauze et al. (1975) divided their 42 patients with OI into mild, moderate, and severe groups according to deformity of long bones. None of the 17 patients in the mild group had scoliosis or white sclerae. The terms 'congenita' and 'tarda' now have limited usefulness, since they do not specify the mode of inheritance or basic biochemical defects. Levin et al. (1980) concluded that dominant type I OI separates clearly into families in which affected persons have opalescent teeth and those in which dentinogenesis imperfecta (DGI) is absent. In 5 families, all members whose teeth were studied radiographically and by scanning electron microscopy had opalescent teeth. In 2 families the teeth of all affected persons were normal. Some members of both classes of families had blue sclerae and others did not. These 2 forms of OI were designated type IA and IB, depending on the presence or absence, respectively, of DGI. Paterson et al. (1983) found that patients with associated DGI (type IA) have more severe disease, with a greater fracture rate and greater likelihood of growth impairment, than do type IB patients. Superti-Furga et al. (2007) discussed the 2006 revisions to the Nosology of Constitutional Disorders of Bone by the Nosology Group of the International Skeletal Dysplasia Society and provided a comprehensive table of the new classification scheme.
Byers (1993) summarized that 'functional null' alleles are the most common genetic features of OI type I. The mechanism by which the synthesis of pro-alpha-1(I) chains is decreased remains a difficult problem to solve. A variety of mutations, ... Byers (1993) summarized that 'functional null' alleles are the most common genetic features of OI type I. The mechanism by which the synthesis of pro-alpha-1(I) chains is decreased remains a difficult problem to solve. A variety of mutations, such as deletion of an allele, promoter and enhancer mutations, splicing mutations, premature termination, as well as other mutations that result in the inability of pro-alpha-1(I) chains to assemble into molecules, would presumably result in the same biochemical picture and the same phenotype. In some individuals, the decreased production of pro-alpha-1(I) chains by fibroblasts results from about half-normal steady-state levels of the mRNA (Rowe et al., 1985). Later studies on these cells indicated that there is a defect in splicing of the pre-mRNA of COL1A1 that prohibits transport of the product of the mutant allele to the cytoplasm; the ratio of pro-alpha-1(I) to pro-alpha-2(I) mRNA was 1:1 in the cytoplasm instead of the normal 2:1, whereas the ratio was 4:1 in the nucleus instead of the normal 2:1 (Genovese and Rowe, 1987). Furthermore, a novel species of alpha-1(I) mRNA present in the nuclear compartment was not collinear with a cDNA probe (Genovese et al., 1989). In another individual with OI type I, Stover et al. (1993) demonstrated a G-A transition in the first position of the splice donor site of intron 26 which resulted in inclusion of the entire succeeding intron in the mature mRNA that accumulated in the nuclear compartment; apparently because no abnormal pro-alpha-1(I) chains were synthesized from the mutant allele, the clinical phenotype of this individual was mild. In a large study, Willing et al. (1992) showed that among 70 individuals with OI type I 23 from 21 families were heterozygous at the COL1A1 polymorphic MnlI site. As shown by primer extension with nucleotide-specific chain termination, there was in each case marked diminution in steady-state mRNA levels from one COL1A1 allele. Loss of an allele through deletion or rearrangement was not the cause of the diminished COL1A1 mRNA levels. Only in one family has the causative mutation been identified; an A-G transition in the obligatory acceptor splice site of intron 16 resulted in skipping of exon 17 in the mRNA which represented only 10% of the total COL1A1 mRNA. Further, linkage studies in 38 additional families have demonstrated no evidence of deletion of those regions of the COL1A1 gene used for linkage analysis (Sykes et al., 1986, 1990) and confirmed that most individuals with the OI type I phenotype have mutations linked to the COL1A1 gene. In some families, a similar phenotype is thought to result from mutations in the COL1A2 gene (Sykes et al., 1986, 1990; Wallis et al., 1986), but the clinical criteria by which the diagnosis of OI type I is made are not always clear. Willing et al. (1990) described a 5-bp deletion near the 3-prime end of one COL1A1 allele that resulted in a reading frame shift 12 amino acid residues from the normal terminus of the chain and predicted an extension of 84 amino acid residues beyond the normal termination site. Although the abnormal mRNA could be translated in vitro, it proved extremely difficult to identify the abnormal chains in cells; it appeared that although the mRNA was present in normal amount, the protein product was unstable. This mutation provides a model of how many different mutations in the COL1A1 gene could produce the OI type I phenotype by resulting in the synthesis of half the normal amount of a functional pro-alpha-1(I) chain. In an effort to further understand the reasons for diminished COL1A1 transcript levels in OI type I, Willing et al. (1995) investigated whether mutations involving key regulatory sequences in the COL1A1 promoter, such as the TATAAA and CCAAAT boxes, are responsible for the reduced levels of mRNA. They used PCR-amplified genomic DNA in conjunction with denaturing gradient gel electrophoresis and SSCP to screen the 5-prime untranslated domain, exon 1, and a small portion of intron 1 of the COL1A1 gene. In addition, direct sequence analysis was performed on an amplified genomic DNA fragment that included the TATAAA and CCAAAT boxes. In a survey of 40 unrelated probands with OI type I in whom no causative mutation was known, Willing et al. (1995) identified no mutations in the promoter region and there was 'little evidence of sequence diversity among any of the 40 subjects.' Although less common than 'functional null' allele mutations, there are several examples in which the synthesis of abnormal procollagen I molecules can produce the OI type I phenotype. In one family (Nicholls et al., 1984), cells cultured from the affected mother and son, but not those from the normal daughter, synthesized alpha-1(I)-chains bearing a cysteine residue within the protease-resistant domain of the collagen molecule, a region from which that residue is normally absent. Although it was initially thought that the cysteine substitution was at the X or Y position of the Gly-X-Y repeating unit of the alpha-1(I) chain in the carboxyl-terminal peptide CB6 (Steinmann et al., 1986), peptide sequence analysis and sequencing of the cDNA demonstrated that the mutation resulted in the substitution of a glycine by cysteine in position 1017 in the telopeptide, 3 amino acid residues from the carboxy-terminal to the end of the triple helix (Cohn et al., 1988; Labhard et al., 1988). Other substitutions of cysteine for glycine within the triple helical domain of the alpha-1(I) chain at residue 94 (Starman et al., 1989; Nicholls et al., 1990; Shapiro et al., 1992; Byers, 1993) also produce mild forms of OI, perhaps compatible with OI type I (see, e.g., 120150.0002 and 120500.0038). Byers et al. (1983) described an isolated patient with a mild to moderate form of OI: blue sclerae, a height of 147 cm, deformity as a consequence of poor orthopedic treatment, and hearing loss. Her cells synthesized a pro-alpha-2(I) chain in which approximately 30 amino acid residues were deleted from the triple-helical domain, in the CB4 peptide, a domain in which phosphoproteins important to bone calcification may bind and in which crosslinks may form. Subsequent studies indicated that a point mutation at the consensus splice-donor site resulted in the skipping of exon 12 (amino acids 91-108) from about half the COL1A2 transcripts (Rowe et al., 1990). Zhuang et al. (1993) showed that deletion of 19 bp from +4 to +22 of intron 13 of COL1A2 caused skipping of exon 13 in about 88% of the transcripts, whereas 12% of the transcripts were normally spliced; procollagen I containing the mutated pro-alpha-2(I) chain had reduced thermal stability and was only poorly secreted from the cells. A woman with 'postmenopausal osteoporosis' was reported by Spotila et al. (1991) to be heterozygous for a serine-to glycine substitution at position 661 of the alpha-2(I) triple-helical domain. Since her 3 sons, who inherited the mutation, had experienced fractures as adolescents, the diagnosis of 'mild OI cannot be fully excluded' according to the authors' view; one of the sons was homozygous for the mutation due to partial isodisomy for maternal chromosome 7 (Spotila et al., 1992). All these findings suggest that other point mutations in the COL1A1 gene, and perhaps in the COL1A2 gene (as suggested also by linkage studies), could lead to a phenotype similar to that produced by 'functional null' allele mutations.
In the county of Fyn, where approximately 9% of the Danish population lives, Andersen and Hauge (1989) identified 48 patients with osteogenesis imperfecta, of whom 17 were born between January 1, 1970 and December 31, 1983. Of the ... In the county of Fyn, where approximately 9% of the Danish population lives, Andersen and Hauge (1989) identified 48 patients with osteogenesis imperfecta, of whom 17 were born between January 1, 1970 and December 31, 1983. Of the 17, 12 had type I, 2 had type II, 2 had type III, and 1 had type IV. The point prevalence at birth was 21.8/100,000 and the population prevalence was 10.6/100,000 inhabitants. All ethnic and racial groups seem to be similarly affected (Byers, 1993).