OSTEOGENESIS IMPERFECTA, TYPE I
Alternative titles; symbols
OI, TYPE I
OSTEOGENESIS IMPERFECTA TARDA
OSTEOGENESIS IMPERFECTA WITH BLUE SCLERAE
The OI type I phenotype can be produced by mutation in either the COL1A1
gene (120150) or the COL1A2 gene (120160) and possibly in other genes.
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
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 are rare
the neonatal period; fracture tendency is constant from childhood to
puberty, decreases thereafter, and often increases following menopause
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%
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).
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
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).
The prevalence and severity of cardiovascular involvement in OI type I
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.
aortic root diameter was slightly but significantly increased and was
associated with aortic regurgitation in 1 to 2%. No patient had suffered
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
persons. Aortic root dilatation was found by echocardiogram to be present
8 of 66 persons with OI syndrome; dilatation was mild and unrelated to
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
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
affected individuals in the absence of systemic arterial hypertension.
In likely heterogenous 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.
The disorder may exhibit considerable interfamilial and intrafamilial
variability in the number of fractures and degree of disability. Rowe et
(1985) reported a spectrum of disease severity within a 5-generation family.
Those most severely affected exhibited more severe short stature and a
degree of scoliosis relative to those who were less severely affected.
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
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
strenuous exercise; her current height was 162 cm (fiftieth 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
the amount of the abnormal pro-alpha-1(I) chains produced or their
intracellular fate, but no differences were observed. They noticed that
more severely affected family members had children with both mild and severe
phenotypes, while the mildly affected individual had an offspring with
mild phenotype. This suggested to them that there might be some other,
identified, factor segregating independently in this family that acts to
modulate the final phenotype.
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 (166200); 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
(259420). The biochemical and linkage studies support the broad validity
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
still unexplained variability of expression seen in many families (Byers,
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.
It has been suggested that OI type I should be subdivided into type IA
IB on the basis of the absence or presence of dentinogenesis imperfecta
(Levin et al., 1978). However, even mild dentinogenesis is uncommon among
individuals with OI type I and has been observed in 4 out of 45 such
individuals, and may be even more uncommon when the type of OI is defined
biochemical findings. Attempts to subdivide OI type I probably reflect
difficulty of distinguishing the blue sclerae in OI type I from the light
blue-gray sclerae in individuals with OI type IV who most often have
clinically apparent dentinogenesis imperfecta.
Byers (1993) summarized that 'functional null' alleles, i.e., silent alleles
or mutations leading to excluded proteins, are the most common biochemical
and genetic features of OI type I , although structural mutations in COL1A1
and COL1A2 leading to the synthesis of abnormal procollagen I can
occasionally produce the OI type I phenotype.
Assessing reports of biochemical findings in the OI syndromes is difficult
because the phenotype and genetics generally are not specified. Most studies
deal, no doubt, with heterogeneous groups of patients. Several forms of
were among the earliest of the inherited disorders of collagen biosynthesis
and structure to be studied using cultured dermal fibroblasts from affected
individuals (Martin et al., 1971; Penttinen et al., 1975). Cells cultured
from patients who, in retrospect, would be considered to have OI type I,
synthesized less procollagen I than did controls, but the mechanism by
production was decreased was not determined. These studies were extended
from culture to tissue.
Francis et al. (1974) concluded that patients with OI and blue sclerae
to have a reduced amount of collagen that has normal stability, as measured
by resistance to depolymerization by pronase, heat, or cold alkali, whereas
those with white sclerae have a normal amount of collagen with reduced
stability; they suggested that a defect in cross-linking of collagen is
present in the severe form of the disease.
Sykes et al. (1977) and, in a slightly extended study, Francis et al.
(1981), found an increased ratio of collagen III to I in dermis and
interpreted this as indicating a deficiency of collagen I. In studies of
patients with OI, Cetta et al. (1983) found in the largest category, the
mild form, also an increased ratio of collagens III to I in skin and, in
addition, an increased ratio of hydroxylysine diglycoside to monoglycoside
in skin collagen.
Rowe et al. (1981) proposed that an additional criterion for OI type I
the production of a reduced quantity of collagen I. Among the cases of
osteogenesis imperfecta with reduced synthesis of pro-alpha-1 chains,
considerable heterogeneity is likely to emerge at the level of gene
structure, as in the case of the globin genes in the thalassemias. Barsh
al. (1982) found that cultured skin fibroblasts from 3 patients produced
half-normal levels of procollagen type I. Furthermore, the OI cells
contained equimolar amounts of pro-alpha-1(I) and pro-alpha-2(I) chains,
which suggested that trimer assembly and secretion were limited by the
of pro-alpha-1(I) chain synthesis. The 'extra' pro-alpha-2(I) chain in
OI cells was in a non-disulfide bonded configuration and apparently
contributed to an increased level of intracellular degradation. The results
of Barsh et al. (1982) suggested that the stoichiometry of the pro-alpha
chains in procollagen I is determined by the conformation of the chains
rather than by the ratio in which they are synthesized, that molecules
containing more than a single pro-alpha-2(I) chain are not assembled, and
that the production of collagen I can be regulated by controlling synthesis
of only one of its subunits.
Rowe et al. (1985) demonstrated that reductions in collagen I production
in the ratio of alpha-1(I) to alpha-2(I) mRNA are clearly segregated with
affected individuals within the 5 generation family. Rowe et al. (1985)
further suggested that the severity of the disorder is roughly correlated
with the reduction in collagen I synthesis.
Wenstrup et al. (1990) correlated clinical severity in nonlethal variants
OI with the nature of the alteration in the alpha chains of procollagen
secreted by cultured fibroblasts. Cells from 40 probands secreted about
the normal amount of normal procollagen I and no identifiable abnormal
molecules; these patients were generally of normal stature, rarely had
deformity or dentinogenesis imperfecta, and had blue sclerae. Cells from
other probands produced and secreted normal and abnormal procollagen I
molecules; these patients were usually short and had bone deformity and
dentinogenesis imperfecta, and many had gray or blue-gray sclerae. In cells
from yet another 18 probands, Wenstrup et al. (1990) were unable to identify
altered procollagen I synthesis or structure.
Dickson et al. (1975) reported a quantitative and qualitative abnormality
noncollagenous proteins of bone.
Lancaster et al. (1975) found a consistent morphologic abnormality of
cultured skin fibroblasts: irregular packing of aggregated cells and an
irregular tessellated appearance of individual fibroblasts. Boright et
(1984) showed that dermal fibroblasts derived from individuals with OI
I take longer than control cells to reach confluency, have a lower cell
density at stationary phase and have an abnormal cell shape as judged by
increased ratio of width to length. An increase in population doubling
of fibroblasts derived from individuals with the milder form of OI was
observed by Rowe and Shapiro (1982).
The mode of inheritance is autosomal dominant. Penetrance of blue sclerae
100 percent, while penetrance of hearing loss is clearly age-dependent
(Garretsen and Cremers, 1991). Paternal age effect for increased risk of
mutations has been documented although it appears to be considerably lower
than, for example, in achondroplasia (100800). In 10 cases with OI type
presumed to have arisen by new mutation, the mean paternal age was increased
by 2.1 years (Sillence et al., 1979), whereas in 38 other cases it was
significantly increased by 2.9 years (Carothers et al., 1986).
In all but 1 of 11 families with OI tarda, Sykes et al. (1986) found that
the disorder segregated with either the COL1A1 locus or the COL1A2 locus.
1 small family, segregation occurred with both genes, but this disorder
clearly cannot be linked to both; had further meioses been available, the
gene would probably have segregated independently of at least 1 of the
loci. Tsipouras (1987), also, concluded that mild OI is genetically
heterogeneous and that 1 or more loci other than COL1A1 and COL1A2 may
involved in the causation of phenotypically indistinguishable autosomal
Sykes et al. (1990) studied segregation of the COL1A1 and COL1A2 genes
dominant osteogenesis imperfecta pedigrees. None of the 38 pedigrees showed
recombination between the OI gene and both collagen loci. All 8 pedigrees
with OI type IV (166220) segregated with COL1A2. On the other hand, 17
I pedigrees segregated with COL1A1 and 7 with COL1A2. The concordant locus
was uncertain in the remaining 6 OI type I pedigrees. The presence or
absence of presenile hearing loss was the best predictor of the mutant
in OI type I families, with 13 of the 17 COL1A1 segregants and none of
COL1A2 segregants showing this feature. By linkage analysis in 7 autosomal
dominant osteogenesis imperfecta families in Italy, Mottes et al. (1990)
showed that the COL1A1 gene was implicated in 2 families and the COL1A2
in 1 family with OI type I. The COL1A2 gene was implicated in 2 families
with OI type IV. In 2 OI type I families, the molecular genetic data were
insufficient for exclusion of one gene.
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.
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
the same phenotype.
In some individuals, the decreased production of pro-alpha-1(I) chains
fibroblasts results from about half-normal steady-state levels of the mRNA
(Rowe et al., 1985). Later studies on these cells indicated that there
defect in splicing of the pre-mRNA of COL1A1 that prohibits transport of
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
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
of intron 26 which resulted in inclusion of the entire succeeding intron
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
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
not the cause of the diminished COL1A1 mRNA levels. Only in one family
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
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
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
abnormal chains in cells; it appeared that although the mRNA was present
normal amount, the protein product was unstable. This mutation provides
model of how many different mutations in the COL1A1 gene could produce
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
the TATAAA and CCAAAT boxes, are responsible for the reduced levels of
They used PCR-amplified genomic DNA in conjunction with denaturing gradient
gel electrophoresis and SSCP to screen the 5-prime untranslated domain,
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
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
(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
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; Byers, 1993;
Shapiro et al., 1992; Nicholls et al., 1990) also produce mild forms of
perhaps compatible with OI type I. 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
amino acid residues were deleted from the triple-helical domain, in the
peptide, a domain in which phosphoproteins important to bone calcification
may bind and in which crosslinks may form. Subsequent studies indicated
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
et al., 1990). Zhuang et al. (1993) showed that deletion of 19 bp from
+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
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.
The diagnosis is based on clinical and genetic criteria. In sporadic cases,
the diagnosis may be difficult, and secondary osteoporosis and nonaccidental
injury has to be ruled out. In women with severe 'postmenopausal
osteoporosis' careful clinical investigation and a thorough personal and
family history quite often reveals OI type I. While the direct molecular
characterization is not feasible in the majority of cases at present,
demonstration of reduced synthesis of procollagen I by dermal fibroblasts
indicative for the disorder. Lynch et al. (1991) discussed the problem
making the prenatal diagnosis of OI type I on the basis of linkage.
No medical treatment for OI type I is known that decreases the frequency
bone fracture or increases bone density; an effective agent would have
increase the production of procollagen I, if the mutation resulted in
diminished synthesis and secretion. Apparent success can be attributed
the natural history of OI, with spontaneous reduction in the fracture rate
with increasing age and/or to placebo effect.
Bembi et al. (1997) described the results of treatment of 3 children with
type I with cyclic intravenous infusions of aminohydroxypropylidene
bisphosphonate (pamidronate). Each of the children had repeated bone
fractures and low bone density. The rationale for pamidronate therapy in
is based on the fact that bisphosphonates inhibit osteoclastic bone
resorption; this leads to increased bone density and possibly to reduced
risk of fracture. Bembi et al. (1997) reported a clear clinical response
over the 22- to 29-month treatments, with a striking reduction in the
frequency of new fractures. They also observed an effect on bone density.
There were no notable adverse effects during therapy.
In an uncontrolled observational study involving 30 children aged 3 to
years with severe osteogenesis imperfecta, Glorieux et al. (1998)
administered pamidronate intravenously at 4- to 6-month intervals for 1.3
5.0 years. They observed a sustained reduction in serum alkaline phosphatase
concentrations and in the urinary excretion of calcium and type I collagen
N-telopeptide. Increases in the size of the vertebral bodies suggested
new bone had formed. The mean incidence of radiologically confirmed
fractures decreased by 1.7 per year (P less than 0.001). Treatment with
pamidronate did not alter the rate of fracture healing, the growth rate,
the appearance of growth plates. Mobility and ambulation improved in 16
children and remained unchanged in the other 14. Marini (1998) commented
that fluoride and calcitonin treatment in OI had proved unsuccessful. The
bisphosphonates are synthetic analogs of pyrophosphate, a natural inhibitor
of osteoclastic bone resorption. They have been useful in the treatment
osteoporosis, Paget disease of bone, and fibrous dysplasia. The children
with severe osteogenesis imperfecta treated by Glorieux et al. (1998) fell
into the type III (259420) and type IV (166220) categories of osteogenesis
Fractures in OI are treated with standard orthopedic procedures appropriate
for the type of fracture and the age, and heal rapidly with evidence of
callus formation (sometimes with hypertrophic callus formation) and without
deformity. Regular hearing evaluations after adolescence and early
stapedectomy or stapedotomy are recommended. In postmenopausal women with
OI, a long-term physical therapy program to strengthen the paraspinal
muscles, together with estrogen and progesterone replacement, adequate
calcium intake, and perhaps calcitonin or fluoride administration, may
specifically indicated (for review, see Steinmann et al., 1990).
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).
Bonadio et al. (1990) reported that the heterozygous Mov-13 mouse, which
a murine retrovirus integrated within the first intron of the COL1A1 gene,
is a good model for the mild autosomal dominant form of OI. The animals
showed morphologic and functional defects in mineralized and nonmineralized
connective tissue and progressive hearing loss.