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PubMed2001

Excess paternal age in apparently sporadic osteogenesis imperfecta.

The objective of this study was to examine whether parental age is associated with the occurrence of apparently sporadic osteogenesis imperfecta (OI). We compared parental age and the joint distribution of maternal and paternal age with expected distributions based on statutory birth records for each year and location of birth. The study included patients with OI based in the United Kingdom. The study was restricted to cases born in England, Wales, and Scotland between 1961 and 1998. Subgroup analysis was by clinical type [Sillence et al., 1979: J Med Genet 16:101-116] and apparent mode of inheritance based on pedigree analysis. Of 730 eligible cases, 357 were apparently sporadic. The mean age of fathers at birth of children with apparently sporadic OI was 0.87 years greater than expected (P = 0.010; 95% confidence interval = 0.21 to 1.54 years). The relative risk was 1.62 for fathers in the highest quintile of paternal age compared with fathers in the lowest quintile. The magnitude of the paternal age excess did not differ significantly between Sillence types (analysis of variance P = 0.534). In sporadic cases, paternal age was 0.51 years greater than expected, given maternal age, year, and location of birth (P = 0.033). In contrast, in familial cases, there was no significant paternal age excess, and paternal age was not significantly different from that expected given maternal age. Increased paternal age is a significant risk factor for sporadic OI. This effect is not accounted for by increasing maternal age. The magnitude of the paternal age excess is small in comparison with that in some other autosomal dominant disorders.

Adult↗
PubMed1980

Scanning electron microscopy of teeth in dominant osteogenesis imperfecta: support for genetic heterogeneity.

Scanning electron microscopic studies were performed on 25 deciduous and permanent teeth from members of 7 kindreds with dominant nonlethal osteogenesis imperfects (OI). Two families had normal teeth on clinical and radiological examination; five families had blue or brown opalescent teeth with specific radiologic findings. Enamel surfaces and prism organization were normal on all teeth. On fractured surfaces, the dentin tubules of normal teeth from patients with OI were evenly distributed and coursed regularly to the dentin-enamel junction. Opalescent teeth had few tubules and those present were short, narrow, and tortuous. Dentin calcification fronts of normal teeth were composed of many nodules with regularly spaced openings on their surfaces. Calcification fronts of opalescent teeth were composed of irregularly spaced, small nodules, which varied greatly in size and the nodules lacked tubule openings on their surfaces. The results of this study support the concept that at least two dominant forms of OI exist--one in which all individuals with IO have normal teeth, and the other in which all with OI have blue or brown opalescent teeth with characteristic changes on SEM.

Dental Enamel↗
PubMed1982

Osteogenesis imperfecta lethal in infancy: case report and scanning electron microscopic studies of the deciduous teeth.

Radiologic evaluation of the skeleton and scanning electron microscopic studies of the teeth were performed on an infant boy with a lethal osteogenesis imperfecta (OI) syndrome who died at 10 mo of pneumonia. The skeletal findings included ribs that were focally expanded by fracture calluses, flat vertebral bodies, and wide limb bones. On fractured tooth surfaces, the enamel and dentin were normal as was the dentin calcification front. Although microscopic abnormalities have been noted in teeth from previously reported infants with lethal OI, a few studies also report infants with normal teeth. These differences in dental findings may indicate heterogeneity in OI lethal in infancy. Results of our study indicate that, until the primary biochemical defects in the OI syndromes are elucidated, examination of teeth from other infants with lethal OI and detailed evaluation of other clinical and skeletal features will aid in delineating heterogeneity and variation in expression in lethal OI.

Humans↗
PubMed1983

Prenatal diagnosis of perinatally lethal osteogenesis imperfecta.

Prenatal diagnosis of osteogenesis imperfecta was achieved at 17 weeks of gestation using ultrasound through recognition of low echogenic properties of all the bones, abnormally shaped skull, bell-shaped rib cage, distally thinned ribs, short and deformed long bones, wide metaphyses, and thin diaphyses. Severely limited abnormal movements, abnormal positioning of the lower limbs also were typical of the condition. The recognition of the signs reported in this paper will allow the identification of the condition in utero in the second trimester.

Adult↗
PubMed1984

Osteogenesis imperfecta type II delineation of the phenotype with reference to genetic heterogeneity.

A group of fetuses with a perinatally lethal variety of osteogenesis imperfecta (O.I. type II) is characterized by short limbs, and clinical and roentgenological evidence of severe osseous fragility and defective ossification. Forty-eight cases were reviewed and can be subdivided into 3 groups on the basis of small but probably significant differences in clinical and radiographic findings. Group A (38 cases): short, broad, "crumpled" long bones, angulation of tibiae and continuously beaded ribs. Group B (6 cases): short, broad, crumpled femora, angulation of tibiae but normal ribs or ribs with incomplete beading. Group C (4 cases): long, thin, inadequately modelled, rectangular long bones with multiple fractures and thin beaded ribs. Consistency of findings within sibships suggests the groups reflect genetic heterogeneity. An increased frequency of parental consanguinity, sib occurrence with normal parents, and normal mean paternal age at birth, suggest that most cases of O.I. type II represent autosomal recessive traits. Some previously reported cases and the biochemical findings in one case suggest still further genetic heterogeneity.

Consanguinity↗
PubMed1984

Prenatal diagnosis of a severe deforming type of osteogenesis imperfecta.

A pregnancy at risk for a severe deforming type of osteogenesis imperfecta (OI) was monitored by ultrasonography and radiography. Long bone measurements were normal at 15 1/2 weeks gestation, but ultrasound detected an abnormality of one femur that appeared to be a fracture. The ultrasound study at 19 weeks revealed severe shortness of the femora, and radiographs showed only vertebral bodies with no other fetal skeletal parts clearly visible. These studies indicate the feasibility of prenatal diagnosis before 20 weeks for the more severe handicapping types of OI that are compatible with survival past the newborn period and that can result in death during later infancy.

Female↗
PubMed1985

Osteogenesis imperfecta with unusual skeletal lesions: report of three families.

Thirteen individuals with osteogenesis imperfecta (OI) from three families were evaluated. All examined persons with OI had multilocular radiolucent, radiopaque, or radiolucent-radiopaque lesions of the maxilla and mandible. In most patients, the lesions involved the tooth bearing areas, but in two, the rami also were involved. Teeth were normal. Radiologic findings in the extragnathic skeleton included marked coarseness of trabeculae and diffuse osteopenia. It is proposed that these patients represent yet another dominantly inherited OI syndrome.

Adolescent↗
PubMed1986

Osteogenesis imperfecta type III. Delineation of the phenotype with reference to genetic heterogeneity.

The existence of a rare form of osteogenesis imperfecta, OI type III, has been postulated. This is characterized by autosomal recessive inheritance with neonatal manifestations of bone fragility or deformability. It is usually nonlethal. Studies of some 345 pedigrees of OI in the last 8 years confirm that patients falling into this group are rare. They should be distinguished as a special group within the group of OI subjects with a progressively deforming OI phenotype delineated in previous publications [Sillence et al, 1979a, b]. The OI type III phenotype does not necessarily equate with progressively deforming OI, and probably only a proportion of cases with severe deformity and normal sclerae have OI type III. On the other hand, distinction between these patients and those with a milder form of perinatally lethal OI type II might be difficult. Whereas the natural history of skeletal deformity and fractures in patients with OI type III has certain similarities, variable severity between families indicates that OI type III is likely to be genetically heterogeneous.

Adolescent↗
PubMed1986

Lethal osteogenesis imperfecta with amniotic band lesions: collagen studies.

An infant was born with osteogenesis imperfecta (OI) and died after 7 days. In addition, there were amniotic constriction bands and amputations of several digits of the upper and lower limbs. The radiologic picture was suggestive of type III OI. Histomorphometric analysis of the bone showed a trabecular bone volume of 15.1% compared to 26.9% for age-matched controls. This was due to a decreased apposition of matrix by the osteoblasts. Because abnormal collagen synthesis has been suggested as the underlying defect in most forms of OI, collagen studies were undertaken using intact tissues. Bone and skin collagen solubilities were strikingly reduced. Shortened type I collagen molecules, representing 25% of the total type I collagen, were produced by pepsin digestion of the demineralized bone matrix. The molecular weight of the shortened collagen, was 10 kd lower than normal for both the alpha 1 and alpha 2 chains as determined by gel electrophoresis. The bone acetic acid-soluble collagen showed few shortened alpha-chains. Twenty-five percent of the acid-soluble bone collagen was cleaved into shortened molecules by a pepsin digestion. The shortened alpha 1 chain was purified by high-performance liquid chromatography (HPLC) and digested with CNBr. The analysis of the resulting fragments by HPLC and by gel electrophoresis unequivocally demonstrated that the shortened alpha 1 chain was derived from the alpha 1(I) chains and that the pepsin sensitivity extends from the amino terminal end of the chain to the alpha 1(I) CB5 peptide, approximately 120 residues inside the triple helix. These studies show a distinct structural abnormality of type I collagen in the bone matrix of this patient resulting in an increased sensitivity of the collagen to general enzymatic proteolysis. The importance of correlating clinical and biochemical information in OI is emphasized; classification and genetic counseling based only on clinical observations are inaccurate.

Amniotic Band Syndrome↗
PubMed1987

Osteogenesis imperfecta type III: an ancient mutation in Africa?

In a survey of institutions for crippled persons in Zimbabwe, 58 patients with osteogenesis imperfecta (OI) were identified; 42 had the rare OI Type III. The Shona and Ndebele people, who comprise the major tribal groups in Zimbabwe, both had a similar and relatively high gene frequency for this disorder. Both tribes were derived from common progenitors, but until 150 years ago had been geographically separated for 2 millenia. Subsequently, they have remained culturally and socially distinct. The implications are that the mutation for OI III in Africa occurred at least 2,000 years ago.

Female↗
PubMed1989

Type I procollagen: the gene-protein system that harbors most of the mutations causing osteogenesis imperfecta and probably more common heritable disorders of connective tissue.

Recent data from several laboratories have established that most variants of osteogenesis imperfecta (OI) are caused by mutations in the 2 structural genes for type I procollagen. There are 2 general reasons for the large number of mutations in type I procollagen in OI. One reason is that most of the structure of the procollagen monomer is essential for normal biological function of the protein. The second reason is that most of the mutations cause synthesis of structurally altered pro alpha chains of type I procollagen. The deleterious effects of the structurally altered pro alpha chains are then amplified by at least 3 mechanisms. One mechanism is a phenomenon referred to as "procollagen suicide" whereby altered pro alpha chains cause degradation of normal pro alpha chains synthesized by the same cell. Another mechanism involves the fact that many of the structurally altered pro alpha chains prevent normal processing of the N-propeptides of procollagen and persistence of the N-propeptide interferes with normal fibril assembly. A third mechanism is a recently discovered phenomenon in which a substitution of a bulkier amino acid for glycine can cause a kink in the triple helix of the molecule. The kinked collagen, in turn, causes formation of abnormally branched fibrils. Because the deleterious effects of abnormal pro alpha chains are amplified by these 3 mechanisms, most of the mutations are dominant and many are dominant lethal. The conclusion that most variants of OI are caused by mutations in the structural genes for type I procollagen has broad implications for other diseases that affect connective tissue, diseases such as chondrodystrophies, osteoarthritis, and osteoporosis.

Amino Acid Sequence↗
PubMed1990

Analysis of cultured chorionic villi in a case of osteogenesis imperfecta type II: implications for prenatal diagnosis.

We examined collagens produced by cultured cells from skin, chorionic villi, and placental membranes of a 32 week fetus with osteogenesis imperfecta (OI) type II. We observed that skin fibroblasts synthesized two populations of pro alpha 1(I) chains of type I procollagen; one population was normal, while the other population had excessive post-translational modification. The thermal stability of helices containing the overmodified chains was reduced 1-2 degrees C. Most significantly, the cells cultured from chorionic villi produced type I collagen chains with the same electrophoretic abnormalities as the skin collagen. This suggests that chorionic villus sampling (CVS) is a means of prenatal diagnosis for families with a previous type II or type IV OI infant.

Cells, Cultured↗
PubMed1993

Thermal stability and folding of the collagen triple helix and the effects of mutations in osteogenesis imperfecta on the triple helix of type I collagen.

Osteogenesis imperfecta (OI) is an inherited disease in which 90% of the cases result from mutations in the 2 genes, pro alpha 1 and pro alpha 2, coding for type I collagen. Type I collagen is a trimeric molecule, (alpha 1)2 alpha 2, which is dominated both structurally and functionally by the 300 nm triple-helical domain. Most OI mutations occur in this domain and almost all point mutations result in the substitution of other amino acids for the obligate glycine which occurs at every third residue. The phenotypic effects of these mutations are frequently attributed in part to alterations in the stability and rate of folding of the triple helix. In order to better understand the relationship between glycine substitutions and stability we review current concepts of the forces governing triple helical stability, denaturational and predenaturational unfolding, and the techniques of measuring stability. From observations on the stability of several collagen types as well as synthetic tripeptides, we present a model for stability based on the contribution of individual and neighboring tripeptide units to the local stability. Although in preliminary form, this empirical model can account for the observed shifts in the Tm of many of the point mutations described. The folding of the triple helix is reviewed. The involvement of peptidyl prolyl cis-trans isomerase in this process in vivo is demonstrated by the inhibition of collagen folding in fibroblasts by cyclosporin A. An hypothesis based on the relationship between the thermal stability at the site of mutation and the propensity for renucleation of folding is proposed.

Amino Acid Sequence↗
PubMed1993

Natural history of blue sclerae in osteogenesis imperfecta.

Scleral hue is an important sign which distinguishes 2 broad groupings of patients, those with and those without blue sclerae with nonlethal osteogenesis imperfecta (OI). Individuals with OI type I have distinctly blue sclerae which remain intensely blue throughout life. In OI type III and OI type IV the sclerae may also be blue at birth and during infancy, but the intensity fades with time such that these individuals have sclerae of normal hue by adolescence and adult life.

Adolescent↗
PubMed1993

Osteogenesis imperfecta: the distinction from child abuse and the recognition of a variant form.

Unexplained fractures are characteristic of both osteogenesis imperfecta (OI) and non-accidental injury (NAI) but in most cases the diagnosis is straightforward. However, in a few OI patients an initial diagnosis of NAI is made. Factors contributing to such difficulties include failure to recognise that OI can occur without a family history, without blue sclerae, without osteopenia, without an excess of Wormian bones, or with metaphyseal fractures. In addition we report on 39 patients with an unusual history in that fractures only occurred in the first year of life. Rib fractures, metaphyseal abnormalities and periosteal reactions were common. The initial diagnosis was usually OI if the fractures occurred in hospital, but NAI if they appeared to have been sustained at home. Additional findings such as anaemia, vomiting, hepatomegaly, and apnoeic attacks were often found in these patients. The disorder has some similarities to the syndrome of infantile copper deficiency. Like the latter it is particularly common in preterm infants and in twins. Therefore, we are attempting to examine the incidence of significant hypocupraemia in unselected preterm infants. We suggest that the likely cause of this "temporary brittle bone disease" is a temporary deficiency of an enzyme, perhaps a metalloenzyme, involved in the post-translational processing of collagen.

Child Abuse↗
PubMed1993

Non-invasive prenatal diagnosis of osteogenesis imperfecta.

The main mode of non-invasive prenatal diagnosis of osteogenesis imperfecta (OI) is fetal imaging, either by radiography or detailed ultrasonography. Radiography is more of historical interest and ultrasonography is in practice virtually exclusively used for non-invasive second trimester diagnosis of OI. Both methods have also been reported later in pregnancy when diagnosis allows the most appropriate method of delivery to be planned. For example, a caesarean section can be avoided if the fetus is shown to have a form of OI associated with limited survival. Ultrasonography is useful mainly for prenatal diagnosis of the severe forms of OI, especially the perinatally lethal forms (Sillence type II) and to a lesser extent for the severe progressively deforming forms (Sillence types III and III/IV). For the milder varieties of OI (Sillence types I and IV), many cases will be missed by scans. Invasive methods of prenatal diagnosis of OI (principally chorion villous sampling) are used for families with the milder dominant forms of OI and in severe forms of OI in which the actual biochemical or molecular defect in type I collagen is known. Many cases of type II OI and a few of type III have now been reported which were detected by scans before 20 weeks gestation, the earliest being at 15 weeks, for type IIA OI. These include cases not only at genetic risk but also sporadic cases in which scans were done either routinely or for obstetric indications. The ultrasonic abnormalities which are found include reduced echogenicity, multiple fractures, and deformity of the long bones, ribs and skull.(ABSTRACT TRUNCATED AT 250 WORDS)

Delivery, Obstetric↗
PubMed1993

Psychosocial aspects of osteogenesis imperfecta: an update.

Osteogenesis imperfecta (OI) is an inherited disorder in which affected individuals are stigmatized by virtue of physical differences from their peers. The extent to which these differences alter life style depend on the severity of the disorder, its natural history, the extent to which it affects social integration, the effect on physical appearance, and the presence of other affected family members. Some of these factors may adversely influence the ability of affected individuals to effectively adjust to their social and work environment and recognition of these factors may aid individuals and helpers in easing the path to a constructive life.

Adolescent↗
PubMed1993

Linkage analysis in dominantly inherited osteogenesis imperfecta.

The only serious attempts at linkage in osteogenesis imperfecta (OI) have shown that the disease is linked to type 1 collagen genes in all families studied in which it segregrates as a clear mendelian dominant trait. For prenatal diagnosis the probability that a new family is linked can be taken as greater than 0.95 and this figure is augmented as more meioses are studied. Some phenotype correlations, notably between the OI type IV phenotype and linkage to COL1A2 and between presenile hearing loss in OI type I and linkage to COL1A1, can be used to improve risk estimates substantially in families where there are no segregation data to distinguish whether COL1A1 or COL1A2 is the mutant locus.

Alleles↗