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Osteogenesis imperfecta is a complex disorder that rarely complicates pregancy. The successful obstetric management of a patient with severe osteogensis imperfecta is presented along with a detailed review of maternal osteogenesis imperfecta in the recent English literature. A review of the disease process, its complications, and associated disorders is presented.

The treatment of osteogenesis imperfecta varies with the age of the patients and the severity of disease. Patients with mild disease rarely develop significant deformities; therefore, the care required is mainly limited to periodic fractures or to associated problems, such as erosion of the teeth, decreased hearing, and difficulties in adjustment. It is the patient with severe disease who often requires an unusual amount of attention. Regardless of the immediate problem, the treatment program should be geared toward the long-term function of the patient; in most cases this will be best served by the prevention and/or correction of long bone deformities, and by encouraging maximum intellectual and academic development. The latter requires contact of the child with normal children by placement in regular school classes. The primary basis of a successful treatment program to maintain acceptable skeletal alignment consists of properly timed operations for insertion of extensible intramedullary rods, together with supportive splints and braces. No other method of treatment, such as the use of systemic medications, has yet been shown to benefit the patient clinically. Progressive improvement in bone strength during childhood permits better eventual function for those patients in whom good skeletal alignment has been maintained. Most patients will become productive members of society, so the combination of optimum physical and optimum academic development will offer maximum opportunity to those who enter the competitive job market.

Seventy percent of published articles on the medical treatment of osteogenesis imperfecta have claimed beneficial results for 20 different agents. This observation conflicts with current practice since no form of treatment has been accepted as effective in dealing with the disease. A few medications or combinations of medications hold some promise, but adequate documentation must be availble before they can be accurately assessed. It is essential that the practitioner maintain a high degree of skepticism toward positive results of treatment regardless of the source. At the present time, no agent is available which will be of any value to the practitioner who has a patient with osteogenesis imperfecta.

A collagen-type pattern of peptide and amino acid spots was obtained when partial hydrolysates of normal human dermis were examined by a specially developed thin-layer chromatographic (TLC) 'finger-printing' technique. The pattern was consistent and independent of age and sex. Two clinically similar cases of osteogenesis imperfecta congenita gave identical patterns which differed in specific regions from those given by their age-matched, normal controls. A single case of osteogenesis imperfecta tarda showed the same overall pattern as the congenita cases. It is concluded that an abnormal amino acid sequence occurs in the collagen molecule of both types of osteogenesis imperfecta.

Collagen and hyaluronic acid syntheses were studied in skin fibroblast cultures from patients with osteogenesis imperfecta and age-matched controls by labeling the cultures either with [3H]proline and separating the collagenous proteins with DEAE- and CM-cellulose chromatographies, or double-labeling the cultures with [3H]glucosamine and [14C]glycine and separating radioactive hyaluronic acid from glycoproteins and sulphated proteoglycans by DEAE-cellulose chromatography. The activities of the cell layer hyaluronate synthesizing enzyme complex (hyaluronate synthetase) were also determined. The osteogenesis imperfecta cultures were classified into three variants on the basis of type III collagen synthesis. Type III collagen amounted to approx. 40--50% from total collagen in the first variety and approx. 25--30% in the second variety. No difference was noted in the ratio of type III collagen to total collagen in the third variety in comparison with control cultures. The radioactivities of 3H-labeled hyaluronic acid in DEAE-cellulose chromatograms were compared with those of the 14C-labeled proteins. The ratios ranged 9.2--17.3 in the cultures from the patients and 4.6--8.8 in the control cultures. Hyaluronate synthetase activities were 1.3--2.0-fold higher in the osteogenesis imperfecta cells than in their controls. Increased hyaluronic acid synthesis in skin fibroblasts correlated with the severity of the disease but not with the increase in type III collagen synthesis.

In an immature male newborn, both the congenital osteogenesis imperfecta and the arteriopathia calcificans were revealed. The simultaneous occurrence of these two different conditions is rare.

Osteogenesis imperfecta is likely to be caused by primary disorders of synthesis of organic components of connective tissues accounting for clinical and laboratory observations in several affected tissues. Defects in the structure of collagen is well documented in several instances. There is no evidence of a primary disorder in the synthesis of glycosaminoglycans. Several studies of pyrophosphate metabolism and the hormonal control or the overall metabolic activity of isolated cells do not implicate a pathogenic mechanism for this disorder. Detailed biochemical and further clinical correlations are necessary in order to elucidate the pathogenesis of osteogenesis imperfecta.

Clinically, the two most prominent features of osteogenesis imperfecta are dwarfing and bone fragility. Radiologic examination reveals severe osteopenia with or without multiple deformities. Histological examination of samples obtained from 16 iliac crest biopsies compared with 21 age-matched controls revealed a significantly diminished amount of bone matrix without an associated decrease in the number of bone cells, suggesting a quantitative deficiency of collagen production. Radiologic studies of 46 affected children and autopsy studies of two children revealed abnormalities in the ossification of the secondary centers of ossification, together with evidence of fracture and fragmentation of the epiphyseal growth plates causing a characteristic radiologic appearance which may be likened to a bag of popcorn. These epiphyseal abnormalities may contribute to the limb shortening in some cases.

The problem of osteoporosis superimposed on the basic collagen defect of osteogenesis imperfecta has been approached by the use of plastic containment orthoses for the lower limbs, in addition to developmentally staged mobility devices that assist early standing and walking. The purpose of forcing early weight-bearing is to provide stress to the lower limb bones in order to minimize osteoporosis, prevent refracture and deformity, and curb subsequent immobilization osteoporosis, thus breaking a vicious cycle. Management goals are based upon adult needs for independence: efficiency in daily living activities and in mobility. These goals were reached in most of our patients via use of plastic orthoses, early weight-bearing, and electrically powered wheelchairs. Manual osteoclasis of the tibia followed by plastic orthoses utilizing principles of fluid compression to support fractured or structurally weak bones appeared successful at the time of follow-up. Intramedullary rodding of the femur was necessary in most of the 12 children with osteogenesis imperfecta congenita. Supplementary plastic orthoses have reduced the refracture rate in both the tibia and the femur. Social integration of the children was reflected by the fact that among the 12 OI congenita cases, ten were attending regular educational institutions. Twelve OI tarda children fared well, all attaining complete independence in daily living, mobility and ambulation. Seven of this group were treated with intramedullary rodding of the femur or tibia and with plastic orthoses. Five patients required no treatment.

A classification of the different types of osteogenesis imperfecta is proposed. There are 3 main groups: the lethal type, the severe type and the so-called regressive type, with a more favorable course. This classification was established to allow for a more precise definition of the prognosis at the time of birth, or even in utero when diagnosis is made by ultrasonography. It should also allow for better classification of the data obtained by the study of the molecular collagen. This project is different from Sillence's one by the exclusion of type II B lethal types, which are often compatible with survival. In view of the frequent occurrence of a dominant mutation in the type II A, the more generally accepted recessive transmission is discussed.

In the osteogenesis imperfecta patient, spinal deformity should be expected, particularly in the severely affected nonambulator with chest deformity. Curves develop early (age five to six) and generally progress rapidly. Early bracing, although somewhat effective, may well compress the soft osteoporotic rib cage without controlling the spinal curvature. The pulmonary compromise created by the scoliosis is compounded by the chest cage deformity secondary to bracing. In the patient with severe disease (thin bones and numerous fractures), posterior correction and fusion, with or without Harrington instrumentation, is the preferred approach. This should be done early as the osteoporotic bone does not tolerate the hook forces well; the correction is correspondingly limited. The use of methylmethacrylate bone cement around the hook provides redistribution of forces and more stable fixation. In the patient with mild disease (thick bones and few fractures) treatment should be similar to that of patients with idiopathic scoliosis. The chest cage should be carefully observed to avoid deformity from placement of the lateral or posterior pad.

Acute bilateral extradural hematomas occurred after apparently trivial trauma in a patient suffering from osteogenesis imperfecta congenita. Factors influencing the development of this dramatic complication are peculiar to this rare disorder of bone and connective tissue development and include bony weakness, increased vascular fragility, and possible coagulopathies.

Quantitative and qualitative abnormalities of collagen were observed in tissues and fibroblast cultures from 17 consecutive cases of lethal perinatal osteogenesis imperfecta (OI). The content of type I collagen was reduced in OI dermis and bone and the content of type III collagen was also reduced in the dermis. Normal bone contained 99.3% type I and 0.7% type V collagen whereas OI bone contained a lower proportion of type I, a greater proportion of type V and a significant amount of type III collagen. The type III and V collagens appeared to be structurally normal. In contrast, abnormal type I collagen chains, which migrated slowly on electrophoresis, were observed in all babies with OI. Cultured fibroblasts from five babies produced a mixture of normal and abnormal type I collagens; the abnormal collagen was not secreted in two cases and was slowly secreted in the others. Fibroblasts from 12 babies produced only abnormal type I collagens and they were also secreted slowly. The slower electrophoretic migration of the abnormal chains was due to enzymic overmodification of the lysine residues. The distribution of the cyanogen bromide peptides containing the overmodified residues was used to localize the underlying structural abnormalities to three regions of the type I procollagen chains. These regions included the carboxy-propeptide of the pro alpha 1(I)-chain, the helical alpha 1(I) CB7 peptide and the helical alpha 1(I) CB8 and CB3 peptides. In one baby a basic charge mutation was observed in the alpha 1(I) CB7 peptide and in another baby a basic charge mutation was observed in the alpha 1(I) CB8 peptide. The primary defects in lethal perinatal OI appear to reside in the type I collagen chains. Type III and V collagens did not appear to compensate for the deficiency of type I collagen in the tissues.

Five neonates with perinatally lethal osteogenesis imperfecta (OI) have come to necropsy at Women & Infants' Hospital of Rhode Island in the past eight years. Four had true hydrocephalus, defined as enlargement of the lateral ventricles with thinning of the cortical mantle. In all 4 hydrocephalus was diagnosed by sonography before birth. All 4 died almost immediately after birth, whereas the neonate without hydrocephalus lived for 22 days. Significant necropsy findings in the 4 with hydrocephalus included healing occipital-bone fractures with stenosis of the foramen magnum, remote and recent cerebral parenchymal and intraventricular hemorrhage, and remote and recent subarachnoid hemorrhage. True hydrocephalus of intrauterine onset has rarely been described in perinatally lethal OI, but its high incidence (80%) in this population suggests that it may be a common phenomenon. Hydrocephalus of intrauterine onset in perinatally lethal OI may indicate relatively more severe disease.

Two patients, aged 13 and 19 years, with osteogenesis imperfecta congenita (Vrolik) have been seen at the rehabilitation centre at Neckargemund. The younger patient showed the typical appearances of osteogenesis imperfecta cystica (Fairbank), while the older patient failed to show these changes in the skeleton. Contrary to the frequently expressed view that patients with osteogenesis imperfecta congenita always die in the perinatal period, they may survive for a considerable length of time. The change of osteogenesis imperfecta congenita (Vrolik) into osteogensis imperfecta cystica (Fairbank) has been described as a sequence in the occasional survivors by Spranger, but is not a necessary condition for survival. Osteogenesis imperfecta cystica should be regarded as an extremely rare special type of Vrolik's disease.

We examined 58 children aged 1-16 years with various forms of osteogenesis imperfecta (OI). Congenital cardiac malformations were diagnosed in 4 children (valvular aortic stenosis, 2 with atrial septal defect II, Fallot Tetralogy). Two additional children developed holosystolic mitral valve prolapse and regurgitation. Children suffering from a severe clinical course (type III according to the Sillence classification) showed aortic root dilatation (28%) and increased septal (40%) and posterior left ventricular wall thickening (68%) on initial evaluation. All three parameters were significantly correlated to body surface area. Kidney stones and renal papillary calcifications were detected in 4 children. Cardiovascular abnormalities and nephrolithiasis may be important extraskeletal manifestations of childhood OI.

Broad boned lethal osteogenesis imperfecta is a severely crippling disease of unknown cause. By means of recombinant DNA technology a 300 base pair deletion in an alpha 1(I)-like collagen gene was detected in six patients and four complete parent-child groups including patients with this disease. One from each set of the patients' clinically unaffected parents also carried the deletion, implying that affected patients were genetic compounds. The study suggests that prenatal diagnosis should be possible with 100% accuracy in subjects without the deletion and with 50% accuracy in those who possess it (who would be either heterozygous--normal, or affected with the disease).

There is now strong evidence for the implication of collagen alpha 1(I), alpha 2(I) and alpha 1(III) mutations in many forms of osteogenesis imperfecta and inherited arterial aneurysms (Ehlers Danlos syndrome type IV). A sizeable proportion of these disorders have detectable abnormalities by conventional protein chemistry, immunofluorescence, or more sophisticated DNA analysis. Everyone of them with specific defects or with linkage to appropriate gene markers is therefore amenable to prevention using conventional prenatal diagnosis by chorionic villus biopsy (with fibroblast culture), fetoscopic biopsy (with fibroblast culture), ultrasound diagnosis of the severely deformed fetus, or gene linkage studies by chorionic villus biopsy or amniocentesis. Already many collagen alpha 1(I), alpha 2(I) and alpha 1(III) mutations have been characterized including point mutations, small and large deletions and regulatory mutations. Many others are likely to be rapidly studied by exploiting recent advances in DNA technology, and other strong candidate genes include collagen II (some chondrodystrophies), collagen VI (certain arterial and cardiovascular diseases) and collagen VII (dystrophic epidermolysis bullosa). Other important common diseases are likely to include osteoporosis, osteoarthritis and cerebral aneurysms. A detailed review is provided of collagen interstitial genes and proteins, together with a description of the various forms of osteogenesis imperfecta and Ehlers Danlos syndrome in which either collagen alpha 1(I), alpha 2(I) or alpha 1(III) mutations have been identified. Appropriate restriction length polymorphisms (RFLPs) useful in identifying carriers of these mutant genes are also described.