Surgery in osteogenesis imperfecta

An analysis of 266 operations on 63 patients with osteogenesis imperfecta, mostly type III and IV, showed that about half had corrections of skeletal deformities and internal splinting with intramedullary stainless steel rods. The remaining operations were for other orthopaedic procedures as well as non-orthopaedic procedures such as hernia repairs. There were no major anaesthetic or post-operative complications. Mild pyrexia was common but without the features of malignant hyperpyrexia. Correction of long deformities and internal splintage of the bones with non-expanding rods effectively reduced the fracture rate but deformities and fractures recurred as the epiphyses grew off the ends of the rods. Expanding rods provided continuing splintage during growth but could not be used in children with very narrow or very fragile bones.     

Arachnoid cyst and chronic subdural haematoma in a child with osteogenesis imperfecta type III resulting from the substitution of glycine 1006 by alanine in the pro alpha 2(I) chain of type I procollagen.

The features of a child with osteogenesis imperfecta type III (OI III) resulting from the heterozygous substitution of glycine 1006 by alanine in the pro alpha 2(I) chain of type I procollagen were studied. He was born at term with the clinical features of severe OI, including deep grey-blue sclerae. He had severe osteopenia and all long bones were smaller than normal with cortical thinning, metaphyseal expansion, poor metaphyseal modelling, and multiple fractures. However, the vertebrae, pelvis, and shoulder girdle were of normal shape and there were few rib fractures. Histological examination of the calvarium and tibial shaft showed woven bone without lamellar bone or Haversian systems. The shafts of the long bones were widened owing to repeated fractures. Progressive enlargement of the calvarium occurred between 3 and 4.5 months of age owing to bilateral chronic subdural haematomata and a large arachnoid cyst in the Sylvian fissure. The cyst was probably developmental in origin while the subdural collections were probably the result of perinatal skull trauma. The cyst and the subdural collections resolved following drainage but ventricular dilatation with normal cerebrospinal fluid pressure followed. The proband is the first reported case of OI with a glycine substitution by alanine in the pro alpha 2(I) chain of type I procollagen.     

A cross‐sectional multicenter study of osteogenesis imperfecta in North America – results from the linked clinical research centers

Osteogenesis imperfecta (OI) is the most common skeletal dysplasia that predisposes to recurrent fractures and bone deformities. In spite of significant advances in understanding the genetic basis of OI, there have been no large‐scale natural history studies. To better understand the natural history and improve the care of patients, a network of Linked Clinical Research Centers (LCRC) was established. Subjects with OI were enrolled in a longitudinal study, and in this report, we present cross‐sectional data on the largest cohort of OI subjects (n = 544). OI type III subjects had higher prevalence of dentinogenesis imperfecta, severe scoliosis, and long bone deformities as compared to those with OI types I and IV. Whereas the mean lumbar spine area bone mineral density (LS aBMD) was low across all OI subtypes, those with more severe forms had lower bone mass. Molecular testing may help predict the subtype in type I collagen‐related OI. Analysis of such well‐collected and unbiased data in OI can not only help answering questions that are relevant to patient care but also foster hypothesis‐driven research, especially in the context of ‘phenotypic expansion’ driven by next‐generation sequencing.     

Heterozygous C-propeptide mutations in COL1A1: osteogenesis imperfecta type IIC and dense bone variant

Osteogenesis imperfecta type IIC (OI IIC) is a rare variant of lethal OI that has been considered to be an autosomal recessive trait. Twisted, slender long bones with dense metaphyseal margins and normal vertebral bodies in OI IIC contrast with crumpled, thick long bones and multiple vertebral compression fractures in OI IIA. Here, we report on two sporadic patients with classical OI IIC and a pair of siblings, with features of OI IIC but less distortion of the tubular bones (OI dense bone variant). One case with OI IIC and the sibs had novel heterozygous mutations in the C-propeptide region of COL1A1, while the second patient with clear-cut OI IIC had no mutation in this region. Histological examination in the two sporadic cases showed a network of broad, interconnected cartilaginous trabeculae with thin osseous seams in the metaphyses. These changes differed from the narrow and short metaphyseal trabeculae found in other lethal or severe cases of OI. Our experience sheds light on the genetics and etiology of OI IIC and on its phenotypic spectrum.     

The clinicopathological features of three babies with osteogenesis imperfecta resulting from the substitution of glycine by valine in the pro alpha 1 (I) chain of type I procollagen.

The features of three babies with perinatal lethal osteogenesis imperfecta (OI II) resulting from substitutions of glycine by valine in the triple helical domain of the alpha 1(I) chain of type I collagen were studied. The babies were heterozygous for this substitution at residue 1006 in case 1 (OI35), 973 in case 2 (OI59), and 256 in case 3 (OI7B). OI35 had the most severe clinical form, OI IIC, with premature rupture of membranes, severe antepartum haemorrhage, stillbirth, severe short limbed dwarfism, and extreme osteoporosis. OI59 was a better formed baby but was also born prematurely as a result of premature rupture of membranes and severe antepartum haemorrhage. She had the radiographic features of OI IIA. OI7B was born at term and also had the radiographic features of OI IIA. Pathological examination of the skeletons of OI35 and OI59 showed grossly deficient intramembranous and endochondral ossification. Trabecular bone was sparse in the long bones and vertebrae. The trabeculae contained a cartilage core and an overlying layer of woven bone or osteoid. The diaphyses lacked cortical bone. The periosteal fibroblasts of OI35 contained grossly distended rough endoplasmic reticulum consistent with the 53% reduction in collagen secretion by cultured dermal fibroblasts. The aorta, skin, and lungs were hypoplastic in OI35 and OI59. The findings in this study show that glycine substitutions by valine in Gly-X-Y triplets, from glycine 256 to glycine 1006, of the triple helical domain of alpha 1(I) chains produce the OI II phenotype. The phenotype was most severe in the baby with the most carboxy-terminal substitution.     

Report on new types of intramedullary rods and treatment effectiveness data for selection of intramedullary rodding in osteogenesis imperfecta

Major advances in the surgical treatment of fractures of long bones in children with Osteogenesis Imperfecta (O.I.) have been made in the last several years. The current mainstay of treatment is bracing and active rehabilitation. When this fails surgery is indicated. The type of fixation device used is generally some type of stainless steel rod. The rod stabilizes the fracture as well as accepts the load across the fracture site thus enabling the fracture to heal. However, the current rods in use have complications. One such complication is cortical atrophy felt to be secondary to the removal of stress from the bone. This phenomena is called stress shielding. Stress shielding in the current rods prompted the study of two new types of rods which more closely approximate the modulus of elasticity of bone. The use of such rods should eliminate the problems of stress shielding. The following paper describes the effectiveness of the various intramedullary rods in the treatment of Osteogenesis Imperfecta fractures. It also reports on the initial results of two new types of intramedullary rods which more closely approximate the modulus of elasticity of bone and therefore may eliminate stress shielding. These rods may replace the stainless steel rods as the "gold standard" of therapy for surgical fixation of long bone fractures in children with Osteogenesis Imperfecta.     

Dental and craniofacial characteristics caused by the p.Ser40Leu mutation in IFITM5

Severe forms of osteogenesis imperfecta (OI) are usually caused by mutations in genes that code for collagen Type I and frequently are associated with craniofacial abnormalities. However, the dental and craniofacial characteristics of OI caused by the p.Ser40Leu mutation in the IFITM5 gene have not been reported. We investigated a 15‐year‐old girl with severe OI caused by this mutation. She had marked deformations of extremity long bones. There were no clinical or radiological signs of dentinogenesis imperfecta, but one tooth was missing and several teeth were impacted. Cone beam computed tomography revealed a generalized osteopenic appearance of the craniofacial skeleton, bilateral enlargement of mandibular bodies, and areas of cortical erosions. The cranial base and skull showed a generalized granular bone pattern with a mixture of osteosclerosis and osteolysis. Sphenoid and frontal sinuses were congenitally missing. Cephalometric analysis indicated a Class III growth pattern. In this case, the IFITM5 p.Ser40Leu mutation did not affect tooth structure but was associated with deformities in craniofacial bones that resemble those in the other parts of the skeleton.     

The clinical features of osteogenesis imperfecta resulting from a non-functional carboxy terminal pro alpha 1(I) propeptide of type I procollagen and a severe deficiency of normal type I collagen in tissues.

The features of a baby with lethal perinatal osteogenesis imperfecta (OI II), owing to a frameshift mutation that resulted in the production of a truncated and functionless carboxy terminal propeptide of the pro alpha 1(I) chain of type I procollagen, were studied. The baby (OI26) was heterozygous for an insertion of a single uridine nucleotide after base pair 4088 of the prepro alpha 1(I) mRNA of type I procollagen. Only normal type I collagen was incorporated into the extracellular matrix of bone and dermis resulting in a type I collagen content of about 20% of control tissues. The baby was born at 35 weeks' gestation and died shortly afterwards. He was small and had the radiographical features most like those of OI IIB. The skeleton was poorly ossified. The ribs were discontinuously beaded and the femora were broad with multiple healed fractures of the diaphyses and metaphyses. Other long bones had broad metaphyses with overmodelled diaphyses. The calvarium contained many hundreds of wormian bones. Histological examination showed grossly deficient endochondral and intramembranous ossification. The bone was of a woven type without evidence of lamellar bone or Haversian systems and the osteoblasts did not mature into osteocytes. The cortex of the femur contained Haversian canals but they were surrounded by loose collagen fibres and a mosaic pattern of woven bone and islands of cartilage. We propose that OI IIB can be sub-classified into two groups, one with helical mutations and both normal and mutant type I collagen in the tissues, and the other with carboxy terminal propeptide mutations and a severe type I collagen deficiency, but without mutant collagen in the tissues.     

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. There is a marked reduction of long bone length on measurement. The abnormalities are more severe in type II OI than in type III. No false negative diagnoses have yet been reported for severe OI. Ultrasonography is a reliable mode of prenatal diagnosis for a pregnancy at risk of type II OI and probably also for type III, although more reports for the latter are needed to give more information about the likelihood of false negative diagnoses in this form of OI. For pregnancies at risk of types II and III OI, serial scans from 14 weeks gestation can be offered. An experienced operator, using a good realitime scanner should be able to detect type II OI by at least 17 weeks gestation, and type III OI by 19 to 20 weeks. In future, it may be possible to diagnose type II OI in the first trimester by ultrasound using an intravaginal transducer.     

A single amino acid substitution (D1441Y) in the carboxyl-terminal propeptide of the proalpha1(I) chain of type I collagen results in a lethal variant of osteogenesis imperfecta with features of dense bone diseases

Osteogenesis imperfecta (OI) is characterised by brittle bones and caused by mutations in the type I collagen genes, COL1A1 and COL1A2. We identified a mutation in the carboxyl-terminal propeptide coding region of one COL1A1 allele in an infant who died with an OI phenotype that differed from the usual lethal form and had regions of increased bone density. The newborn female had dysmorphic facial features, including loss of mandibular angle. Bilateral upper and lower limb contractures were present with multiple fractures in the long bones and ribs. The long bones were not compressed and their ends were radiographically dense. She died after a few hours and histopathological studies identified extramedullary haematopoiesis in the liver, little lamellar bone formation, decreased osteoclasts, abnormally thickened bony trabeculae with retained cartilage in long bones, and diminished marrow spaces similar to those seen in dense bone diseases such as osteopetrosis and pycnodysostosis. The child was heterozygous for a COL1A1 4321G→T transversion in exon 52 that changed a conserved aspartic acid to tyrosine (D1441Y). Abnormal proα1(I) chains were slow to assemble into dimers and trimers, and abnormal molecules were retained intracellularly for an extended period. The secreted type I procollagen molecules synthesised by cultured dermal fibroblasts were overmodified along the full length but had normal thermal stability. These findings suggest that the unusual phenotype reflected both a diminished amount of secreted type I procollagen and the presence of a population of stable and overmodified molecules that might support increased mineralisation or interfere with degradation of bone.     

Total knee arthroplasty in osteogenesis imperfecta: case report

Osteogenesis imperfecta (OI) is a rare congenital disorder of type capital I, Ukrainian collagen production that results in brittle bones and affects body systems containing collagen. The increasing life span of patients with OI has recently revealed a high incidence of osteoarthritis of the knee. A 53 year-old man with OI presented with bilateral knee pain. He had severe deformities of the proximal part of the femur with subsegment post-traumatic osteoarthritis of both sides of the knees. However, the frequency of fracture gradually decreased and he had not experienced a fracture for 17 years. His bone mineral density was extremely low for his age. He underwent cemented total knee arthroplasty (TKA) on the left knee. One year later, the patient had relief of pain and he could walk without assistance. To our knowledge, only three knee replacements in two patients with OI have been reported, so this case is extremely rare. Although whether a patient with OI is a suitable candidate for knee replacement, it was a useful treatment for osteoarthritis in this case.     

Genetic heterogeneity in osteogenesis imperfecta.

An epidemiological and genetical study of osteogenesis imperfecta (OI) in Victoria, Australia confirmed that there are at least four distinct syndromes at present called OI. The largest group of patients showed autosomal dominant inheritance of osteoporosis leading to fractures and distinctly blue sclerae. A large proportion of adults had presenile deafness or a family history of presenile conductive hearing loss. A second group, who comprised the majority of newborns with neonatal fractures, all died before or soon after birth. These had characteristic broad, crumpled femora and beaded ribs in skeletal x-rays. Autosomal recessive inheritance was likely for some, if not all, of these cases. A third group, two thirds of whom had fractures at birth, showed severe progressive deformity of limbs and spine. The density of scleral blueness appeared less than that seen in the first group of patients and approximated that seen in normal children and adults. Moreover, the blueness appeared to decrease with age. All patients in this group were sporadic cases. The mode of inheritance was not resolved by the study, but it is likely that the group is heterogeneous with both dominant and recessive genotypes responsible for the syndrome. The fourth group of patients showed dominant inheritance of osteoporosis leading to fractures, with variable deformity of long bones, but normal sclerae.     

Incidence and treatment of adult femoral fractures with osteogenesis imperfecta: An analysis of a center of 72 patients in Taiwan

Background: Osteogenesis imperfecta (OI) is a rare disease characterized by increased bone fragility and susceptibility for fractures. Only few studies have compared the management for femoral fractures in children with OI. Nevertheless, no cohort studies have described the treatment for femoral fractures in adults with OI in Taiwan. This study aimed to investigate and compare the incidence of union and non-union femoral fractures and the best treatment options to avoid non-union fractures.Methods: We enrolled 72 patients with OI who were older than 18 years at MacKay Memorial Hospital between January 2010 and December 2018. Femoral fracture incidence, non-union rate, and treatment modality were analyzed.Results: Of 72 patients with OI, 11 patients had femoral fractures and 4 patients of them had >1 femoral fracture. The incidence for all types of femoral fractures was 651 fractures per 100,000 person-years annually. In 15 total fractures, 4 fractures resulted in non-union, and patients with type 4 OI mostly had shaft fractures. The best outcomes for non-union shaft fracture is achieved by surgical treatment.Conclusion: Adults with OI tended to develop femoral fractures and non-unions. Adults with type 4 OI were particularly at high risk for non-unions in shaft fractures with conservative treatment.     

Osteogenesis imperfecta, current and future medical treatment

Physiotherapy, rehabilitation, and orthopedic surgery are the mainstay of treatment in moderate to severe forms of osteogenesis imperfecta (OI). Nevertheless, medical treatment with bisphosphonates can bring significant additional improvements. Benefits include decreased pain, lower fracture incidence, and better mobility. Among the various bisphosphonates, intravenous pamidronate has been studied in most detail. It is unclear whether oral bisphosphonates are as effective as intravenous pamidronate. As the effect of bisphosphonates on the skeleton is largest during growth, it appears logical to start medical therapy of OI patients as early as possible. However, the optimal treatment regimen and the long-term consequences of pamidronate treatment in children are currently unknown. Given these uncertainties, treatment with bisphosphonates during growth should be reserved for patients who have significant clinical problems, such as vertebral compression fractures or long bone deformities. Medical therapies other than bisphosphonates, such as growth hormone and parathyroid hormone, play a minor role at present. Gene-based therapy currently remains in the early stages of preclinical research.     

A family with homozygous and heterozygous p.Gly337Ser mutations in COL1A2

Osteogenesis imperfecta (OI) is commonly caused by monoallelic mutations in COL1A1 or COL1A2. Biallelic mutations are extremely rare. Only five previous reports have identified seven OI patients with homozygous mutations in COL1A2. OI is a genetically and phenotypically heterogeneous disorder which challenges an establishment of genotype-phenotype correlation. Notably, more than thirty patients with OI possess the heterozygous mutation, p.Gly337Ser, in COL1A2. Their clinical severity ranges from mild OI type I to severe types III and IV. Here, we report a 17-year-old Thai female with recurrent bone fractures, short stature, blue sclerae, triangular face, missing teeth, dentinogenesis imperfecta (DI), skeletal deformities, and scoliosis. She was diagnosed with OI type III. Her parents were second-cousin-once-removed. The father was a professional Thai boxer. Both had normal bone mineral density, no history of bone fractures, and only teeth problems. They were diagnosed with DI without OI. Whole exome sequencing identified that the proband harbored the homozygous mutation, c.1009G > A (p.Gly337Ser), in exon 19 of COL1A2 while her parents were heterozygous for this mutation. This study reports the eighth child with OI and the homozygous mutation in COL1A2; and the first two individuals with the heterozygous p.Gly337Ser mutation in COL1A2 causing an isolated DI without OI.     

Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study

PurposeOsteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI.MethodsUsing data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves.ResultsIn children, the median z-scores for height in OI types I, III, and IV were −0.66, −6.91, and −2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was −4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P < 0.001), age, bisphosphonate use, and rodding (P < 0.05).ConclusionFrom the largest cohort of individuals with OI, we provide median values for height, weight, and BMI z-scores that can aid the evaluation of overall growth in the clinic setting. This study is an important first step in the generation of OI-specific growth curves.     

Popcorn calcification in osteogenesis imperfecta: incidence, progression, and molecular correlation

Osteogenesis imperfecta (OI) is a heritable disorder characterized by osteoporosis and increased susceptibility to fracture. All children with severe OI have extreme short stature and some have "popcorn" calcifications, areas of disorganized hyperdense lines in the metaphysis and epiphysis around the growth plate on lower limb radiographs. Popcorn calcifications were noted on radiographs of two children with non-lethal type VIII OI, a recessive form caused by P3H1 deficiency. To determine the incidence, progression, and molecular correlations of popcorn calcifications, we retrospectively examined serial lower limb radiographs of 45 children with type III or IV OI and known dominant mutations in type I collagen. Popcorn calcifications were present in 13 of 25 type III (52%), but only 2 of 20 type IV (10%), OI children. The mean age of onset was 7.0 years, with a range of 4-14 years. All children with popcorn calcifications had this finding in their distal femora, and most also had calcifications in proximal tibiae. While unilateral popcorn calcification contributes to femoral growth deficiency and leg length discrepancy, severe linear growth deficiency, and metaphyseal flare do not differ significantly between type III OI patients with and without popcorn calcifications. The type I collagen mutations associated with popcorn calcifications occur equally in both COL1A1 and COL1A2, and have no preferential location along the chains. These data demonstrate that popcorn calcifications are a frequent feature of severe OI, but do not distinguish cases with defects in collagen structure (primarily dominant type III OI) or modification (recessive type VIII OI).     

足副骨的X线观察

观察３４３５例儿童和１８１例成人足部Ｘ线片，确定国人民副骨的出现率和探讨其临床意义。共发现１６种副骨，儿童组出现率１６．８３％，成人组５８．５６％，两组间有显著差异，男１６．９７％，女２１．２９％，性别间有显著差异。外胫骨最多见，跖间骨出现最早（５岁）。足副骨较易诊断，但少数副骨可与骨折混淆，如外胫骨（４％）和三角骨（７％）形似撕脱骨折。     

Bruck syndrome (osteogenesis imperfecta with congenital joint contractures): Review and report on the first North American case

We describe a patient who was born with flexion contractures and pterygia at the elbows, clubfeet, torticollis, and several rib fractures. During infancy and childhood, multiple fractures of the lower limbs occurred with minimal trauma and led to disabling deformities. When evaluated at age 19 years, he was normally intelligent, but extremely short, with severe kyphoscoliosis compromising his pulmonary function. Pterygia limited elbow extension to 90°, and severe lower limb deformities prevented ambulation. He did not have blue sclerae, dentinogenesis imperfecta, or hearing loss. X-ray studies showed demineralized bones, severe deformity and cystic change at old fracture sites, and vertebral wedging. Collagen studies on skin fibroblasts were normal. Am. J. Med. Genet. 70:28–31, 1997. © 1997 Wiley-Liss, Inc.