Osteogenesis imperfecta: practical treatment guidelines.

Osteogenesis imperfecta (OI), an inherited connective tissue disorder of remarkable clinical variability, is caused by a quantitative or qualitative defect in collagen synthesis and is characterised by bone fragility. The number of fractures and deformities, and the age at which they begin greatly influence the prognosis and the achievement of walking and autonomy. A multidisciplinary team approach is essential for diagnosis, for communication with patient and parents, and to tailor treatment needs to the severity of the disease and the age of the patient. Three types of treatment are available: nonsurgical management (physical therapy, rehabilitation, bracing and splinting), surgery (intramedullary rod positioning, spinal and basilar impression surgery), and drugs to increase the strength of bone and decrease the number of fractures. An aggressive rehabilitative approach is indicated to optimise functional ability and walking capacity; appropriately timed surgery to insert intramedullary rods provides improved function of extremities. Despite a high rate of complications, intramedullary telescopic roding has proven to be the most successful method for preventing and correcting fractures and deformities of long bones, improving walking capability and leading to successful rehabilitation of even severely affected patients. Surgery may be required in patients with progressive spinal deformity and in those with symptomatic basilar impression. Hearing function, dentinogenesis imperfecta, cardiac and respiratory function, and neurological changes must be monitored. The causal defect of the disease cannot be corrected with medical treatment and, currently, only symptomatic therapy is available. In recent years growth hormone (GH) and bisphosphonate agents have been used in OI therapy. GH is beneficial in patients with moderate forms of OI, showing a positive effect on bone turnover, bone mineral density and height velocity rate. Bisphosphonates have proved beneficial in children with severe OI, increasing bone mineral density and reducing the fracture rate and pain with no adverse effects reported. These data require confirmation in double-blind controlled studies; however, bisphosphonates have markedly improved morbidity in patients with OI. Future developments in genetic therapy may be directed towards either replacing cells carrying the mutant gene with normal cells or silencing the mutant allele using antisense suppression therapy, thus transforming a biochemically severe form of OI into a mild form.

[Etiology and precipitating factors of cyclic vomiting]. / Eziologia e fattori precipitanti del vomito ciclico.

The aim of the study was to determine the nature, severity, precipitants and associated features of attacks and the incidence of potential aetiological factors of cyclic vomiting syndrome (CVS). Ten patients (6 boys and 4 girls aged 2-12 years) with CVS, defined as recurrent episodes of vomiting with symptom-free intervals occurring two or more times per year, with episodes having a similar pattern and for which no other cause could be found, ten patients (7 boys and 3 girls aged 7-14 years) with migraine, defined as recurrent headache with symptom-free intervals and at least three of the following symptoms or associated findings: abdominal pain, nausea or vomiting, throbbing headache, unilateral location, associated aura (visual, sensory, motor), relief after sleeping and ten controls (6 boys and 4 girls aged 4-13 years) were studied. The mean age at onset of symptoms in patients with CVS was 3.9 years and the mean number of attacks per year was 4, the average duration of episodes was 20.5 hours and the mean number of school missed days were 6 per year. The mean age at onset of symptoms in patients with migraine was 7.6 years and the mean number of attacks per year was 9.9, the average duration of episodes was 8 hours and the mean number of school missed days were 6.4 per year. A family history of migraine was significantly higher in both groups of patients, compared with controls (p = 0.009). A personal history of headache and/or migraine and associated sign or symptoms like recurrent abdominal pains, limb pain and kinetosis was significantly higher in both patients compared with controls (p < 0.001). CVS is a chronic, disabling condition and is a migraine variant, with attacks usually precipitated by stress and intercurrent infections.

Severe (type III) osteogenesis imperfecta due to glycine substitutions in the central domain of the collagen triple helix.

The molecular defects responsible for three cases of severe (type III) osteogenesis imperfecta (OI) were investigated. The mutation sites were localized in pro alpha 1(I) and pro alpha 2(I) mRNA molecules, respectively, by chemical cleavage of mismatch in heteroduplex nucleic acids. Mutation identification was achieved by reverse transcription-polymerase chain reaction-DNA amplification, followed by cloning and sequencing. Two unrelated patients were demonstrated to bear the same G-A transition at nucleotide 2418 of the pro alpha 1(I) coding region, leading to G589S substitution and resulting in very similar clinical manifestations. In the latter patient, a G-T transversion at nucleotide 2166 was found in one pro alpha 2(I) allele, which caused a G586V substitution and again severe OI. Presumably all three mutations occurred de novo in the probands, since they were not found in their parents' DNA. The biochemical findings on type I collagen were very similar in all the probands: the mutations here described had little destabilizing effects on triple helix formation, secretion and stability. The half-life of the collagen incorporated into the insoluble matrix was comparable with that of controls. These mutations are localized in the gap zone of the fibrils where mineral nucleation occurs. This fact suggests that they probably do not exert destabilizing effects on the individual collagen molecules, but rather on the mineralization process, once the defective molecules are incorporated into the fibrils, hence causing severe phenotypes.

Phenotypic variability and abnormal type I collagen unstable at body temperature in a family with mild dominant osteogenesis imperfecta.

Autosomal dominant inheritance of a mild form of osteogenesis imperfecta (osteogenesis imperfecta type I) with different phenotypic expression was found in a family. Phenotypic expression was different for the affected mother and son, in the presence of the same biochemical results. Dermal fibroblast cultures synthesized normal and mutant type I collagen alpha chains. Collagen heterotrimers containing abnormal chains were overmodified along the entire triple helical domain and showed an unusually low denaturation temperature, so far found only in lethal cases. The mild phenotype in the family is probably due to the fact that abnormal type I collagen molecules are more likely to be degraded than utilized in the extracellular matrix.

Corrective femoral osteotomy and telescopic nailing in osteogenesis imperfecta.

Six cases of osteogenesis imperfecta with femoral deformity treated by Bailey telescopic nailing are discussed. In 4 cases the operation was bilateral. The long-term results show that this nail lengthens without compromising longitudinal growth of the bone, while providing protection from fracture and recurrence of the deformity. Thinning of the diaphyseal cortex was a significant complication in 3 femurs out of 10. Although it is more difficult to apply, the telescopic nail is preferable to traditional nailing because of its better mechanical features which allow for early weightbearing and walking.

[A case of bilateral tibial agenesis with multiple malformations and an unusual face: a new syndrome?]. / Su di un caso di agenesia tibiale bilaterale con malformazioni multiple e faccia inusuale: nuova sindrome?

This paper deals with a patient affected with total bilateral tibial agenesis, multiple congenital deformities and a very unusual face. After a review of the literature this case has resembled interesting to point out because it is probably an autonomous nosologic form.

Surgical treatment of the deformities of the long bones in severe osteogenesis imperfecta.

The authors report their experience in the surgical treatment of bone deformities in osteogenesis imperfecta, based upon 45 operations in 13 severely affected patients. Three different procedures were used. Fragmentation and temporary fixation by means of a wire does not guarantee a sufficient protection of the bone and shows a relapse of deformity at the lower limbs; fragmentation, realignment and intramedullary rods, technically easier, is indicated in patients who are near the end of osseous growth; the extensible Bailey-Dubow rod, being an even more complicated application, is absolutely indicated in the bone in growth. Functional recovery of the patients was satisfactory, and complications were scarse, with the exception of a significant incidence of diaphyseal atrophy.

Localization of a structural defect in type I procollagen in a patient affected with the severe non-lethal form of Osteogenesis imperfecta.

A case of severe non-lethal Osteogenesis imperfecta was studied. The patient's cultured skin fibroblasts synthesised a mixed population of type I collagen chains some of which showed abnormal behaviour on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Further analysis revealed that two types of alpha 1(I) chains were synthesised, both an abnormal, slower migrating and a normal species. A small defect in one allele of one of the type I procollagen chains could lead to the larger size of the abnormal chains, probably caused by overmodifications of the triple helical region. CNBr peptide mapping allowed us to localise the defect midway along the triple helix: the defect site could be assigned to the region between the alpha 1(I)CB-3 and CB-7 peptides. The abnormal alpha 1(I) chains synthesised by the patient's cells had a melting temperature which was about 2 degrees C lower than normal chains. The results appear to be in agreement with the defect localisation and the phenotype.

Computerized axial tomography in obstetrical paralysis of the brachial plexus.

For the past two years we have been using CT scan of the shoulders and humeri for all our patients affected with obstetrical paralysis of the upper limb, in addition to the routine clinical, electromyographic and radiographic examinations, thus integrating all the results. It opens up new perspectives in the study of the pathological anatomy of the shoulder and the upper extremity in obstetrical paralysis and has proved essential in the study of the following parameters: declination angle of the humerus; shape of the humeral head; joint congruence of the shoulder; orientation of the scapula. The non-invasiveness, tolerability, and precisation of this method have produced interesting results in 23 patients.