Progressive Collapse of the Thoracic Cage

A 48-year-old patient presented with severe and progressive painful shrinkage of the thoracic cage as the result of repetitive minor fractures. Chest radiographs showed a severe form of flail chest, and the lateral spine was overwhelmed by severe rigid scoliosis. At the age of 35 years and because of repetitive episodes of vertebral fractures and low bone mass, the diagnosis of idiopathic osteoporosis was established. The patient was treated with 20 μg teriparatide (subcutaneous injection of parathyroid hormone 1-34) and 0.5 μg calcitriol per day for 18 months to improve his osteoporotic status. In addition, he received supplemental calcium and vitamin D. His bone mineral density in L1-L4 improved and increased to 0.927 g/cm2 corresponding to a T-score of −2.1 and in the femoral neck to 0.833 g/cm2 corresponding to a T-score of −1.4. Unfortunately, this treatment protocol converted his backbone into a more rigid spine, resulting in a collapse of the thoracic cage. Family pedigree search was the baseline tool to reject the diagnosis of idiopathic osteoporosis. The clinical and radiographic phenotypes of the patient's 2 daughters were the key element to refute the diagnosis of idiopathic osteoporosis. Osteogenesis imperfecta was identified. At the age of 30 years, the patient progressively reported back pain. Radiographs and magnetic resonance imaging were performed. He had vertebral fractures of T 6, 7, 9, 12, and L2 amid rigid scoliosis. The dual-energy X-Ray absorptiometry scan showed a low bone mineral density of 0.661 g/cm2 in L1-L4 corresponding to a T-score of −4.3 and a low bone mineral density of 0.705 g/cm2 in the femoral neck corresponding to a T-score of −2.5. He showed normal serum calcium and a low serum phosphate of 0.71 mmol/L (normal, 0.83-1.48 mmol/L). Serum CrossLaps (2.9 nM; normal, 0.00-7.78 nM) and parathyroid hormone parameters (8.73 pg/mL; normal, 8.3-68.0) were within the normal range. Serum 25-hydroxy vitamin D was estimated by radioimmunoassay to be 36 ng/mL (desirable 25(OH)D levels are 36-48 ng/mL). At this stage, the diagnosis of idiopathic osteoporosis was established. Therefore, 20 μg teriparatide (subcutaneous injections) 1-34 and 0.5 μg calcitriol per day were prescribed for 18 months. Bone mineral density in L1-L4 increased to 0.927 g/cm2 corresponding to a T-score of −2.1 and in the femoral neck increased up to 0.833 g/cm2 corresponding to a T-score of −1.4. In response to this treatment, there was a dramatic improvement in his bone mineral density. Nevertheless, the spine rigidity became more profound, and over time the ribs were rendered too fragile. Idiopathic osteoporosis was the adopted diagnosis for more than a decade, until we decided to examine the rest of the family subjects. The key element in establishing the diagnosis of osteogenesis imperfecta was the clinical and radiographic examination of the 2 daughters. Clinical examination showed normal stature despite rigid scoliosis. Craniofacial examination showed normal phenotype, concomitant reduction of the lung capacity, and a remarkable thoracic muscle weakness associated with tenderness on palpation, crepitus, and enormous chest wall deformity. There were chest cavities observed during inspiration, bulging outward in expiration. Musculoskeletal examination was based on measuring the range of joint motion, using the anatomic landmark method. In the upper extremities, range of motion of the shoulder joint (flexion and abduction), elbow joints (flexion and extension), and wrist joint (dorsal and palmar flexion), and flexion and extension in the second metacarpophalangeal joint were measured. In the lower extremities, flexion, extension, abduction, and external rotation were measured in the hip joint. In the knee joint, flexion and extension were measured along with plantar and dorsal flexion in the ankle joint. Manual muscle strength was tested, which includes muscle strength of the anteflexors and abductors of the shoulder, flexors and extensors of the elbow and wrist, and flexors of the fingers. In the lower limbs, the flexors, abductors, and extensors of the hip joint, the flexors and extensors of the knee joints, and the dorsal flexors and plantar flexors of the ankle joint also were tested. We observed a notable decrease in muscle strength, particularly in the periarticular hip muscles. We also observed that the degree of muscle strength was almost similar between the upper and lower limbs. The diagnosis of osteogenesis imperfecta was established after examining his 2 daughters. The patient's first daughter was an 8-year-old who manifested ligamentous hyperlaxity with no history of fractures. A lateral skull radiograph showed multiple wormian bones (Figure 1). The patient's youngest daughter, aged 3 years, had a history of bilateral hip dysplasia associated with bowing of the femur (Figure 2).Figure 2Anteroposterior radiograph of the pelvis and lower limbs shows acetabulo-femoral dysplasia associated with bilateral bowing/incurvation of the femora.View Large Image Figure ViewerDownload Hi-res image Download (PPT) A 3-dimensional reconstruction computed tomography scan of the father's thorax showed excessive thinning and stretching of fragile ribs against the severe tilting of the rigid spine, with subsequent development of thoracic cage collapse and development of thread-like ribs (Figure 3). The accumulated data of the family were suggestive of osteogenesis imperfecta type I. By using next-generation sequencing panel, the father was found to be a carrier of the heterozygous mutation of COL1A2, NM_000089.3: c.1801G>A, p.(Gly601Ser)*. The identification of this mutation was performed by using the next-generation sequencing panel described by Sule et al1Sule G. Campeau P.M. Zhang V.W. et al.Next-generation sequencing for disorders of low and high bone mineral density.Osteoporos Int. 2013; 24: 2253-2259Crossref PubMed Scopus (46) Google Scholar and confirmed by Sanger sequencing. Both daughters were carriers of the heterozygous mutation of COL1A2. This testing was performed on a research basis with the collaboration of Victor Zhang of the Medical Genetics Laboratories of the Baylor College of Medicine. Osteoporosis is defined as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue and decreased bone mass.2Khosla S. Lufkin E.G. Hodgson S.F. Fitzpatrick L.A. Melton 3rd, L.J. Epidemiology and clinical features of osteoporosis in young individuals.Bone. 1994; 15: 551-555Abstract Full Text PDF PubMed Scopus (146) Google Scholar This results in fragile, weakened bones that fracture easily even in the absence of trauma. The incidence of osteoporotic vertebral fractures in the United States is greater than 500,000 per year.3Cooper C. Atkinson E.J. O'Fallon W.M. Melton III, L.J. Incidence of clinically diagnosed vertebral fractures: a population-based study in Rochester, Minnesota, 1985-1989.J Bone Miner Res. 1992; 7: 221-227Crossref PubMed Scopus (1263) Google Scholar The majority of these heal uneventfully with conservative management; acute pain symptoms abate over a period of 6 to 8 weeks, and only mild backache recurrence is noted. However, some patients develop persistent pain symptoms and may require intervention to relieve pain or decompress the neural elements in cases of neurologic compromise. All these fractures have been due to osteoporosis, and no definite diagnosis has been given. Osteoporosis usually manifests in the axial skeleton first, especially in the vertebral bodies, which contain a high proportion of metabolically active, high turnover trabecular bone. The horizontal trabeculae are reabsorbed first, leading to an early accentuation of the vertical trabeculae. In more severe cases, thinning and loss of bone density give the vertebral column a washed-out appearance, followed by a collapse of the vertebral body.3Cooper C. Atkinson E.J. O'Fallon W.M. Melton III, L.J. Incidence of clinically diagnosed vertebral fractures: a population-based study in Rochester, Minnesota, 1985-1989.J Bone Miner Res. 1992; 7: 221-227Crossref PubMed Scopus (1263) Google Scholar Osteogenesis imperfecta type I is a genetic collagen disorder characterized by generalized osteoporosis with abnormal bony fragility, distinct blue sclerae throughout life, and presenile conductive hearing loss. Osteogenesis imperfecta type I is the most common type of osteogenesis imperfecta. Osteogenesis imperfecta type I is inherited as an autosomal dominant condition, although spontaneous mutations occur. Molecular genetic studies have revealed that this type is characterized by a quantitative defect in type I collagen.2Khosla S. Lufkin E.G. Hodgson S.F. Fitzpatrick L.A. Melton 3rd, L.J. Epidemiology and clinical features of osteoporosis in young individuals.Bone. 1994; 15: 551-555Abstract Full Text PDF PubMed Scopus (146) Google Scholar In some families, dentinogenesis imperfecta is a feature. The majority of patients (∼90%) with a clinical diagnosis of osteogenesis imperfecta have a mutation in COL1A1 or COL1A2, the genes encoding collagen type I.3Cooper C. Atkinson E.J. O'Fallon W.M. Melton III, L.J. Incidence of clinically diagnosed vertebral fractures: a population-based study in Rochester, Minnesota, 1985-1989.J Bone Miner Res. 1992; 7: 221-227Crossref PubMed Scopus (1263) Google Scholar A number of skeletal disorders can have features similar to osteogenesis imperfecta. Patients with osteoporosis pseudoglioma, Cole-Carpenter, and Bruck syndromes have severe bone fragility with low bone mineral content.4Sillence D.O. Rimoin D.L. Danks D.M. Clinical variability in osteogenesis imperfecta - variable expressivity or genetic heterogeneity.Birth Defects Orig Artic Ser. 1979; 15: 113-129PubMed Google Scholar In general, bisphosphonates are the treatment of choice for osteogenesis imperfecta. The administration of calcium should be given with care through radiographic and laboratory monitoring. Some patients adversely develop progressive ossification of the spinal ligaments, particularly the longitudinal anterior ligament, which subsequently leads to the development of spinal ankylosis. Once ankylosis is established, the spine biomechanics worsen and the patient is then at an increased risk for sustaining more vertebral fractures. On the other hand, it is important for patients with osteogenesis imperfecta to have a diet with adequate levels of calcium and vitamin D. In some patients, diet is not sufficient, and vitamin D3 and calcium should be prescribed in accordance with serum levels and exposure to early- and late-day sunlight. It is mandatory to assess patients with osteogenesis imperfecta via serum calcium, cross-linked C-telopeptide, complete hormonal assessment, 25-hydroxy viatmin D3, liver and renal function parameters, lipid profile, and homocysteine and alkaline phosphatase levels. The distinction between idiopathic osteoporosis as a causation of fractures in adults and the mild types of osteogenesis imperfecta is eminent because the pathophysiology of osteoporosis varies. In our experience, patients with osteogenesis imperfecta can present at any age, from the intrauterine stage to late in life. This reflects the confusing range of severity of the disease. The diagnosis can be straightforward when there is a positive family history and several typical features are present (blue sclera, hearing loss, discoloration of teeth, and ligamentous hyperlaxity in childhood).