- Email: [email protected]
Clinical Features of Osteogenesis Imperfecta in Taiwan
ORIGINAL ARTICLE
Clinical Features of Osteogenesis Imperfecta in Taiwan Hsiang-Yu Lin,1,2,3,4 Shuan-Pei Lin,1,2,3,5* Chih-Kuang Chuang,2,6 Ming-Ren Chen,1,3 Chia-Ying Chang,1 Dau-Ming Niu4,7 Background/Purpose: Osteogenesis imperfecta (OI) (MIM 166200, 166210, 259420 and 166220) is a congenital disorder characterized by increased bone fragility and low bone mass. Information regarding the clinical features of this genetic disorder is lacking in Taiwan. This study aimed to characterize the clinical features of OI patients in Taiwan to establish a practical correlation for distinguishing different clinical subtypes of the disorder. Methods: A review of medical records identified 48 patients with OI (33 female and 15 male; age range, 2 months to 53 years) from January 1996 to June 2008. Diagnosis and classification, using the classification system outlined by Sillence et al, were based on clinical and radiological characteristics. We also analyzed the clinical presentation, physical examination and bone mineral density (BMD) among the different subtypes of OI. Results: Retrospective analysis of the medical records revealed that 48 OI patients could be classified into types I (n = 19), III (n = 10), and IV (n = 19). There were statistically significant differences between these three types in terms of height, weight, BMD, dentinogenesis imperfecta, bone deformity, scoliosis, walking ability, annual fracture rate, and family history. However, no significant differences were noted for blue sclera (p = 0.075) and hearing loss (p = 0.832). Conclusion: Nine of the 11 clinical features examined—height, weight, BMD, dentinogenesis imperfecta, bone deformity, scoliosis, walking ability, fracture rate, and family history—were significantly different among the three types of OI patients. This finding may be of help in evaluating patients and establishing their prognosis. [J Formos Med Assoc 2009;108(7):570–576] Key Words: bone mineral density, dentinogenesis imperfecta, osteogenesis imperfecta, scleral diseases, scoliosis
extra-skeletal manifestations associated with this disorder, including blue sclera, dentinogenesis imperfecta (DI), hearing loss, and hyperlaxity of ligaments and skin.3 Most patients have mutations in the COL1A1 or COL1A2 genes localized on chromosomes 17 and 7, respectively.4 The most
Osteogenesis imperfecta (OI) (MIM 166200, 166210, 259420 and 166220) is a congenital disorder characterized by increased bone fragility, low bone mass, and other connective-tissue manifestations. It is estimated to affect 1 in 15,000 to 1 in 25,000 individuals.1,2 There are a variety of
©2009 Elsevier & Formosan Medical Association .
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Departments of 1Pediatrics and 2Medical Research, Mackay Memorial Hospital, 3Mackay Medicine, Nursing and Management College, 4Institute of Clinical Medicine, National Yang-Ming University, 5Department of Infant and Child Care, National Taipei College of Nursing, 6Medical College, Fu-Jen Catholic University, and 7Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan. Received: August 20, 2008 Revised: October 18, 2008 Accepted: January 8, 2009
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*Correspondence to: Dr Shuan-Pei Lin, Department of Pediatrics, Mackay Memorial Hospital, 92, Section 2, Chung-Shan North Road, Taipei 104, Taiwan. E-mail: [email protected]
J Formos Med Assoc | 2009 • Vol 108 • No 7
Clinical features of osteogenesis imperfecta
commonly used classification is the one developed by Sillence et al,5 which classifies OI into four major types according to different degrees of phenotypic severity. Type I is the mildest form, with normal or only slightly affected growth and minimal bone deformities. Bones start to break after several months of age. Type II is the most severe form and is fatal in the perinatal period, with multiple intrauterine fractures and bone deformities of the extremities. Type III is severely deforming, with fractures often present at birth. Patients have extremely short stature with progressive limb and spine deformities secondary to multiple fractures. Physical activity is restricted and growth retardation is extremely severe. Type IV is the most phenotypically heterogeneous group, and encompasses all patients who do not meet the criteria for types I–III. The phenotype can vary from severe to mild. Recently, type IV has been further divided into types V, VI and VII, based on bone architecture and histological characteristics.6 Despite its prevalence, information concerning the clinical features of this genetic disorder is lacking in Taiwan. Thus, this study aimed to characterize the clinical features of OI patients in Taiwan, to establish a practical correlation for distinguishing different clinical subtypes of OI.
Patients and Methods Subjects The medical records of 48 patients with OI were reviewed retrospectively from January 1996 to June 2008, at Mackay Memorial Hospital, Taipei, Taiwan.
scores (SDSs), walking ability, annual fracture rate, family history, and, if present, blue sclera, DI, hearing loss, bone deformity, and scoliosis. Height and weight were transformed to SDSs on the basis of a standard growth table for the Taiwanese population.7 BMD was assessed by dual energy X-ray absorptiometry (DEXA) of the lumbar spine (L1–L4), using the Hologic QDR 4500 system (Bedford, MA, USA). Since there is a lack of adequate reference data in Taiwanese children for BMD assessment using this method, we used normative reference data taken from the literature.8,9 The BMD results were converted to age- and gender-specific SDSs. According to the classification used by our radiologists, osteopenia was defined as BMD SDS < −1, and osteoporosis as BMD SDS < −2. The annual fracture rate was calculated based on the reports of parents or medical records. Despite the clinical finding that pamidronate therapy increases BMD, decreases fracture rate, and substantially improves functional status for OI patients,10–12 none of these patients received pamidronate treatment at the time of assessment.
Statistical analysis SPSS version 11.5 (SPSS Inc., Chicago, IL, USA) was used to analyze the clinical and radiological data among the different subtypes of patients. The relationship between age and the presence of each clinical feature of OI types I, III and IV was tested using Pearson’s correlation, and significance was tested using Fisher’s r-z transformations. Differences were considered to be statistically significant when p was < 0.05.
Assessment
Results
Diagnosis and classification were based on clinical and radiological characteristics, according to the Sillence classification system.5 Every patient was reviewed at the clinic by a single author in person. No patients were classified as OI type II— we therefore analyzed only three different groups. For each patient, we recorded height, weight and bone mineral density (BMD) standard deviation
The clinical characteristics of the 48 participants are listed in Table 1. There were 33 female and 15 male patients with ages ranging from 2 months to 53 years. Nineteen patients were classified as type I, 10 as type III, and 19 as type IV. Height SDSs were −0.76 ± 0.91 in type I, −9.54 ± 4.36 in type III, and −3.02 ± 2.70 in type IV. BMD SDSs
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Sex
F M F M F F F M F M F F F F F F M F F F F M F F M F M F M F F F F M F
Patient no.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
2 3 4 4 9 10 10 12 13 14 16 28 28 29 31 33 44 46 48 0.2 0.6 8 12 14 14 23 25 31 32 2 2 3 3 3 5
Age (yr)
I I I I I I I I I I I I I I I I I I I III III III III III III III III III III IV IV IV IV IV IV
Type
W (SDS) −0.62 −0.22 −0.85 −0.43 0.90 −0.89 −1.05 0.62 −0.16 −0.75 −0.46 −0.06 −2.18 −0.06 −1.84 −0.47 −1.13 −1.68 1.15 −0.68 −4.00 −3.56 −3.76 −4.88 −1.43 −4.42 −2.28 −4.58 −5.06 −1.38 −1.54 −0.50 0.64 −0.78 −2.74
H (SDS) −0.57 −0.09 −0.85 −0.60 −0.25 −0.55 −1.18 0.19 −1.86 −0.52 0.20 −0.12 −2.08 1.25 −1.69 −0.71 −0.84 −2.37 −1.78 −4.35 −3.85 −7.61 −11.26 −13.31 −6.36 −11.20 −7.86 −11.69 −17.95 −1.20 −1.45 −0.79 −0.02 −0.18 −4.42
−5.05 −4.43 −4.94 −4.73 −3.38 −6.98 −1.67 −2.76 −1.50 −2.21 −2.10 −1.53 −6.88 −0.57 −1.75 −1.47 −1.12 −5.34 −1.72 −4.58 −9.10 −6.98 −4.91 −5.05 −2.34 −3.59 −2.95 −7.05 −6.92 −3.98 −6.63 −4.99 −3.58 −4.74 −6.04
BMD (SDS) + + + + + + + + + + + − + + − + + + + + + + + + + + − + − + + + + − +
Blue sclera − − − − − − − − − + − − − − − − − − − + + − + + + + + + − − + − − − +
DI − − − − − − − − − − − − − + − − − − + − − − − − − − − + − − − − − − −
Hearing loss
Table 1. Clinical characteristics of 48 patients with osteogenesis imperfecta
− − − − − − − − − − − − + − − + − − + + + + + + + + + + + + + − − + +
Bone deformity − − − − − + + − − − + + − − − − − + − + + + + + + + + + + + + − − − +
Scoliosis + + + + + + + + + + + + + + + + + + + Undefined Undefined − − − − − − − − − − + + − +
Walking without aids or devices − − − − − − − − − − − − − − − − − − − Undefined Undefined + + + + + + + + + + − − − −
Wheelchair bound 1.5 1.0 0.5 0.5 1.5 2.0 0.0 0.0 1.0 1.0 0.0 0.5 2.0 0.0 0.0 0.5 1.0 1.5 0.0 Undefined Undefined 5.0 4.5 4.0 3.5 5.0 3.5 5.0 4.5 2.0 3.0 2.0 1.0 2.5 2.5
Annual fracture rate + + + + − + + + + − + + + + + + + − + − − − − − − − − − − − − − + − −
Family history
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18.1 14.2 Mean SD
H = height; SDS = standard deviation score; W = weight; BMD = bone mineral density; DI = dentinogenesis imperfecta; F = female; M = male.
−1.23 1.64 −3.48 4.20
−4.03 2.07
1.02 1.34 −0.69 −2.44 −2.06 1.43 −0.62 −2.65 −1.51 0.26 −1.11 −0.87 −0.06 36 37 38 39 40 41 42 43 44 45 46 47 48
M F F F M M M F M F F F F
8 11 12 13 16 16 18 23 26 27 37 45 53
IV IV IV IV IV IV IV IV IV IV IV IV IV
−1.56 1.39 −2.54 −5.14 −4.40 −0.60 −6.11 −9.18 −6.46 −4.63 −2.08 −5.12 −2.86
−3.52 −6.39 −8.53 −2.34 −3.62 −2.26 −3.29 −5.45 −2.73 −1.59 −3.86 −2.79 −3.29
+ − + + − − − + − − + − +
+ − + − + + − − + − − − +
− − − − − − − − − − − − +
+ − + + − + + − + + + + −
− − + + + + + − + − + + −
+ + − + − + − + − + + + +
− − + − − − − − + − − − −
1.9 1.4
2.0 3.0 3.0 2.0 2.5 1.0 1.5 2.5 1.0 1.0 2.0 2.0 1.0
+ − + − − + − − − − + + +
Clinical features of osteogenesis imperfecta
were −3.16 ± 2.00 in type I, −5.35 ± 2.13 in type III, and −4.19 ± 1.77 in type IV (Table 2). The clinical feature of blue sclera was present in 89% of type I patients, 80% of type III, and 58% of type IV. Eighty percent of type III patients had DI, in contrast to 5% in type I and 42% in type IV. Annual fracture rate was 0.8 ± 0.7 in type I patients, 4.4 ± 0.6 in type III, and 2.0 ± 0.7 in type IV. In type I patients, 84% had a family history of OI, compared with none in type III, and 37% in type IV (Table 3). Among the three subtypes, there were statistically significant differences (p < 0.05) in the following clinical features: height SDS, weight SDS, BMD SDS, DI, bone deformity, scoliosis, walking ability, annual fracture rate, and family history. However, no significant differences were found in blue sclera (p = 0.075) and hearing loss (p = 0.832). In OI type I, the presence of bone deformity was associated with increased age (r = 0.47, p < 0.05). In OI type IV, the presence of hearing loss was associated with increased age (r = 0.58, p < 0.05). No other clinical features were associated with increased age in OI types I, III and IV (Table 4).
Discussion In general, there is no reported gender difference in the incidence of OI. However, we found a predominance of female patients in our population, a ratio of 2.2 to 1, a finding similar to that reported by Santili et al.13 Growth retardation is an important symptom of OI, and is especially severe in OI type III.14 Our results in this regard are similar to those of a national survey of OI patients in Japan, which reported that height SDSs were −3.36 ± 3.59, −7.83 ± 3.54, and −4.63 ± 3.13 in types I, III and IV, respectively.15 DEXA is one of the most sensitive methods for detecting low BMD in children—a condition that may be missed when using plain radiographs.16 DEXA may help to establish the diagnosis, assess the prognosis, and possibly monitor the response to medical treatment. For OI patients, even in the milder form, decreased BMD can be detected 573
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Table 2. Clinical profiles of 48 patients with osteogenesis imperfecta (OI) types I, III and IV OI type
Sex (M/F)
Age range (yr)
H (SDS)
W (SDS)
BMD (SDS)
5/14 4/6 6/13
2–48 0.2–32 2–53
−0.76 ± 0.91 −9.54 ± 4.36 −3.02 ± 2.70 0.001
−0.54 ± 0.87 −3.47 ± 1.51 −0.75 ± 1.28 0.001
−3.16 ± 2.00 −5.35 ± 2.13 −4.19 ± 1.77 0.020
Type I (n = 19) Type III (n = 10) Type IV (n = 19) p
M = male; F = female; H = height; SDS = standard deviation score; W = weight; BMD = bone mineral density.
Table 3. Clinical characteristics of 48 patients with osteogenesis imperfecta (OI) types I, III and IV OI type
Blue sclera
DI
Hearing loss
Bone deformity
Scoliosis
Walking without aids or devices
Wheelchair bound
Annual fracture rate
Family history
Type I (n = 19) Type III (n = 10) Type IV (n = 19) p
89% 80% 58% 0.075
5% 80% 42% 0.001
11% 10% 5% 0.832
16% 100% 68% 0.001
26% 100% 58% 0.001
100% 0% 63% 0.001
0% 100% 21% 0.001
0.8 ± 0.7 4.4 ± 0.6 2.0 ± 0.7 0.001
84% 0% 37% 0.001
DI = dentinogenesis imperfecta.
Table 4. Relationships between age and clinical features of patients with osteogenesis imperfecta types I, III and IV Type I (n = 19)
Clinical features Blue sclera DI Hearing loss Bone deformity Scoliosis Walking without assistance Wheelchair bound Family history Annual fracture rate
Type III (n = 10)
Type IV (n = 19)
r
p
r
p
r
p
−0.22 −0.10 0.42 0.47 0.07 Undefined Undefined 0.08 −0.12
NS NS NS < 0.05 NS Undefined Undefined NS NS
−0.57 −0.18 0.46 Undefined Undefined Undefined Undefined Undefined −0.12
NS NS NS Undefined Undefined Undefined Undefined Undefined NS
−0.19 0.01 0.58 −0.05 0.04 0.30 −0.23 0.41 0.40
NS NS < 0.05 NS NS NS NS NS NS
DI = dentinogenesis imperfecta; NS = not significant.
by DEXA.17,18 In our study, all patients showed reduced BMD, and 81% had osteoporosis. Blue sclera is a distinctive feature of unknown etiology in OI.19 Most patients with OI type I have blue sclera throughout life. In OI types III and IV, the sclera may also be blue at birth and during infancy, but the blue color disappears with time during childhood.20 In our study, the majority of our patients (75%) presented with blue sclera. DI, another important symptom of OI, is associated with molecular abnormality of type I 574
collagen. Discoloration and pulpal obliteration are the major presentations. The manifestation of OI with bone fragility is helpful for differential diagnosis from other fracture conditions in children, including child abuse. In the study by Lukinmaa et al,21 DI was not common in OI type I, but was observed frequently in types III and IV, a finding in accordance with our results. Progressive hearing loss is one of the principal symptoms of OI, and the most common age of onset is in the second, third, and fourth decades of life. At the age of 50 years, about half of the J Formos Med Assoc | 2009 • Vol 108 • No 7
Clinical features of osteogenesis imperfecta
A
B
C
Figure. Radiograph of whole spine and lower extremities in case 29, a 32-year-old male patient with osteogenesis imperfecta type III. (A) Anteroposterior image of whole spine showing severe thoracolumbar scoliosis. (B) Lateral image of whole spine showing marked deformity and severe thoracolumbar kyphoscoliosis. (C) Anteroposterior image of lower extremities showing bowing deformity of bilateral femurs and healed fracture of the proximal third of the right femur.
patients have symptoms of hearing loss.22–25 In our study, four adult patients (8%) suffered from hearing loss, and they were aged 29, 31, 48 and 53 years, respectively, at the time of the study. In patients with OI, deformities are frequently observed in the long bones, and scoliosis, spinal deformities, and compression fractures are also common (Figure). The causes of bone deformities are imperfect healing after fracture, as well as weight bearing itself, without apparent fracture.15 In our study, 54% of patients had bone deformities. The pathology of scoliosis is based on vertebral fragility, and it deteriorates progressively with increasing age.26 Karbowski et al27 carried out a nationwide cross-sectional study for patients with OI, and reported that scoliosis was observed in 74.5% (76/102) of the subjects, with an average age of 24.6 years. Engelbert et al28 performed another cross-sectional study, and found that 47% (22/47) of patients with OI had scoliosis, with a mean age of 7.7 years. Our data showed that scoliosis was presented in 54% (26/48) of patients, with a mean age of 18.1 years. A positive family history is useful for the diagnosis and classification of OI. It is difficult to distinguish OI from child abuse in the absence of affected family members and obvious extraskeletal features.29,30 Our study showed that 48% of J Formos Med Assoc | 2009 • Vol 108 • No 7
patients had a positive family history, which was similar to that reported by Santili et al (41%).13 Since several clinical features in OI are progressive (e.g. scoliosis26 and hearing loss22–25). For these features, we investigated age-related factors. We found that increased age was associated with bone deformity and hearing loss in OI types I and IV, respectively. OI is a congenital disorder with clinically diverse presentations, from minimal symptoms to perinatal fatality. In this study of 48 patients with OI, we found that height SDS, weight SDS, BMD SDS, DI, bone deformity, scoliosis, walking ability, fracture rate, and family history were significantly different between types I, III, and IV. Patients with OI type III had the most severe phenotypes or the highest incidence of all these nine clinical features, except family history, which was found most often in OI type I. Conversely, patients with OI type I had the mildest phenotypes or the lowest incidence of the other eight clinical features. These clinical characteristics may help to evaluate patients and establish their prognosis.
Acknowledgments This work was partially supported by a research grant (MMH-E-97004) from Mackay Memorial 575
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Hospital, Taipei, Taiwan. The authors thank Ms Tsai-Feng Ho for her professional assistance with the biostatistics.
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References 1. Orioli IM, Castilla EE, Barbosa-Neto JG. The birth prevalence rates for the skeletal dysplasias. J Med Genet 1986; 23:328–32. 2. Stoll C, Dott B, Roth MP, et al. Birth prevalence rates of skeletal dysplasias. Clin Genet 1989;35:88–92. 3. Smith R. Osteogenesis imperfecta: from phenotype to genotype and back again. Int J Exp Pathol 1994;75: 233–41. 4. Sykes B, Ogilvie D, Wordsworth P, et al. Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen loci: COL1A1 and COL1A2. Am J Hum Genet 1990;46:293–307. 5. Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 1979;16:101–16. 6. Roughley PJ, Rauch F, Glorieux FH. Osteogenesis imperfecta—clinical and molecular diversity. Eur Cell Mater 2003;5:41–7. 7. Chen W, Tsai CY, Chen AC, et al. Growth charts of Taiwanese youth: norms based on health-related physical fitness. Mid Taiwan J Med 2003;8(Suppl 2):85–93. 8. van der Sluis IM, de Ridder MA, Boot AM, et al. Reference data for bone density and body composition measured with dual energy x ray absorptiometry in white children and young adults. Arch Dis Child 2002;87:341–7. 9. Bachrach LK, Hastie T, Wang MC, et al. Bone mineral acquisition in healthy Asian, Hispanic, Black, and Caucasian youth: a longitudinal study. J Clin Endocrinol Metab 1999; 84:4702–12. 10. Åström E, Söderhäll S. Beneficial effect of long term intravenous bisphosphonate treatment of osteogenesis imperfecta. Arch Dis Child 2002;86:356–64. 11. Falk MJ, Heeger S, Lynch KA, et al. Intravenous bisphosphonate therapy in children with osteogenesis imperfecta. Pediatrics 2003;111:573–8. 12. Lin HY, Lin SP, Chuang CK, et al. Intravenous pamidronate therapy in Taiwanese patients with osteogenesis imperfecta. Pediatr Neonatol 2008;49:161–5. 13. Santili C, Akkari M, Waisberg G, et al. Clinical, radiographic and laboratory evaluation of patients with osteogenesis imperfecta. Rev Assoc Med Bras 2005;51:214–20. 14. Zeitlin L, Rauch F, Plotkin H, et al. Height and weight development during four years of therapy with cyclical intravenous pamidronate in children and adolescents with
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Clinical Features of Osteogenesis Imperfecta in Taiwan Hsiang-Yu Lin,1,2,3,4 Shuan-Pei Lin,1,2,3,5* Chih-Kuang Chuang,2,6 Ming-Ren Chen,1,3 Chia-Ying Chang,1 Dau-Ming Niu4,7 Background/Purpose: Osteogenesis imperfecta (OI) (MIM 166200, 166210, 259420 and 166220) is a congenital disorder characterized by increased bone fragility and low bone mass. Information regarding the clinical features of this genetic disorder is lacking in Taiwan. This study aimed to characterize the clinical features of OI patients in Taiwan to establish a practical correlation for distinguishing different clinical subtypes of the disorder. Methods: A review of medical records identified 48 patients with OI (33 female and 15 male; age range, 2 months to 53 years) from January 1996 to June 2008. Diagnosis and classification, using the classification system outlined by Sillence et al, were based on clinical and radiological characteristics. We also analyzed the clinical presentation, physical examination and bone mineral density (BMD) among the different subtypes of OI. Results: Retrospective analysis of the medical records revealed that 48 OI patients could be classified into types I (n = 19), III (n = 10), and IV (n = 19). There were statistically significant differences between these three types in terms of height, weight, BMD, dentinogenesis imperfecta, bone deformity, scoliosis, walking ability, annual fracture rate, and family history. However, no significant differences were noted for blue sclera (p = 0.075) and hearing loss (p = 0.832). Conclusion: Nine of the 11 clinical features examined—height, weight, BMD, dentinogenesis imperfecta, bone deformity, scoliosis, walking ability, fracture rate, and family history—were significantly different among the three types of OI patients. This finding may be of help in evaluating patients and establishing their prognosis. [J Formos Med Assoc 2009;108(7):570–576] Key Words: bone mineral density, dentinogenesis imperfecta, osteogenesis imperfecta, scleral diseases, scoliosis
extra-skeletal manifestations associated with this disorder, including blue sclera, dentinogenesis imperfecta (DI), hearing loss, and hyperlaxity of ligaments and skin.3 Most patients have mutations in the COL1A1 or COL1A2 genes localized on chromosomes 17 and 7, respectively.4 The most
Osteogenesis imperfecta (OI) (MIM 166200, 166210, 259420 and 166220) is a congenital disorder characterized by increased bone fragility, low bone mass, and other connective-tissue manifestations. It is estimated to affect 1 in 15,000 to 1 in 25,000 individuals.1,2 There are a variety of
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Departments of 1Pediatrics and 2Medical Research, Mackay Memorial Hospital, 3Mackay Medicine, Nursing and Management College, 4Institute of Clinical Medicine, National Yang-Ming University, 5Department of Infant and Child Care, National Taipei College of Nursing, 6Medical College, Fu-Jen Catholic University, and 7Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan. Received: August 20, 2008 Revised: October 18, 2008 Accepted: January 8, 2009
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*Correspondence to: Dr Shuan-Pei Lin, Department of Pediatrics, Mackay Memorial Hospital, 92, Section 2, Chung-Shan North Road, Taipei 104, Taiwan. E-mail: [email protected]
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Clinical features of osteogenesis imperfecta
commonly used classification is the one developed by Sillence et al,5 which classifies OI into four major types according to different degrees of phenotypic severity. Type I is the mildest form, with normal or only slightly affected growth and minimal bone deformities. Bones start to break after several months of age. Type II is the most severe form and is fatal in the perinatal period, with multiple intrauterine fractures and bone deformities of the extremities. Type III is severely deforming, with fractures often present at birth. Patients have extremely short stature with progressive limb and spine deformities secondary to multiple fractures. Physical activity is restricted and growth retardation is extremely severe. Type IV is the most phenotypically heterogeneous group, and encompasses all patients who do not meet the criteria for types I–III. The phenotype can vary from severe to mild. Recently, type IV has been further divided into types V, VI and VII, based on bone architecture and histological characteristics.6 Despite its prevalence, information concerning the clinical features of this genetic disorder is lacking in Taiwan. Thus, this study aimed to characterize the clinical features of OI patients in Taiwan, to establish a practical correlation for distinguishing different clinical subtypes of OI.
Patients and Methods Subjects The medical records of 48 patients with OI were reviewed retrospectively from January 1996 to June 2008, at Mackay Memorial Hospital, Taipei, Taiwan.
scores (SDSs), walking ability, annual fracture rate, family history, and, if present, blue sclera, DI, hearing loss, bone deformity, and scoliosis. Height and weight were transformed to SDSs on the basis of a standard growth table for the Taiwanese population.7 BMD was assessed by dual energy X-ray absorptiometry (DEXA) of the lumbar spine (L1–L4), using the Hologic QDR 4500 system (Bedford, MA, USA). Since there is a lack of adequate reference data in Taiwanese children for BMD assessment using this method, we used normative reference data taken from the literature.8,9 The BMD results were converted to age- and gender-specific SDSs. According to the classification used by our radiologists, osteopenia was defined as BMD SDS < −1, and osteoporosis as BMD SDS < −2. The annual fracture rate was calculated based on the reports of parents or medical records. Despite the clinical finding that pamidronate therapy increases BMD, decreases fracture rate, and substantially improves functional status for OI patients,10–12 none of these patients received pamidronate treatment at the time of assessment.
Statistical analysis SPSS version 11.5 (SPSS Inc., Chicago, IL, USA) was used to analyze the clinical and radiological data among the different subtypes of patients. The relationship between age and the presence of each clinical feature of OI types I, III and IV was tested using Pearson’s correlation, and significance was tested using Fisher’s r-z transformations. Differences were considered to be statistically significant when p was < 0.05.
Assessment
Results
Diagnosis and classification were based on clinical and radiological characteristics, according to the Sillence classification system.5 Every patient was reviewed at the clinic by a single author in person. No patients were classified as OI type II— we therefore analyzed only three different groups. For each patient, we recorded height, weight and bone mineral density (BMD) standard deviation
The clinical characteristics of the 48 participants are listed in Table 1. There were 33 female and 15 male patients with ages ranging from 2 months to 53 years. Nineteen patients were classified as type I, 10 as type III, and 19 as type IV. Height SDSs were −0.76 ± 0.91 in type I, −9.54 ± 4.36 in type III, and −3.02 ± 2.70 in type IV. BMD SDSs
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Sex
F M F M F F F M F M F F F F F F M F F F F M F F M F M F M F F F F M F
Patient no.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
2 3 4 4 9 10 10 12 13 14 16 28 28 29 31 33 44 46 48 0.2 0.6 8 12 14 14 23 25 31 32 2 2 3 3 3 5
Age (yr)
I I I I I I I I I I I I I I I I I I I III III III III III III III III III III IV IV IV IV IV IV
Type
W (SDS) −0.62 −0.22 −0.85 −0.43 0.90 −0.89 −1.05 0.62 −0.16 −0.75 −0.46 −0.06 −2.18 −0.06 −1.84 −0.47 −1.13 −1.68 1.15 −0.68 −4.00 −3.56 −3.76 −4.88 −1.43 −4.42 −2.28 −4.58 −5.06 −1.38 −1.54 −0.50 0.64 −0.78 −2.74
H (SDS) −0.57 −0.09 −0.85 −0.60 −0.25 −0.55 −1.18 0.19 −1.86 −0.52 0.20 −0.12 −2.08 1.25 −1.69 −0.71 −0.84 −2.37 −1.78 −4.35 −3.85 −7.61 −11.26 −13.31 −6.36 −11.20 −7.86 −11.69 −17.95 −1.20 −1.45 −0.79 −0.02 −0.18 −4.42
−5.05 −4.43 −4.94 −4.73 −3.38 −6.98 −1.67 −2.76 −1.50 −2.21 −2.10 −1.53 −6.88 −0.57 −1.75 −1.47 −1.12 −5.34 −1.72 −4.58 −9.10 −6.98 −4.91 −5.05 −2.34 −3.59 −2.95 −7.05 −6.92 −3.98 −6.63 −4.99 −3.58 −4.74 −6.04
BMD (SDS) + + + + + + + + + + + − + + − + + + + + + + + + + + − + − + + + + − +
Blue sclera − − − − − − − − − + − − − − − − − − − + + − + + + + + + − − + − − − +
DI − − − − − − − − − − − − − + − − − − + − − − − − − − − + − − − − − − −
Hearing loss
Table 1. Clinical characteristics of 48 patients with osteogenesis imperfecta
− − − − − − − − − − − − + − − + − − + + + + + + + + + + + + + − − + +
Bone deformity − − − − − + + − − − + + − − − − − + − + + + + + + + + + + + + − − − +
Scoliosis + + + + + + + + + + + + + + + + + + + Undefined Undefined − − − − − − − − − − + + − +
Walking without aids or devices − − − − − − − − − − − − − − − − − − − Undefined Undefined + + + + + + + + + + − − − −
Wheelchair bound 1.5 1.0 0.5 0.5 1.5 2.0 0.0 0.0 1.0 1.0 0.0 0.5 2.0 0.0 0.0 0.5 1.0 1.5 0.0 Undefined Undefined 5.0 4.5 4.0 3.5 5.0 3.5 5.0 4.5 2.0 3.0 2.0 1.0 2.5 2.5
Annual fracture rate + + + + − + + + + − + + + + + + + − + − − − − − − − − − − − − − + − −
Family history
H.Y. Lin, et al
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18.1 14.2 Mean SD
H = height; SDS = standard deviation score; W = weight; BMD = bone mineral density; DI = dentinogenesis imperfecta; F = female; M = male.
−1.23 1.64 −3.48 4.20
−4.03 2.07
1.02 1.34 −0.69 −2.44 −2.06 1.43 −0.62 −2.65 −1.51 0.26 −1.11 −0.87 −0.06 36 37 38 39 40 41 42 43 44 45 46 47 48
M F F F M M M F M F F F F
8 11 12 13 16 16 18 23 26 27 37 45 53
IV IV IV IV IV IV IV IV IV IV IV IV IV
−1.56 1.39 −2.54 −5.14 −4.40 −0.60 −6.11 −9.18 −6.46 −4.63 −2.08 −5.12 −2.86
−3.52 −6.39 −8.53 −2.34 −3.62 −2.26 −3.29 −5.45 −2.73 −1.59 −3.86 −2.79 −3.29
+ − + + − − − + − − + − +
+ − + − + + − − + − − − +
− − − − − − − − − − − − +
+ − + + − + + − + + + + −
− − + + + + + − + − + + −
+ + − + − + − + − + + + +
− − + − − − − − + − − − −
1.9 1.4
2.0 3.0 3.0 2.0 2.5 1.0 1.5 2.5 1.0 1.0 2.0 2.0 1.0
+ − + − − + − − − − + + +
Clinical features of osteogenesis imperfecta
were −3.16 ± 2.00 in type I, −5.35 ± 2.13 in type III, and −4.19 ± 1.77 in type IV (Table 2). The clinical feature of blue sclera was present in 89% of type I patients, 80% of type III, and 58% of type IV. Eighty percent of type III patients had DI, in contrast to 5% in type I and 42% in type IV. Annual fracture rate was 0.8 ± 0.7 in type I patients, 4.4 ± 0.6 in type III, and 2.0 ± 0.7 in type IV. In type I patients, 84% had a family history of OI, compared with none in type III, and 37% in type IV (Table 3). Among the three subtypes, there were statistically significant differences (p < 0.05) in the following clinical features: height SDS, weight SDS, BMD SDS, DI, bone deformity, scoliosis, walking ability, annual fracture rate, and family history. However, no significant differences were found in blue sclera (p = 0.075) and hearing loss (p = 0.832). In OI type I, the presence of bone deformity was associated with increased age (r = 0.47, p < 0.05). In OI type IV, the presence of hearing loss was associated with increased age (r = 0.58, p < 0.05). No other clinical features were associated with increased age in OI types I, III and IV (Table 4).
Discussion In general, there is no reported gender difference in the incidence of OI. However, we found a predominance of female patients in our population, a ratio of 2.2 to 1, a finding similar to that reported by Santili et al.13 Growth retardation is an important symptom of OI, and is especially severe in OI type III.14 Our results in this regard are similar to those of a national survey of OI patients in Japan, which reported that height SDSs were −3.36 ± 3.59, −7.83 ± 3.54, and −4.63 ± 3.13 in types I, III and IV, respectively.15 DEXA is one of the most sensitive methods for detecting low BMD in children—a condition that may be missed when using plain radiographs.16 DEXA may help to establish the diagnosis, assess the prognosis, and possibly monitor the response to medical treatment. For OI patients, even in the milder form, decreased BMD can be detected 573
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Table 2. Clinical profiles of 48 patients with osteogenesis imperfecta (OI) types I, III and IV OI type
Sex (M/F)
Age range (yr)
H (SDS)
W (SDS)
BMD (SDS)
5/14 4/6 6/13
2–48 0.2–32 2–53
−0.76 ± 0.91 −9.54 ± 4.36 −3.02 ± 2.70 0.001
−0.54 ± 0.87 −3.47 ± 1.51 −0.75 ± 1.28 0.001
−3.16 ± 2.00 −5.35 ± 2.13 −4.19 ± 1.77 0.020
Type I (n = 19) Type III (n = 10) Type IV (n = 19) p
M = male; F = female; H = height; SDS = standard deviation score; W = weight; BMD = bone mineral density.
Table 3. Clinical characteristics of 48 patients with osteogenesis imperfecta (OI) types I, III and IV OI type
Blue sclera
DI
Hearing loss
Bone deformity
Scoliosis
Walking without aids or devices
Wheelchair bound
Annual fracture rate
Family history
Type I (n = 19) Type III (n = 10) Type IV (n = 19) p
89% 80% 58% 0.075
5% 80% 42% 0.001
11% 10% 5% 0.832
16% 100% 68% 0.001
26% 100% 58% 0.001
100% 0% 63% 0.001
0% 100% 21% 0.001
0.8 ± 0.7 4.4 ± 0.6 2.0 ± 0.7 0.001
84% 0% 37% 0.001
DI = dentinogenesis imperfecta.
Table 4. Relationships between age and clinical features of patients with osteogenesis imperfecta types I, III and IV Type I (n = 19)
Clinical features Blue sclera DI Hearing loss Bone deformity Scoliosis Walking without assistance Wheelchair bound Family history Annual fracture rate
Type III (n = 10)
Type IV (n = 19)
r
p
r
p
r
p
−0.22 −0.10 0.42 0.47 0.07 Undefined Undefined 0.08 −0.12
NS NS NS < 0.05 NS Undefined Undefined NS NS
−0.57 −0.18 0.46 Undefined Undefined Undefined Undefined Undefined −0.12
NS NS NS Undefined Undefined Undefined Undefined Undefined NS
−0.19 0.01 0.58 −0.05 0.04 0.30 −0.23 0.41 0.40
NS NS < 0.05 NS NS NS NS NS NS
DI = dentinogenesis imperfecta; NS = not significant.
by DEXA.17,18 In our study, all patients showed reduced BMD, and 81% had osteoporosis. Blue sclera is a distinctive feature of unknown etiology in OI.19 Most patients with OI type I have blue sclera throughout life. In OI types III and IV, the sclera may also be blue at birth and during infancy, but the blue color disappears with time during childhood.20 In our study, the majority of our patients (75%) presented with blue sclera. DI, another important symptom of OI, is associated with molecular abnormality of type I 574
collagen. Discoloration and pulpal obliteration are the major presentations. The manifestation of OI with bone fragility is helpful for differential diagnosis from other fracture conditions in children, including child abuse. In the study by Lukinmaa et al,21 DI was not common in OI type I, but was observed frequently in types III and IV, a finding in accordance with our results. Progressive hearing loss is one of the principal symptoms of OI, and the most common age of onset is in the second, third, and fourth decades of life. At the age of 50 years, about half of the J Formos Med Assoc | 2009 • Vol 108 • No 7
Clinical features of osteogenesis imperfecta
A
B
C
Figure. Radiograph of whole spine and lower extremities in case 29, a 32-year-old male patient with osteogenesis imperfecta type III. (A) Anteroposterior image of whole spine showing severe thoracolumbar scoliosis. (B) Lateral image of whole spine showing marked deformity and severe thoracolumbar kyphoscoliosis. (C) Anteroposterior image of lower extremities showing bowing deformity of bilateral femurs and healed fracture of the proximal third of the right femur.
patients have symptoms of hearing loss.22–25 In our study, four adult patients (8%) suffered from hearing loss, and they were aged 29, 31, 48 and 53 years, respectively, at the time of the study. In patients with OI, deformities are frequently observed in the long bones, and scoliosis, spinal deformities, and compression fractures are also common (Figure). The causes of bone deformities are imperfect healing after fracture, as well as weight bearing itself, without apparent fracture.15 In our study, 54% of patients had bone deformities. The pathology of scoliosis is based on vertebral fragility, and it deteriorates progressively with increasing age.26 Karbowski et al27 carried out a nationwide cross-sectional study for patients with OI, and reported that scoliosis was observed in 74.5% (76/102) of the subjects, with an average age of 24.6 years. Engelbert et al28 performed another cross-sectional study, and found that 47% (22/47) of patients with OI had scoliosis, with a mean age of 7.7 years. Our data showed that scoliosis was presented in 54% (26/48) of patients, with a mean age of 18.1 years. A positive family history is useful for the diagnosis and classification of OI. It is difficult to distinguish OI from child abuse in the absence of affected family members and obvious extraskeletal features.29,30 Our study showed that 48% of J Formos Med Assoc | 2009 • Vol 108 • No 7
patients had a positive family history, which was similar to that reported by Santili et al (41%).13 Since several clinical features in OI are progressive (e.g. scoliosis26 and hearing loss22–25). For these features, we investigated age-related factors. We found that increased age was associated with bone deformity and hearing loss in OI types I and IV, respectively. OI is a congenital disorder with clinically diverse presentations, from minimal symptoms to perinatal fatality. In this study of 48 patients with OI, we found that height SDS, weight SDS, BMD SDS, DI, bone deformity, scoliosis, walking ability, fracture rate, and family history were significantly different between types I, III, and IV. Patients with OI type III had the most severe phenotypes or the highest incidence of all these nine clinical features, except family history, which was found most often in OI type I. Conversely, patients with OI type I had the mildest phenotypes or the lowest incidence of the other eight clinical features. These clinical characteristics may help to evaluate patients and establish their prognosis.
Acknowledgments This work was partially supported by a research grant (MMH-E-97004) from Mackay Memorial 575
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Hospital, Taipei, Taiwan. The authors thank Ms Tsai-Feng Ho for her professional assistance with the biostatistics.
15.
16.
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