High Prevalence of Coxa Vara in Patients with Severe Osteogenesis Imperfecta

ORIGINAL ARTICLE

High Prevalence of Coxa Vara in Patients With Severe Osteogenesis Imperfecta

Mehdi Aarabi, MD, Frank Rauch, MD, Reggie C. Hamdy, MD, and Francxois Fassier, MD, FRCSC

type IV.In most cases, the disease can be linked to the presence Abstract: The purpose of this study was to determine the incidence of mutations in one of the two genes that code for collagen and clinical presentation of coxa vara in 283 patients with osteo- type I.2 This traditional classification comprising four OI types genesis imperfecta (OI). The charts and x-rays of 150 girls and has recently been expanded by the addition of OI types V to 133 boys with OI were reviewed. The patients were classified accord- VII.3–5 These newly characterized OI types can be distin- ing to the Sillence classification modified by Glorieux: 94 type I, guished from the other forms of the disease on the basis of 90 type IV, 67 type III, 18 type V, 10 type VI, and 4 type VII. The clinical appearance, bone histology findings, and the lack of mean age was 9.4 years (range 0.3–23.3). Twenty-nine patients collagen type I mutations.6–8 The hallmark of all forms of OI is (10.2%) had coxa vara (23 left and 20 right). Fifty-five percent of bone fragility. The incidence of fractures can be high, es- them were type III, 24% type IV, 13.8% type VI, and 3.4% each of pecially in the lower extremities, often leading to bowing of types V and VII. The incidence of coxa vara was 6% in type V,8% in femoral and tibial diaphyses. Acetabular protrusion is also type IV, 24% in type III, 25% in type VII, and 40% in type VI (P , common, affecting the majority of OI type III patients.9 A less 0.001 for difference between types I, III, and IV). The mean neck– well recognized feature of OI is coxa vara (CV), which in our shaft angle was 99 degrees (range 80–110 degrees), the average head– experience is not rare in the more severely affected patients. shaft angle was 104 degrees (range 90–120 degrees), and the mean CV has been defined as any decrease in the femoral neck–shaft Hilgenreiner–epiphyseal angle was 68 degrees (range 40–90 degrees). angle to below 110 degrees (Fig. 1).6,10 The femoral neck– Twenty-five patients (36 hips) had previous femoral rodding before shaft normally is about 150 degrees at birth, 126 degrees in diagnosis and seven hips (all type III) had no history of rodding. adults, and 120 degrees in the elderly.7,11 At present, there is Abduction and internal rotation of the hip joints were restricted in all little information about the morbidity that CV may cause in OI patients with this deformity. All children with coxa vara had a patients. The aim of this report was to evaluate CV in a large Trendelenburg gait. In conclusion, coxa vara in OI is not rare, espe- population of children with OI and its associated clinical cially in severe forms of the disease. Regular clinical and radiologic features. follow-up is indicated in children with previous femoral rodding and in severely affected children, particularly those with OI type III. Key Words: coxa vara, osteogenesis imperfecta METHODS This was a retrospective evaluation of all children with (J Pediatr Orthop 2006;26:24–28) OI examined at the Shriners Hospital for Children in Montreal between October 1999 and October 2003. The diagnosis of OI was based on clinical findings, as described by Sillence et al.1 steogenesis imperfecta (OI) is a genetic disorder that All patients in whom anteroposterior radiographs of at least Ocauses increased bone fragility and low bone mass. The one hip had been performed were included in the study, and the most commonly used classification distinguishes four clinical last available x-ray was assessed for the present study. A total types.1 Patients with OI type I have a mild phenotype with of 283 patients fulfilled these criteria (150 girls, 133 boys). normal or near-normal height and typically blue sclera. Type II The patients were classified according to the Sillence clas- 2 is lethal in the perinatal period. Type III is the most severe form sification, as expanded by Glorieux. The diagnostic distribu- in children surviving the neonatal period. These patients have tion of the patients is shown in Table 1. Mean age at the time of extremely short stature, with limb and spinal deformities sec- analysis was 9.4 (range 0.3–23.3) years. One hundred seventy- ondary to multiple fractures. Patients with mild to moderate eight patients had received medical therapy with intravenous 2 bone deformities and variable short stature are classified as OI pamidronate before the radiographic study. In 273 patients radiographs from both hips were available. In 10 patients only one side had undergone radiographic examination. Thus, a total of 556 hips could be assessed. From Shriners Hospital for Children, Division of Orthopaedics, McGill University, Montreál, Que´bec, Canada. Study conducted at Shriners Hospital for Children, Montreal, Canada. Radiologic Measurements None of the authors received financial support for the study. Figure 1 is an example of coxa vara in OI patients. All Reprints: Francxois Fassier, MD, FRCSC, Chief of Staff, Shriners Hospital for Children, 1529 Cedar Avenue, Montreál, Que´bec, Canada H3G 1A6 measurements were performed on standard anteroposterior (e-mail: [email protected]). radiographs of the hip (Figs. 2 and 3). The femoral neck–shaft Copyright Ó 2006 by Lippincott Williams & Wilkins angle was measured as the intersection of a line drawn through

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(range 0–25 degrees).6 We also measured the head–shaft angle, the angle between the longitudinal axis of the femoral shaft and a line perpendicular to the largest diameter of the femoral head.6 The lateral radiographs were also assessed in the patients with CV to evaluate femoral bowing and to identify false CV (Fig. 4). The ratio between tibia and femur length was evaluated in patients with CV in whom anteroposterior radiographs of the entire extremity (femurs and tibias on the same ﬁlm) were available (n = 29). Results were compared with reference data published by Robinow.13

Statistical Analysis The statistical difference of the CV between the femurs that had been previously rodded and the femurs with no rodding procedure was evaluated by the chi-square test.

RESULTS CV was present in 29 of the 283 OI patients (10.2%). The highest prevalence of CV was found in OI types III, VI, and VII, whereas no case was found among the 94 patients with OI type I (see Table 1). Fifteen patients with CV had unilateral involvement, and in 14 patients both hips were affected. Thus, 43 of the 556 evaluated hips (7.7%) were affected with CV (23 left and 20 right hips). In addition, four cases of false coxa vara were identified; these were associated with anterolateral angulation in the proximal third of the femur. On the other hand, 28 femurs had bowing in the proximal third without either false or true coxa vara. In 41 of the 43 cases of true CV, the deformity was located in the base or in the middle of the femoral neck. The trochanteric region was affected in the remaining two hips. The neck–shaft angle of the affected hips averaged 99 degrees (range 80–110 degrees) and the mean Hilgenreiner–epiphyseal angle was 68 degrees (range 40–90 degrees). The head–shaft angle averaged 104 degrees (range 78–120 degrees). Intramedullary rodding had been performed in 25 of the 29 patients (83%) and in 36 of the 43 femurs (84%) with CV. Thus, only four patients (all OI type III) with seven affected femora had no rodding procedures. In contrast, intramedullary rodding had been performed in only 140 of 513 femurs (27%) that were not affected by CV (P = 0.007 for the difference in prevalence of rods between femurs with and without CV). The tibia-to- femur length ratio was above the reference range in 24 of the 29 lower limbs with CV (83%) that could be evaluated. Intramedullary rodding procedures had previously been performedin21ofthese24femurs. In 21 patients with 33 affected hips, we could retrieve information on the functional clinical status at the time point FIGURE 1. Anteroposterior x-ray of hip and femur in a child considered in the present study. In 24 hips (72%), flexion with OI showing true CV. The child also had an elongating nail and external rotation were full. In 31 hips (93%), more than for correction of femoral bowing. Multiple growth-arrest lines 90 degrees of flexion was possible. Eleven hips (33%) had no are seen in the distal femur. extension, and 15 hips (45%) had varying degrees of flexion contracture. Twenty-one hips (63%) had normal external ro- the shaft of the femur with another line passing through the tation, and in 7 hips (21%) the range of external rotation was long axis of the femoral neck. The Hilgenreiner–epiphyseal above normal. The average abduction in the 33 hips was angle was determined according to Beals’ modification of the 21 degrees. In 10 hips (30%), abduction was less than method originally described by Weinstein et al.6,12 The normal 10 degrees. In 9 hips (27%) it was between 11 and 20 degrees, value of the Hilgenreiner–epiphyseal angle is 16 degrees in 11 hips (33%) between 20 and 30 degrees, and in 2 hips q 2006 Lippincott Williams & Wilkins 25

TABLE 1. Diagnostic Distribution of the Study Population and Results of Radiologic Evaluation OI No. of No. of Patients With CV No. of Hips No. of Hips With CV Type Pts. Examined (% of all patients with same type) Examined (% of hips of patients with same type) I 94 0 (0%) 185 0 (0%) III 67 16 (24%) 131 26 (20%) IV 90 7 (8%) 178 8 (4%) V 18 1 (6%) 36 1 (3%) VI 10 4 (40%) 18 6 (33%) VII 4 1 (25%) 8 2 (25%) Total 283 29 556 43

(6%) more than 30 degrees. In 17 hips (51%) internal rotation was absent or very limited. Six hips (18%) had 5 to 10 degrees of internal rotation, 2 hips (6%) 15 degrees, and one hip (3%) more than 15 degrees. Seven hips (21%) had varying degrees of external rotation contracture. Most patients with CV had a Trendelenburg gait.

DISCUSSION In the present study we observed a high prevalence of CV in patients with severe forms of OI but an absence of this deformity in patients with OI type I. Thus, CV clearly was associated with the severity of bone fragility in OI. Assessment of CV in severe OI is not always simple, as the radiologic picture is often complicated by bowing of the femoral dia- physis. As previously described by the senior author (F.F.),14 a curvature in the proximal third of the femoral shaft can decrease the distance between the femoral head and shaft, mimicking the pattern of CV on anteroposterior radiographs, even if the neck–shaft angle is normal. In the present study we avoided this pitfall by also evaluating lateral radiographs of the femur. If CV is suspected in the presence of anterior bowing of the proximal third of the femur, a radiograph of the hip in extension should be obtained. In this manner false CV can be identified (see Fig. 4). The pathogenesis of CV in OI is unclear. Generally speaking, CV in children could be classified as developmental, congenital, dysplastic, or traumatic.12 Many of these factors may have contributed to the development of CV in our patients. In developmental CV, there is an intrinsic defect in cartilage maturation and bone formation involving the proximal femoral physis and femoral neck.12 Its pathognomonic radiologic sign is a triangular metaphyseal fragment in the medial side of the femoral neck.6,15 Such fragments were seen in both hips of one of our patients with OI type III. In dysplastic CV,the deformity usually affects the trochanteric area; this was found in two of our patients.12,16 However, the large majority of our patients had CV secondary to deformity in the base of the femoral neck. It appears plausible that many of these cases could be classified as traumatic CV and may have been caused by malunion of a fracture or repeated subclinical fractures of the FIGURE 2. A, Anteroposterior x-ray of the pelvis and both hips in femoral neck. The majority of patients with CV had undergone a child with type III OI showing severe CV with decreased femoral femoral rodding procedures. It is possible that the bio- neck–shaft angle. B, Drawing of the femoral neck–shaft angle. mechanical effects of femoral rods contributed to the

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FIGURE 3. A, Anteroposterior x-ray of the pelvis and both hips in a child with type III OI showing severe CV with increased Hilgenreiner–epiphyseal angle. B, Drawing of the Hilgenreiner– epiphyseal angle. development of CV. However, the statistical association location of the deformity was mostly around the base of the between femoral rodding and CV does not necessarily prove femoral neck. The addition of the head–shaft angle to the list a causal link. Our observation may simply reflect the fact that of measured indices therefore did not provide much clinically the more severely affected OI patients are more prone to useful information. develop CV and at the same time are more likely to require As CV has been described in association with rodding. Nevertheless, it may be prudent to closely evaluate rhizomelia (shortness of the upper leg relative to the lower such patients for the development of CV. Although CV is leg) in some cases of OI,5 we assessed our CV cases for usually defined on the basis of the femoral neck–shaft rhizomelia as well. In 24 lower limb x-rays that we reviewed, angle,10,17 Weinstein et al suggested measuring the head–shaft we found rhizomelia in all of them. Because more than 85% of angle to evaluate the varus angulation of the femoral neck.6 the femurs (21/24) had already been corrected surgically and According to these authors, the head–shaft angle is more rodded, and most femurs are osteotomized, this could be an reproducible than the neck–shaft angle and more indicative of interpretation for this finding. We indeed found short femurs in the actual deformity. We found that the mean neck–shaft angle a considerable proportion of cases. However, the large ma- was lower than the head–shaft angle in our patients, probably jority of these femurs had undergone intramedullary rodding because there was no defect in the femoral neck in CV and the to correct bowing deformity. It therefore appears most likely

FIGURE 4. A, Anteroposterior x-ray of the right hip and femur in a child with type III OI, showing false CV with decreased femoral neck–shaft angle. B, Lateral view of the hip and femur of the same child, showing that the true deformity lies in the proximal femur and not in the femoral neck. C, Anteroposterior view showing a normal neck–shaft angle of the femur of the same child, after femoral rodding and correction of bowing of the proximal femur. D, Lateral view of the femur of same child showing normal alignment of the proximal femur, after femoral rodding and correction of deformity of the proximal femur. q 2006 Lippincott Williams & Wilkins 27

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Aarabi et al J Pediatr Orthop Volume 26, Number 1, January/February 2006 that short femurs were due to bony resections during rod- REFERENCES ding surgery rather than being caused by developmental 1. Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis abnormalities. imperfecta. J Med Genet. 1979;16:101–116. As to the clinical consequences of CV, it is well known 2. Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet. 2004;363:1377– 1385. that a decrease in the neck–shaft angle will shorten the lever 3. Glorieux FH, Rauch F, Plotkin H, et al. Type V osteogenesis imperfecta: arm of the abductor mechanism and thereby cause abductor a new form of brittle bone disease. J Bone Miner Res. 2000;15:1650– insufficiency with a positive Trendelenburg sign.8,18 This was 1658. present in most of our patients. In addition, the range of 4. Glorieux FH, Ward LM, Rauch F, et al. Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J Bone Miner motion of the hip in all of our patients was limited in abduction Res. 2002;17:30–38. and internal rotation, as has also been reported in non-OI 5. Ward LM, Rauch F, Travers R, et al. Osteogenesis imperfecta type VII: an patients with CV.6,11,19 autosomal recessive form of brittle bone disease. Bone. 2002;31:12–18. All but the most mildly affected patients in the present 6. Weinstein JN, Kuo KN, Millar EA. Congenital coxa vara. A retrospective cohort had received bisphosphonates at some point. In the review. J Pediatr Orthop. 1984;4:70–77. 7. Duthie RB, ed. Mercer’s Orthopedic Surgery, 7th ed. Baltimore: Williams absence of an untreated control group, we therefore cannot & Wilkins, 1973. judge the effect of bisphosphonates on hip development. The 8. Tauber C, Ganel A, Horoszowski H, et al. Distal transfer of the greater long-term effects of bisphosphonates on hip development trochanter in cox vara. Acta Orthop Scand. 1980;51:661–666. remain to be addressed in the future. Thus, our data cannot be 9. Violas P, Fassier F, Hamdy R, et al. Acetabular protrusion in osteogenesis imperfecta. J Pediatr Orthop. 2002;22:622–625. used to make recommendations about medical treatment mea- 10. Carroll K, Coleman S, Stevens PM. Coxa vara: surgical outcomes of sures that could prevent such a deformity. valgus osteotomies. J Pediatr Orthop. 1997;17:220–224. In conclusion, we observed a high incidence of CV in 11. Pavlov H, Goldman AB, Freiberger RH. Infantile coxa vara. Radiology. children and adolescents with severe forms of OI, particularly 1980;135:631–640. OI type III. We believe that the presence of CV may aggravate 12. Beals RK. Coxa vara in childhood: evaluation and management. JAm Acad Orthop Surg. 1998;6:93–99. the functional status of these children, which is already impaired 13. Robinow M, Chumlea WC. Standards for limb bone length ratios in by bone fragility and multiple deformities. A high index of children. Radiology. 1982;143:433–436. suspicion should be maintained in children with severe OI and 14. Fassier F, Glorieux F. Osteogene`se imparfaite de l’enfant; Cahiers regular radiologic follow-up is warranted. It is plausible that the d’enseignement de la SOFCOT. Confe`rences d’enseignement 1999, p. 241. 15. Currarino G, Birch JG, Herring JA. Developmental coxa vara associated most severely affected patients may benefit from surgical with spondylometaphyseal dysplasia (DCV/SMD): ‘‘SMD-corner fracture correction, but it is probably not possible to unequivocally type’’ (DCV/SMD-CF) demonstrated in most reported cases. Pediatr demonstrate the functional benefit of such interventions in Radiol. 2000;30:14–24. a single-center study such as the present one. Rather, the current 16. Langer LO Jr, Brill PW, Ozonoff MB, et al. Spondylometaphyseal study attempts to set the scene for future intervention trials. dysplasia, corner fracture type: a heritable condition associated with coxa vara. Radiology. 1990;175:761–766. 17. Burns KA, Stevens PM. Coxa vara: another option for fixation. J Pediatr ACKNOWLEDGMENTS Orthop B. 2001;10:304–310. 18. Tachdijian MO. Developmental coxa vara. In: Tachdijian MO, ed. The authors thank Mr. Denis Alves and Ms. Guylaine Pediatric Orthopedics. Philadelphia: WB Saunders, 1990:584–588. Bedard in the audiovisual department. We are also grateful to 19. Desai SS, Johnson LO. Long-term results of valgus osteotomy for Ms. Paula Wall and Ms. Josee Perron for their secretarial help. congenital coxa vara. Clin Orthop. 1993;294:204–210.

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