Spinal Deformity in Bethlem Myopathy

Spine Deformity 2 (2014) 143e151 www.spine-deformity.org

Spinal Deformity in Bethlem Myopathy Ozgur Dede, MDa,*, Hoda Z. Abdel-Hamid, MDb, Vincent F. Deeney, MDa a

Department of Orthopaedic Surgery, Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center, 4401 Penn Avenue, Pittsburgh, PA 15224, USA b Department of Pediatrics, Division of Child Neurology, Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center, 4401 Penn Avenue, Pittsburgh, PA 15224, USA Received 9 July 2013; revised 27 August 2013; accepted 23 November 2013

Abstract Study Design: Retrospective review. Objectives: To report the characteristics of spinal deformity in a series of 3 patients with Bethlem myopathy. Summary of Background Data: Bethlem myopathy presents with mild muscular weakness and typically has a benign course. Severe scoliosis in patients affected with Bethlem myopathy has not been previously reported. Methods: Clinical records of 3 brothers with Bethlem myopathy were reviewed. Clinical and radiographic features of the spinal deformity are presented. Results: All 3 patients had progressive scoliosis with coronal and sagittal imbalance. At a minimum of 26 months of follow-up after posterior instrumented fusion, there were no complications and deformity correction was maintained. Posterior instrumentation and fusion did not negatively affect the pulmonary function in this group of patients with Bethlem myopathy. Conclusions: Bethlem myopathy may present with severe scoliosis along with proximal muscle weakness. This condition should be included in the differential diagnosis of adolescent patients with progressive spinal deformity. Ó 2014 Scoliosis Research Society. Keywords: Scoliosis; Syndromic; Muscular dystrophy

Introduction Collagen VIerelated disorders are a group of muscle diseases of variable severity, classified under muscular dystrophies [1]. The milder end of the spectrum is Bethlem myopathy, which is characterized by proximal muscle weakness, joint contractures, and hyperlaxity. The other end of the spectrum, Ullrich myopathy, causes weakness early in life; the affected children may never walk [1,2]. Although one of the clinical features of Bethlem myopathy has been reported to be a rigid spine [3], the authors of the current study were not able to retrieve a description of scoliosis or severity of the spinal deformity in Bethlem myopathy from the extant medical literature. Author disclosures: OD (none); HZA (none); VFD (none). *Corresponding author. Department of Orthopaedic Surgery, Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center, 4401 Penn Avenue, Pittsburgh, PA 15224, USA. Tel.: (412) 692-9888; fax: (412) 692-6088. E-mail addresses: [email protected] or [email protected] (O. Dede). 2212-134X/$ - see front matter Ó 2014 Scoliosis Research Society. http://dx.doi.org/10.1016/j.jspd.2013.11.003

The aim of this study was to report the association of severe scoliosis with Bethlem myopathy in a series of 3 patients. Materials and Methods Since 2005, the authors have seen 3 brothers with scoliosis and a diagnosis of Bethlem myopathy at their pediatric orthopaedic surgery clinic. A diagnosis of Bethlem myopathy was confirmed by a pediatric neurologist (HZD). All patients underwent posterior instrumentation and fusion by the senior author (VD). One patient with more severe deformity was operated on using an allepedicle screw construct; the other 2 patients with less severe curves were operated on using hybrid constructs consisting of hooks, sublaminar wires, and lumbar pedicle screws. Surgical technique involved facetectomies on every level; however, no other extensile anterior or posterior release was done and no preoperative or intra-operative traction was used. Deformity correction was attempted with rod derotation maneuver and in situ rod bending. Stainless-steel

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Fig. 1. Preoperative radiographs of Case 1, demonstrating the spinal deformity.

implants were used in all patients. Intra-operative neuromonitoring consisted of somatosensory evoked potentials and there were no changes in intra-operative signals. Shoulder balance (the angle formed by a line subtending the highest points of the clavicles and the horizontal), pelvic obliquity (the angle formed by a line tangential to both iliac crests and the horizontal), and coronal and sagittal spinal deformity measurements (using the sagittal vertical axis and central sacral vertical line as reference lines) were done on preoperative, postoperative, and follow-up radiographs. Preoperative and postoperative pulmonary function studies were assessed to evaluate the effect of posterior spinal fusion on pulmonary parameters. Case 1 A 16-year-old boy with a prior history of progressive scoliosis was transferred to the authors’ hospital with a diagnosis of respiratory failure. The patient had no other systemic signs or symptoms. History revealed that he had been an active adolescent, played basketball, and had had no symptoms (other than scoliosis) until recently. His

mother noticed that his breathing had been labored during the previous day and he was difficult to arouse on the morning of hospital admission. When he was taken to the hospital, he was unresponsive and was subsequently intubated. His condition improved during the hospital course, with ventilator support. He was discharged to home with part-time bilevel positive airway pressure (BIPAP) support. During the evaluation, the patient was noted to have contractures of the elbows and the joints of both hands, and proximal muscle weakness. He had no previously known family history of muscle weakness. However, on further questioning, it was noted that his younger brother also had scoliosis and the same pattern of muscle weakness. The patient was examined for a variety of muscular disorders with muscle biopsy, electromyelogram, and genetics testing, and a diagnosis of Bethlem myopathy was established. Assessment of the spine showed a double major curve pattern with an 86 right thoracic curve between T2 and T11 and an 85 left lumbar curve between T11 and L4 (Fig. 1). Iliac apophyses were graded as Risser 4. On sidebending X-rays, thoracic curve corrected to 47 and lumbar

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curve corrected to 43 . He had 4 pelvic obliquity with the concave side of the lumbar curve elevated. Left shoulder was elevated by 5 . The coronal balance was off to the right side by 57 mm, and there was a trunk shift of 17 mm to the right. Lumbar lordosis was 35 between L1 and S1, and there was a local kyphosis between T10 and L2 of 36 . T4 to T12 kyphosis was 24 with 22 kyphosis between T10 and 12 and the more proximal part of thoracic spine being almost straight. Sagittal balance was 40 mm positive with respect to the sagittal vertical axis. He underwent posterior instrumentation and fusion between T3 and L4 1 year after acute respiratory failure. He was operated on using an allepedicle screw construct. There were no perioperative complications. Postoperatively, the shoulders were level and pelvic tilt stayed the same, with 4 pelvic tilt on the concavity of the lumbar curve. The coronal correction was to 60 for the thoracic curve and 49 for the lumbar curve; postoperative T4e12 kyphosis was 2 , lumbar lordosis was 38 and the local thoracolumbar kyphosis corrected to neutral. Coronal balance was 65 mm to the right and sagittal balance was 102 mm positive. At 7-year follow-up, the spinal correction was maintained with no signs of

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implant failure (Fig. 2) and no clinical symptoms related to the spine. Preoperative pulmonary function tests (PFT) revealed a forced expiratory volume in 1 second (FEV1) of 39% and a forced vital capacity (FVC) of 45%. At 2 years postoperatively, these values declined to FEV1 1.13 L (27%) and FVC 1.44 (29%); however, at the latest followup, the patient required no pulmonary support. Case 2 An 18-year-old boy was seen in the outpatient clinic for spinal deformity. His initial examination revealed thoracic hypokyphosis and a right thoracic scoliosis. The patient had a phenotype similar to that of his older brother, the first presented case, in that he had a thin body habitus, with a narrow chest diameter both in anteroposterior and lateral planes. This patient underwent pulmonary, genetic, and neurologic evaluation before evaluation, because of a hypoxic episode similar to that of his older brother (Case 1). Radiographs showed a 60 scoliotic curve between T3 and T11, and the iliac apophyses were graded as Risser 4 (Fig. 3). There was a fractional left curve between T11 and

Fig. 2. Seven-year follow-up radiographs of Case 1, showing the maintenance of correction with no signs of pseudarthrosis.

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Fig. 3. Preoperative radiographs of Case 2, demonstrating the spinal deformity.

S1 measuring 29 . T4 to 12 kyphosis measured 10 , sagittal balance was 100 mm positive, and coronal balance was 40 mm to the right with a trunk shift of 44 mm. The right shoulder was elevated by 4 and the pelvis was level. He was operated with a posterior-only approach using a hybrid construct. Fusion was achieved between T3 and L3. At the 37-month follow-up, there were no signs of loss of correction or implant failure (Fig. 4). Major Cobb was maintained at 40 . T4 to 12 kyphosis improved to 22 , sagittal balance was 41 mm positive, and coronal balance was 27 mm to the right with a trunk shift of 13 mm. Shoulder and pelvic balance were not affected by the instrumentation. Preoperative PFT showed FEV1 0.95 L (24%) and FVC 1.11 L (24%). At 20 months postoperatively, these values remained unchanged, with FEV1 1.06 L (26%) and FVC 1.12L (23%). This patient was receiving nocturnal part-time BIPAP at the latest follow-up. Case 3 A 15-year-old boy was seen at the authors’ scoliosis clinic, to be evaluated for a spinal deformity. On initial

examination, he was noted to have no apparent muscular weakness, thin body habitus, and thoracic hypokyphosis. The left main thoracic curve was measured 33 from T2 to L3 and the iliac apophyses were Risser 1 (Fig. 5). At that time, the authors discussed brace treatment with the patient and family. The patient’s medical history was insignificant other than having 2 older brothers with scoliosis and Bethlem myopathy. Because of the positive family history, he was referred to the pulmonology, genetics, and neurology clinics. Subsequently, he was diagnosed with Bethlem myopathy along with restrictive lung disease and sleep apnea requiring nocturnal respiratory support. At the 6-month follow-up, the main thoracic curve increased to 44 (11 progression in 6 months) and the iliac apophyses were Risser 2. Despite bracing, at 1-year followup, the spinal deformity progressed to 64 (20 the in 6 months), with grade 2 rotation according to Nash and Moe system; the Risser sign was grade 3 (Fig. 6). The authors decided to surgically address the spinal deformity. At that time, T4e12 kyphosis measured 8 , sagittal balance was 66 mm positive, and coronal balance was 86 mm off to the left

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Fig. 4. Three-year follow-up radiographs of Case 2, showing the maintenance of correction.

side. The left shoulder was up by 4 and the right hemipelvis was elevated by 2 . He was operated on with a posterior-only approach, using a hybrid construct with lumbar pedicle screws, thoracic sublaminar wires, and hooks. At 26 months’ follow-up, there was no loss of correction and no signs of implant failure on X-ray examination (Fig. 7). The major Cobb was maintained at 44 and T4e12 kyphosis was 14 . He had 60 mm positive sagittal balance. The central sacral vertical line was off to the left by 31 mm. Shoulder and pelvic balance remained unaffected by the posterior instrumentation. Preoperatively, PFT demonstrated FEV1 1.36 L (39%) and FVC 1.47 (36%). These values minimally changed at 18 months postoperatively, with FEV1 1.44 L (37%) and FVC 1.44 L (32%). This patient was also receiving nocturnal BIPAP at the latest follow-up. Results The phenotype was similar in all patients, with thin, asthenic features. Mild proximal muscle weakness, mild

elbow and Achilles tendon contractures were present, but all patients were independent ambulators with no functional limitations during activities of daily living. All patients had sagittal deformity as thoracic hypokyphosis. One patient with the double curve also had thoracolumbar kyphosis, which was corrected with instrumentation. All patients had positive sagittal balance, and all had coronal off-balance along with trunk shift. Although coronal deformity extending to the mid-cervical spine was observed in all patients, this deformity was well compensated for and no patients had clinically apparent torticollis or head tilt. There was minimal shoulder imbalance or pelvic obliquity. However, deformity in all patients was rigid and extended to the cervical spine. There were no noticeable congenital vertebral anomalies or dysplastic features in the spine. There was no previous family history of myopathy or scoliosis. Posterior instrumentation and fusion resulted in modest coronal deformity correction and maintenance at a minimum of 26 months’ follow-up. However, spinal balance and sagittal alignment were minimally affected by the procedure. There was no sign of implant failure, loss of

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Fig. 5. Spine radiographs of Case 3 at first presentation.

correction, infection, or pseudarthrosis. The patients had no problems related to their spines at the latest follow-up. Discussion Bethlem and van Wijngaarden [4] first described Bethlem myopathy in 28 individuals with a Dutch pedigree. Clinically, contractures of fingers, wrists, elbows, and ankles along with proximal mild muscle weakness are the hallmarks of this group of muscle disorders. The severity of muscle weakness may be variable, ranging from mild (Bethlem) with a limb girdle distribution to a severe (Ullrich) form with inability to ambulate independently. In the mild form of the disease, distal hyperlaxity (of the distal

interphalangeal joint) also is a frequently reported characteristic. Bethlem myopathy is usually symptomatic during the second decade of life, with a limb girdle distribution of muscle weakness; however, occasionally severe respiratory muscle weakness may present as respiratory failure. The presence of scoliosis may exacerbate the manifestations of respiratory involvement, necessitating nocturnal respiratory support, as was the case in some of our patients. The mode of inheritance is autosomal dominant, or autosomal recessive, and de novo mutations are also present [2]. These patients have normal cognitive abilities and typically no cardiac abnormalities. Skin abnormalities such as follicular hyperkeratosis and hypertrophic scars have been reported [1]. Patients affected with Bethlem myopathy are expected

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Fig. 6. At 1-year follow-up after initial presentation (Case 3), there had been considerable progression of the spinal deformity despite bracing.

to be ambulatory until their 5th decade, and then some may need walking aids or a wheelchair. More recently, a variety of collagen VI gene abnormalities have been reported in patients with Bethlem myopathy; however, the diagnosis was based on clinical and pathology findings. Bethlem and Ullrich myopathies are considered to be the 2 extreme sides of the spectrum of collagen VIerelated disorders. Treatment of scoliosis in Ullrich syndrome has previously been reported [5,6]. On the other hand, a review of the literature failed to show any description of a spinal deformity in Bethlem myopathy [1,2,4,7-9]. There appears to be a difference between other myopathic conditions and Bethlem myopathy; as in most inherited myopathies, severe muscular weakness is typically seen in patients with scoliosis. However, our patients with Bethlem had near normal muscle function, and were completely independent and ambulatory. This may indicate that the development of scoliosis in Bethlem myopathy may result from collagen abnormality or another molecular abnormality, but not exclusively from muscle weakness. It is known that some other collagen abnormalities, such as EhlersDanlos syndrome, may present with scoliosis. Collagen abnormalities have been studied as a potential mechanism

for the development of idiopathic scoliosis [10,11]. This potential association of collagen abnormalities and the development of spinal deformity provides justification for future research efforts to further analyze collagen genes in patients with presumed idiopathic scoliosis. Although our patients with Bethlem myopathy expressed features similar to idiopathic scoliosis, such as hypokyphosis of the thoracic spine, thin body habitus and presentation and worsening of the deformity during the growth spurt, other features such as rigidity of the curve, sagittal and coronal off-balance, and long curves extending into the cervical spine make them distinctively different. Patients with Bethlem myopathy share similarities with Shprintzen-Goldberg syndrome in their slender habitus and the presence of coronal and sagittal off-balance [12]. However there are many additional abnormalities in Shprintzen-Goldberg syndrome that would help with the differential diagnosis. In the authors’ experience, posterior instrumentation and fusion provided a modest correction in patients with Bethlem myopathy. The limited coronal correction and minor change in sagittal alignment resulted from the rigidity of the deformity, which is known to be characteristic

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Fig. 7. Two-year follow-up radiographs of Case 3, demonstrating the maintenance of correction and no signs of implant failure or pseudarthrosis.

of Bethlem myopathy. A better 3-plane correction could possibly be achieved by using advanced corrective measures such as preoperative halo gravity traction, intraoperative halo-femoral traction, anterior discectomies and posterior osteotomy techniques. However, at a minimum of 26 months’ follow-up (range, 26e82 months), initial modest correction was maintained in all patients, with no implant failure and no signs of pseudarthrosis. Pulmonary function studies were not affected by the posterior spinal fusion. Another interesting common aspect of the deformity is extension of the long scoliosis to the cervical spine along with loss of lordosis in the sagittal plane. This cervical spine deformity persisted in all patients after the posterior fusion surgery. Although the persistence of deformity above the upper instrumented vertebra presents the risk of deformity progression in the future, the authors opted to avoid extension of the fusion to the cervical spine so as not to limit cervical mobility. Further follow-up is required to be able to comment on the outcome of the cervical spine deformity in these patients.

The major limitations of this study are the small number of patients and the difficulty of making a solid connection between Bethlem myopathy and scoliosis, based on 3 patients from the same family. The coexistence of scoliosis and Bethlem myopathy in these patients may be a coincidence and the spinal deformity may be the result of another heritable condition. Nevertheless, because of the previously known links between myopathies, collagen abnormalities, and scoliosis, and the known association between more severe types of collagen VI disorders and scoliosis, the authors believe that this is a real association. This study presented 3 patients with Bethlem myopathy and progressive scoliosis requiring surgical treatment. All 3 patients with spinal deformity presented at or after age 10 years, and the deformity progressed during the growth spurt, with increasing rotation and hypokyphosis of the thoracic spine. The findings from these 3 patients indicate that in an adolescent patient with progressive spinal deformity, off-balance, and mild muscular weakness, Bethlem myopathy must be considered in the differential diagnosis.

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