1

Thoracolumbar kyphosis in patients with mucopolysaccharidoses:

clinical outcomes and predictive radiographic factors for

progression of deformity

1. Simon B. Roberts, MSc, MRCS(Ed);

2. Ross Dryden, Medical Student;

3. Athanasios I. Tsirikos, MD, FRCS, PhD.

Study conducted at the Scottish National Spine Deformity Centre, Royal Hospital for

Sick Children, Edinburgh, United Kingdom.

Address all correspondence to:

Athanasios I. Tsirikos, MD, FRCS, PhD

Consultant Orthopaedic and Spine Surgeon,

Honorary Clinical Senior Lecturer University of Edinburgh,

Scottish National Spine Deformity Centre,

Sciennes Road, Edinburgh, EH9 1LF, United Kingdom.

Email: atsirikos@hotmail.com, Tel. number: 0044-131-662-1265, Fax number: 0044-131-

536-0924.

Conflict of Interest Statement: No benefits in any form have been received or will be

received from a commercial party related directly or indirectly to the subject of this article.

Word Count: 4351 (abstract and text)

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Abstract

Clinical and radiological data were reviewed for all mucopolysaccharidoses (MPS) patients

with thoracolumbar kyphosis managed non-operatively or operatively in our institution. 16

patients were included (8 female-8 male). Nine patients had Hurler, 5 Morquio and 2 Hunter

syndrome. Six patients were treated non-operatively (mean age at presentation 6.3 years;

kyphosis progression +1.5o/year; follow-up 3.1 years) and 10 patients operatively (mean age

at presentation 4.7 years; kyphosis progression +10.8o/year; follow-up 8.2 years) by

circumferential arthrodesis with posterior instrumentation in patients with flexible

deformities.

In the surgical group (mean age at surgery 6.6 years; mean post-operative follow-up 6.3

years), mean preoperative thoracolumbar kyphosis of +74.3o was corrected to mean +28.6o

post-operatively, relating to a mean deformity correction of 66.9%. Surgical complications

included a deep wound infection treated by early debridement, apical non-union treated by

posterior re-grafting, and stable adjacent segment spondylolisthesis managed non-operatively.

Thoracolumbar kyphosis >+38o at initial presentation was identified as predicting

progressively severe deformity with 90% sensitivity and 83% specificity.

In conclusion, severe thoracolumbar kyphosis in patients with MPS can be effectively treated

by circumferential arthrodesis. Severity of kyphosis at initial presentation may predict

progression of thoracolumbar deformity. Patients with MPS may be particularly susceptible to

post-operative complications due to the underlying connective tissue disorder and inherent

immunological compromise.

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Introduction

Mucopolysaccharidoses (MPS) are a group of rare genetic disorders characterised by

deficiency in enzymes required for glycosaminoglycan catabolism. Accumulation of

glycosaminoglycans leads to progressive cellular damage, multiple organ failure, and reduced

life expectancy. Musculoskeletal manifestations are a prominent early feature of MPS. In

particular, thoracolumbar kyphosis develops in up to 80% of MPS patients.1 The advent of

haematopoetic stem cell transplantation and enzyme replacement therapy has significantly

improved morbidity and mortality in MPS, with improvement of most antecedent organ

damage.2-4 However, the natural history of musculoskeletal manifestations is relatively

unaffected by haematopoetic stem cell transplantation or enzyme replacement therapy.5,6 This

is a result of incomplete penetrance of the replenished enzyme into musculoskeletal tissue and

extracellular matrix disruption occurring early in the aetiopathogenesis of MPS.7,8 The

underlying problems associated with progressive skeletal deformity remain unresolved by

current enzyme replacement therapy.9-12 Following medical treatment, MPS patients are,

therefore, increasingly developing progressive and severe thoracolumbar kyphosis requiring

surgical intervention.

There is limited evidence guiding the strategy for surgical stabilisation of thoracolumbar

kyphosis in MPS. In 2004, Dalvie et al.13 reported the first series of MPS patients with

thoracolumbar kyphosis treated by anterior instrumented fusion with good correction and no

complications. Yasin et al.6 described good correction of kyphosis following excision of the

apical vertebra and adjacent discs with anterior autologous bone grafting and posterior

instrumented fusion extending 3 levels proximal and distal to the apical vertebra. Genevois et

al.14 recorded successful fusion and correction of thoracolumbar kyphosis in MPS patients

managed by anterior corpectomies and discectomies, anterior reconstruction with autologous

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tibial strut graft, and short posterior instrumented fusion. The optimal surgical strategy to

achieve acceptable correction and stabilisation of thoracolumbar deformity in MPS patients

remains undetermined.

The principal indications for surgical treatment of thoracolumbar kyphosis in MPS patients

include a progressively severe deformity and impending or evident neurological dysfunction.

In 2014, Yasin et al.6 suggested that a kyphosis angle greater than +45o at initial presentation

could predict subsequent progression of deformity greater than 10o. It is unclear whether other

patient factors such as age at diagnosis or commencement of haematopoetic stem cell

transplantation or enzyme replacement therapy also affect subsequent progression of

thoracolumbar kyphosis.

The aims of our study were: 1) to investigate the efficacy of combined antero-posterior fusion

with or without posterior segmental pedicle screw instrumentation in the treatment of

progressively severe thoracolumbar kyphosis in MPS; 2) to investigate patient factors

predictive of kyphosis progression and the development of a severe thoracolumbar deformity.

Patients and Methods

We retrospectively reviewed prospectively-collected data of all patients with MPS presenting

with thoracolumbar kyphosis between 2001 and 2013 in our centre. All patients met the

following inclusion criteria: biochemically-confirmed diagnosis of MPS; patient information

comprising demographics, clinical manifestations of MPS, and haematopoetic stem cell

transplantation or enzyme replacement therapy; radiographic data available from initial

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assessment to final follow-up; and operative details including pre- and post-operative

radiographic parameters, and peri-operative complications.

The study cohort comprised 16 patients (8 female-8 male) including 9 patients with Hurler

(type I MPS), 5 with Morquio (type IV MPS), and 2 with Hunter syndrome (type II MPS).

Mean follow-up was 6.2 years (range: 1 to 11.8), at which stage 6 patients (38%) were

skeletally mature. Our patients were divided into 2 groups: patients managed non-operatively

throughout available follow-up (n = 6), and those treated by surgical stabilisation of spinal

deformity (n = 10). The demographic characteristics, extra-spinal manifestations, and spinal

features of all patients are shown in Tables 1 & 2.

Radiological parameters of thoracolumbar kyphosis and associated scoliosis were measured

using the Cobb method15 on an electronic system by 2 authors (AIT, SBR) based on

consensus agreement regarding anatomical landmarks as to the extent of the thoracolumbar

deformity. The same landmarks were used for measurements on consecutive radiographs.

Thoracic kyphosis was measured between T2 and T12 vertebrae. Deformity correction was

determined as follows: Correction Rate (%) = (pre-operative Cobb angle– post-operative

Cobb angle) / (pre-operative Cobb angle) x 100. Baseline magnetic resonance imaging of the

whole neural axis was performed in all patients to assess for cranio-cervical junction or intra-

spinal anomalies. No intraspinal anomalies were detected on radiological assessment.

Flexion-extension radiographs were also performed in all patients to assess for atlanto-axial

instability. If detected patients were referred to the regional neurosurgical unit for

consideration of occipito-cervical fusion prior to surgical stabilisation of thoracolumbar

kyphosis.

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Patients with thoracolumbar kyphosis <+40o and no neurological deficits, or in whom surgery

was contraindicated (Tables 2 & 3; patient 3 – surgery contraindicated due to severe cognitive

and functional impairment subsequent to perinatal cerebral infarction), were managed with

observation. Bracing was not attempted, as this is ineffective to control the deformity and

often poorly tolerated in patients with MPS.13,16 Indications for surgical stabilisation in our

group of patients included the presence of severe, progressive thoracolumbar kyphosis >+40o

in order to prevent neurological complications and back pain.

Surgical technique. Surgery comprised single-stage circumferential arthrodesis performed

through a thoraco-abdominal retroperitoneal and a midline posterior spinal approach. The

fibro-cartilaginous extents of the abnormal apical vertebrae were excised and complete

discectomies were performed across the levels of the deformity. The apical defect following

the corpectomy was bridged with autologous rib strut grafts and morsellised rib graft was

placed into the intervening disc spaces. If the thoracolumbar kyphosis remained inflexible

after the anterior spinal release upon testing intraoperatively (n = 4; 40% of operated

patients), a long rib strut graft was placed anteriorly under compression between the proximal

and distal end vertebrae to be included in the fusion to achieve fusion with positional

correction [non-vascularised rib strut in 3 patients (Figure 1) - vascularised rib strut in one

patient].

Posterior arthrodesis was then performed with autologous and allograft bone across the extent

of deformity. Instrumentation was used in patients in whom the thoracolumbar kyphosis

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became flexible and correctable after the extensive anterior release as assessed intra-

operatively (ability to manually correct the kyphosis at completion of anterior discectomies

and apical vertebral body resection) (Figure 2; n = 6; 60% of operated patients). The posterior

instrumented arthrodesis included the cephalad end vertebra of the kyphosis and caudally the

first lordotic lumbar disc to prevent the development of distal junctional deformity. The

fusion extended distally to L3 or L4 in order to preserve maximum motion segments as all

patients retained walking capacity at the time of surgery. In only one patient (patient 9, Table

4) the lowest vertebra was selected at L5 as revision instrumented arthrodesis was required

due to proximal and distal junctional kyphosis developing following previous limited anterior

apical fusion performed at another centre. Bilateral paediatric segmental pedicle screw/hook

instrumentation was used in all patients undergoing instrumented spinal arthrodesis. Intra-

operative spinal cord monitoring was performed recording transcranial motor and

cortical/cervical somatosensory evoked potentials, which remained stable throughout in all

patients. The postoperative protocol included immediate transfer of all patients to the

intensive care unit, weaning from invasive to non-invasive ventilatory support as soon as

possible and subsequent transfer to regular ward care. All patients were immobilised in a

custom-moulded plaster jacket for 4 months post-operatively until fusion was evident on

radiographs, and were permitted to ambulate as able.

Statistical analysis. Demographics, chronology of medical therapy, and radiological

parameters between non-operated/operated patients and non-instrumented/instrumented

fusions were compared using the two-tailed Student’s t-test. Chi-squared test was used to

analyse nominal data between groups. Receiver-Operator Characteristics (ROC) analysis was

used to evaluate the initial kyphosis severity predictive of subsequent progression of

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deformity. Statistical significance was set at p<0.05. All statistical analyses were performed

using SPSS v 21.0.0 software (SPSS Inc., Chicago, Illinois).

Results

Our cohort comprised 16 MPS patients with thoracolumbar kyphosis and mean age at clinical

presentation 5.3 years (range: 0.4 to 14.4 years) of which 6 patients were managed non-

operatively and 10 patients were treated surgically. There was no significant difference in the

distribution of MPS sub-type between patients treated non-operatively or operatively

(X2=2.110, p=0.35). All patients with Hurler syndrome had received haematopoetic stem cell

transplantation at mean age 1.2 years (range: 0.6 to 1.6). Patients with Hunter or Morquio

syndrome were all treated by enzyme replacement therapy, commencing at mean age 6.9

years (range: 5 to 9.5), except 3 patients for whom enzyme replacement therapy was not

available from the regional health boards. Occipito-cervical fusion for atlanto-axial instability

was performed in 4 patients (3 Morquio; 1 Hurler) prior to management of thoracolumbar

kyphosis.

The characteristics of spinal deformity in patients managed non-operatively are shown in

Table 3. Mean age at presentation was 6.3 years (range: 0.4 to 13). Mean extent of

thoracolumbar kyphosis was 6.2 vertebrae (range: 4 to 9). The thoracolumbar kyphosis

progressed from mean +30.5o (range: +8 to +60o) to +35.3o (range: +15 to +75o) over a mean

follow-up of 3.1 years (range: 1 to 5.1). The mean rate of kyphosis progression was +1.5o per

year. A patient (patient 3, Table 3) with severe thoracolumbar kyphosis and untreated Hunter

syndrome continued non-operative management (+60o kyphosis at presentation progressing to

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+75o at follow-up) as he had suffered a perinatal cerebral infarct with resultant hemiplegia and

surgical intervention was contra-indicated following discussion with the patient’s family and

the multidisciplinary team. Two patients had an associated thoracic and/or thoracolumbar

scoliosis, which was also kept under monitoring (Table 3).

The characteristics of spinal deformity and peri-operative complications in patients treated

surgically are shown in Table 4. Mean age at initial presentation was 4.7 years (range: 2.4 to

16.8). Mean extent of thoracolumbar kyphosis was 4.3 vertebrae (range: 3 to 6). Mean

thoracolumbar kyphosis at presentation was +54.6o (range: +36 to +95o), progressing to mean

+74.3o (range: +42 to +110o) prior to surgical stabilisation over a mean 1.9 years pre-operative

follow-up (range: 1.1 to 3.2). The mean rate of kyphosis progression was +10.8o per year prior

to surgical treatment. The mean age at surgery was 6.6 years (range 2.4 to 16.8) and mean

post-operative follow-up was 6.3 years (range: 3.5 to 10.3). The mean post-operative

thoracolumbar kyphosis was +28.6o (range: 0 to +65o), corresponding to a mean correction of

66.9% (range: 31 to 100%). Patients treated by un-instrumented arthrodesis (Figure 1) had a

greater mean pre-operative kyphosis [+92.3o (range: +55 to +110o) compared to +62.3o (range:

+37 to +78o); p=0.04], and less absolute [+39o (range: +27 to +55o) compared to +50.2o

(range: +37 to +64o); p=0.09] and percentage correction of kyphosis [42.7% (range: 30.9 to

50%) compared to 83.1% (range: 55.1 to 100%); p=0.002], compared to patients who

underwent an instrumented arthrodesis (Figure 2). There was no significant loss of kyphosis

correction between immediate post-operative and latest follow-up radiographs for all patients.

Thoracic kyphosis improved from mean -0.7o (range: -50 to +14o) pre-operatively to mean

+20.7o (range: -15 to +37o) postoperatively. Two patients had a thoracolumbar and 2 a

thoracic scoliosis in association with the thoracolumbar kyphosis. The thoracolumbar

scoliosis was corrected from mean +35.5o (range: +26 to +45o) pre-operatively to mean +7.5o

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(range: 0 to +15o) post-operatively; the thoracic scoliosis improved spontaneously from mean

+29o (range: +25 to +33o) pre-operatively to mean +17o (range: +14 to +20o) post-operatively

following correction of the thoracolumbar kyphosis.

Prior to spinal surgery, 2 patients required establishment of an elective tracheotomy. Mean

surgical time was 170 minutes (range: 150 to 240), and mean intra-operative blood loss was

387 mls (range: 200 to 1000). Three patients developed surgical complications in our cohort.

One patient developed an early deep wound infection treated with surgical debridement and

intravenous antibiotics, permitting retention of instrumentation with no subsequent loss of

deformity correction. The same patient also developed proximal junctional kyphosis which

remained stable at follow-up and did not require extension of the fusion. Another patient who

underwent an un-instrumented fusion developed non-union at the apex of the kyphosis

posteriorly treated with posterior re-grafting using allograft bone followed by application of a

custom-moulded plaster jacket for 3 months. The only patient with Hunter syndrome treated

operatively developed a stable grade II spondylolisthesis at the adjacent segment distal to the

instrumentation; as the patient remained asymptomatic, this was managed conservatively to

skeletal maturity and the spondylolisthesis showed no evidence of deterioration. Post-

operative medical complications included chest infection in 3 patients, prolonged ileus and

need for tracheotomy for prolonged mechanical ventilation in one patient each. Mean hospital

stay was 31 days (range: 10 to 142). All patients had been ambulant pre-operatively and there

was no alteration in ambulatory status post-operatively and at follow-up. Mean post-operative

follow-up was 6.3 years (range: 3.5 to 10.3), at the conclusion of which the mean age of

operated patients was 14.5 years (range: 7 to 24).

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The demographics, surgical techniques, radiographic outcomes and peri-operative

complications in our cohort of MPS patients with thoracolumbar deformity are compared with

previously published series in Table 5.

Variables at initial presentation that may predict progression to severe thoracolumbar

kyphosis and need for surgical stabilisation were investigated. Significant association was

found for neither age at presentation (p=0.836) nor age at commencement of haematopoetic

stem cell transplantation or enzyme replacement therapy (p=0.513). The size of

thoracolumbar kyphosis at initial clinical presentation was associated with progression to

severe deformity and need for surgical treatment (p<0.001). ROC analysis demonstrated that

an initial thoracolumbar kyphosis >+38o predicts progression to severe deformity and need for

surgical correction with 90% sensitivity and 83% specificity (AUC = 0.892).

Discussion

We believe this is one of the largest reported series reviewing the outcomes of treatment for

thoracolumbar kyphosis in patients with MPS and contains the longest reported follow-up

after non-operative management or single-stage circumferential arthrodesis, with 38% of the

study cohort reaching skeletal maturity. Consensus treatment recommendations have not yet

emerged due to the limited reports of both the natural history and management of

thoracolumbar kyphosis in patients with MPS. In our series, there was similar distribution of

patients with each MPS subtype (I, II, and IV) in the non-operative and operative groups.

Hurler syndrome patients in our cohort under the age of 2 years at presentation had a mean

initial thoracolumbar kyphosis of +42.5o, which is similar to the mean +38o described by

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Yasin et al.6 Despite all patients with Hurler syndrome receiving haematopoetic stem cell

transplantation and tending to present at a younger age, a higher proportion of these patients

(7 of 9; 78%) developed progressively severe thoracolumbar kyphosis requiring surgical

stabilisation than did patients with Hunter (1 of 2; 50%) or Morquio (2 of 5; 40%). The mean

age at presentation in this cohort was slightly greater than previously reported cohorts of MPS

patients6,14 due to the inclusion of patients with Hunter and Morquio syndromes who may

present at a later age. The thoracolumbar deformity in our series does not appear to

universally progress in patients of each MPS subtype, as has been recognised previously.6

Thoracolumbar kyphosis appears to follow a variable course within each subtype, but Hurler

syndrome patients are more likely than patients with other MPS to develop early a

progressively severe thoracolumbar kyphosis. Factors influencing the heterogeneity of

phenotypic severity of thoracolumbar deformity remain unclear, but may include genotype,

engraftment, or enzyme levels.6,17

The surgical techniques described for correction of thoracolumbar deformity in patients with

MPS include anterior instrumented fusion, anterior fusion using vascularised rib graft, and

combined anterior/posterior instrumented fusion.6,13,14 Dalvie et al.13 described good correction

of kyphosis in MPS patients treated by anterior-only instrumented fusion, though this series

included predominantly patients with Morquio syndrome and less severe kyphosis. Although

no complications were described, the duration of post-operative follow-up was limited.

Anterior fusion using vascularised rib graft has also been described for MPS patients with

thoracolumbar kyphosis but is associated with a high rate of post-operative complications and

progression of deformity.6 This was also the experience in our study in which a single patient

was managed by anterior reconstruction using a vascularised rib graft; the patient required

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prolonged post-operative ventilatory support and a tracheotomy, underwent re-grafting

surgery to address an apical non-union, and developed long-term chest wall disruption across

the harvesting site. In contrast, non-vascularised rib grafting permits placement of a strut

across the deformity, while the defect at the donor rib site gradually heals as the vascular

supply across the rib bed is preserved. This produces, in our experience, much less disruption

of the chest wall when compared to a vascularised rib which creates a permanent thoracic

defect across the harvesting site. The disadvantage of a non-vascularised rib graft is that it

takes longer to consolidate to the vertebral bodies and therefore postoperative support in the

form of a custom-moulded spinal jacket is recommended. Posterior-only fusion is also

associated with a higher risk of pseudoarthrosis. By comparison with the management of

other skeletal dysplasias, surgical correction of developmental kyphosis secondary to failure

of anterior vertebral body formation may be optimally achieved by anterior spinal release with

strut graft correction and circumferential arthrodesis with the use of posterior

instrumentation.18-21 Antero-posterior arthrodesis is also associated with a reduced risk of

neurological complications,22,23 and has been successfully described in the management of

patients with Hurler syndrome (Table 5).6,14

Thus, in our series of MPS patients, the preferred surgical technique was to perform a

circumferential arthrodesis supported by either an anterior strut graft in patients with rigid

thoracolumbar kyphosis or posterior instrumentation in patients in whom thoracolumbar

deformity became almost fully correctable after the anterior release. Deformities in which the

thoracolumbar kyphosis remained inflexible after the extensive anterior release were

supported by an additional long anterior rib strut graft between the proximal and distal end

vertebrae of the fusion. This permitted positional correction with the strut graft keyed into the

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vertebrae under compression in order to promote fusion. Posterior instrumentation was not

used in this group of patients as this would not have increased the ability to significantly

correct the rigid kyphosis. Posterior instrumentation in this case would have also been at a

high risk of pull-out failure and become prominent under the skin in the presence of a severe

residual sagittal deformity. In contrast, if the thoracolumbar kyphosis became flexible after

the anterior release posterior instrumentation was used in order to maximally correct the

deformity and maintain stability of the thoracolumbar junction to enhance a circumferential

fusion. We included the proximal end vertebra of the kyphosis, as well as the first lordotic

disc distally within the area of the fusion in order to reduce the risk of junctional add-on

deformity and preserve growth of the spine by limiting the fusion segments. We performed

preoperative whole spinal MRI and CT across the levels of the deformity in all patients but no

preoperative bone mineral density scans. In the presence of very small pedicles, thoracic

pedicle hooks instead of screws were placed at the proximal end of the construct to resist pull-

out failure and supplement the pedicle screws at adjacent levels.

There is no consensus regarding the relative timing of reconstructive hip surgery and spinal

stabilisation in patients with MPS. Pain and arthrosis associated with hip dysplasia, as well as

deformity and risk of neurological compromise associated with progressive thoracolumbar

kyphosis must be assessed in all patients and a decision on relative timing of interventions

made dependent on the immediacy of each on an individual patient basis.

In our cohort of patients, the thoracolumbar kyphosis was managed by combined antero-

posterior spinal arthrodesis at a similar mean age at surgery but with a greater preoperative

sagittal deformity when compared to previously reported MPS cohorts (Table 5). Differences

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between series in the mean pre-operative kyphotic angle and age at time of surgery are likely

due to variation in the proportion of MPS subtypes, indications for surgery, and whether or

not other interventions, such as reconstructive hip surgery, were scheduled before or after

spinal surgery.14 Despite our patients developing a greater kyphosis pre-operatively, we

achieved a mean kyphosis correction of 66.9%, which is comparable to the 60 to 70%

correction reported in previous series. As can be expected, patients whose thoracolumbar

deformity became flexible after completion of the anterior stage of the procedure and

therefore underwent instrumented arthrodesis posteriorly had a less severe kyphotic deformity

pre-operatively, and achieved greater kyphosis correction, than patients in whom the

deformity was rigid who underwent an un-instrumented circumferential arthrodesis. In our

cohort, no patient had failure of instrumentation and correction of kyphosis was maintained at

follow-up in all patients. Circumferential arthrodesis also achieved improvement in thoracic

kyphosis and associated thoracic or thoracolumbar scoliosis.

Despite good correction of thoracolumbar deformity in our cohort, a few patients developed

post-operative complications. Significant medical and anaesthetic risks are associated with

spinal surgery in patients with MPS.14 In our cohort, respiratory complications were frequent

with 2 patients requiring a pre-operative tracheotomy, and 3 patients developing post-

operative pulmonary infections. This was reflected in the mean duration of hospital stay of 31

days in our cohort. One patient developed a deep wound infection that resolved with early

management and had no effect on maintenance of deformity correction. One patient who

underwent an un-instrumented arthrodesis developed non-union at the apex of the deformity

posteriorly. Fusion was achieved by a revision re-grafting procedure. The only other

complication was the development of grade II spondylolisthesis at the distal adjacent segment

in a patient with Hunter syndrome. This was reported as a relatively frequent complication by

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Genevois et al.14 (3 of 13 patients; 23%), with only one patient requiring revision surgery. The

patient in our series was kept under close monitoring to skeletal maturity with no deterioration

in spondylolisthesis or neurological function. Interestingly, mild proximal adjacent segment

spondylolisthesis occurred in 50% of patients in a previous series, but did not require revision

surgery.14 These complications highlight the risk of developing wound healing problems and

segmental instability producing spondylolisthesis adjacent to the extents of fusions in patients

with MPS. MPS patients may be particularly susceptible to such complications as they

frequently develop a severe flexed posture with marked positive sagittal imbalance and fixed

hip flexion deformity, as well as due to the underlying connective tissue disorder and inherent

immunological compromise.

Significant variation in the rate of progression of thoracolumbar kyphosis in patients with

MPS has previously been reported.6 We found that only the magnitude of kyphosis at initial

presentation was significantly associated with progression to severe deformity and need for

surgical treatment. We identified that initial thoracolumbar kyphosis >+38o predicted

deformity progression and need for surgical intervention with high sensitivity and specificity.

Our finding is similar to that of Yasin et al.6 who found an initial kyphosis angle of +45o to be

predictive of a progressive deformity. Differences in the subtypes of MPS and proportion of

non-operative and operative patients included within each series may account for the small

variability in predictive thresholds. Additional factors are likely to contribute to the natural

history of thoracolumbar kyphosis progression and future investigation in larger surgical MPS

cohorts will permit more accurate prediction of deformity progression and prophylactic

intervention. Our results indicate that patients presenting with a thoracolumbar kyphosis

>+38o should be considered for surgical stabilisation, in addition to patients presenting with a

progressive deformity.

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Our study has limitations. It is a retrospective analysis of clinical and radiological data.

Although the follow-up of patients managed non-operatively and operatively was longer in

our cohort, only 38% (n = 6) of our patients had reached skeletal maturity at the available

final follow-up. Further studies following patients through to skeletal maturity will allow a

more complete understanding of the outcomes of non-operative and surgical interventions for

thoracolumbar kyphosis in MPS. Our study reported clinical and radiological outcomes, but

patient function and carer/relative satisfaction were not directly assessed. Further studies to

develop and validate functional outcome scores and to assess satisfaction using quality of life

scores specific to MPS may be beneficial adjuncts in assessing treatments for spinal

deformity. Finally, MPS are a heterogeneous group of disorders and larger cohorts examining

outcomes of treatment for spinal deformity according to subtype will be useful to further

optimise indications, timing and strategies for surgical intervention.

In conclusion, thoracolumbar kyphosis in patients with MPS may follow a variable course.

Patients with MPS have significant medical co-morbidities and anaesthetic risks. Successful

surgery depends on applying the optimum procedure at the most appropriate time. Progressive

thoracolumbar kyphosis and the need for surgical treatment is best predicted by an initial

kyphosis angle >+38o. Patients that develop progressively severe thoracolumbar kyphosis can

be adequately treated by combined antero-posterior arthrodesis, with the use of a supportive

long anterior rib strut graft in patients whose deformity remains rigid after anterior release,

and the use of posterior instrumentation in patients in whom the deformity becomes flexible

allowing for maximum kyphosis correction. This is an effective strategy for treating severe

thoracolumbar kyphosis in patients with mucopolysaccharidoses. In our series,

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circumferential spinal arthrodesis resulted in satisfactory deformity correction, which was

maintained at follow-up. Patients with MPS may be particularly susceptible to post-operative

complications including wound infections and adjacent segment instability due to the

underlying connective tissue disorder and immunological compromise, as well as the

frequently pre-existing marked positive global sagittal imbalance.

Acknowledgement

The authors would like to acknowledge Mr Christopher I. Adams, Consultant Orthopaedic

and Spine Surgeon in our Unit who contributed one surgical patient in the current series.

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References

1. van der Linden MH, Kruyt MC, Sakkers RJ, de Koning TJ, Oner FC, Castelein RM. Orthopaedic management of Hurler's disease after hematopoietic stem cell transplantation: a systematic review. J Inherit Metab Dis 2011;34-3:657-69.2. Souillet G, Guffon N, Maire I, Pujol M, Taylor P, Sevin F, Bleyzac N, Mulier C, Durin A, Kebaili K, Galambrun C, Bertrand Y, Froissart R, Dorche C, Gebuhrer L, Garin C, Berard J, Guibaud P. Outcome of 27 patients with Hurler's syndrome transplanted from either related or unrelated haematopoietic stem cell sources. Bone Marrow Transplant 2003;31-12:1105-17.3. Clarke LA, Wraith JE, Beck M, Kolodny EH, Pastores GM, Muenzer J, Rapoport DM, Berger KI, Sidman M, Kakkis ED, Cox GF. Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I. Pediatrics 2009;123-1:229-40.4. Muenzer J, Beck M, Eng CM, Giugliani R, Harmatz P, Martin R, Ramaswami U, Vellodi A, Wraith JE, Cleary M, Gucsavas-Calikoglu M, Puga AC, Shinawi M, Ulbrich B, Vijayaraghavan S, Wendt S, Conway AM, Rossi A, Whiteman DA, Kimura A. Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome. Genet Med 2011;13-2:95-101.5. Weisstein JS, Delgado E, Steinbach LS, Hart K, Packman S. Musculoskeletal manifestations of Hurler syndrome: long-term follow-up after bone marrow transplantation. J Pediatr Orthop 2004;24-1:97-101.6. Yasin MN, Sacho R, Oxborrow NJ, Wraith JE, Williamson JB, Siddique I. Thoracolumbar kyphosis in treated mucopolysaccharidosis 1 (Hurler syndrome). Spine (Phila Pa 1976) 2014;39-5:381-7.7. Heppner JM, Zaucke F, Clarke LA. Extracellular matrix disruption is an early event in the pathogenesis of skeletal disease in mucopolysaccharidosis I. Mol Genet Metab 2015;114-2:146-55.8. Xing EM, Knox VW, O'Donnell PA, Sikura T, Liu Y, Wu S, Casal ML, Haskins ME, Ponder KP. The effect of neonatal gene therapy on skeletal manifestations in mucopolysaccharidosis VII dogs after a decade. Mol Genet Metab 2013;109-2:183-93.9. Tomatsu S, Almeciga-Diaz CJ, Montano AM, Yabe H, Tanaka A, Dung VC, Giugliani R, Kubaski F, Mason RW, Yasuda E, Sawamoto K, Mackenzie W, Suzuki Y, Orii KE, Barrera LA, Sly WS, Orii T. Therapies for the bone in mucopolysaccharidoses. Mol Genet Metab 2015;114-2:94-109.10. Tomatsu S, Sawamoto K, Almeciga-Diaz CJ, Shimada T, Bober MB, Chinen Y, Yabe H, Montano AM, Giugliani R, Kubaski F, Yasuda E, Rodriguez-Lopez A, Espejo-Mojica AJ, Sanchez OF, Mason RW, Barrera LA, Mackenzie WG, Orii T. Impact of enzyme replacement therapy and hematopoietic stem cell transplantation in patients with Morquio A syndrome. Drug Des Devel Ther 2015;9:1937-53.11. Pastores GM, Meere PA. Musculoskeletal complications associated with lysosomal storage disorders: Gaucher disease and Hurler-Scheie syndrome (mucopolysaccharidosis type I). Curr Opin Rheumatol 2005;17-1:70-8.12. Dornelles AD, de Camargo Pinto LL, de Paula AC, Steiner CE, Lourenco CM, Kim CA, Horovitz DD, Ribeiro EM, Valadares ER, Goulart I, Neves de Souza IC, da Costa Neri JI, Santana-da-Silva LC, Silva LR, Ribeiro M, de Oliveira Sobrinho RP, Giugliani R, Schwartz IV. Enzyme replacement therapy for Mucopolysaccharidosis Type I among patients followed within the MPS Brazil Network. Genet Mol Biol 2014;37-1:23-9.13. Dalvie SS, Noordeen MH, Vellodi A. Anterior instrumented fusion for thoracolumbar kyphosis in mucopolysaccharidosis. Spine (Phila Pa 1976) 2001;26-23:E539-41.14. Abelin Genevois K, Garin C, Solla F, Guffon N, Kohler R. Surgical management of thoracolumbar kyphosis in mucopolysaccharidosis type 1 in a reference center. J Inherit Metab Dis 2014;37-1:69-78.15. Cobb JR. Outline for the study of scoliosis. In: Instructional course lectures. Vol. 5: Ann Arbor: JW Edwards, 1948.16. White KK. Orthopaedic aspects of mucopolysaccharidoses. Rheumatology (Oxford) 2011;50 Suppl 5:v26-33.17. Field RE, Buchanan JA, Copplemans MG, Aichroth PM. Bone-marrow transplantation in Hurler's syndrome. Effect on skeletal development. J Bone Joint Surg Br 1994;76-6:975-81.

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18. McMaster MJ, Singh H. The surgical management of congenital kyphosis and kyphoscoliosis. Spine (Phila Pa 1976) 2001;26-19:2146-54; discussion 55.19. Ain MC, Browne JA. Spinal arthrodesis with instrumentation for thoracolumbar kyphosis in pediatric achondroplasia. Spine 2004;29-18:2075-80.20. Auregan JC, Odent T, Coyle RM, Miladi L, Wicart P, Dubousset J, Le Merrer M, Padovani JP, Glorion C. Ischiovertebral dysplasia: a retrospective analysis of 30 consecutive cases pointing out the specifics and risks of the spine management. Spine (Phila Pa 1976) 2014;39-9:E564-75.21. Mason DE, Sanders JO, MacKenzie WG, Nakata Y, Winter R. Spinal deformity in chondrodysplasia punctata. Spine (Phila Pa 1976) 2002;27-18:1995-2002.22. Saraph VJ, Bach CM, Krismer M, Wimmer C. Evaluation of spinal fusion using autologous anterior strut grafts and posterior instrumentation for thoracic/thoracolumbar kyphosis. Spine (Phila Pa 1976) 2005;30-14:1594-601.23. Kim YJ, Otsuka NY, Flynn JM, Hall JE, Emans JB, Hresko MT. Surgical treatment of congenital kyphosis. Spine (Phila Pa 1976) 2001;26-20:2251-7.

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Table 1. Demographics, extra-spinal features and previous operations in our MPS patients.

Patient No

MPS Type

Age at Presentation

(years)Gender

Medical Therapy

Age BMT/ERT commenced

Extraspinal Features and Previous Operations

1 Hurler 1.08 Female BMT 1.42 Macrocephaly, mild coarctation of aorta, hypoplastic and lateralised hips

2 Hurler 0.42 Female BMT 0.66Hearing impairment, obstructive sleep apnoea, inguinal hernia repair, joint

contractures

3 Hunter 13 Male None N/APerinatal cerebral infarct causing hemiplegia, learning difficulties, hearing

impairment, mitral regurgitation, sleep apnoea, umbilical hernia repair

4 Morquio 12.91 Male None N/A High tetraplegia following previous occipito-cervical fusion

5 Morquio 3.91 Female ERT 5 None

6 Morquio 6.5 Male ERT 9.5 Hemi-epiphysiodesis for genu valgum

7 Hurler 4.83 Male BMT 0.58 Sleep apnoea, inguinal hernia repair, bilateral carpal tunnel release

8 Hurler 5.66 Male BMT 1Learning difficulties, mitral regurgitation, bilateral carpal tunnel

decompression, bilateral hernia repair, bilateral genu valgum, bilateral congenital talipes equinovarus

9 Hurler 14.42 Male BMT 1.6Mitral regurgitation, bilateral carpal tunnel decompression, bilateral hernia

repair, bilateral hip dysplasia, bilateral hemi-epiphysiodesis for genu valgum

10 Hurler 1.5 Female BMT 1Learning difficulties, hearing impairment, suppraglottoplasty, tracheo-

bronchal malacia, adrenal insufficiency, bilateral genu valgum

11 Hurler 0.91 Female BMT 1.42Macrocephaly, developmental delay, cardio-myopathy and mitral

regurgitation, bilatera umbilical hernia repair, bilateral hip dysplasia

12 Hurler 1.91 Male BMT 1.33 Hyposplenism

13 Hurler 1.25 Female BMT 1.42 Aortic valve stenosis, hypoadrenalism, umbilical hernia repair

14 Hunter 12.5 Male ERT 5.5Learning difficulties, hearing impairment, mitral stenosis, gastro-

oesophageal reflux, bilateral hip dysplasia, bilateral congenital talipes equinovarus

15 Morquio 1.83 Female None N/A Mitral regurgitation, left hip dislocation

16 Morquio 2.75 Female ERT 7.58 Sleep apnoea, bilateral hip dysplasia, bilateral genu valgum

22

Table 2. Spinal features in our MPS patients.

Patient No

MPS Type

Spinal DeformityManagement of

Spinal Deformity

Cervical Spine Features Thoracolumbar Spine Features

1 Hurler Thoracolumbar kyphosis Non-operative None Hypoplastic beaked L2 vertebra

2 Hurler Thoracolumbar kyphosis Non-operativeDynamic cranio-cervical junction

narrowing affecting CSF flowHypoplastic beaked L3 vertebra

3 HunterThoracolumbar kyphosis,

left thoracolumbar scoliosisNon-operative

Narrowing of cranio-cervical junction

Hypoplastic beaked L1 & L2 vertebrae

4Morqui

oThoracolumbar kyphosis Non-operative

Previous occipito-cervical fusion for occipito-cervical instability

Hypoplastic vertebrae T11-L2

5Morqui

oThoracolumbar kyphosis Non-operative

Hypoplastic odontoid process, with hyperplastic peri-odontoid soft

tissue, mild cervical spine instability

Hypoplastic beaked T12 vertebra, elliptical L1 & L2 vertebra

6Morqui

o

Thoracolumbar kyphosis, right thoracic scoliosis, left

thoracolumbar scoliosisNon-operative None

Hypoplastic beaked T11, vertebral platyspondyly at several levels

7 Hurler Thoracolumbar kyphosis Operative NoneHypoplastic beaked T12 vertebra, anterior

spinal subluxation T11/T12

8 HurlerThoracolumbar kyphosis, thoracolumbar scoliosis

OperativePrevious occipito-cervical fusion

for C1-C2 instabilityHypoplastic beaked L1 vertebra

9 HurlerThoracolumbar kyphosis

(add-on junctional kyphosis)

OperativeHyperplasia of peri-odontoid soft tissue with impingement of cord

Hypoplastic beaked L1 vertebra, previous antero-posterior fusion for thoracolumbar

kyphosis

10 Hurler Thoracolumbar kyphosis Operative NoneMultiple vertebral platyspondyly, short and narrow pedicles, hypoplastic and beaked L2

vertebra

11 HurlerThoracolumbar kyphosis,

right thoracic scoliosisOperative None

Hypoplastic beaked L1 & L2 vertebrae, T12-L1 segmental instability

12 Hurler Thoracolumbar kyphosis Operative NoneHypoplastic beaked T12 vertebra, T12-L1

spondylolisthesis

13 HurlerThoracolumbar kyphosis,

left thoracic scoliosisOperative None

Hypoplastic beaked L1 & L2 vertebra, T11/T12 and T12/L1 spondylolisthesis

14 HunterThoracolumbar kyphosis,

left thoracolumbar scoliosisOperative None

Hypoplastic beaked T12 vertebra, T11/T12 segmental instability, bilateral L5 isthmic

spondylolysis

15Morqui

oThoracolumbar kyphosis Operative

Previous occipito-cervical fusion for C1-C2 instability

Hypoplastic beaked L1 & L2 vertebrae, grade II spondylolisthesis T12/L1

16Morqui

oThoracolumbar kyphosis Operative

Absent odontoid process, cranio-cervical junction stenosis, previous occipito-cervical fusion for C1-C2

instability

Hypoplastic beaked T12 vertebra

23

Table 3. Spinal deformity in our MPS patients managed conservatively.

Patient No

MPS Type

Age at Presentation

(years)Spinal Deformity Extent of

Deformity

Initial Deformity

Cobb Angle

Final Deformity

Cobb Angle

Follow-Up

(years)

1 Hurler 1.08 Thoracolumbar kyphosis T12-L3 30 33 1

2 Hurler 0.42 Thoracolumbar kyphosis T12-L4 30 30 1

3 Hunter 13

Thoracolumbar kyphosis

Left thoracolumbar scoliosis

T8-L4

T6-L3

60

15

75

223

4 Morquio 12.91 Thoracolumbar kyphosis T7-L3 27 27 5.1

5 Morquio 3.91 Thoracolumbar kyphosis T9-L1 8 15 4.1

6 Morquio 6.5

Thoracolumbar kyphosis

Right thoracic scoliosis

Left thoracolumbar scoliosis

T9-L1

T11-L3

T5-T10

28

26

17

32

33

30

4.5

24

Table 4. Spinal deformity in our MPS patients treated surgically.

Patient No

MPS Type

Age at Presentation

(years)

Age at Surgery (years)

Spinal Deformity Extent of Deformity

Surgical Procedure (extent)

Initial Deformity

Cobb Angle

Pre-operative Deformity

Cobb Angle

Post-operative Deformity

Cobb Angle

Surgical Complications

Post-Operative Follow-Up

(years)

7 Hurler 4.8 6.8 Thoracolumbar kyphosis T10-L2 Circumferential arthrodesis (T10-L3) 95 110 65 None 7.2

8 Hurler 5.7 7.7Thoracolumbar kyphosis Thoracolumbar scoliosis

T11-L3 T11-L3

Circumferential arthrodesis (T10-L4)78 14

94 26

65 15

None 9.3

9 Hurler 14.4 16.8

Thoracolumbar kyphosis (proximal & distal junctional

kyphosis after anterior arthrodesis at other centre)

T12-L4Circumferential arthrodesis with posterior

instrumentation (T10-L5)60 78 35 None 4.6

10 Hurler 1.5 2.8 Thoracolumbar kyphosis T11-L3Circumferential arthrodesis with posterior

instrumentation (T11-L4)44 56 0

Deep wound infection managed by debridement &

IV antibiotics; stable proximal junctional kyphosis

3.5

11 Hurler 0.9 4.1Thoracolumbar kyphosis

Thoracic scoliosisT10-L3 T5-T9

Circumferential arthrodesis (T10-L4)45 19

110 25

55 14

None 6.6

12 Hurler 1.9 3.1 Thoracolumbar kyphosis T10-L2Circumferential arthrodesis with posterior

instrumentation (T10-L3)60 62 22 None 5.1

13 Hurler 1.3 2.4Thoracolumbar kyphosis

Thoracic scoliosisT12-L2 T11-L3

Circumferential arthrodesis with posterior instrumentation (T10-L3)

44 22

69 33

12 20

None 5.8

14 Hunter 12.5 13.7Thoracolumbar kyphosis Thoracolumbar scoliosis

T11-L3 T11-L3

Circumferential arthrodesis with posterior instrumentation (T9-L4)

42 30

68 45

4 0

Adjacent distal segment grade II spondylolisthesis

4.5

15 Morquio 1.8 3.8 Thoracolumbar kyphosis T11-L3Circumferential arthrodesis with posterior

instrumentation (T10-L4)36 42 0 None 6.2

25

16 Morquio 2.8 4.3 Thoracolumbar kyphosis T10-L1 Circumferential arthrodesis (T9-L4) 40 55 28Non-union at apex of kyphosis managed by posterior re-grafting

10.3

Table 5. Comparison of our study with published series of spinal stabilisation in MPS patients.6,9,10

Series Author (Year)

Number of

patients

MPS Types (n=)

Mean Age at Surgery

(Years)

Surgical Technique

Mean Pre-operative TL Kyphosis

(degrees; range)

Mean Post-operative TL Kyphosis

(degrees; range)

Mean Operative

Correction of TL Kyphosis (%; range)

Mean Post-operative

Follow-up (years; range)

Major Complications

Dalvie (2001)

7Morquio (4), Martoux-Lamy (2), Hurler (1)

8.7 (4 - 14)

Anterior segmental instrumented arthrodesis

52.5 (42 - 64)

15 (3 - 29)

70.6 (45.5 - 93.3)

1.2 (0.4 - 3)

None

Genevois (2014)

14 Hurler (14)7.8

(3.5 - 15)

Combined antero-posterior arthrodesis

57.5 (30 - 90)

14.1 (-14 - +52)

66 (30.8 - 100)

3.7 (0.8 - 8.7)

Adjacent segment listhesis (n = 3), transient paraperesis (n=1), progressive scoliosis (n=1)

Yasin (2014)

7 Hurler (7)4.1

(2.4 - 10)

Anterior vascularised rib graft (n = 5). Combined antero-posterior instrumented arthrodesis (n = 1). VEPTR (n = 1)

67.3 (N/A)

35 (combined arthrodesis & VEPTR cases

only)

59.5 (58.3 - 59.8; combined

arthrodesis & VEPTR cases

only)

0.8 (0.5 - 1;

combined arthrodesis and VEPTR cases

only)

Proximal junctional kyphosis after anterior-only surgery (n = 3)

26

Current Study (2015)

10Hurler (7), Hunter (1), Morquio (2)

6.6 (2.4 – 16.8)

Combined antero-posterior arthrodesis +/-posterior instrumentation

74.3 (37 - 110)

28.6 (0 - 65)

66.9 (31 - 100)

6.3 (3.5 - 10.3)

Proximal junction kyphosis (n = 1); deep wound infection (n = 1); adjacent distal segment spondylolisthesis (n = 1); non-union at kyphosis apex (n = 1)

27

Figure legends.

Figure 1. Radiographs of patient 7 (Table 4) showing pre-operative a) postero-anterior (PA) and b) lateral radiographs of the spine with 110o thoracolumbar kyphosis (T10-L2). Post-operative c) PA and d) lateral radiographs at 2 years following un-instrumented circumferential arthrodesis (T10-L3) show correction of kyphosis to 65o.

Figure 2. Radiographs of patient 12 (Table 4) showing pre-operative a) postero-anterior (PA) and b) lateral radiographs of the spine with 62o thoracolumbar kyphosis (T10-L2). Post-operative c) PA and d) lateral radiographs at 2 years following circumferential arthrodesis with the use of posterior instrumentation (T10-L3) achieved correction of kyphosis to 22o.