Abstract
Introduction
Mucopolysaccharidosis type IV (MPS IV) often leads to instability and spinal cord compression at the craniocervical junction in children, confronting surgeons with technical challenges associated with young age.
Research question
This systematic review examines the effects of age at surgery and type of fixation on achieving craniocervical bony fusion and the impact of decompression and solid fusion on neurological outcomes.
Material and methods
We systematically searched PubMed/MEDLINE, Embase, Web of Science, Scopus and Cochrane Library for cohorts reporting on ‘Craniocervical instability’, ‘Spinal cord compression’ and ‘Mucopolysaccharidosis type IV’ up till April 27, 2024. Inclusion criteria were MPS IV, craniocervical instability treatment and age ≤ 16 years.
Results
Eighteen studies were included, comprising 114 patients with a median age at surgery of 72.0 months (range: 17.0-191.0). A total of 88.6% (n = 101/114) of patients underwent craniocervical junction surgery, with rigid fixation used in 17.8% (n = 13/73) and decompression performed in 63.8% (n = 44/69) of cases. Craniocervical bony fusion was achieved in 93.8% (n = 91/97) of patients. Rigid fixation was less often used in children younger than three years (20.0%, n = 2/10), but fusion rate remained as high as 77.8% (n = 7/9). No statistically significant association between fixation type and bony fusion was detected (OR = 2.44, 95% CI 0.24-330.60, p = 0.51). There was a trend for neurological outcome to be better after performing decompression (OR = 4.48, 95% CI 0.87-23.26, p = 0.07).
Discussion and conclusion
Although rigid fixation was less often applied in children below the age of three, fusion and neurological outcomes were reasonably favorable. There was a trend toward better neurological outcome in patients undergoing decompression.
Keywords: Mucopolysaccharidosis type IV, Craniocervical instability, Spinal Cord Compression, Occipitocervical fusion, Rigid fixation, Semi-rigid fixation, Spinal cord decompression
1. Introduction
Mucopolysaccharidosis type IV (MPS IV), also known as Morquio Syndrome, is a rare hereditary lysosomal storage disease (Visocchi, 2020; Liu et al., 2023). In the USA, the incidence rate of MPS IV is estimated to be between 1 in 200 000 and 1 in 300 000 live births (Visocchi, 2020). Morquio syndrome is inherited in autosomal recessive manner (Downs and Hewitt, 1988).
Two forms of MPS IV have been described: MPS IVA results from a deficiency of N-acetyl galactosamine 6-sulphatase (GALNS), whereas MPS IVB is caused by a deficiency of β-galactosidase (Downs and Hewitt, 1988). A deficit of these lysosomal enzymes leads to impaired degradation and subsequent accumulation of keratan sulphate and chondroitin-6-sulphate, two mucopolysaccharides (Downs and Hewitt, 1988; Charrow et al., 2015). The connective tissue, cartilage, ligaments and bones are particularly affected, resulting in multisystem involvement: skeletal, visual, auditory, digestive, cardiovascular, neurological and respiratory systems (Charrow et al., 2015).
MPS IV is characterized by systemic skeletal dysplasia and ligamentous laxity. Odontoid hypoplasia and ligamentous laxity at the occipitocervical junction result in craniocervical instability, leading to potential spinal cord compression. Neurological deficits are often caused by a fall (Liu et al., 2023; Charrow et al., 2015; Dede et al., 2013).
There is currently no evidence that existing MPS-specific therapies, including enzyme replacement therapy (ERT), gene therapy and hematopoietic stem cell transplantation (HSCT), have any impact on craniocervical instability, making surgical intervention crucial for patient outcomes in case instability is diagnosed (Liu et al., 2023). However, surgical treatment in children with MPS IV can be technically challenging – especially when attempting rigid fixation with screw constructs – due to small anatomical structure, soft bone, immature ossification, high structural variability and deformed joints (Visocchi, 2020; Liu et al., 2023). Moreover, the problem of instability can be present in very young children, and their young age and small size substantially increases this difficulty.
The management of craniocervical instability in the pediatric population has evolved over the past decade, shifting from wiring techniques to screw-rod constructs. However, when the bony fixation points are too small to accommodate screws, wiring techniques are most often used (Martinez-Del-Campo et al., 2016).
However, despite technical advances, the optimal fixation technique in children with MPS IV remains debated. Wiring and semi-rigid constructs are often considered safer in very young patients with small or dysplastic bone, whereas screw-based rigid fixation provides superior stability, but may be anatomically unfeasible or risky. This ongoing debate reflects the lack of consensus on how to balance biomechanical stability against anatomical limitations and growth potential in this fragile population.
Decompression is typically added when radiological or clinical evidence of spinal cord compression is present, yet the timing and extent of decompression remain variable among centers.
To date, only case reports and retrospective studies with a limited number of patients have been published in the literature. The aim of this review is to consolidate available data to investigate the effect of variables such as age at surgery and type of fixation on craniocervical fusion. Additionally, we aim to assess the impact of achieving bony fusion and decompression on neurological outcomes.
2. Methods
The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Page et al., 2021). The study was not prospectively registered.
2.1. Data source and study searching
We conducted an electronic search in PubMed/MEDLINE, Embase, Web of Science, Scopus and Cochrane Library. We also searched grey literature sources such as Clinicaltrials.gov, International Clinical Trials Registry Platform (ICTRP), Europe PubMed Central, Open Access Theses and Dissertations (OATD), and ProQuest Dissertations and Theses Global (PQDT). Relevant keywords included ‘Craniocervical instability’, ‘Spinal cord compression’ and ‘Mucopolysaccharidosis type IV’. The full search strategy is available in Appendix A. To ensure that no relevant articles were missed, an additional search using 'NOT' was performed in PubMed. This additional search is explained in appendix B. The last search was conducted on April 27, 2024.
2.2. Data collection process
Two investigators (PA and DB) independently conducted the screening by title and abstract, and by full text in a second round. Consensus was reached for all articles. Inclusion criteria were MPS IV, conservative or surgical treatment for craniocervical instability and age of 16 years or younger. We excluded articles that were not in English or French, had insufficient reported data or contained non-extractable data.
Data were extracted from the included studies, and the following information was recorded: sex, age at presentation, age at surgery, clinical and radiological presentation, intervention, neurological and surgical outcomes, and follow-up. In the case of surgery, the following details were registered: levels of fusion, instrumentation used, type of screws in case of rigid fixation, type of bone graft, type of decompression, type and duration of immobilization, and complications.
To address the potential duplication of patients across publications, we manually examined all included studies for overlapping recruitment periods, identical institutions, and matching patient characteristics: age, sex, clinical presentation and surgical details. When two articles originated from the same center and covered similar time frames, patient descriptions were compared to determine whether individuals were reported more than once.
2.3. Definitions of key variables
Given the heterogeneity of surgical techniques and reporting standards across the included literature, we applied uniform definitions throughout this review. Rigid fixation was defined as screw-rod constructs, whereas semi-rigid fixation referred to wiring techniques. Craniocervical instability was assessed based on the radiological interpretation provided in each study. Bony fusion was defined according to the radiological judgement reported in the original articles.
Neurological outcome was harmonized across studies by categorizing patients as improved, stable or worsened based on the authors’ descriptions. Neurological improvement was coded as present when any postoperative or post-treatment neurological parameter, such as motor strength, gait, myelopathic signs, reflex abnormalities or subjective functional status, was reported as better than at baseline. If no change was described, the patient was classified as stable. Deterioration was coded when postoperative or post-treatment findings were worse than the initial presentation.
2.4. Risk of bias and study quality assessment
We assessed the quality of each study using the Methodological Items for Non-Randomized Studies (MINORS) instrument for retrospective studies and the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports.
A sensitivity analysis was performed by repeating the main descriptive analyses and logistic regression models after excluding patients from studies with the lowest quality scores, MINORS ≤ 8/16 and JBI < 4/8.
2.5. Statistical analysis
Given the limited number of patients included in each study, the heterogeneity among studies and the absence of standardized outcome measures, a formal meta-analysis could not be appropriately performed. Nevertheless, individual patient data was pooled to explore associations at the patient level. We transcribed the data from each study in tabular form. Categorical variables were summarized by counts and percentages, while continuous variables were reported as medians with minimum and maximum values.
We used SPSS Statistics for descriptive analyses and to calculate univariable logistic regressions to assess the relationship between achievement of bony fusion and various independent variables (age at surgery and type of fixation), as well as between decompression and neurological outcome. A firth-logistic regression was performed using R Statistics to evaluate the relationship between achievement of bony fusion and type of fixation because a perfect correlation existed between both variables. We used a significance level of 5%. Missing data were not included in the statistical analyses and percentages were calculated from available cases rather than the entire cohort.
3. Results
3.1. Search results
The search strategy yielded 142 studies after duplicate removal. An additional 12 studies were included after checking for missed articles with ‘NOT’ in PubMed, bringing the total to 154 studies. After screening the titles and abstracts, 118 articles were excluded, while the remaining 36 papers were selected for full-text assessment. After applying the inclusion and exclusion criteria, a total of 18 studies, 10 retrospective studies and 8 case reports, were included in our systematic review. Fig. 1 presents a flow chart of the study identification process. Table 1 lists general study characteristics.
Fig. 1.
Flow diagram of the study identification process (Page et al., 2021).
Table 1.
General study characteristics.
| Author (year) | Study design | Biasa | No. MPS IVb | Sex (F:M) | Age at surgeryc | Surgery | Complications | Fusion outcome | Follow-upd |
|---|---|---|---|---|---|---|---|---|---|
| Ain et al. (2006) (Ain et al., 2006) | Retrospective study | 12/16 | 7 | 3:3 | 67.00 | N = 6 | No complications (n = 4) NM (n = 2) |
Fusion (n = 6) | 79.00 |
| Ashraf et al. (1991) (Ashraf et al., 1991) | Case report | 5/8 | 1 | 0:1 | 42.00 | N = 1 | NM | Fusion | NM |
| Broomfield et al. (2018) (Broomfield et al., 2018) | Retrospective review | 12/16 | 27 | NM | 77.00 | N = 27 | No complications (n = 18) Myelopathy (n = 1) Mild paresthesia (n = 1) Swelling of tongue (n = 1) Respiratory problems (n = 1) Perioperative apnea (n = 1) Perioperative bradycardia (n = 1) Loosening of the pin of the halo (n = 1) Leak out of pin site of the halo (n = 1) Postoperative bleeding out of pin site of the halo (n = 1) Postoperative pain at pin site of the halo (n = 1) Insufficient fusion of graft (n = 1) Loss of function in upper and lower limb (n = 1) NM (n = 3) |
Fusion (n = 25) No fusion (n = 1) NM (n = 1) |
20.25 |
| Giussani et al. (2009) (Giussani et al., 2009) | Retrospective review | 12/16 | 1 | 1:0 | 72.00 | N = 1 | No complications | Fusion | 36.00 |
| Grover et al. (2020) (Grover et al., 2020) | Observational studye | 11/16 | 4 | 0:4 | 42.50 | N = 4 | Not further specified | Fusion (n = 4) | 82.00 |
| Hardy et al. (1985) (Hardy et al., 1985) | Case report (French) | 7/8 | 6 | 4:2 | 100.00 | N = 6 | No complications (n = 5) Pseudoarthrosis C0-C1 (n = 1) |
Fusion (n = 6) | NM |
| Muthukumar (2019) (Muthukumar, 2019) | Retrospective review | 9/16 | 2 | 0:2 | 108.00 | N = 2 | NM | Fusion (n = 2) | 30.00 |
| Pouliquen et al. (1982) (Pouliquen et al., 1982) | Case report (French) | 5/8 | 6 | 3:3 | 103.50 | N = 6 | No complications (n = 3) Peroperative bradycardia (n = 1) NM (n = 2) |
Fusion (n = 5) NM (n = 1) |
24.00 |
| Prabhu et al. (2022) (Prabhu et al., 2022) | Case report | 6/8 | 1 | NM | 22.00 | N = 1 | No complications | No fusion | NM |
| Ransford et al. (1996) (Ransford et al., 1996) | Retrospective review | 6/16 | 17 | 5:7 | 84.00 | N = 12 | NM | Fusion (n = 11) Death (n = 1) |
NM |
| Rigante et al. (1999) (Rigante et al., 1999) | Case report | 5/8 | 8 | NM | NM | N = 3 | NM | NM | NM |
| Singh and Cree (2015) (Singh and Cree, 2015) | Retrospective study | 8/16 | 2 | 0:2 | 24.00 | N = 2 | No complications (n = 2) | Fusion (n = 2) | 2.00 |
| Singh et al. (2020) (Singh et al., 2020) | Case report | 3/8 | 4 | 1:3 | 48.00 | N = 4 | NM | Fusion (n = 4) | 66.00 |
| Sitoula et al. (2014) (Sitoula et al., 2014) | Retrospective cohort | 11/16 | 6 | 3:2 | 70.00 | N = 5 | Loosening of the pin of the halo (n = 1) NM (n = 3) |
Fusion (n = 5) | 39.00 |
| Svensson and Aaro, 1988 (Svensson and Aaro, 1988) | Case report | 4/8 | 1 | 0:1 | 60.00 | N = 1 | Mild decubitus | Fusion | 96.00 |
| Visocchi et al. (2019) (Visocchi et al., 2019) | Retrospective study | 11/16 | 1 | 1:0 | 96.00 | N = 1 | No complications | Fusion | 202.00 |
| White et al. (2009) (White et al., 2009) | Case report | 8/8 | 1 | 0:1 | 120.00 | N = 1 | No complications | Fusion | 312.00 |
| Williams et al. (2018) (Williams et al., 2018) | Retrospective case series | 12/16 | 27 | 10:17 | 68.00f | N = 18 | No complications (n = 12) Basilar invagination (n = 1) Spinal canal narrowing (n = 2) Transient muscle weakness (n = 1) Iatrogenic injury to urethra (n = 1) Perioperative cervicothoracic ischemia (n = 1) |
Fusion (n = 17) No fusion (n = 1) |
87.00 |
Abbreviations: F female, M male, NM not mentioned.
MINORS for retrospective studies (16 points), JBI Critical Appraisal Checklist for Case Reports (8 elements).
Number of patients with MPS IV, regardless of age.
Median age at surgery in months.
Median age at follow-up in months.
Single-center, retrospectively collected, prospective, observational study.
Median age at presentation in months.
3.2. Quality and risk of bias of included studies
The risk of bias assessment revealed variability in study quality. The MINORS score for retrospective studies ranged from 6/16 to 12/16, while three to eight of the eight elements of the JBI Critical Appraisal Checklist for Case Reports were met. Table 1 lists the MINORS score and JBI Critical Appraisal Checklist for Case Reports for each study.
Sensitivity analyses excluding patients from the poorest-quality studies yielded odds ratios and confidence intervals that were similar in magnitude and direction to those of the primary analyses, suggesting that the principal findings were not driven by low-quality reports.
3.3. Outcomes in children aged 16 years or younger at the time of surgery
3.3.1. Patient characteristics
The included studies comprised a total of 114 patients (female/male ratio: 31/48) with a median age at presentation of 43.0 months (range: 14.0-191.0) and a median age at surgery of 72.0 months (range: 17.0-191.0). We identified one duplicate case across the included studies. This patient was counted only once in the final dataset.
3.3.2. Clinical and radiological presentation
At presentation, 42.2% (n = 43/102) of the patients were asymptomatic, but exhibited abnormalities on imaging. Among symptomatic children, the most common clinical presentations were hyperreflexia (23.5%; n = 24/102), muscle weakness/loss of strength (13.7%; n = 14/102) and paresis/plegia (11.8%; n = 12/102). The most common radiological finding was spinal canal narrowing (55.8%, n = 53/95). Other frequently observed abnormalities on imaging (X-ray, CT and MRI) were spinal cord compression (29.5%, n = 28/95), atlantoaxial involvement manifesting as instability, subluxation or dislocation (41.1%, n = 39/95) and odontoid involvement characterized by hypoplasia, aplasia, dysplasia, agenesis or ossiculum terminale (55.8%, n = 53/95).
3.3.3. Treatment of craniocervical instability
Most patients underwent surgery (88.6%, n = 101/114). Rigid fixation using screws was documented in a minority of children (17.8%, n = 13/73). Table 2 provides an overview of the screw types used in rigid fixation. In patients in whom semi-rigid fixation was performed, a sublaminar wiring technique was executed in most of the cases (96.7%, n = 58/60). For the remaining two patients in whom cables were used, the specific technique was not further described.
Table 2.
Type of screw used in rigid fixation.
| Type of screw | Frequency | Percent (%) |
|---|---|---|
| Laminar | 5 | 15.2 |
| C2 | 4 | 12.1 |
| C3 | 1 | 3.0 |
| Lateral mass | 11 | 33.3 |
| C1 | 5 | 15.2 |
| C3 | 6 | 18.2 |
| Pars interarticularis (C2) | 5 | 15.2 |
| Pedicle (C2) | 6 | 18.2 |
| Translaminar (C2) | 6 | 18.2 |
Decompression was carried out in 63.8% (n = 44/69) of cases. A laminectomy of C1 was performed in 18 patients (78.2%, n = 18/23). In two patients, additional decompression was carried out at the level of the foramen magnum. In three patients, a resection of a transverse fibrous band was executed in addition to the C1 laminectomy. Other decompression techniques at the level of C1 included laminotomy (4.3%, n = 1) and laminoplasty (8.7%, n = 2). Ashraf et al. described a transoral decompression consisting of transoral excision of the odontoid, the vertebral body of C2 and the anterior extradural soft tissues in one patient (Ashraf et al., 1991).
3.3.4. Neurological and surgical outcomes
Most patients for whom complications were reported, whether present or absent, experienced no postoperative complications (75.0%, n = 48/64). Among those who did, most complications were neurological or neurosurgical in nature (20.8%, n = 13/64), though general complications such as anaesthetic, urological and dermatological complications were also reported (12.8%; n = 8/64). Two patients experienced more than one complication. Table 3 lists all documented complications.
Table 3.
Complications.
| Complication | Frequency | Percent (%) |
|---|---|---|
| Anaesthetic complications | 6 | 9.6 |
| Perioperative apnea | 1 | 1.6 |
| Perioperative bradycardia | 1 | 1.6 |
| Perioperative cervicothoracic ischemia | 1 | 1.6 |
| Peroperative bradycardia | 1 | 1.6 |
| Respiratory problems | 1 | 1.6 |
| Swelling of the tongue | 1 | 1.6 |
| Surgical complications | 13 | 20,8 |
| Leak out of the pin site of the halo | 1 | 1.6 |
| Loosening of the pin of the halo | 2 | 3.1 |
| Postoperative bleeding out if the pin site | 1 | 1.6 |
| Postoperative pain at the pin site | 1 | 1.6 |
| Loss of functions in upper and lower limb | 1 | 1.6 |
| Transient muscle weakness | 1 | 1.6 |
| Mild paresthesia | 1 | 1.6 |
| Myelopathy | 1 | 1.6 |
| Spinal cord narrowing | 2 | 3.1 |
| Basilar invagination | 1 | 1.6 |
| Pseudoarthrosis C0-C1 | 1 | 1.6 |
| Medical complications | 2 | 3.2 |
| Mild decubitus | 1 | 1.6 |
| Iatrogenic injury to the urethra | 1 | 1.6 |
At follow-up, 41 out of 100 patients were asymptomatic, of whom 30 patients had no symptoms at presentation. Neurological improvement occurred in 37.1% (n = 26/70) of patients. The median follow-up period was 40.0 months (range: 1.8-312.0). One patient died due to respiratory complications unrelated to surgery. Craniocervical fusion, assessed via X-ray or computed tomography, was achieved in 93.8% (n = 91/97) of children who underwent surgery.
3.3.5. Factors affecting the achievement of craniocervical fusion
Based on data from the included studies, we analyzed the relationship between fusion achievement and variables such as age at surgery and rigid versus semi-rigid fixation. The patient's age at the time of surgery did not appear to have a significant impact on the likelihood of achieving fusion (OR = 1.00, 95% CI 0.98-1.02, p = 0.75). The use of rigid fixation was associated with a higher chance of successful fusion, although this association was not statistically significant (OR = 2.44, 95% CI 0.24-330.60, p = 0.51). Additionally, bony fusion and decompression were linked to better neurological outcomes, but these associations did not reach statistical significance (bony fusion: OR = 3.48, 95% CI 0.53-22.73, p = 0.19; decompression: OR = 4.48, 95% CI 0.87-23.26, p = 0.07).
3.4. Outcomes in children aged three years or younger at the time of surgery
3.4.1. Patient characteristics
The included studies comprised a total of 10 patients (female/male ratio: 1/5) with an age at surgery of three years or younger. The median age at surgery was 30.5 months (range: 17.0-36.0).
3.4.2. Clinical and radiological presentation
At presentation, 66.7% (n = 6/9) of patients were asymptomatic, but exhibited abnormalities on imaging. Among symptomatic children, the most common clinical presentations were hyperreflexia (33.3%, n = 3/9), hypertonicity/spasticity (33.3%, n = 3/9) and paresis/plegia (22.2%, n = 2/9). The most common radiological findings were atlantoaxial instability (60.0%, n = 3/5) and spinal cord signal change (60.0%, n = 3/5). Other frequently observed abnormalities on imaging were spinal cord compression (40.0%, n = 2/5) and spinal canal stenosis (40.0%, n = 2/5).
3.4.3. Treatment of craniocervical instability
All 10 patients underwent surgery. Rigid fixation using screws was performed in only two children. In one patient, the surgeon placed two laminar screws in the C2 vertebra. In the other patient, two laminar screws were placed in the C2 vertebra, and both a laminar screw and a lateral mass screw were inserted in the C3 vertebra. In patients who underwent semi-rigid fixation, a sublaminar wiring technique was performed in most cases (87.5%, n = 7/8), except for one patient in whom polyester cables were used to fix the bone graft. Decompression was carried out in 33.3% (n = 2/6) of cases. In both cases, a laminoplasty of C1 was performed.
3.4.4. Neurological and surgical outcomes
No postoperative complications were reported. At follow-up, 42.9% (n = 3/7) of patients were asymptomatic, and neurological improvement was observed in 50.0% (n = 2/4). The median follow-up period was 21.0 months (range: 2.0-172.0). One patient died due to respiratory complications unrelated to surgery. Craniocervical fusion, assessed via X-ray or computed tomography, was achieved in 77.8% (n = 7/9) of children who underwent surgery.
4. Discussion
Craniocervical bony fusion was achieved in 93.8% of children following surgery for MPS IV-related craniocervical instability reported in literature. Rigid fixation was less often used in children younger than three years (20.0%, n = 2/10), but reported fusion rate remained as high as 77.8%. No statistically significant association between fixation type and fusion was detected, and we found no relationship between obtaining solid fusion and outcome. There was a trend for better neurological outcome when decompression was applied. Overall, reported outcomes were good with 41.0% of patients remaining asymptomatic and 37.1% of patients improving. 25.0% of patients had complications, which were usually minor.
It seems that stabilizing and decompressing surgery at the craniocervical junction in children with MPS IV is favorable, while in practice this surgery is rather challenging. Patients are young and bony anatomy is small to very small due to age and dysplasia, with normal screw trajectories often impossible.
Nevertheless, Martinez-del-Campo et al. reported occipitocervical fusion success rates in children ranging from 84.0% to 100.0%, with complication rates ranging from 7.8% to 26.0%. Complications related to wiring techniques were generally more frequent and severe than those associated with screw-based techniques (50.0% vs 14.0%, respectively). Visocchi M. stated that screw-based constructs provide superior stabilization and biomechanical profiles compared to sublaminar wires (Visocchi, 2020; Visocchi et al., 2019).
In a systematic review of 285 patients with occipitocervical fixation for several indications, Hwang et al. aimed to better understand the risks and outcomes of instrumented spine surgery in the pediatric population, regardless of etiology. They reported a fusion rate of 99.0% after three months in patients with screw constructs, compared to 95.0% in those with wire constructs, with an overall average of 94.4%. The difference was not statistically significant (Martinez-Del-Campo et al., 2016; Hwang et al., 2012).
The choice between rigid and semi-rigid fixation in children with MPS IV is inherently influenced by age, size, anatomy, bone quality, degree of ossification and surgeon preference. These factors explain much of the heterogeneity observed across the included studies. Although rigid screw-rod constructs should be pursued whenever anatomically feasible, our findings suggest that neurological and fusion outcomes are not uniformly poor when rigid fixation cannot be achieved. Adequate decompression appears to be one of the drivers for postoperative neurological improvement across techniques. Taken together, the available evidence supports a pragmatic, anatomy-driven surgical strategy with rigid fixation when possible and semi-rigid constructs when required by patient size or bone quality, and meticulous decompression in all cases with spinal cord compromise.
Dede et al. reported better neurologic outcomes with prophylactic surgery than with surgery performed after neurological compromise had already occurred. Furthermore, it has been documented that in patients with upper cervical instability, cervical fusion can prevent the otherwise progressive neurological deterioration (Dede et al., 2013).
Cardiac and pulmonary comorbidities as well as tracheal deformities in this population may significantly impact postoperative course. This is why this surgery should be part of specialized care in experienced multidisciplinary teams. In the present review, overall outcomes appeared to be relatively favorable. It was not possible to extract from the reported cases the setting in which the surgery took place. Publication bias may significantly impact the results of the present systematic review, while in reality perioperative problems and adverse outcomes could be much higher.
This study has several limitations. The systematic review is based on case reports and retrospective studies, which are characterized by a low level of evidence and inherent bias. Furthermore, the relevant data was not available for all patients. Although we manually assessed all studies for overlapping recruitment periods, institutions and patient characteristics, identifying one duplicate case, complete exclusion of additional overlap cannot be guaranteed due to limited reporting in several case reports. Finally, the exclusion of publications in languages other than English and French may have introduced a degree of selection bias. Given the rarity of MPS IV, even a small number of non-English case reports could theoretically influence aggregated findings. However, most contemporary reports on MPS IV are published in English and limiting inclusion to languages in which accurate clinical and radiological interpretation was guaranteed was necessary to ensure data reliability.
Since MPS IV is a rare disease, only small patient populations can be analyzed, limiting statistical significance in this systematic review. Larger study populations would be needed to obtain statistically significant results. However, to date, this study represents the largest cohort of children with craniocervical instability and spinal cord compression in the context of MPS IV described in the literature. The authors advocate the establishment of an international registry for metabolic syndrome-related craniocervical junction pathologies.
5. Conclusion
Craniocervical junction surgery in children with MPS IV remains technically demanding because of small anatomical structure, incomplete ossification, considerable variability in bony morphology, joint deformities and relevant comorbidities. Nevertheless, published series consistently report relatively low complication rates and generally favorable neurological outcomes, with many children remaining asymptomatic or improving postoperatively. High fusion rates have been described even in very young patients. There was a trend for decompression to add to neurological outcome. Given the rarity of MPS IV, an international registry dedicated to metabolic syndrome related craniocervical junction pathology would be essential to generate more robust evidence and guide future surgical decision-making.
Author contributions
Anton Peene and Bart Depreitere conceptualized the study and conducted the literature searches independently. Anton Peene extracted data from the included studies, assessed the quality of each study, designed the search strategy, performed the statistical analyses, drafted the initial manuscript and revised the manuscript. Bart Depreitere supervised the project and critically reviewed the manuscript for significant intellectual content.
Ethical approval
Not applicable.
Funding
There was no primary source of funding for this review. Some full-text articles were not freely available during the screening process and were purchased by the authors.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
The authors wish to thank Thomas Vandendriessche, Chayenne Van Meel, Norin Hamouda and Krizia Tuand for their assistance in conducting the systematic literature search.
The authors express their gratitude to Dries De Witte for reviewing the interpretation of the statistical analyses.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.bas.2026.106658.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
References
- Ain M.C., Chaichana K.L., Schkrohowsky J.G. Retrospective study of cervical arthrodesis in patients with various types of skeletal dysplasia. Spine (Phila Pa 1976) 2006;31(6):E169–E174. doi: 10.1097/01.brs.0000202758.61848.61. [DOI] [PubMed] [Google Scholar]
- Ashraf J., Crockard H.A., Ransford A.O., Stevens J.M. Transoral decompression and posterior stabilisation in Morquio's disease. Arch. Dis. Child. 1991;66(11):1318–1321. doi: 10.1136/adc.66.11.1318. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Broomfield A., Zuberi K., Mercer J., Moss G., Finnegan N., Hensman P., et al. Outcomes from 18 years of cervical spine surgery in MPS IVA: a single center's experience. Childs Nerv. Syst. 2018;34(9):1705–1716. doi: 10.1007/s00381-018-3823-9. [DOI] [PubMed] [Google Scholar]
- Charrow J., Alden T.D., Breathnach C.A., Frawley G.P., Hendriksz C.J., Link B., et al. Diagnostic evaluation, monitoring, and perioperative management of spinal cord compression in patients with Morquio syndrome. Mol. Genet. Metabol. 2015;114(1):11–18. doi: 10.1016/j.ymgme.2014.10.010. [DOI] [PubMed] [Google Scholar]
- Dede O., Thacker M.M., Rogers K.J., Oto M., Belthur M.V., Baratela W., Mackenzie W.G. Upper cervical fusion in children with Morquio syndrome: intermediate to long-term results. J. Bone Jt.Surg. Am. 2013;95(13):1228–1234. doi: 10.2106/JBJS.J.01135. [DOI] [PubMed] [Google Scholar]
- Downs J., Hewitt C. Physiotherapy management of occipito-cervical fusion in patients with Morquio Syndrome (mucopolysaccharidosis type IVA) Physiotherapy. 1988;74(7):321–324. [Google Scholar]
- Giussani C., Roux F.E., Guerra P., Pirillo D., Grimaldi M., Citerio G., Sganzerla E.P. Severely symptomatic craniovertebral junction abnormalities in children: long-term reliability of aggressive management. Pediatr. Neurosurg. 2009;45(1):29–36. doi: 10.1159/000202621. [DOI] [PubMed] [Google Scholar]
- Grover P.J., Harris L.S., Thompson D.N.P. Craniovertebral junction fixation in children less than 5 years. Eur. Spine J. 2020;29(5):961–969. doi: 10.1007/s00586-020-06313-x. [DOI] [PubMed] [Google Scholar]
- Hardy J.R., Pouliquen J.C., Penneçot G.F. [Posterior arthrodesis of the upper cervical spine in children and adolescents. Apropos of 19 cases] Rev Chir Orthop Reparatrice Appar Mot. 1985;71(3):153–166. [PubMed] [Google Scholar]
- Hwang S.W., Gressot L.V., Rangel-Castilla L., Whitehead W.E., Curry D.J., Bollo R.J., et al. Outcomes of instrumented fusion in the pediatric cervical spine. J. Neurosurg. Spine. 2012;17(5) doi: 10.3171/2012.8.SPINE12770. 397-40. [DOI] [PubMed] [Google Scholar]
- Liu H.T., Liang Z.H., Song J., Zhang H.W., Zhou F.C., Zhang Q.Q., et al. Posterior atlantoaxial fusion with C1-2 pedicle screw fixation for atlantoaxial dislocation in pediatric patients with mucopolysaccharidosis IVA (Morquio a syndrome): a case series. World Neurosurg. 2023;175:e574–e581. doi: 10.1016/j.wneu.2023.03.145. [DOI] [PubMed] [Google Scholar]
- Martinez-Del-Campo E., Turner J.D., Rangel-Castilla L., Soriano-Baron H., Kalb S., Theodore N. Pediatric occipitocervical fixation: radiographic criteria, surgical technique, and clinical outcomes based on experience of a single surgeon. J. Neurosurg. Pediatr. 2016;18(4):452–462. doi: 10.3171/2016.2.PEDS15544. [DOI] [PubMed] [Google Scholar]
- Muthukumar N. Problems in instrumentation of syndromic craniovertebral junction anomalies - case reports. Neurospine. 2019;16(2):277–285. doi: 10.14245/ns.1938176.088. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Page M.J., McKenzie J.E., Bossuyt P.M., Boutron I., Hoffmann T.C., Mulrow C.D., et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj. 2021;372 doi: 10.1136/bmj.n71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pouliquen J.C., Pennecot G.F., Beneux J., Chadoutaud F., Lacert P., Duval-Beaupere G., Durand J. [Cranio-vertebral junction and Morquio disease. Apropos of 6 cases] Chir. Pediatr. 1982;23(4):247–255. [PubMed] [Google Scholar]
- Prabhu A., Vivek V., Visvanathan K., Gupta J., Bhaskar Naidu K., Ganesh K. Early foramen magnum decompression in a 22-month-old child with Morquio Syndrome: case report and literature review. Interdiscip. Neurosurg. Adv. Tech. Case Manage. 2022;30 [Google Scholar]
- Ransford A.O., Crockard H.A., Stevens J.M., Modaghegh S. Occipito-atlanto-axial fusion in Morquio-Brailsford syndrome. A ten-year experience. J Bone Joint Surg Br. 1996;78(2):307–313. [PubMed] [Google Scholar]
- Rigante D., Antuzzi D., Ricci R., Segni G. Cervical myelopathy in mucopolysaccharidosis type IV. Clin. Neuropathol. 1999;18(2):84–86. [PubMed] [Google Scholar]
- Singh B., Cree A. Laminar screw fixation of the axis in the pediatric population: a series of eight patients. Spine J. 2015;15(2):e17–e25. doi: 10.1016/j.spinee.2014.10.009. [DOI] [PubMed] [Google Scholar]
- Singh S., Sardhara J., Raiyani V., Srivastava A.K., Behari S. Lessons learned from surgical management of craniovertebral instability in Morquio syndrome: a series of four unusual cases. J. Craniovertebral Junction Spine. 2020;11(3):243–247. doi: 10.4103/jcvjs.JCVJS_95_20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sitoula P., Mackenzie W.G., Shah S.A., Thacker M., Ditro C., Holmes L., Jr., et al. Occipitocervical fusion in skeletal dysplasia: a new surgical technique. Spine (Phila Pa 1976) 2014;39(15):E912–E918. doi: 10.1097/BRS.0000000000000381. [DOI] [PubMed] [Google Scholar]
- Svensson O., Aaro S. Cervical instability in skeletal dysplasia. Report of 6 surgically fused cases. Acta Orthop. Scand. 1988;59(1):66–70. doi: 10.3109/17453678809149348. [DOI] [PubMed] [Google Scholar]
- Visocchi M. Craniovertebral junction reducible and irreducible compressive pathologies: free hands or free tools? Light and shadows in pediatric practice. Childs Nerv. Syst. 2020;36(8):1791–1794. doi: 10.1007/s00381-020-04619-1. [DOI] [PubMed] [Google Scholar]
- Visocchi M., Signorelli F., Olivi A., Caldarelli M. Wiring or screwing at the craniovertebral junction in childhood: past and present personal experience. Acta Neurochir. Suppl. 2019;125:253–258. doi: 10.1007/978-3-319-62515-7_36. [DOI] [PubMed] [Google Scholar]
- White K.K., Steinman S., Mubarak S.J. Cervical stenosis and spastic quadriparesis in Morquio disease (MPS IV). A case report with twenty-six-year follow-up. J. Bone Jt.Surg. Am. 2009;91(2):438–442. doi: 10.2106/JBJS.H.00148. [DOI] [PubMed] [Google Scholar]
- Williams N., Narducci A., Eastwood D.M., Cleary M., Thompson D. An evidence-based approach to the management of children with morquio A syndrome presenting with craniocervical pathology. Spine (Phila Pa 1976) 2018;43(24) doi: 10.1097/BRS.0000000000002743. E1443-e53. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.