Mihir M. Thacker

Mucopolysaccharidosis Type IVA (Morquio A Disease): Clinical Review and Current Treatment: A Special Review

Mucopolysaccharidosis IVA (MPS IVA), also known as Morquio A, is a rare, autosomal recessive disorder caused by a deficiency of the lysosomal enzyme N-acetylgalatosamine-6-sulfate-sulfatase (GALNS), which catalyzes a step in the catabolism of glycosaminoglycans (GAGs), keratan sulfate (KS) and chondroitin-6-sulfate (C6S). It leads to accumulation of the KS and C6S, mainly in bone and cornea, causing a systemic skeletal chondrodysplasia. MPS IVA has a variable age of onset and variable rate of progression. Common presenting features include elevation of urinary and blood KS, marked short stature, hypoplasia of the odontoid process, pectus carinatum, kyphoscoliosis, genu valgum, laxity of joints and corneal clouding; however there is no central nervous system impairment. Generally, MPS IVA patients with a severe form do not survive beyond the third decade of life whereas those patients with an attenuated form may survive over 70 years. There has been no effective therapy for MPS IVA, and care has been palliative. Enzyme replacement therapy (ERT) and hematopoietic stem cell therapy (HSCT) have emerged as a treatment for mucopolysaccharidoses disorders, including Morquio A disease. This review provides an overview of the clinical manifestations, diagnosis and symptomatic management of patients with MPS IVA and describes potential perspectives of ERT and HSCT. The issue of treating very young patients is also discussed.

Use of the foot abduction orthosis following Ponseti casts: Is it essential?

The purpose of this study was to evaluate the need for the use of a foot abduction orthosis (FAO) in the treatment of idiopathic clubfeet using the Ponseti technique. Forty-four idiopathic clubfeet were treated with casting using the Ponseti method followed by FAO application. Compliance was defined as full-time FAO use for 3 months and part-time use subsequently. Noncompliance was failure to fulfill the criteria during the first 9 months after casting. Feet were rated according to the Dimeglio and Pirani scoring systems at initial presentation, at the time of FAO application, and at 6 to 9 months of follow-up. At the time of application, no significant differences in scores were found between the groups. At follow-up, the compliant groups scores were significantly (P < 0.01) better than those of the noncompliant group. From the time of application to follow-up, for the compliant group, the Dimeglio scores improved significantly (P = 0.005). For the noncompliant group, the Dimeglio scores deteriorated significantly (P = 0.001). The feet of patients compliant with FAO use remained better corrected than the feet of those patients who were not compliant. Proper use of FAO is essential for successful application of the Ponseti technique.

Current treatment for Ewing's sarcoma

Ewing’s sarcoma is the second most common primary bone tumor seen in children and adolescents, and was described by James Ewing in 1921 as a diffuse endothelioma of bone. It is one of the differential diagnoses of pediatric small round blue cell tumors. This is not a single condition, but a group of morphologically and clinically closely related disorders with similar molecular biology – expression of tumor-specific chimeric oncoproteins through balanced chromosomal translocations involving the EWS gene – often referred to as the Ewing family of tumors. This includes Ewing’s sarcoma of bone, extra-osseous Ewing’s sarcoma, Askin tumor and peripheral neuroectodermal tumor. These are aggressive neoplasms with almost 25% of patients having clinically evident metastases at presentation. Ewing’s sarcoma has therefore been considered as a systemic disease necessitating local as well as systemic treatment. An aggressive multidisciplinary approach has resulted in significant improvement in prognosis for patients with these tumors. Despite aggressive treatment, 20–40% of patients with localized disease and almost 80% of patients with metastatic disease at presentation succumb to the illness. Advances in understanding the molecular biology of these tumors will hopefully result in the development of novel treatment approaches. The aim of this article is to review the existing treatment methods and to highlight the more recent approaches to the treatment of this condition.

Current and emerging treatments and surgical interventions for Morquio A syndrome: a review.

Patients with mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome) have accumulation of the glycosaminoglycans, keratan sulfate, and chondroitin-6-sulfate, in bone and cartilage, causing systemic spondyloepiphyseal dysplasia. Features include lumbar gibbus, pectus carinatum, faring of the rib cage, marked short stature, cervical instability and stenosis, kyphoscoliosis, genu valgum, and laxity of joints. Generally, MPS IVA patients are wheelchair-bound as teenagers and do not survive beyond the second or third decade of life as a result of severe bone dysplasia, causing restrictive lung disease and airway narrowing, increasing potential for pneumonia and apnea; stenosis and instability of the upper cervical region; high risk during anesthesia administration due to narrowed airway as well as thoracoabdominal dysfunction; and surgical complications. Patients often need multiple surgical procedures, including cervical decompression and fusion, hip reconstruction and replacement, and femoral or tibial osteotomy, throughout their lifetime. Current measures to intervene in disease progression are largely palliative, and improved therapies are urgently needed. A clinical trial for enzyme replacement therapy (ERT) and an investigational trial for hematopoietic stem cell transplantation (HSCT) are underway. Whether sufficient enzyme will be delivered effectively to bone, especially cartilage (avascular region) to prevent the devastating skeletal dysplasias remains unclear. This review provides an overview of historical aspects of studies on MPS IVA, including clinical manifestations and pathogenesis of MPS IVA, orthopedic surgical interventions, and anesthetic care. It also describes perspectives on potential ERT, HSCT, and gene therapy.

Soft tissue sarcomas of the foot and ankle: impact of unplanned excision, limb salvage, and multimodality therapy.

Background: Foot and ankle sarcomas have historically been treated with amputation because of the difficulty in achieving local disease control and maintaining a functional foot. Potential opportunities for limb salvage may be further compromised by unplanned excisions. Materials and Methods: We reviewed 52 consecutive patients with soft tissue sarcomas of the foot and ankle and analyzed the impact of planned versus unplanned initial excision, limb salvage, and multimodality therapy on treatment and outcomes. Results: Unplanned excisions had been performed in 29 (55.8%) patients. Limb salvage was performed in 38 patients, with 14 requiring free soft tissue transfers. At an average followup of 99 (range, 24 to 216) months, the 5-year overall survival estimate was 76.3%. Although not statistically significant, we noted clinically relevant potential differences in local recurrence-free, disease-free, and oncologic survival between the planned and unplanned excision groups. Seven patients (13.5%) had a local recurrence, five of these following an unplanned excision. Functional scores averaged 83.2% for all patients which were similar between planned versus unplanned and amputation versus limb salvage groups. Significantly more patients with unplanned excisions required free flaps for limb salvage (p = 0.017) and received adjuvant radiotherapy (p = 0.0004). Conclusion: Unplanned surgery for soft tissue sarcomas of the foot and ankle often results in the need for more aggressive surgery and/or adjuvant radiotherapy and may impact oncologic outcomes, but does not necessarily portend worse functional outcomes. Multi-modal therapy and judicious use of soft tissue flap reconstruction allows limb salvage in most patients with favorable outcomes.

The lower extremity in Morquio syndrome.

Background: The modalities and results of surgical intervention in the lower extremity in children with Morquio syndrome type A [mucopolysaccharidosis-IV (MPS-IVA)] have not been well described. The aims of this study are to define the lower extremity deformities, and describe the results of intervention in MPS-IVA patients. Methods: Retrospective chart and radiograph review of 23 MPS-IVA patients with a minimum follow-up of >2 years. Patients were divided into no intervention and surgical groups. Demographic data, surgical details, clinical results, and complications were recorded. Standard lower extremity radiographic measurements made on standing radiographs at initial presentation, preoperatively (in surgical group), and at the final follow-up were used to study the deformities and effects of hip, knee, and ankle surgery. Descriptive statistics were performed. Results: There were 11 boys and 12 girls. The average age at presentation was 6.8±3.4 years and at the last visit was 13.5±5 years with a mean follow-up of 6.7±3.7 years. Progressive hip subluxation, genu valgum, and ankle valgus were observed in all patients without intervention. Twenty patients had a total of 159 lower extremity surgical procedures (average, 8 procedures per patient). There were 61 hip, 78 knee, and 20 ankle procedures. Surgery resulted in improvement of the center edge angle, femoral head coverage, lateral distal femoral angle, medial proximal tibial angle, tibiofemoral angle, and lateral distal tibial angle. Mechanical axis of the lower extremities improved after intervention. Six patients (12 hips) had recurrence of hip subluxation after acetabular osteotomies and/or femoral varus derotation osteotomy, and 8 patients (16 knees) had postoperative genu valgum recurrence requiring subsequent intervention. There was no recurrent hip subluxation after shelf acetabuloplasty. Conclusions: Progressive hip subluxation, genu valgum, and ankle valgus were seen and often needed surgery. After shelf acetabuloplasty and varus derotation osteotomy, there was no recurrent hip subluxation. Recurrence after genu valgum correction was common. Level of Evidence: Level IV, therapeutic case series.

Upper Cervical Fusion in Children with Morquio Syndrome: Intermediate to Long-term Results

BACKGROUND Paraplegia or death secondary to upper cervical spine instability and spinal cord compression are known consequences of Morquio syndrome. Decompression and fusion of the upper cervical spine are indicated to treat spinal cord compression. The purpose of this study was to report the intermediate to long-term results of upper cervical spine fusion in children with Morquio syndrome. METHODS Twenty patients (nine female and eleven male) with Morquio syndrome who underwent upper cervical spine fusion at a mean age of sixty-three months were retrospectively analyzed with use of hospital records. Radiographic and clinical results were reported. RESULTS The average follow-up period was eight years and ten months. Fusion was achieved in all patients except one; this patient underwent a revision with transarticular C1-C2 screw fixation. Seven patients developed symptomatic instability below the fusion mass that required extension of fusion to lower levels at a mean of ninety-one months after the initial operation. Two patients required decompression and fusion of a site other than the upper cervical spine. Asymptomatic cervicothoracic and thoracolumbar kyphosis was prevalent among our patients. All patients were neurologically stable at the time of the latest follow-up visit. CONCLUSIONS Upper cervical spine fusion provides reliable fusion and a stable neural outcome in patients with Morquio syndrome. However, distal junctional instability is a major problem at long-term follow-up. Kyphotic deformity of the cervicothoracic and thoracolumbar junction may be present in a large number of patients with Morquio syndrome and evaluation for spinal stenosis at these levels should also be considered.

Correction of lower extremity angular deformities in skeletal dysplasia with hemiepiphysiodesis: a preliminary report.

Background: Lower extremity angular deformities are common in children with skeletal dysplasia and can be treated with various surgical options. Both acute correction by osteotomy with internal fixation and gradual correction by external fixation have been used with acceptable results. Recently, the Guided Growth concept using temporary hemiepiphysiodesis for correction of angular deformities in the growing child has been proposed. This study presents the results of temporary hemiepiphysiodesis using eight-Plates and medial malleolus transphyseal screws in children with skeletal dysplasia with lower extremity angular deformities. Methods: Twenty-nine patients (50 lower extremities) with skeletal dysplasia of different types were treated for varus or valgus deformities at 2 centers. The mean age at the time of hemiepiphysiodesis was 10±2.9 years. A total of 66 eight-Plates and 12 medial malleolus screws were used. The average follow-up time between the index surgery and the latest follow-up with the eight-Plate in was 25±13.4 months. Erect long-standing anteroposterior and lateral view radiographs were obtained for deformity planning before the procedure. Angular deformities on radiograph were evaluated by mechanical axis deviation, mechanical lateral distal femoral angle, medial proximal tibial angle, and lateral distal tibial angle. Mechanical axis deviation was also expressed as a percentage to one half of the width of the tibial plateau, and the magnitude of the deformity was classified by determining the zones through which the mechanical axis of the lower extremity passed. Four zones were determined on both the medial and lateral side of the knee and the zones were labeled 1, 2, 3, and 4, corresponding to the severity of the deformity. A positive value was assigned for valgus alignment and a negative for varus alignment. Results: Patients were analyzed in valgus and varus groups. There was correction in 34 of 38 valgus legs and 7 of 12 varus legs. In the valgus group, the mean preoperative and postoperative mechanical lateral distal femoral angles were 82.1±3.7 and 91.1±4.9 degrees, respectively (P<0.001). The mean preoperative and postoperative medial proximal tibial angles were 98.5±8 and 87.8±7.1 degrees, respectively (P<0.001). Six patients with bilateral ankle valgus deformities (12 ankles) underwent single-screw medial malleolus hemiepiphysiodesis. The mean preoperative and postoperative lateral distal tibial angles were 73.9±8.7 and 86.1±6.8 degrees, respectively (P<0.001). The numbers of plates in each anatomic location were not enough to make statistical conclusions in varus legs. Four patients in the valgus group and 3 patients in the varus group did not benefit from the procedure. Mechanical axes were in zone 2 or over in 94% of the legs preoperatively, whereas postoperatively, only 23% of the legs had mechanical axes in zone 2 or over in varus and valgus groups. Conclusions: Growth modulation with an eight-Plate is a relatively simple surgery and has low risk of mechanical failure or physeal damage. It can be performed in very young patients, which is an important advantage in skeletal dysplasia. Screw purchase is reliable even in the abnormal epiphysis and metaphysis. Our results show that Guided Growth using eight-Plates in skeletal dysplasia is safe and effective. Level of Evidence: Level IV.

Orthopedic management of the extremities in patients with Morquio A syndrome.

BackgroundMusculoskeletal involvement in Morquio A syndrome (mucopolysaccharidosis IVA; MPS IVA) contributes significantly to morbidity and mortality. While the spinal manifestations of the disorder have received considerable attention in the literature, there have been few reported studies to date to guide the management of the orthopedic problems associated with the lower and upper extremities.PurposeThe objective was to develop recommendations for the management of the extremities in patients with Morquio A syndrome.MethodsA group of specialists in orthopedics, pediatrics and genetics with experience in the management of Morquio A patients convened to review and discuss current clinical practices and to develop preliminary recommendations. Evidence from the literature was retrieved. Recommendations were further refined until consensus was reached.Results and conclusionsThis present article provides a detailed review and discussion of the lower and upper extremity deformities in Morquio A syndrome and presents recommendations for the assessment and treatment of these complications. Key issues, including the importance of early diagnosis and the implications of medical therapy, are also addressed. The recommendations herein represent an attempt to develop a uniform and practical approach to managing patients with Morquio A syndrome and improving their outcomes.

Limb length discrepancy and congenital limb anomalies in fibular hemimelia.

The aim of this study was to determine the prevalence of ipsilateral congenital musculoskeletal anomalies associated with fibular hemimelia. We also attempted to determine the corelation between the eventual limb length discrepancy at maturity and these associated anomalies, as well as the Achterman–Kalamchi class of these patients. The records and roentgenograms of 45 patients with fibular hemimelia were reviewed retrospectively. All patients were classified into three groups (types I-A, I-B, and II) according to the Achterman–Kalamchi system. The prevalence of congenital limb anomalies, lower extremity discrepancy percentage, and ultimate limb length discrepancy at skeletal maturity were evaluated. There was no significant statistical association between the number of congenital limb anomalies and severity of the limb length discrepancy, but patients included in the mildly affected group (type I-A) had a higher average prevalence of congenital limb anomalies than those classified as types I-B and II. There was a substantial correlation between congenital short femur as well as the Achterman–Kalamchi classification system and the predicted limb length discrepancy. A similar percentage of limb length discrepancy in types I-B and II was seen. In conclusion, the numbers of associated congenital limb anomalies are not predictive of the eventual limb length discrepancy. Presence of a congenital short femur and ball and socket ankle are predictive of a higher limb length discrepancy. Achterman–Kalamchi types I-B and II show a similar percentage of limb length discrepancy and this is significantly higher than that seen in type I-A.