Prevalence and development of orthopaedic symptoms in the dutch hurler patient population after haematopoietic stem cell transplantation

Abstract

Hurler syndrome (MPS-IH) is a rare autosomal recessive lysosomal storage disease. Besides a variety of other features, Hurler syndrome is characterized by a range of skeletal abnormalities known as dysostosis multiplex. Despite the successful effect of haematopoietic stem cell transplantation on the other features, dysostosis remains a disabling symptom of the disease. This study analyzed the status and development of the orthopaedic manifestations of 14 Dutch Hurler patients after stem cell transplantation.Data were obtained retrospectively by reviewing patients' charts, radiographs and MRIs. Existing methods to measure the deficiencies were modified to optimally address the dysostosis. These measurements were done by two of the authors independently. The odontoïd/body ratio, kyphotic angle, scoliotic angle and parameters for hip dysplasia and genu valgum were measured and plotted against age. The degree of progression was determined. The intraclass correlation coefficient (ICC) was calculated to determine the reliability of the measurements.All patients showed hypoplasia of the odontoïd, which significantly improved during growth. Kyphosis in the thoracolumbar area was present in 13 patients and proved to be progressive. Scoliosis was observed in eight patients. Hip dysplasia was present in all patients and showed no tendency of improvement. In all but one patient, knee valgus remained more than two standard deviations above normal.Dysostosis remains a major problem after haematopoietic stem cell transplantation in Hurler patients. Moreover, except for dens hypoplasia, it appears to be progressive and therefore surgical interventions may be necessary in the majority of these patients.

Fig. 1

Radiological measurements: (a) The odontoïd/body ratio was calculated by dividing the length of the odontoïd process (o) by the length of the body of the 2nd cervical vertebra (b). (b) The kyphotic angle was defined as the angle over the 4 thoracolumbar vertebrae with the largest angle of kyphosis. (c) The acetabular index (AI) was defined as the angle between the horizontal Hilgenreiner’s line and the line connecting the superolateral edge of the acetabulum with the triradiate cartilage. The percentage of bony coverage was calculated by drawing the Hilgenreiner’s line and perpendicular to this a line touching the lateral border of the bony acetabulum. A line parallel to the Hilgenreiner’s line through the lateral subcapitalphyses was drawn next. By virtually connecting the metaphyseal and epiphyseal medial and lateral edges, the contour of the caput femoris was reconstructed and the intersection point with the transphyseal line was taken medially and laterally. The distance m represents the bony coverage. The percentage of coverage was calculated by dividing m by the distance m + l. (d) The medial proximal tibial angle (MPTA) was measured as the medial angle between a line drawn at the level of the tibial epiphysis, parallel to the growth plate of the proximal tibia and a line connecting the centre of the proximal tibial epiphysis to the midwidth of the talus at the ankle mortise

Fig. 2

Progression of the skeletal abnormalities of the Hurler patient population over time: (a) odontoid/body ratio, (b) maximum kyphotic angle, (c) acetabular index, (d) percentage of bony coverage of the caput femoris, and (e) medial proximal tibial angle (MPTA). All measurements are plotted against patient age. Each line represents an individual patient. Reference lines of ± 2 standard deviations (SD) of the mean, are based on the data of Tonnis and Brunken (1968) for the acetabular index (c) and Sabharwal et al. (2008) for the MPTA (e)

Fig. 3

Example of odontoïd hypoplasia. Illustrated is a T2 weighted MRI of the midsagittal cervical spine of a 5 year old female patient. The body of C2 and odontoid process can clearly be observed with in-between the dentocentral synchondrosis. This patient had an odontoid/body ratio of 1.4, which was classified as moderate hypoplasia

Fig. 4

Example of a thoracolumbar kyphosis. (a) Lateral radiograph of the thoracolumbar spine of a 5 year old sitting male patient. There is an obvious kyphosis of 78°, measured between T11 and L2, in addition to anterior beaking of T12 and L1 and severe spondylolisthesis of T11. (b) Radiograph after revision of an initial short segment posterior spinal fusion (Th11-L3) in the patient shown in Fig. 4a. To maintain correction, the segment above was fixated with a growing rod system

Fig. 5

Example of hip dysplasia. Illustrated is a pelvic radiograph of a 3.5 year old female patient with bilateral hip dysplasia. Note the lateral acetabular failure of ossification. The AI in this patient was 38° on the right and 36° on the left side. The percentage of bony coverage was, respectively, 43 % and 46 %

Fig. 6

Example of genu valgum. Illustrated is a long leg radiograph of a 3.5 year old male patient. The left valgus angle was 12° with an MPTA of 100°