Hurler syndrome

This case study describes the clinical evaluation and diagnosis of Hurler's syndrome in a 7-month-old child who was noted to have a thoracolumbar kyphosis (gibbus deformity), coarse facial features, and possible evidence of gross motor delay. The diagnosis of Hurler's syndrome was aided specifically by the identification of the gibbus deformity. Children with Hurler's syndrome appear nearly normal at birth, and the most common early presenting features are the nonspecific symptoms of rhinitis and inguinal hernia. Most often, the earliest possible diagnosis of Hurler's syndrome is contingent on the recognition of the initial pattern of musculoskeletal abnormalities, which become increasingly pronounced after the 6th month. Because of the characteristic progression of neurological and intellectual deterioration found in children with Hurler's syndrome, early diagnosis and treatment are critical to the preservation of long-term intellectual development. The pathophysiology of Hurler's syndrome and the causes of kyphosis in infancy and childhood are discussed.

Introduction

The mucopolysaccharidoses are a group of disorders characterized by a deficiency of specific lysosomal enzymes required for the degradation of glycosaminoglycans. In type 1 mucopolysaccharidosis, also known as Hurler's syndrome, the deficiency of the lysosomal enzyme a-L-iduronidase allows the accumulation of deposits of dermatan sulfate and heparan sulfate within tissues such as those found in the brain, viscera, heart, lung, and joints. Individuals with this deficiency may appear normal at birth; however, there is a characteristic worsening clinical progression, which includes coarse facial features, hepatosplenomegaly, chronic airway obstruction, cardiac disease, major skeletal abnormalities (dysostosis multiplex), and central nervous system (CNS) damage. Patients with Hurler's syndrome exhibit delayed speech development and severe mental handicap with extensive neuronal abnormalities. Hurler's syndrome is the most severe mucopolysaccharidosis, and most patients die from cardiorespiratory complications in the first decade of life. With bone marrow transplantation as a treatment for lysosomal storage diseases such as Hurler's syndrome, early diagnosis and treatment is becoming increasingly more important to ensure the most positive clinical outcome for the patient.

Case Report

A 7-month-old female presented for evaluation for a possible mucopolysaccharidosis. She was a first-born child, the product of a 40-week gestation, who was born by normal spontaneous vaginal delivery without any significant prenatal or neonatal problems. There was no family history of birth defects, neurological disorders, or lysosomal storage disorders. Her 4-month well-baby check was noteworthy for a thoracolumbar kyphosis, coarse facial features, and possible evidence of gross motor delay (i.e., unable to roll over). Further evaluation by an otolaryngologist revealed recurrent nasal congestion and four episodes of otitis media since birth.

Physical examination revealed the patient to be slightly macrocephalic, with an anterior fontanelle that was open and soft. She had moderate frontal bossing, with a depressed nasal ridge. Tympanic membranes were remarkable for decreased light reflex and erythema on the right, with decreased movement to insulation. Cardiovascular examination was normal, and the lungs were clear to auscultation. The liver was palpated 3.5 cm below the costal margin and was firm and nontender. The spleen tip was also palpable. Neurological examination was noteworthy for mildly decreased central tone, slightly increased deep tendon ankle reflexes, mild corneal clouding, and bilateral flexor Babinski responses. Developmentally, the patient showed skills in the age-appropriate range in the areas of gross motor, fine motor, adaptive, social/personal, audiological, and visual function. The back was notable for a thoracolumbar kyphosis. The hands were noted to be slightly shortened. The rest of the musculoskeletal examination was within normal limits.

Radiographic examination revealed a thoracolumbar kyphosis with the apex at the L1-2 level, with beaking of the vertebrae and oar-shaped ribs (Figs. 1 and 2), all of which were suggestive of Hurler's syndrome. The patient had a blood enzyme assay for a-L-iduronidase activity, which showed no level of activity. The patient was referred to another medical center, which confirmed the initial diagnosis of Hurler's syndrome and initiated her evaluation as a candidate for bone marrow transplantation.

Discussion

The deficiency of a-L-iduronidase is an autosomal recessive disorder with an incidence of approximately 1 in 100,000 live births.I The a-L-iduronidase gene locus has been determined to be on chromosome 22pter-qI 1.2 The presence of multiple different mutant alleles at the a-L-iduronidase gene locus is thought to be responsible for the spectrum of clinical phenotypes, but biochemical characterization of residual a-L-iduronidase activity has enabled discrimination only between the extremes of clinical phenotypes.34 The different clinical manifestations range from the very severe Hurler's syndrome to the relatively mild Scheie's syndrome, in which patients present with joint stiffness, corneal clouding, and only mild somatic changes without mental retardation.5

Because there is no newborn screening for the disease, the early diagnosis of Hurler's syndrome is dependent on the clinical acumen of the physician. In a study by Cleary and Wraith, the presenting features of 39 patients with Hurler's syndrome were analyzed, and the presenting symptoms and signs were found to vary with age.6 The earliest abnormalities were noted to be rhinitis and recurrent inguinal hernia, which, because of their high incidence in the general pediatric population, would not independently raise suspicion for the diagnosis of Hurler's syndrome. At 6 months of age, skeletal abnormalities became an increasingly common presentation. In the case of untreated Hurler's syndrome, the pattern of musculoskeletal abnormalities is referred to as the dysostosis multiplex and follows a developmental course with several of the characteristic abnormalities present at the end of the second year. Characteristic abnormalities include a deformity of the rib cage with flaring of its lower portion, thoracolumbar kyphosis, asymmetric chest, prominent sternum, enlarged forehead, subluxated hips, valgus deformities of the knees, and widespread flexion contractures. From 12 months onward, the coarse facial features and the aforementioned skeletal abnormalities associated with the dysostosis multiplex begin to appear fully, making the diagnosis more readily apparent. In this series of patients, the mean age at the time of diagnosis was 9.4 months (range, 3-18 months).

In the Cleary and Wraith study, the most common of all the presenting features was the thoracolumbar kyphosis, or gibbus deformity, which was found in more than 41% of the patients and therefore is at least suggestive of a diagnosis of Hurler's syndrome.6 Kyphosis is defined as the excessive posterior deviation of the spine in the sagittal plane. It is generally agreed upon that normal measurements of the posterior thoracic roundness, or kyphosis, is between 20 and 400 using the Cobb system. At the thoracolumbar junction, where there is normally a transition from the thoracic kyphosis to the lumbar lordosis, the angle is usually 00.7 The great danger of kyphosis is that the deformity may lead to spinal cord compression and paraplegia if it progresses to a significant degree and is left untreated. A number of conditions can cause thoracolumbar kyphosis during infancy and childhood. Kyphosis is a frequent complication of many metabolic diseases and bone dysplasias. The structural weakness caused by the abnormal metabolism of bone or by the disruption of the bony architecture may lead to kyphosis and scoliosis in the trunk and to bowing and shortening of the long bones. The cause of a kyphosis discovered in infancy or childhood that is accompanied by other bony dysplasia generally may be classified into one of the following categories: osteopenic conditions, skeletal dysplasias, storage diseases, or mesenchymal disorders such as neurofibromatosis (Table 1).s It is important to identify and classify the cause of the kyphotic deformity, because the natural histories and subsequent prognoses differ.9

In Hurler's syndrome, the development of the gibbus deformity occurs because of the failure of ossification of the upper anterior part of the thoracolumbar vertebral bodies. Postmortem examination of children with Hurler's syndrome revealed normal end-plate anatomy, but the anterosuperior quadrant of the vertebral body had failed to ossify.lo Because the failure of ossification is most often caused by Hurler's syndrome, another mucopolysaccharidosis, spondyloepiphyseal dysplasia, or achondroplasia, it is necessary to evaluate the patient for a possible inborn metabolic disorder.ll A finding of elevated urine glycosaminoglycan levels (>6 mg uronic acid/24 hours) is diagnostic of Hurler's syndrome.lz Also, a determination of the level of a-L-iduronidase activity can be made with assessment by restriction fragment length polymorphism analysis. 13

Once a diagnosis of Hurler's syndrome has been established, the most positive long-term clinical outcome is likely dependent on successful bone marrow transplantation. The use of bone marrow transplantation in the treatment of lysosomal storage diseases was first proposed by Hobbs et al. in 1981.14 The basic assumption behind the use of allogenic bone marrow transplantation for the treatment of Hurler's syndrome is that the bone marrow-derived cells from normal or heterozygote donors would be an ongoing source of a-L-iduronidase that would be capable of gaining access to the sites of dermatan sulfate and heparan sulfate accumulation in adequate concentrations to produce clinically significant substrate degradation.15

Recent clinical studies investigating the use of bone marrow transplantation in the treatment of Hurler's syndrome have required that patients be diagnosed before the age of 2 years and have experienced facial changes, corneal clouding, and hepatosplenomegaly.ls The studies have also required radiographic evidence of the dysostosis multiplex and biochemical abnormalities to establish the diagnosis.'6 Once these criteria have been met, patients and potential donors participate in an extensive protocol to ensure the donor-recipient relationship most likely to yield engraftment and to have the fewest complications. The initial reports of bone marrow transplantation for Hurler's syndrome found a reduction in mucopolysacchariduria and a reversal of extra-CNS clinical manifestations, including hepatosplenomegaly and corneal clouding.l4,17 Episodes of sleep apnea, heart failure, and pneumonia have also been reported to be significantly reduced.ls,ls The drawbacks of this procedure include its cost, prolonged hospitalization, and significant morbidity and mortality. Furthermore, long-term clinical outcomes, including the physiological response of the CNS and skeletal effects after bone marrow transplantation, are just now being fully elucidated.

Initial reports indicate positive long-term results of early bone marrow transplantation in limiting progressive brain damage and preserving intellectual function in children with Hurler's syndrome.4 ls Whitley et al. evaluated the long-term intellectual and neurological outcomes of the 9 survivors among 11 children who underwent bone marrow transplantation from 0.9 to 3.4 years (median, 2.0 years).16 The subjects ranged from 3.8 to 8.9 years (median, 5.5 years) at evaluation. Follow-up evaluation consisted of assessment of donor engraftment by restriction fragment length polymorphism analysis, determination of leukocyte a-L-iduronidase level, measurement of lumbar cerebrospinal fluid (CSF) pressure, computerized tomography (CT) of the brain, and psychometric testing. On initial evaluation, 7 of 8 children had occult intracranial hypertension (>20 cm of CSF pressure), and all of the children had CT changes typical of Hurler's syndrome, including ventriculomegaly. All nine children, whether they had mixed or complete donor engraftment by a-L-iduronidase levels, showed metabolic correction with normal urine glycosaminoglycan levels within 3 months of transplantation. By 18 months after transplantation, all children had CSF pressures that were normal or nearly normal. Follow-up CT did not show any worsening of CNS disease after transplantation. The progression of neurological and intellectual deterioration uniformly found in untreated Hurler's syndrome appears to have been curbed, and in some cases halted, by bone marrow transplantation. All four survivors who had normal developmental quotient/intelligence quotient scores (defined as >80) before transplantation continued to function at that normal level. The benefits of bone marrow transplantation on the CNS are thought to be attributable to a reduction in the CSF pressure and metabolic correction within the brain parenchyma.

The outcomes of bone marrow transplantation in the treatment of the skeletal disorders of Hurler's syndrome have been less promising than the outcomes in the treatment of the neurological disorders. Field et al. followed 11 children who underwent successful bone marrow transplantation from 0.5 to 2.4 years (median, 1.6 years).1o The subjects ranged from 5.3 to 13.2 years (median, 9.3 years) at evaluation. After transplantation, the children experienced improved modeling of the facial bones, which resulted in the reduction of the typically coarse facial features. Subsequently, however, each child developed the clinical and radiographic appearance of the dysostosis multiplex, which did not differ significantly from the appearance in the untreated syndrome. It is thought that a-L-iduronidase from the transplanted leukocytes is unable to adequately penetrate the musculoskeletal tissues. The poor perfusion of these tissues is a result of the relatively avascular ground substance that is necessary for their growth and cellular maturation. Progressive isolation of the fibrocytes and chondrocytes in the maturing process accounts for the development over time of the typical abnormal skeletal appearance.

Bone marrow transplantation is currently believed to be the most viable treatment alternative to decrease mortality and minimize long-term complications. Although bone marrow transplantation does not appear to remarkably alter the development of the dysostosis multiplex of Hurler's syndrome, transplantation can curb and in some cases halt the progression of the neurological and intellectual deterioration associated with the disorder. By recognizing the initial pattern of musculoskeletal abnormalities, particularly the gibbus deformity, at the earliest opportunity, physicians may take a critical step toward preserving the long-term intellectual development of children with Hurler's syndrome.

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Orthopaedic Surgery Service, Department of Surgery, Walter Reed Army Medical Center, Washington, DC 20703.

This manuscript was received for review in November 1997. The revised manuscript was accepted for publication in February 1998. Reprint & Copyright by Association of Military Surgeons of U.S., 1998.

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