Hurler syndrome was named for Gertrude Hurler, a general practitioner who described two children with the syndrome in 1919.1 Hurler syndrome, the most severe form of mucopolysaccharidosis I (MPS I), is an autosomal recessive syndrome characterized by a primary lysosomal hydrolase alpha-L-iduronidase (IUDA) deficiency.2 IUDA is responsible for breaking down the glycosaminoglycans (mucopolysaccharides), heparan sulfate, and dermatan sulfate. Therefore, IUDA deficiency results in a buildup of glycosaminoglycans in the parenchymal and mesenchymal tissues and storage of lipids in neuronal tissues.2,3 Children diagnosed with Hurler syndrome typically have retarded growth, coarse facial features, enlarged tongues, broad misshapen bones, joint range of motion limitations, thickening of cardiac values, hernias, deafness, liver and spleen enlargement, and abnormal hair growth. Life expectancy is typically less than 10 years.2 The incidence of Hurler syndrome has been reported at 1:100,000 livebirths in British Columbia4 and 1.19 per 100,000 livebirths in the Netherlands.5
To date, treatment options for children diagnosed with Hurler syndrome have been limited, although bone marrow transplantation has been successful in halting the disease progression.6–8 However, finding a bone marrow donor can be very difficult. Treatment has higher risks for children without a sibling who is genotypically matched as a marrow donor.7 Enzyme-replacement therapy has led to clinical and biochemical improvements in children diagnosed with the least severe phenotypes of MPS I.9,10 However, the lack of enzyme transference to the central nervous system may limit the benefits of this treatment in children diagnosed with Hurler syndrome.10 A promising new treatment for children with Hurler syndrome is hematopoietic stem cell transplantation (HSCT) using umbilical cord blood, referred to as umbilical cord blood transplant (UCBT).11 Duke University Medical Center (DUMC), located in Durham, NC, is one of the centers involved in the development and advancement of UCBT, and physicians there have been performing this procedure for children with Hurler syndrome since December 1995.11
The prevalence of Hurler syndrome will increase as experimental treatments improve the life span of children with this rare disorder.6,7,9,11,12 Physical and occupational therapists may encounter an increasing number of children with Hurler syndrome in their clinical practice as the life expectancy of children with Hurler syndrome increases and there is hope of facilitating improvement in motor function. Therefore, the ability to distinguish both the specific nature of motor skill development and longitudinal progress of children diagnosed with Hurler syndrome is vital to the identification of rehabilitation options and selection of therapeutic treatment methods.
Standardized assessments of the developmental abilities of children with Hurler syndrome are frequently conducted at the Center for Development and Learning at the University of North Carolina at Chapel Hill to monitor their progress after UCBT. Clinicians administering the motor scale of the Bayley Scales of Infant Development II (BSID-II) to children with Hurler syndrome began to suspect the children were demonstrating discrete differences in their fine and gross motor abilities. However, the standardized scoring procedure of the BSID-II does not allow for determination of separate scores of gross and fine motor function.13 Rather, the motor scale encompasses both domains rendering a comparison of gross and fine motor skill development more difficult to conduct. Findings elucidating this problem are presented in a case study presented by Washington14 in which the child's psychomotor developmental index (PDI) on the BSID-II was reported to be inflated by the child's strong fine motor skills even though the child's gross motor skills were significantly delayed. Additionally, commentaries have suggested that a child may earn multiple different scores on the BSID-II depending on which item set the administrator chooses to begin.14,15 Since the BSID-II was not designed to differentiate between gross and fine motor developmental skills and Washington's report14 suggested overall score inflation the authors of this study were prompted to investigate alternative assessment tools to identify discrepancies between the fine and gross motor skills of children with Hurler syndrome.
The purpose of this case series was to describe the differences in fine and gross motor abilities of two children with Hurler syndrome post-UCBT. The authors postulated that a discrepancy between gross and fine motor skills in children with Hurler syndrome would be identified, warranting vigilance in the selection of the motor assessment tool for future clinical assessment. Identification of such a discrepancy and subsequent selection of a motor assessment tool would provide useful information for sites conducting assessments of children with Hurler syndrome and similar disorders.
CATEGORIZATION OF ITEMS ON BSID-II MOTOR SCALE
In order to establish a distinction between BSID-II items as measuring fine or gross motor function, six therapists (four physical and two occupational therapists) were asked to categorize each item on the BSID-II Motor Scale as being similar to items in a subtest of the Peabody Developmental Motor Scales, Second Edition (PDMS-2). The PDMS-2, unlike the BSID-II, makes a clear distinction between gross and fine motor items allowing for independent scoring of gross and fine motor abilities. The participating therapists had a mean of 24.5 years (range 13–33) of experience as a pediatric occupational or physical therapist. All the participating therapists had a doctoral degree. The therapists were asked to respond to a survey in which they would categorize items on the BSID-II using the subtests of the PDMS-2 as a reference. Items that were categorized as being “similar” to items in the stationary, locomotion, or object manipulation subtests of the PDMS-2 by at least 75% of the respondents were labeled as measuring gross motor skills. Those items categorized as similar to items in the grasp or visual motor integration subtests of the PDMS-2 by greater than 75% of the respondents were labeled as fine motor skills.
Based on the respondent categorization, 80 of the 111 items (72%) on the BSID-II motor scale were labeled as measuring gross motor skills. Twenty-six items (23%) were labeled as measuring fine motor skills. The remaining five items (5%) were not labeled as measuring fine or gross motor skill by at least 75% of the participating therapists who categorized them as similar to items in a subtest on the PDMS-2.
Child A was the product of a full-term gestation and born by cesarean section due to his large size. He was diagnosed with a heart murmur at two months of age and corneal clouding at six months of age. At nine months of age, he was diagnosed with congenital hypoplastic hemivertebra at L2 with kyphotic deformity after which he was referred to a geneticist who confirmed a diagnosis of Hurler syndrome at 10 months of age. Child A was referred to DUMC for an UCBT at 21 months of age and received the intervention at 24 months of age. His hospital course was complicated by stage II graft-versus-host disease, hypertension, mucositis, and scrotal cellulites. He was discharged one month after receiving his transplant. He was briefly readmitted for antibiotic treatment of a bacterial infection.
Child B was the product of a 36-week gestation pregnancy. The child required respiratory support initially and oxygen for the first five months of life. He was born with bilateral hip dislocations and a kyphosis. Child B sat by 10 months of age and had speech delays and a hearing loss. Child B was diagnosed with Hurler syndrome at 19 months of age and was referred to DUMC for UCBT, which he received at 21 months of age. Post-transplantation complications included anemia, fevers, mucositis, upper airway congestion, wheezing, and mild hypertension. He was hospitalized for five weeks post-transplantation.
LONGITUDINAL BSID-II ASSESSMENTS
Child A's motor skills were assessed at three and 10 months post-transplantation (28 and 34 months of age) using the BSID-II Motor Scales as one portion of an interdisciplinary assessment. Child A's scores on the BSID-II are presented in Table 1.
At 28 months of age, Child A was able to squat and take a few steps backward. He was able to grasp a pencil, hold paper with his hand, and place pellets in a bottle. Child A's ceiling on the BSID-II was established after he was unable to walk up or down stairs, stand on one foot, walk sideways, or run. No further fine motor items were assessed above the ceiling, per standardization. Items in the 14- to 16-month item set were the most advanced items administered to Child A. Child A was able to complete 100% of the fine motor items and only 25% of the gross motor items in the 14- to 16-month item set.
At 34 months of age, Child A was able to complete more items on the BSID-II motor scale than at the 28-month assessment, as illustrated by his increased raw score in Table 1. He was able to walk sideways, stand on one foot, and run. Child A missed all the gross motor items that were more advanced than standing on one foot but continued to receive credit for the fine motor items including lacing beads and grasping and manipulating a pencil. Thus, in the 23- to 25-month item set, Child A received credit for five of seven (71%) fine motor items and only two of 12 (17%) gross motor items.
Child B's motor skills were assessed at four, seven, and 10 months post-transplantation (26, 29, and 32 months of age) using the BSID-II Motor Scales as a portion of an interdisciplinary assessment. Child B's scores on the BSID-II are presented in Table 2.
At 26 months, child B was able to roll from prone to supine and sit independently. He was able to bring cubes to midline and grasp a pellet. In the seven-month item set, Child B received credit for seven of 12 (58%) gross motor items and all four (100%) fine motor items. In the eight-month item set, he received credit for three of 13 (23%) gross motor items and two of five (40%) fine motor items.
During the subsequent assessment (29 months), Child B was able to crawl, creep up stairs, pull to stand, throw a ball, and scribble with a crayon. In the 11-month item set, Child B received credit for five of 12 (40%) gross motor items and all three (100%) fine motor items. In the 12-month item set, the child received credit for three of 12 (25%) gross motor items and for both (100%) fine motor items.
At 32 months of age, Child B was able to creep well, walk independently, kick a ball, walk backward, run, grasp a pencil, and use a pincer grasp. He received credit for one of 12 (8%) gross motor items and two of three (67%) fine motor items in the 20- to 22-month item set. He also received credit for one fine motor item in the next item set, but was unable to complete any gross motor items.
Using the results of a survey completed by experienced therapists classifying BSID-II items as either fine or gross motor items, the evaluators distinguished those items on the BSID-II motor scale that were measures of gross or fine motor skill. Using the results of this survey, the evaluators demonstrated notable discrepancies in the fine and gross motor skills for the two children with Hurler syndrome post-UCBT presented in this case series.
The examination of raw scores for fine and gross motor performance on the BSID-II in these cases, while not part of the standardized scoring process, revealed numerous concerns with the psychometric properties of the measure when used with children who are diagnosed with degenerative disorders. First, given that the “floor” standard score of this measure is 50, the performance of children with severe impairment is imperfectly captured by scores below 50, and improvement in either gross or fine motor skills over time cannot be demonstrated with variations in scores reported as less than 50.12 Comparison of raw scores, while not providing normative information, can demonstrate improvement in performance over time in an individual child. While it is inadvisable to use raw scores to compare the performance of children, it appears to be the best available tool on the BSID-II for tracking change over time, as well as for demonstrating differences between fine and gross motor skills.
Hurler syndrome is a progressive disorder in which children gain motor skills at a very slow rate and begin to lose motor skills as the disease progresses. Both of the children presented in this case series had significant motor delays and, according to parental reports, had begun to lose some motor skills prior to UCBT. The children had not been assessed prior to undergoing transplantation, limiting the evaluators' ability to report on the pre-transplantation motor skills of these children. The two children presented in this case series were evaluated in the early stages of developing a clinical assessment protocol prior to beginning pre-transplantation assessments. However, post-transplantation evaluation results indicated that both children gained new skills with each successive assessment and had more advanced fine motor skills than gross motor skills at each assessment.
The finding that the BSID-II was not adequate for documenting discrepancies in fine motor and gross motor skills supported the evaluators' plan to reevaluate the standardized assessment instruments used to assess motor skills in children with Hurler syndrome. The results of this study support the need to use an evaluation tool that provides separate standardized measures of fine and gross motor skill in this population of children. Among current evaluation tools, the authors suggest that the PDMS-2 is the best tool for children from birth to 70 months of age with Hurler syndrome.
Therapists assessing children with Hurler syndrome should consider the cases presented in this paper. Children who are diagnosed with Hurler syndrome may present with discrepancies between their fine and gross motor abilities that may not be distinguished with some standardized assessment instruments. As Washington14 documented, children with discrepancies between fine and gross motor skills may not qualify for therapeutic services because their scores may be artificially inflated by their fine motor skills when the BSID-II is used to determine eligibility for services. Therefore, it is recommended that motor skills be assessed using standardized measures, such as the PDMS-2, that separate fine and gross motor skills in to discrete subtests.
Future research is needed using standardized measures with separate fine and gross motor subtests to evaluate the efficacy of UCBT and to determine whether fine and gross motor discrepancies exist at various ages and at various times post-UCBT.
The two children with Hurler syndrome presented in this case series appeared to have more proficient fine motor skills than gross motor skills post-UCBT. Therapists should consider using standardized assessment instruments with separate fine and gross motor subtests when evaluating children with Hurler syndrome.
1. National MPS Society. A Guide to Understanding Hurler, Hurler-Scheie and Scheie Syndromes
. Bangor, ME: National MPS Society, Inc; 2000.
2. Muenzer J. Mucopolysaccharidoses. Adv Pediatr
3. Jones K. Smith’s Recognizable Patterns of Human Malformation
. Philadelphia: WB Saunders; 1997.
4. Lowry RB, Renwick DH. Relative frequency of the Hurler and Hunter syndromes. N Engl J Med
5. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in the Netherlands. Hum Genet
6. Hobbs JR, Hugh-Jones K, Barrett AJ, et al. Reversal of clinical features of Hurler disease and biochemical improvement after treatment by bone-marrow transplantation. Lancet
7. Peters C, Balthazor M, Shapiro EG, et al. Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome. Blood
8. Hugh-Jones K. Psychomotor development of children with mucopolysaccharidosis type 1-H following bone marrow transplantation. Birth Defects Orig Artic Ser
9. Kakkis ED, Muenzer J, Tiller GE, et al. Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med
10. Wraith JE. Enzyme replacement therapy in mucopolysaccharidosis type I: progress and emerging difficulties. J Inherit Metab Dis
11. Staba SL, Escolar ML, Poe M, et al. Cord-blood transplants from unrelated donors in patients with Hurler’s syndrome. N Engl J Med
12. Kakavanos R, Turner CT, Hopwood JJ, et al. Immune tolerance after long-term enzyme-replacement therapy among patients who have mucopolysaccharidosis I. Lancet
13. Bayley N. Bayley Scales of Infant Development, Second Edition
. New York: The Psychological Corporation; 1993.
14. Washington K. The Bayley Scales of Infant Development-II and children with developmental delays: a clinical perspective. J Dev Behav Pediatr
15. Nellis L, Gridley BE. Review of the Bayley Scales of Infant Development-Second Edition. J Sch Psychol