Pediatric Transplants

Growth and endocrine function in patients with Hurler syndrome after hematopoietic stem cell transplantation


Short stature is characteristic of Hurler syndrome, or mucopolysaccharidosis type IH (MPS IH). Hematopoietic stem cell transplantation (HSCT) is used to treat children with MPS IH. While HSCT corrects some of the metabolic features of MPS IH, its effects on growth are not well delineated. We investigated growth in patients with MPS IH after HSCT and described accompanying endocrine abnormalities. A cohort of 48 patients with MPS IH who had received HSCT between 1983 and 2005 were included. The prevalence of short stature (height <−2 s.d. score, SDS) before HSCT was 9%, and increased to 71% at last follow-up (6.9±5.1 years after HSCT). Short stature was positively associated with increased age at HSCT (P=0.002) and TBI (P=0.009). In total, 23% had growth hormone deficiency and/or low insulin-like growth factor-1, one female patient had premature adrenarche, one precocious puberty and 27% had clinical or subclinical hypothyroidism. Growth failure is highly prevalent in children with MPS IH after HSCT. Children who had no TBI exposure and were younger at the time of HSCT had a better height outcome.


Hurler syndrome, or mucopolysaccharidosis type IH (MPS IH), is an autosomal recessive, lysosomal storage disease caused by deficiency of α-L-iduronidase (IDUA), an enzyme required for the breakdown of the glycosaminoglycans (GAG) heparan and dermatan sulfates.1 Lysosomal accumulation of GAG results in multisystem disease. Clinically, MPS IH is characterized by short stature, characteristic facial features, cognitive and gross motor delays, corneal clouding, dysostosis multiplex, cardiac manifestations and hepatosplenomegaly.2, 3, 4, 5, 6 MPS IH is typically diagnosed in patients less than 2 years of age.

Short stature is characteristic of patients with MPS IH, as well as other types of MPS, and is likely secondary to a combination of skeletal (for example, kyphosis, scoliosis, genu valgum), metabolic and endocrine abnormalities. Without treatment children with MPS IH typically have marked growth deceleration starting between 6 and 18 months of age. The maximum reported height for these patients when untreated is approximately 110 cm.3 The mechanism of poor growth in the different types of MPS is not entirely understood, but may be related to GAG accumulation in the growth plate.7, 8, 9, 10 In addition, lysosomal GAG accumulation has been documented in the pituitary gland, thyroid gland and testes of children with MPS II,11, 12 and in ovarian tissue of a murine model of MPS VII.13 One report of three brothers with MPS II documented low insulin-like growth factor-1 (IGF-1) levels,14 and precocious puberty has been reported in MPS IIIA.15 In summary, current literature suggests that pituitary dysfunction, hypothyroidism and pubertal disruption may be associated with MPS, and therefore may contribute to the short stature in these patients.

Without treatment, children with MPS IH typically die by 10 years of age due to cardiac or respiratory complications.3, 4 Currently, most children with MPS IH are treated with hematopoietic stem cell transplantation (HSCT).16, 17, 18, 19, 20 HSCT as an intervention, however, compounds the problem of short stature. HSCT has been associated with growth suppression, growth hormone (GH) deficiency, abnormal gonadal and thyroid function, and damage to the epiphyseal growth plate and pituitary gland,21, 22, 23, 24, 25, 26, 27, 28, 29 all potential causes of short stature.

With HSCT, children with MPS IH are living into their adult years and therefore determining long-term outcomes and complications has become clinically important. Early diagnosis and replacement of hormonal deficiencies are critical for optimizing growth and development. While many studies have examined long-term growth for other conditions following HSCT,22, 23, 24, 25, 26, 27, 28 there are few growth data specific to patients with MPS IH.17, 19 Even less is known about endocrine function in patients with MPS IH after HSCT. One study of five children by Vellodi et al.17 found two had primary ovarian failure, one had sexual infantilism and two had normal pubertal development. We performed a retrospective chart review of all of our patients with MPS IH who received HSCT at the University of Minnesota between 1983 and 2005, primarily to characterize growth patterns, but also to begin to address the question of endocrine function in these patients.


Experimental subjects

The medical records of 66 patients with MPS IH who received HSCT (marrow from unrelated or related donor, or umbilical cord blood) at the University of Minnesota between September 1983 and April 2005, and who survived at least 1 year after HSCT, were reviewed to collect height, weight, endocrine and clinical data. All HSCT-related data were obtained from the University of Minnesota Pediatric Blood and Marrow Transplantation Database. The diagnosis of MPS IH was confirmed by absent IDUA activity. One patient received 14 weekly i.v. doses of enzyme replacement therapy (IDUA, Laronidase; dose 0.58 mg/kg per dose) before HSCT and 8 doses after HSCT.

The following exclusions were made to reduce potential biases in expected growth after HSCT: nine patients who died less than 2 years after HSCT, one patient who had no height data after HSCT, two patients who developed graft rejection and did not receive a second HSCT, six patients who were treated with GH for either GH (n=4) and/or IGF-1 deficiency30 (n=2). All data points were excluded for these six patients due to the diagnosis of GH and/or IGF-1 deficiency. Two patients who received GH for short stature with normal GH secretion were included up until treatment with GH was initiated for one patient and until the onset of precocious puberty (prior to GH treatment) in the other patient. These exclusions left a final cohort of 48 patients.

The transplant procedures and retrospective chart review were approved by the Institutional Review Board. Informed consent for the chart review was waived because of the retrospective nature of this study.

Analysis of growth patterns and associations

The children were often measured in several different clinical settings. For consistency, it was assumed that the height measurements taken in the endocrine clinic were more accurate than those taken in other settings. Height measurements were excluded if they were taken within 1 month's time of a corresponding measurement at the endocrine clinic and if they differed from the endocrine clinic measurement by more than 0.6 cm (approximately twice the anticipated measurement error). If no endocrine clinic data were available, then available data points were averaged within 1-month intervals. Finally, individual data points were excluded in one patient at the first signs of precocious puberty by parental report (later confirmed by laboratory evaluation), and in two patients during treatment with GH for short stature (both patients were GH sufficient). This selection process yielded a series of 418 semi-longitudinal height measurements.

Analysis of growth in 48 MPS IH patients (20 girls) was conducted separately for each gender. Height measurements were organized into 6-month categories. Smoothed and extrapolated means were obtained by fitting a cubic polynomial of age to the observed mean measurements spanning the age range. At the older ages, where sample sizes within age and gender group were less than four, the curves were fitted, but because of the small samples, these means were considered extrapolated and no s.d.s are provided. S.d.s calculated within the age groups were smoothed across ages using a resistant nonlinear smoother before calculating the ±2 s.d. limits. Values for the smoothed parameters were plotted relative to percentiles from the Centers for Disease Control and Prevention (CDC) 2000 growth charts.31 Height s.d. score (SDS, z-scores) were calculated relative to the CDC growth charts and a quadratic polynomial of age was fitted to the z-scores to describe the age-related pattern. There were no significant effects or interactions with gender.

Endocrine evaluation

Prior to 2001, endocrine evaluation was obtained at the discretion of the transplant physician; this typically included thyroid studies, measurement of height and weight, and GH screening if height was less than −2 SDS. Currently, a standard endocrine screening protocol is in place, which requires yearly thyroid-stimulating hormone (TSH), free thyroxine (FT4), IGF-1, insulin-like growth factor binding protein-3, leutinizing hormone (LH) and follicle-stimulating hormone (FSH) (along with estradiol or testosterone according to gender) for girls 11 years and older and boys 12 years and older, and pubertal staging by physical exam. Short stature was defined as a height less than −2 SDS for age and gender.30 Puberty before 8 years in girls and 9 years in boys was considered precocious, puberty after 13 years in girls and 14 years in boys was considered delayed and puberty onset between 8 and 13 years in girls and 9 and 14 years in boys was considered normal.32 Primary gonadal failure was defined as an FSH (chemiluminescent immunoassay) greater than 40 IU/l. Central puberty was defined as a random LH by immunochemiluminometric membrane assay (ICMA) greater than 2 mIU/ml and/or a stimulated LH (chemiluminescent immunoassay) greater than 7 IU/l.32 Thyroid disease was classified as subclinical hypothyroidism when the TSH (chemiluminescent immunoassay; reference range 0.4–5 mU/l) was greater than 5 mU/l and the FT4 (competitive immunoassay) or total thyroxine (chemiluminescent immunoassay) was normal (0.7–1.85 ng per 100 ml and 6.8–13.5 μg per 100 ml, ages 1 month to 3 years; 5.5–12.8 μg per 100 ml, ages 3–9 years or 5.0–11.0 μg per 100 ml, ages 10 and above, respectively), primary hypothyroidism when the TSH was greater 5 mU/l and the free or total thyroxine was below the normal range for age, central hypothyroidism when the TSH was less than 0.4 mU/l and the free or total thyroxine was below the normal range for age and hyperthyroidism when the FT4 was greater than 1.85 ng per 100 ml or the total thyroxine greater than 13.5 μg per 100 ml for ages 1 month to 3 years, 12.8 μg per 100 ml for ages 3–9 years and greater than 11.0 g per 100 ml for ages 10 and above.33 Low IGF-1 was defined as an IGF-1 level (chemiluminescent immunoassay) less than −2 SDS for age and gender, and GH deficiency as a peak GH level less than 10 μg/l during arginine and clonidine GH stimulation testing.30 No patients received priming with sex steroids before GH stimulation testing.

Statistical analysis

Statistical analyses were performed using SAS software. Associations between discrete variables (conditioning regimen, donor type, gender) with endocrine dysfunction were calculated by the χ2-test or Fisher's exact test, as appropriate. Associations between age at HSCT, date of HSCT and length of follow-up were calculated by Pearson's correlation analysis. Analysis of variance (ANOVA) was used to determine associations between donor type, conditioning regimen, age at last height evaluation, IDUA activity in the white blood cells at last evaluation and age at HSCT, with height at the last evaluation. The statistical significance level was set at P<0.05.


Characteristics of the patients

A total of 48 MPS IH patients (20 females) were included in the analysis. A description of age at HSCT, duration of follow-up, age at last visit, number of HSCT, donor type and prevalence of GVHD are presented in Table 1. HSCT conditioning regimens were divided by exposure to TBI for statistical analysis. Details of conditioning regimens are presented in Table 2. Twenty-two patients received TBI as part of their conditioning regimen (first or second HSCT). All nine recipients of second stem cell infusion received TBI as a part of the first or second conditioning regimen. As a second graft, six received unrelated and three received related BM.

Table 1 Characteristics of 48 patients with MPS IH and their stem cell donors
Table 2 Description of conditioning regimens

Growth patterns

Overall, short stature was present in 71% of patients (n=34) after HSCT at the most recent evaluation. The growth patterns for both genders demonstrated a progressive falling behind relative to the CDC reference percentiles (Figure 1). Height z-scores were plotted against age (Figure 2), showing curvilinear decline in z-scores as the children grew older. Mean body mass indices (BMIs) were above the 50th percentile for each age category (Figure 2). Forty-four patients had baseline height data prior to HSCT. Four patients had no height measurements at the University of Minnesota prior to HSCT. Pre-HSCT mean height was −0.1±1.5 SDS and short stature was present in 9% of patients (n=4 of 44). By 10 years of age, mean height decreased to −3.2±1.6 SDS and the prevalence of short stature increased to 87% (n=13 of 15).

Figure 1

Growth patterns of boys (a) and girls (b) from time of hematopoietic stem cell transplantation (HSCT) to time of last follow-up visit superimposed on standard Centers for Disease Control and Prevention (CDC) percentiles for height by age.

Figure 2

Negative curvilinear relationship of all measured height s.d. scores (SDS, z-score) relative to age and body mass index (BMI) by age group. The drawn curve is a quadratic curve that best fit the data. This pattern corresponds to the progressive falling behind seen in Figure 1. Number of patients and BMI data for age ranges 0–4, 4–8, 8–12 and 12–18 are identified.

Older age at HSCT was positively associated with last measured height SDS (r=0.44, P=0.002). The conditioning regimens using TBI were significantly associated with short stature (P=0.009): short stature was found in 54% (n=14 of 26) of children who did not receive TBI, and in 86% (n=19 of 22) of children who received TBI. Second HSCT and gender were not significantly associated with short stature. The association between donor type and short stature at last evaluation approached statistical significance (P=0.05). Short stature was diagnosed in 46% of children who had a cord blood donor, 72 and 88% (related and unrelated, respectively) of children who received BM. However, the cord blood recipients were younger at HSCT (1.3±0.6 years), and younger at the time of last follow-up (4.1±2.0 years) compared to related (2.1±0.9 and 12.4±3.5 years, respectively) and unrelated (1.6±0.6 and 7.0±3.7 years, respectively) BM donor recipients. Since short stature becomes more pronounced with age, we analyzed whether the relationship between donor and short stature persisted when the age at last follow-up was accounted for, and as expected, this association was not statistically significant when adjusting for the age at last height evaluation. Age at HSCT remained significantly associated with last measured height SDS when accounting for age at last follow-up (P=0.006). Finally, enzyme level at last follow-up was classified as normal (>70% of normal mean level), impaired (50–70% of normal mean level) and low (<50% of normal mean level). Enzyme level was then compared by one-way ANOVA to last height SDS and approached statistical significance (P=0.05): mean height SDS for normal enzyme level was −2.6±1.8 SDS, impaired was −4.2±2.1 SDS and low was −4.4±3.2 SDS.

Endocrine abnormalities

Endocrine function data are presented in Table 3. All prevalence percentages were calculated based on the total cohort (n=48), except for the children who were diagnosed with GH deficiency and/or low IGF-1 after HSCT (n=54) since six were excluded from the growth cohort due to early treatment with GH. All patients with low IGF-1 had normal BMI SDS (mean 0.4, range −1.9 to +1.9). All patients were prepubertal at the time of HSCT. The five children with IGF-1 levels less than −2 SDS for age and gender had normal pubertal status for age. One female patient was diagnosed with precocious puberty at age 7 years and 11 months by Lupron stimulation testing (stimulated LH 59.7 IU/l, FSH 70.6 IU/l). She had Tanner 3 pubic hair and indeterminate breast development due to significant subcutaneous tissue. One patient developed precocious puberty at age 7 years and 7 months (LH-ICMA 2.0 mIU/ml, estradiol 19 pg/ml). Two patients had laboratory results consistent with precocious puberty, however no clinical signs of puberty. No patients were diagnosed with gonadal failure, however the majority of patients in the cohort were younger than 10 years. Pubertal abnormalities, thyroid disease and IGF-1 were not significantly associated with conditioning regimen, donor type, age at HSCT or gender.

Table 3 Prevalence of abnormal endocrine function


The first HSCT for MPS IH was performed at Westminster Children's Hospital in 1980; this was shortly thereafter followed by the first HSCT for MPS IH in the United States at the University of Minnesota in 1983 under the guidance of Dr William Krivit. Since then, HSCT has become the standard of care as treatment for MPS IH. In this report, we describe for the first time the long-term effects of HSCT in children with MPS IH with respect to growth and endocrine function. The reported maximum height in patients with MPS IH, without HSCT, is 110 cm.3 Our study shows that HSCT improves the expected adult height, because the mean height at 10 years of age (117.8 cm) already exceeds 110 cm and growth is not yet completed at this age. Short stature, however, remains highly prevalent in this population (87% at 10 years of age). The prevalence of short stature in our population is quite high compared to that found in other studies of patients without MPS IH after HSCT,21, 25, 28 as 14–31% of patients in these reports had short stature at last follow-up. We found that children who had no TBI exposure, and were younger at the time of HSCT, had a better height prediction.

Endocrine abnormalities are common in all populations of children who receive HSCT, in particular those who were exposed to TBI. It is difficult to separate out the effects of the HSCT and those innate to MPS IH. The children in our cohort had a relatively high prevalence of GH deficiency, low IGF-1 and hypothyroidism. It is difficult to make any conclusions about the prevalence of delayed puberty in our population since only 31% of the patients in this study had reached 10 years of age at the time of last evaluation. Except for height, no associations were found between the prevalence of endocrine dysfunction and any of the predictor variables tested, although the small number of cases may have precluded detection of small effects.

Our growth pattern results are similar to those found in smaller case studies by both Vellodi et al.17 and Staba et al.19 In 10 patients with MPS IH who received an HSCT, Vellodi et al.17 found normal growth velocity in the first few years after HSCT but then a decrease in growth velocity resulting in the mean height falling beneath the third percentile by approximately 5 years of age. Staba et al.19 found normal growth velocity after cord blood HSCT in the majority of the children with MPS IH, who were less than 7 years of age at the last follow-up, suggesting that cord blood HSCT may improve height prediction. However, in our population, this association was lost with increased length of follow-up. Currently, there are insufficient long-term data to draw definitive conclusions about the impact of donor type on growth, or the expected final adult height in this population.

Although HSCT resulted in improved growth compared to untreated historical controls, there was worsening growth failure with age in our patients with MPS IH after HSCT. We found that early HSCT significantly improved the height of patients in our population, in contrast to other non-MPS IH populations after HSCT.22, 23, 34 Our patients were all young (0.5–3.7 years) at the time of HSCT, even so, we still found a greater impact on height for those who were transplanted at an older age, regardless of the age at last height evaluation. This effect is consistent with other studies of children with MPS IH, which also suggested improved outcomes for those children who were transplanted at a younger age.35, 36 In addition, the characteristic skeletal abnormalities (kyphosis, scoliosis, genu valgum) have been reported to continue to progress after HSCT in children with MPS IH17, 37 and likely affect final height as well. TBI has also frequently been associated with a considerable impact on growth compared to non-TBI conditioning regimens.23, 27, 38, 39 We found that 86% of children who had TBI as part of their conditioning regimen had short stature.

The limitation of this study is its retrospective nature. There are selection and temporal biases in the referral for endocrine evaluation. Endocrine testing became more common later in the study period. Routine testing of all patients would have likely detected more subtle endocrine dysfunction. Our calculation of the prevalences of endocrine diseases is based on the total number of patients and not only on the number of patients tested. Therefore, these biases would result in an underestimate of the true prevalence of endocrine diseases in this cohort and do not weaken our conclusions.


This report has the longest follow-up in patients with MPS IH after HSCT of any other currently published. We conclude that a later age at HSCT and exposure to TBI are associated with an increased prevalence of short stature in children with MPS IH after HSCT. Based on the currently available data, we recommend annual systematic screening for endocrine dysfunction in children with MPS IH following HSCT, including thyroid, GH, IGF-1 and pubertal evaluations. The diagnosis of hormonal deficiencies, and early treatment, would be expected to minimize complications due to undiagnosed disease, and improve growth, development and bone health. Further studies are needed to determine the impacts of these treatments.


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This work was partially funded by the Children's Cancer Research Fund, Minneapolis, MN (JT, PO), NIH T32-DK065519 (LP) and the Minnesota Medical Foundation (JT, MP). We would like to recognize Dr William Krivit, now deceased, for his pioneering work in the field of transplant for Hurler syndrome, the outstanding nursing staff who have cared for these patients over the years and the support of the families in furthering our understanding of MPS IH. We also thank Eileen Hanson and Teresa Kivisto for their dedication and persistence in the care of the families and in obtaining the necessary data.

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Correspondence to A Petryk.

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Polgreen, L., Tolar, J., Plog, M. et al. Growth and endocrine function in patients with Hurler syndrome after hematopoietic stem cell transplantation. Bone Marrow Transplant 41, 1005–1011 (2008).

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  • Hurler syndrome
  • HSCT
  • growth
  • endocrine function

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