Short stature in MPS is linked to dysostosis multiplex. Typical signs of this skeletal dysplasia are gibbus, scoliosis, epiphyseal dysplasia and degenerative joint disease (Areu et al. 1995
). A follow-up study on patients with MPS I on ERT for 6 years did not reveal any distinct changes in dysostosis multiplex (Muenzer et al. 2006
). We assume, therefore, that ERT in patients with MPS II will also have little or no effect on these symptoms. Histological examinations of a biopsy from a Hurler syndrome patient or from animal models with different types of MPS revealed pathology of the growth plate possibly related to GAG accumulation (Areu et al. 1995
; Silveri et al. 1991
; Russell et al. 1998
). Pathophysiological studies of the skeletal manifestations of MPS II may also help to understand the effects of ERT.
Although short stature is common to most types of MPS, there are few published data on the effects of ERT on growth in patients with other mucopolysaccharidoses, other than one study in patients with MPS I (Sifuentes et al. 2007
). In this report, we describe the first long-term analysis of the effects of ERT on height in children with MPS II. Height measurements were analysed within two age-stratified cohorts. The age cut-off of 10 years was selected because growth in patients with MPS II tends to follow a normal trajectory until 8 years of age after which growth is markedly reduced (Schwartz et al. 2007
). Our cohorts reflect this growth pattern; in group 1 (<10 years of age at the start of ERT) only one of the nine patients was considered to be of short stature compared with all nine patients in group 2 (>10 years of age at the start of ERT).
ERT with idursulfase improved growth when given before the age of 10 years. With one exception, the height of boys in group 1 remained above –2 SD even beyond the age of 10 years. The exception was a boy who was already below –2 SD before starting treatment. His relatively poor response may have been associated with the development of antibodies that, in vitro, appear to have had some neutralizing activity. Further studies, however, are needed to determine the clinical significance of the development of antibodies.
The boys in group 2, who were above 10 years of age at the start of ERT, also showed an increase of growth velocity in their first 2 years of ERT compared with the year before ERT; growth rate in the third year was similar to that in the year before ERT. It is possible that this slower growth rate during the third year of treatment is related to the completion of puberty in these older boys. However, this cannot be confirmed, as the stage of puberty was not documented in this population. Also, patients with MPS II may have delayed puberty. It is important to note that the height of two of the boys in this group was above the 3rd percentile for age at the start of treatment and that one of the patients was particularly short, with a height Z score of approximately –7 at the start of treatment.
The continued increase in height over 3 years, particularly in the group aged under 10 years at the start of ERT, almost certainly represents real growth and is not due to patients standing straighter because of a reduction in joint contractures. In fact, an increase in height can contribute to joint contractures until the muscles and tendons adapt to the new bone growth. Physiotherapy may be beneficial in this respect, resulting in reduction of joint contractures and an apparent increase in height.
A recent non-age-stratified analysis of data from HOS revealed a similar growth acceleration in patients with MPS II given ERT with idursulfase for at least 1 year (Beck et al. 2008
). HOS is a multinational long-term outcomes survey covering the natural history of Hunter syndrome and the safety and effectiveness of ERT with idursulfase. Ongoing collection of data in HOS, including analysis of the response to ERT and pubertal development status, will further elucidate the effect of ERT with idursulfase on growth.
Studies into the effects of short stature and the response to ERT are important as there is an assumption that short stature may lead to psychosocial stress in childhood and adolescence (Siegel et al. 1991
), which may be at least partially relieved by bringing height closer to the mean for age. One study has shown a significant correlation between adult short stature and health-related quality of life (HRQoL), which suggests that increasing final height in children with short stature may be beneficial and could enhance HRQoL outcomes (Christensen et al. 2007
There has been limited research on the psychological and social effects of stature in patients with MPS II, although one study reports significant psychosocial problems in teenagers and young adults (Young and Harper 1981
). For young adults with short stature due to growth hormone deficiency, childhood onset of renal failure or Turner syndrome, the opportunity for having a partner was low (Busschbach et al. 1998
). Young adults with MPS II in our clinics also report problems in finding a partner.
It is unwise, however, to extrapolate the findings from general research into the effects of short stature. Individuals with MPS II have dysmorphism, pain and other medical complications and so might encounter very different psychosocial and HRQoL problems than those with other causes of short stature. Nevertheless, as in many similar diseases, short stature serves as a distinguishing characteristic for MPS II. An increase of height towards normal would remove one of the most visible features of the disease, which may have a positive impact on both the patients and their parents.