Childhood onset of Scheie syndrome, the attenuated form of mucopolysaccharidosis I

Natural history data were reviewed for 78 patients with Scheie syndrome, representing the largest cohort with this rare genetic disorder examined to date. Strikingly, the pattern of disease progression indicates that most clinical features associated with MPS I first appeared before the age of 12 years in the majority of patients. Among individuals, the first clinical feature(s) to emerge varied, but the most common first sign to appear before age 2 years was hernia and after age 2 years joint contractures. Some early signs, such as hernias and enlarged tonsils, are relatively common in the general pediatric population and in isolation would not raise suspicion for MPS I. More indicative of MPS I are the flexion contractures, especially of the fingers and hands, that children with Scheie syndrome often develop. In MPS I, joint pain, stiffness, and immobility are not accompanied by inflammation, as in some other rheumatological conditions that arise in childhood (Cimaz et al. 2006). The wide variability observed in the age at onset for each clinical feature underscores the heterogeneity of Scheie syndrome, with disease pathology emerging in individual patients at different times in different organs. While there is no typical clinical profile for the Scheie phenotype, cardiac valve abnormalities, joint contractures, and corneal clouding were each reported by >80% of patients. Only 7% had none of these signs, whereas 53% reported all three. In 1962, Dr. Harold Scheie, an ophthalmologist, provided the first biochemical evidence linking the corneal haze he observed in ten patients to an attenuated forme fruste of Hurler syndrome (Scheie et al. 1962). Flexion contractures and heart murmurs were frequently noted among his patients. Recent reports emphasize that children and adults with Scheie syndrome most often present with rheumatological symptoms, usually accompanied by ocular and cardiac valve pathology (Cimaz et al. 2006; Vieira et al. 2008; Vijay and Wraith 2005). In addition to the triad of joint, cardiac valve, and corneal abnormalities, the majority of the registry patient cohort reported carpal tunnel syndrome, hernia, coarse facial features, and hepatomegaly. Chronic ear, nose, and throat and respiratory problems, including sleep apnea and recurrent otitis media, also have been noted in patients (Vijay and Wraith 2005; Wraith 2005). Furthermore, MPS I patients commonly require multiple, often unrelated, surgical interventions, and 40% of children with Scheie syndrome reported two or more surgeries by 10 years of age (Arn et al. 2009).

Following the onset of signs and symptoms, MPS I diagnosis was established for the registry patients with Scheie syndrome between infancy and the sixth decade. Analyses performed to explore this broad range suggested that patients diagnosed early express phenotypes that are more pronounced and that evolve more rapidly than patients diagnosed later. Prior to diagnosis, the facial dysmorphia that is characteristic of MPS I appeared in almost two thirds—and joint contractures in more than half—of the patients diagnosed before age 5 years. Among patients diagnosed after age 5, joint contractures occurred in the majority, but less than one third displayed coarse facial features before diagnosis. Patients diagnosed after age 20 years had, on average, slightly more clinical signs of MPS I at the time of diagnosis than patients diagnosed earlier, but no feature predominated as in the subgroups diagnosed earlier. For most clinical features, strong correlations were found between the age at which the feature was reported and the age at which the patient was diagnosed. Taken together, these observations suggest that MPS I manifestations emerged more slowly and variably in patients diagnosed after the age of 20 years. Yet, it is also noteworthy that the number of patients diagnosed has increased annually since 1962, when Scheie syndrome was first described, most likely mirroring a growing awareness of the attenuated phenotype. For the registry patients with Scheie syndrome born before 1970 and diagnosed in adulthood despite symptom onset in childhood, the lack of disease awareness is most likely responsible for the delayed diagnosis.

The limitations in interpreting the data presented here begin with the diagnosis of Scheie syndrome. MPS I spans a continuum of disease, and the three syndromes are not rigorously defined and cannot currently be distinguished by biochemical criteria or genotype in most cases. Hence, syndrome designation depends on the clinical judgment of the reporting physician. Subgroup analyses presented in Fig. 3 emphasize the likelihood that some registry patients express phenotypes that border the intermediate, Hurler-Scheie part of the disease spectrum. Indeed, two patients who were diagnosed before 18 months of age had coarse facial features and cognitive impairment present at diagnosis. Although early onset of these manifestations is more typical of Hurler or Hurler-Scheie syndromes, data are included from one patient up to 10.3 years of age when ERT was initiated and for the other up to 1.8 years of age when HSCT was performed. Another limitation of the reported data stems from the fact that MPS I is rare, and the attenuated phenotype is the rarest form of the disease (Meikle et al. 1999; Neufeld and Muenzer 2001). Even though the registry cohort is the largest examined thus far, the sample size is relatively small. Finally, limitations associated with any voluntary, observational disease registry must be considered, including selection bias, reporting bias, and unverified data entries (Pastores et al. 2007).

Clinical management of patients with Scheie syndrome requires an individualized approach best coordinated by a multidisciplinary team (Muenzer et al. 2009). ERT is approved in more than 55 countries worldwide for treatment of the non-neurological manifestations of MPS I. A phase 3 extension trial demonstrated stabilization or improvement of several clinical parameters in Scheie and Hurler-Scheie patients after approximately 4 years of ERT (Clarke et al. 2009). Improvement of cardiomyopathy with ERT has been reported, but cardiac valve disease appears to be less responsive, possibly because the treatment period was too short or because treatment was initiated late in the disease process (Braunlin et al. 2006). A recent case report of two siblings with Hurler-Scheie syndrome who began ERT at 5 months and 5 years of age, respectively, suggests that many MPS I disease manifestations, including cardiac valve disease, can be prevented if ERT is begun at an early age, but only partially reversed or stabilized if begun at a later age (Gabrielli et al. 2009). Thus, ERT is expected to provide the greatest clinical benefit when initiated before permanent tissue damage has ensued and attention has been drawn to patients with Scheie syndrome whose disease may not be recognized. Timely disease recognition also provides potential benefits with regard to genetic counseling for families and more timely interventions for patients, which, in turn, may produce better outcomes, slow disease progression, and/or improve quality of life. As reported here, clinical signs usually emerge during childhood in the attenuated phenotype, and prompt diagnosis requires awareness of the multisystemic manifestations and diverse presentation of MPS I.