Initial report from the Hunter Outcome Survey

PurposeHunter syndrome (Mucopolysaccharidosis II) is a rare, X-linked disorder of glycosaminoglycan metabolism. It is caused by a deficiency in the lysosomal enzyme iduronate-2-sulfatase, and in affected patients glycosaminoglycan accumulates in lysosomes of various tissues and organs and contributes to the pathophysiology of Hunter syndrome. The Hunter Outcome Survey (HOS) was established to better describe the natural history of this disorder and to evaluate the long-term effect of enzyme replacement therapy.MethodsHOS is an international, multicenter, long-term observational survey that will collect data on participating patients with a confirmed diagnosis of Hunter syndrome. Data will be collected during regular physician examinations and entered into an electronic database. Examples of observations include vital signs, laboratory values, signs and symptoms of organ involvement, and the results of selected functional tests (e.g., audiometry, echocardiogram, joint mobility, etc.).ResultsAs of May 15, 2007, 263 patients from 16 countries have enrolled in HOS; 24% of these patients were currently being treated with enzyme replacement therapy. The median age at enrollment was 12.2 years. The median age of onset of symptoms and diagnosis of Hunter syndrome were 1.5 and 3.5 years, respectively. Otitis media and abdominal hernia were the earliest presenting symptoms. Facial dysmorphism and hepatosplenomegaly were demonstrated by 95% and 89% of patients, respectively.ConclusionsHOS will be a valuable resource for enhancing the understanding of Hunter syndrome and will provide important information about the natural history of the disease and the role of enzyme replacement therapy in its treatment. Patients and their physicians should be encouraged to participate.     

Importance of surgical history in diagnosing mucopolysaccharidosis type II (Hunter syndrome): Data from the Hunter Outcome Survey

PurposeTo characterize surgical histories typical of patients with mucopolysaccharidosis type II, thereby broadening understanding of the natural history of these patients and helping physicians recognize the disease.MethodsData on surgical interventions from the Hunter Outcome Survey—a multinational, observational database of patients with mucopolysaccharidosis type II—were analyzed. The study population comprised 527 patients for whom surgical data were reported on/before July 23, 2009.ResultsSurgical interventions were performed in 83.7% of the study population. Patients underwent their first operation at a median age of 2.6 years. Tympanostomies, repairs of inguinal hernias, and operations for carpal tunnel syndrome were performed in a greater proportion of the study population than the general population. A median of 3.0 operations was performed per patient; repeat operations for hernia or carpal tunnel syndrome were common. The majority of patients (221/389) underwent at least one surgical intervention before diagnosis of mucopolysaccharidosis type II.ConclusionPatients with mucopolysaccharidosis type II typically undergo surgical intervention at a young age, often before diagnosis. Repeated early surgical interventions, particularly for hernias or carpal tunnel syndrome, are characteristic of patients with mucopolysaccharidosis type II. We recommend that such patients are carefully examined for manifestations of mucopolysaccharidosis disorders and referred for diagnostic testing.     

First experience of enzyme replacement therapy with idursulfase in Spanish patients with Hunter syndrome under 5 years of age: Case observations from the Hunter Outcome Survey (HOS)

Hunter syndrome (mucopolysaccharidosis type II [MPS II], OMIM309900) is a rare X-linked lysosomal storage disorder caused by deficiency of the enzyme iduronate-2-sulphatase, resulting in accumulation of glycosaminoglycans (GAGs), multisystem organ failure and early death. Enzyme replacement therapy (ERT) with idursulfase is commercially available since 2007. Early access programs were established since 2005. However, limited information on the effects of ERT in young children is available to date. The aim of this analysis was therefore to determine the effects of ERT on patients younger than 5 years of age. We report data from six Spanish patients with confirmed Hunter syndrome who were younger than 5 years at the start of ERT, and had been treated with weekly intravenous infusions of idursulfase between 6 and 14 months. Baseline and treatment data were obtained from the Hunter Outcome Survey (HOS). HOS is an international database of MPS II patients on ERT or candidates to be treated, that collects data in a registry manner. HOS is supported by Shire Human Genetic Therapies, Inc. (Cambridge, MA, USA). At baseline, all patients showed neurological abnormalities, including ventriculomegaly, hydrocephaly, cerebral atrophy, perivascular changes and white matter lesions. Other signs and symptoms included thoracic deformity, otitis media, joint stiffness and hepatosplenomegaly, demonstrating that children under 5 years old can also be severely affected. ERT reduced urinary GAG levels, and reduced spleen (n = 2) and liver size (n = 1) after only 8 months. Height growth was maintained within the normal range during ERT. Joint mobility either stabilized or improved during ERT. In conclusion, this case series confirms the early onset of signs and symptoms of Hunter syndrome and provides the first evidence of ERT beneficial effects in patients less than 5 years of age. Similar efficacy and safety profiles to those seen in older children can be suggested, although further studies including a direct comparison with older patients would still be required.     

Intrafamilial variability in the clinical manifestations of mucopolysaccharidosis type II: Data from the Hunter Outcome Survey (HOS)

Several cases of phenotypic variability among family members with mucopolysaccharidosis type II (MPS II) have been reported, but the data are limited. Data from patients enrolled in the Hunter Outcome Survey (HOS) were used to investigate intrafamilial variability in male siblings with MPS II. As of July 2015, data were available for 78 patients aged ≥5 years at last visit who had at least one affected sibling (39 sibling pairs). These patients were followed prospectively (i.e., they were alive at enrollment in HOS). The median age at the onset of signs and symptoms was the same for the elder and younger brothers (2.0 years); however, the younger brothers were typically diagnosed at a younger age than the elder brothers (median age, 2.5 and 5.1 years, respectively). Of the 39 pairs, eight pairs were classified as being discordant (the status of four or more signs and symptoms differed between the siblings); 21 pairs had one, two, or three signs and symptoms that differed between the siblings, and 10 pairs had none. Regression status of the majority of the developmental milestones studied was generally concordant among siblings. Functional classification, a measure of central nervous system involvement, was the same in 24/28 pairs, although four pairs were considered discordant as functional classification differed between the siblings. Overall, this analysis revealed similarity in the clinical manifestations of MPS II among siblings. This information should help to improve our understanding of the clinical presentation of the disease, including phenotype prediction in affected family members.     

Discordance between aeroallergen specific serum IgE and skin testing in children younger than 4 years

BackgroundAtopic sensitization to aeroallergens in early life has been found to be a strong risk factor for the development of persisting asthma in young children with recurrent wheeze.ObjectiveTo assess the yield of skin prick test (SPT) compared with allergen specific serum IgE (sIgE) testing at identifying aeroallergen sensitization in atopic children younger than 4 years.MethodsConcordance between SPT and allergen-specific sIgE testing for 7 common aeroallergens was analyzed in 40 atopic inner-city children 18 to 48 months of age (mean [SD], 36 [9] months) with recurrent wheezing and family history of asthma and/or eczema.ResultsIn 80% of children one or more allergen sensitizations would have been missed if only SPT had been performed, and in 38% of children one or more sensitizations would have been missed if only sIgE testing had been performed. Agreement between the SPT and sIgE test was fair for most allergens (κ = ?0.04 to 0.50), as was correlation between sIgE levels and SPT grade (ρ = 0.21 to 0.55). Children with high total sIgE (≥300 kU/L) were more likely to have positive sIgE test results, with negative corresponding SPT results (P = .02).ConclusionOur study revealed a significant discordance between allergen-specific SPT and sIgE testing results for common aeroallergens, suggesting that both SPT and sIgE testing should be performed when diagnosing allergic sensitization in young children at high risk of asthma.Trial Registrationclinicaltrials.gov Identifier: NCT01028560     

Skin cancer in adults younger than 40 years at the General Hospital of Mexico

Skin cancer is the most common malignant neoplasm reported worldwide. Over the last 20 years, skin cancer has been recognized in a high proportion among young people not associated with genetic disorders or other diseases. In Mexico there is no epidemiological information about this topic, so we made a retrospective study from 2006 to 2009 in the Dermatology service of the General Hospital of Mexico. We included 730 patients with diagnosis of primary skin cancer; 51 cases occurred in people younger than 40 years with an average age of 38 years, and with an estimated accumulated incidence of 6.8% for the elapsed time. In this study, skin cancer in young people showed a predominance of women (67% of patients); basal cell carcinoma was the most common type. Most of the lesions were found in sun-exposed areas. Skin cancer in people younger than 40 years is increasing dramatically, so we recommend avoiding ultraviolet radiation exposure in childhood and adolescence, and implementing sun-protection campaigns in order to educate this sector of the population and make them more aware of the potential dangers.     

3～6岁儿童抚养人孤独症相关信息知晓现况调查

目的:探讨3～6岁儿童抚养人对孤独症相关信息知晓现状,为开展社区宣传教育提供依据.方法:采用横断面调查方法,在哈尔滨市8个行政区内抽取44所幼儿园,以其中所有3～6岁儿童的主要抚养人作为调查对象.采用自编问卷,从孤独症的症状识别、一般知识了解、病因、就诊态度等多方面评价对孤独症相关知识的知晓现况.共回收合格问卷4947份.结果:样本中,2786人(57.8％)能够准确识别孤独症的症状;3115人(64.8％)认为孤独症属于心理疾病;2484人(68.1％)认为应首选心理门诊就诊;1730人(36.4％)认为孤独症存在特殊能力或才能;2680人(67.0％)认为教育不当是导致孤独症发病的主要原因.多因素分析显示,居住在城市(OR=1.66)、女性(OR=1.34)、接触过孤独症(OR=1.50)、受教育水平较高(OR=2.04、5.39、9.12)的人群能更好的识别孤独症.结论:3～6岁儿童抚养人对孤独症的认识还存在很多误区,有必要积极开展社区宣传教育,提高家长对孤独症认知程度,改变错误认知,以早期识别孤独症儿童.     

Long-term prospective study of recurrent venous thromboembolism in patients younger than 50 years

Long-term incidence of recurrent venous thromboembolism (VTE) in patients younger than 50 years, not affected by a malignancy or chronic diseases, are poorly characterized. After the initial episode of VTE and cessation of oral anticoagulation, 98 patients, mean age 32.2+/-9.2 years were followed for a median of 117 months (range 6-165). Congenital risk factors for VTE were present in 36% of patients, acquired persistent (positive antiphospholipid antibodies during the whole follow-up) in 19%, and acquired transitory in 44%. Thirty episodes of recurrent VTE were documented. The cumulative incidence of VTE after 1 year of follow-up was 5.1%, 9.8% after 2 years, 14% after 4 years, and 34.2% after 8 years. In the univariate analysis, the relative risk of recurrent VTE was 2.66 [95% confidence interval (CI) 1.03-6.90] for congenital risk factors, 4.97 (95% CI 1.75-14.0) for persistent acquired (antiphospholipid antibodies), 2.64 (95% CI 1.23-5.66) for male gender and 2.27(1.00-5.15) for body mass index>30 kg/m2. In the multivariate analysis, male gender [hazard ratio (HR) 4.23, 95% CI 1.88-9.77) the presence of congenital factors (HR 3.28, 95% CI 1.25-8.63) and acquired persistent factors (HR 8.50, 95% CI 2.84-25.50) were independent risk factors for recurrent VTE. In patients under 50 years of age without malignancy or underlying chronic disease, hospitalized for an acute thromboembolic event, the presence of antiphospholipid antibodies, congenital defects of coagulation, male sex, and obesity were risk factors for recurrent VTE. These data raise the possibility that selected patients with VTE may require prolonged anticoagulation to prevent recurrent disease.     

Fabry disease in children and response to enzyme replacement therapy: results from the Fabry Outcome Survey

The Fabry Outcome Survey (FOS) was established to extend the knowledge of the natural history of Fabry disease and to assess the effects of enzyme replacement therapy (ERT) with agalsidase alfa. As of March 2009, 64 boys and 34 girls with Fabry disease had enrolled in the FOS and been treated with agalsidase alfa for at least 6 months. The prevalence of symptoms tended to be reduced after 12 and 24 months of ERT in patients who experienced symptoms at baseline. In the entire population, non-significant decreases in the prevalence of gastrointestinal problems in boys and pain crises in girls were observed after 12-24 months. Kidney function and left ventricular mass indexed to height remained stable. Fifty-eight treatment-related adverse events were reported in 23 patients (21 boys and 2 girls), including 55 infusion reactions. Anti-agalsidase alfa IgG antibodies were found in two boys. No IgE antibodies were reported. This study represents the largest observational study of paediatric Fabry disease patients treated with ERT and indicates continued safety of long-term ERT in children. Continued long-term follow-up is recommended to determine early initiation of ERT, which could potentially slow or prevent the progression of serious morbidities of Fabry disease.     

Long-term,open-labeled extension study of idursulfase in the treatment of Hunter syndrome

PurposeThis study evaluated the safety and effectiveness of long-term enzyme replacement therapy with idursulfase (recombinant human iduronate-2-sulfatase) in patients with Hunter syndrome.MethodsAll 94 patients who completed a 53-week double-blinded study of idursulfase enrolled in this open-labeled extension study and received intravenous idursulfase at a dose of 0.5 mg/kg weekly for 2 years, and clinical outcomes and safety were assessed.ResultsNo change in percent predicted forced vital capacity was seen, but absolute forced vital capacity demonstrated sustained improvement and was increased 25.1% at the end of the study. Statistically significant increases in 6-minute walking test distance were observed at most time points. Mean liver and spleen volumes remained reduced throughout the 2-year extension study. Mean joint range of motion improved for the shoulder and remained stable in other joints. Both the parent- and child-assessed Child Health Assessment Questionnaire Disability Index Score demonstrated significant improvement. Infusion-related adverse events occurred in 53% of patients and peaked at Month 3 of treatment and declined thereafter. Neutralizing IgG antibodies were detected in 23% of patients and seemed to attenuate the improvement in pulmonary function.ConclusionsWeekly infusions of idursulfase result in sustained clinical improvement during 3 years of treatment. Genet Med 2011:13(2):95–101.