Hunter syndrome, also called mucopolysaccharidosis type II (MPSII), is a rare X-linked lysosomal storage disease. Mutations in the IDS gene cause a deficiency in the iduronate 2-sulfatase enzyme, which reduces glycosaminoglycan (GAG) catabolism in lysosomes. Consequently, there is an accumulation of dermatan sulfate and heparan sulfate in the cells of many tissues and organs, and it is this accumulation of GAGs that is responsible for the clinical phenotype of the disease.
The estimated incidence of MPSII in live male newborns is 1:162,000. However, the incidence varies widely in different countries and regions, ranging from 1:49,000 to 1:526,000. Data from the Hunter Outcomes Survey (HOS) Registry show just 45 diagnosed patients in Spain. Since it is an X-linked disorder, there are very few female patients, although some heterozygous female patients develop signs and symptoms of the disease.[4,5]
MPSII is a variable, progressive, and multisystem condition. Traditionally, it has been classified as mild or severe, with the severe subtype characterized by central nervous system (CNS) involvement and poorer survival. However, MPSII is currently described as a continuum of phenotypes that range from attenuated to severe disease.[1,4] Patients may present with facial dysmorphism, hepatosplenomegaly, hernias, musculoskeletal abnormalities, respiratory dysfunction, cardiac abnormalities, carpal tunnel syndrome, CNS involvement, impaired intellect, behavioral disorders, and visual and hearing problems.[1,6] Because of the wide spectrum of clinical presentation and severity of the disease, MPSII management is complex and requires a multidisciplinary approach.[3,4,7] Notably, specific enzyme replacement therapy (ERT) using idursulfase (Elaprase, Shire) became available in 2007. ERT has changed the prognosis and evolution of the disease[9–21] and strengthened the importance of early diagnosis.[1,22]
There are several guidelines for the diagnosis and management of MPSII .[2,5,23,24] The aims of this study were to investigate whether Spanish pediatricians who are experts in managing the disease agreed with current international guidelines regarding MPSII patient diagnosis and follow-up; and to reach a consensus regarding which items are essential for the diagnosis and follow-up of these patients in Spain.
A modified Delphi method was used to obtain expert consensus on the diagnosis and follow-up of MPSII patients in clinical practice in Spain. The Delphi method is a process to reach consensus using sequential questionnaires that are answered anonymously by an expert panel. Among other uses, the Delphi method has been utilized to develop clinical guidelines.
The advisory panel included 5 members of the Hunter Spanish Working Group, a Spanish multidisciplinary team with physicians who are experts in the diagnosis and management of MPSII patients. First, we reviewed a bibliography to determine which topics merited discussion. The Hunter Spanish Working Group published clinical practice guidelines for the management of MPSII in 2013, so the key variables were determined based on the references in that manuscript as well as on studies that were published later. Afterward, we had a face-to-face meeting to choose the questionnaire items and to review the survey online.
Spanish pediatricians with present or past experience with MPSII were invited to participate in the study. The selection criteria were as follows: knowledge of MPSII (publications and participation in scientific meetings), clinical experience (working at a specialized clinic at a reference center), and level of scientific influence. The final questionnaire had 83 items divided into 4 categories: diagnosis, ERT considerations after diagnosis, periodic assessments, and ERT considerations during follow-up. The items were worded to establish the recommendation grade, with 4 possible answers to the “center-stage effect”: 4 (“Strongly agree”), 3 (“Quite agree”), 2 (“Somewhat agree”), and 1 (“Totally disagree”).
The survey was released using a web-based platform that was specifically designed for the study. Weekly reminder emails were sent to 85 selected experts in April and May of 2015. After the response deadline, the medians and means of the response scores were analyzed. The median scores were calculated in order to cancel out the possible influence of extreme and divergent answers. The equivalence between the median scores and the recommendation grades were determined (Table 1).
The advisory panel members reviewed the responses and then held a face-to-face meeting to discuss the results and, where appropriate, to reach a consensus on the recommendations. A second Delphi round was planned in case the responses in the first round were not conclusive.
3.1 First round results
Of the 85 experts that were invited to participate in the survey, 28 (35%) completed the questionnaire. The first round results are shown in Table 2.
3.2 Review of the results
The advisory panel members reviewed the first round results and found a strong consensus for most of the answers (43 of 56 items in “Diagnosis,” 4 of 6 items in “ERT considerations after diagnosis,” 6 of 16 items in “Periodic assessments,” and 3 of 5 items in “ERT considerations during follow-up”). Therefore, there was no need for a second Delphi round.
However, for some items, there was disagreement between the survey results and the advisory panel members that merited further analysis. These items were considered controversial. The decisions about whether to include these items in the final recommendations were based on specific literature searches and on our own experience and opinions. For clarification, these items needed further explanations.
3.2.1 Controversial items related to diagnosis
- Item 20. Lipid profile (Median response: Quite agree). This was a verification/validation item. The lipid profile may be performed, but it is not required.
- Item 30. Intraocular pressure (Quite agree). The measurement of intraocular pressure is not essential, but in some cases in which it seems of clinical interest, it could be performed (if possible in the hospital). In such patients, evaluation of the central corneal thickness is recommended to adequately assess intraocular pressure and possibly coexistent glaucoma. However, glaucoma is rare in MPSII.[27,28]
- Item 31. Oxygen saturation (Quite agree). In uncooperative patients, it is easier to determine this than to have the patient complete the 6-minute walk test (6MWT).
- Item 38. Holter (Somewhat agree). This is another verification/validation item that is not essential in MPSII patients unless it is indicated after a cardiologist evaluation using electrocardiogram (ECG) and echocardiogram (ECC).
- Item 41. Magnetic resonance imaging (MRI) volumetric measurement of the liver and spleen (Quite agree). Abdominal echography is usually performed to measure the liver and spleen volume. However, abdominal MRI can also be performed if anesthesia is not needed or at the same time as a spine MRI.
- Item 46. Spine MRI (Quite agree). MPSII patients show a wide spectrum of brain and spine abnormalities that should be thoroughly assessed. Moreover, white matter atrophy, hydrocephalus, and spinal stenosis might be markers of disease severity for evaluating treatment efficacy. In addition, abnormalities in the cervical spine MRI are common in MPSII, although there are currently no clear correlations between MRI findings and patient phenotype.
- Item 47. Electroencephalography (EEG) (Quite agree). MPSII patients may suffer from seizures during disease evolution. Therefore, it would be useful to get a baseline EEG to compare with later EEGs.
- Item 48. Brain computed tomography (CT) (Somewhat agree). Spanish guidelines recommend brain CT as needed during patient follow-up.[3,5] However, this test should not be performed in children except in emergency situations.
- Item 50. Electromyography (EMG) (Somewhat agree) and 51. Electroneurogram (Somewhat agree). EMG records muscular electric activity and does not provide any useful data in MPSII. In addition, it is a painful test that requires the insertion of needle electrodes. In contrast, electroneurography is important in the diagnosis and follow-up of patients because carpal tunnel syndrome (CTS) is common in MPSII patients.[1,7,24] However, the typical symptoms of median nerve compression are rare in children with other types of mucopolysaccharidoses and more common in those with MPSII.[32,33] These symptoms have an insidious onset and can be hidden by skeletal dysplasia and joint stiffness, thereby delaying the CTS diagnosis. Cognitive impairment may contribute to the lack of a diagnosis. Moreover, CTS can cause behavioral problems in patients with MPSII. Therefore, electroneurography is recommended in patients with MPSII at age 3 to 4 years and every 1 to 2 years thereafter to exclude CTS. Notably, previous studies have reported that all MPSII patients over 2 years old are affected with CTS, mainly pulp atrophy and thenar eminence, thumb weakness, and decreased sweating; less often, there is an alteration in surface sensitivity and trophic changes.[7,24,32] As the compression progresses, there is a functional deficit in thumb functionality that can be very disabling in children older than 3 to 4 years old, depending on its severity. Item 56. Quality of life (QoL) measurement by a patient- and parent/caregiver-completed generic pediatric questionnaire (Quite agree). Several generic questionnaires have been used in MPSII patients and parents/caregivers: the Pediatric Quality of Life Inventory (PedsQL), the Childhood Health Assessment Questionnaire (CHAQ), the Childhood Health Questionnaire (CHQ), and Health Utilities Index (HUI), and the KIDSCREEN questionnaire. However, there is also a patient- and parent/caregiver-completed disease-specific instrument, the Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) Questionnaire. The shortened version has 6 domains (walking/standing, grip/reach, school/work, activities, breathing, and overall function score) and 18 items (patient) or 21 items (parents).[36,38]
3.2.2 Controversial items related to periodic assessments
- Item 3. Complete assessment, including complementary tests, every 12 months during the first 2 years after the diagnosis (Quite agree). Published guidelines do not recommend complete assessment every 12 months during the first 2 years.[2–5]
- Item 4. Every 6 months, only clinical assessment (only case history and physical exam) (Somewhat agree). The advisory panel concluded that clinical assessment alone is inadequate.
- Item 5. Further testing according to clinical signs and symptoms (Totally disagree). This item was rejected because of its lack of specificity.
- Item 6. Periodic further testing according to patient age, independent of disease severity (Quite agree). Several manifestations of MPSII usually appear after age 5 years, including CTS, cardiac valve involvement, retinal dysfunction, respiratory failure, hydrocephalus, seizures, and spinal cord compression.[3,5] Therefore, there is a series of tests that should be performed in all patients who are at least 5 years old.
- Item 7. Further testing according to disease severity (Quite agree). Further testing may be needed for some conditions, such as chest radiography and/or bronchoscopy for pulmonary problems or polysomnography if apnea occurs. In case of rapid progression, more frequent assessments are recommended.
- Item 10. Periodic polysomnography (Quite agree). Obstructive sleep apnea and impaired gas exchange during sleep are common in patients with MPSII. Polysomnography should be performed at baseline and should be repeated in case of sleep apnea or nocturnal snoring.
- Item 11. Periodic cervical MRI (Quite agree). Abnormalities on the cervical spine MRI are common in MPSII.
- Item 12. Periodic electroneurography (Somewhat agree). As noted above, electroneurography helps detect CTS.
- Item 15. Periodic measurement of antibody titer (Quite agree). The advisory panel agreed that periodic measurements of serum IgG anti-idursulfase antibodies could be useful in the future.
- Item 16. Periodic GAG measurement (Quite agree). ERT reduces urine GAG excretion, so this should be monitored.[4,24]
3.3 Recommendations for the diagnosis and follow-up of patients with MPSII
A series of recommendations for the diagnosis and follow-up of patients with MPSII was developed based on the results of this Delphi survey, on the bibliographical review, and on the clinical experience and opinions of the advisory panel (Table 3). An MPSII expert should be involved both at the first assessment and at the periodic follow-up visits.
3.4 Recommendations for ERT
Recommendations regarding ERT were developed based on the results of this study.
3.4.1 After diagnosis
- Early ERT can change the course of the disease.
- Oral and written information about ERT should be provided to the patient and/or to parents or caregivers regarding the consequences of ERT therapy, the possible effects, and situations in which it should be discontinued.
- Initiate ERT in patients with mild disease.
- Initiate ERT in patients with severe phenotype.
- Do not initiate ERT in patients with very severe neurological disease since ERT will not improve their disease state.
- Provide genetic counselling and screening to female relatives of patients who are at risk of being carriers.
3.4.2 During follow-up
- Do not discontinue ERT in patients with mild disease.
- ERT should be reassessed periodically in patients with severe disease.
- Adult reference centers should continue patient care.
- Regional/national expert committees should assess ERT indications and follow-up on the use of ERT.
This is the first Delphi study carried out with Spanish pediatricians with experience in MPSII patient diagnosis and/or management of such pediatricians.
One limitation of this study was due to the organization of the Spanish National Health System and the absence of reference centers in Spain. However, during the course of this research and despite the decentralization of patients throughout Spain, we observed little disagreement between international guidelines for the diagnosis and follow-up of patients with MPSII and the opinions and clinical practices of clinicians in Spain.
As the clinical manifestations of MPSII affect multiple systems,[3,16,24], it is important to routinely assess various affected organs and systems, and each specialist should be included in the multidisciplinary team and should oversee continuing evaluations once a clinical problem is identified. Accordingly, the recommendations for the diagnosis and follow-up of patients with MPSII described here include the involvement of an expert in MPSII both at the first assessment and at the periodic follow-up visits, in order to provide advice.
Based on the results of Delphi survey, the bibliographical review, and the clinical experience and opinions of the advisory panel, a consensus was reached and a series of recommendations for the diagnosis and follow-up of patients with MPSII were developed. In terms of the controversial items related to diagnosis, it is notable that brain CT is not recommended in children, except in emergency situations, due to the difficulties associated with anesthesia. Also, experience with MPSII patients has shown that electroneurography is important for the diagnosis and follow-up of patients with this syndrome because CTS is common and very disabling in MPSII patients 3 to 4 years old or older.[1,7,23,24] This type of recommendation might be known by experts but not by all pediatricians.
The controversy regarding periodic assessments is based on the classification of patients by age and disease severity. Several manifestations of MPSII typically appear after age 5. The multidisciplinary team should consider age, the disease severity and complications, which may vary not only between phenotypes but also within members of the same family, in order to decide which tests should be performed.
There were no controversial issues regarding ERT initiation/cessation in MPSII patients. They were in agreement with the recommendations of Muenzer et al and with other MPSII guidelines, which note that an improvement in quality of life as perceived by the family of a patient with severe disease should be considered a benefit of ERT treatment. Moreover, the expert panel noted that the benefits of early treatment with ERT have been clearly demonstrated by HOS data[12,13] as well as by studies of siblings who were diagnosed and treated at different ages. This highlights the importance of genetic counselling and prenatal diagnosis. Moreover, this consensus reflects the fact that the course of MPSII has been changed by ERT, and adult reference centers should be identified that can provide continued patient care. Supporting this idea, a series of recommendations were recently published for the best clinical management of the transitions of care of patients with inborn errors of metabolism.
In conclusion, this study illustrates the usefulness of a modified Delphi method applied to clinical guidelines and provides extended recommendations for the diagnosis, management, and treatment of MPSII patients. These might be useful not only to pediatricians but also to other clinicians that are involved in the management of these patients.
LGGS was the coordinator of the expert panel. All authors reviewed the bibliography, developed the questionnaire, selected the experts, and reviewed the results. All authors edited, reviewed, and critically revised the manuscript and approved the final version.
Conceptualization: Luis González-Gutiérrez-Solana, Encarna Guillén-Navarro, Mireia del Toro, Jaime Dalmau, Antonio González-Meneses, María Luz Couce.
Data curation: Luis González-Gutiérrez-Solana, Encarna Guillén-Navarro, Mireia del Toro, Jaime Dalmau, Antonio González-Meneses, María Luz Couce.
Formal analysis: Luis González-Gutiérrez-Solana, Encarna Guillén-Navarro, Mireia del Toro, Jaime Dalmau, Antonio González-Meneses, María Luz Couce.
Investigation: Luis González-Gutiérrez-Solana, Encarna Guillén-Navarro, Mireia del Toro, Jaime Dalmau, Antonio González-Meneses, María Luz Couce.
Methodology: Luis González-Gutiérrez-Solana, Encarna Guillén-Navarro, Mireia del Toro, Jaime Dalmau, Antonio González-Meneses, María Luz Couce.
Supervision: Luis González-Gutiérrez-Solana.
Writing – original draft: Luis González-Gutiérrez-Solana, Encarna Guillén-Navarro, Mireia del Toro, Jaime Dalmau, Antonio González-Meneses, María Luz Couce.
Writing – review & editing: Luis González-Gutiérrez-Solana, Encarna Guillén-Navarro, Mireia del Toro, Jaime Dalmau, Antonio González-Meneses, María Luz Couce.
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