- Email: [email protected]
Characterization of Surgical Procedures in Patients with Mucopolysaccharidosis Type I: Findings from the MPS I Registry
Characterization of Surgical Procedures in Patients with Mucopolysaccharidosis Type I: Findings from the MPS I Registry PAMELA ARN, MD, J. EDMOND WRAITH, MB, CHB,
AND
LISA UNDERHILL, MS
Objective
To clarify the extent and chronology of surgical burden in relation to symptom onset and diagnosis in patients with mucopolysaccharidosis I (MPS I) as reported in the MPS I Registry, an international observational database. Study design Analysis of surgical data from 544 patients enrolled in the MPS I Registry. Among all patients with at least 1 reported surgery, the number and frequency of procedures, and age at procedure, diagnosis, and symptom onset were collected overall, by patient, and by reported phenotype (Hurler, Hurler-Scheie, Scheie). Results Overall and by phenotype, ⬃75% of patients in the MPS I Registry reported at least 1 surgery. The most common were myringotomies and related procedures, hernia repair, adenoidectomy/tonsillectomy, and carpal-tunnel release. Median age at first surgery was <5 years. A median of 3 to 4 surgeries was reported per patient. By age 1.5, 4, and 10 years, respectively, 22%, 44%, and 54% of patients reported >2 surgeries. At least 1 surgery preceded diagnosis in 36%, 46%, and 63% of patients with Hurler, Hurler-Scheie, and Scheie, respectively. Conclusions Pediatricians and pediatric surgeons need to be aware of the surgical burden of MPS I and be alert to its presenting signs and symptoms in children scheduled for surgery. (J Pediatr 2009;154:859-64)
ucopolysaccharidosis type I (MPS I ) is caused by deficiency of the lysosomal enzyme ␣-L-iduronidase,1 causing accumulation of its major substrates, the glycosaminoglycans dermatan and heparan sulfate, in lysosomes, resulting in progressive multisystem tissue and organ dysfunction, including respiratory, cardiac, and musculoskeletal manifestations. MPS I encompasses a spectrum of disease with variable age of onset, progression, and organ involvement. Patients have been divided into 3 clinical phenotypes: Hurler, Hurler-Scheie, and Scheie syndromes. At one end of the spectrum, “Hurler” denotes patients with onset in infancy, rapid progression, mental retardation, and life expectancy of less than 10 years. “Hurler-Scheie” denotes patients with an intermediate phenotype consisting of onset in childhood, little or no cognitive impairment, and a life expectancy of approximately 25 years. “Scheie” denotes From The Nemours Children’s Clinic (P.A.), Jacksonville, FL; Willink Biochemical patients with onset in later in childhood, no cognitive impairment, and slower somatic Genetics Unit (J.W.), Royal Manchester progression. Alternatively, the term “severe MPS I” is used to describe patients with early Children’s Hospital, Manchester, United Kingdom; and Genzyme Corporation onset and rapidly progressive disease and “attenuated MPS I” is used to describe patients (L.U.), Global Medical Affairs, Cambridge, with a more variable and protracted disease course. MA. Diagnosis of MPS I is often delayed due to lack of recognition and the nonspecific Supported by Genzyme Corporation. P.A. receives honoraria for presentations and nature of some of the early manifestations. With improved protocols for hematopoietic board meetings, travel expenses to meetstem cell transplantation and the availability of enzyme replacement therapy with laroniings, and paid and unpaid consultancy work 2-6 dase (recombinant human ␣-L-iduronidase), prompt diagnosis of MPS I has assumed from Genzyme. J.W. receives honoraria for presentations and board meetings, travel new importance. expenses to meetings, and paid and unpaid The MPS I Registry (www.mpsiregistry.com) is an observational, voluntary disease consultancy work and has been a principal investigator in Genzyme-sponsored clinical registry program initiated in June 2003 by BioMarin/Genzyme LLC and currently trials. L.U. is an employee of Genzyme Corsupported by Genzyme Corporation. Its purpose is to track the clinical onset, symptoms, poration, Global Medical Affairs. and outcomes of confirmed patients with MPS I, regardless of disease severity or Submitted for publication Aug 19, 2008; last revision received Oct 23, 2008; actreatment status, by capturing information prospectively and retrospectively from routine cepted Dec 10, 2008. clinical and laboratory assessments.7 Information regarding surgical procedures is colReprint requests: Dr Pamela Arn, Departlected on all patients. Using data from the MPS I Registry, we sought to clarify the extent ment of Pediatrics, The Nemours Chil-
M
CNS ERT
Central nervous system Enzyme replacement therapy
HSCT MPS I
Hematopoietic stem cell transplantation Mucopolysaccharidosis type I
dren’s Clinic, 807 Children’s Way, Jacksonville, FL 32207. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright © 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2008.12.024
859
Table II. Characteristics of patients in the MPS I Registry who reported at least 1 surgical procedure Reported phenotype Hurler (n ⴝ 235)
Hurler-Scheie (n ⴝ 100)
Scheie (n ⴝ 45)
Overall* (n ⴝ 391)
7.7 (4.1, 11.5) 131:104 75, 32%
14.1 (8.5, 22.3) 52:48 9, 9%
21.0 (16.6, 33) 19:26 1, 2%
9.4 (5.8, 17.2) 209:182 85, 22%
85, 36% 72, 31% 30, 13% 48, 20%
3, 3% 82, 82% 1, 1% 14, 14%
1, 2% 37, 82% 0 7, 16%
91, 24% 198, 51% 31, 8% 71, 18%
Characteristic Median age in years at last data entry (25th, 75th percentiles) Male to female ratio Deceased (n, %) Treatment status HSCT (n, %) ERT (n, %) HSCT and ERT (n, %) No treatment (n, %) HSCT, hematopoietic stem cell transplantation; ERT, enzyme replacement therapy. *“Overall” includes 61 patients whose phenotype was undetermined or missing.
and chronology of surgical burden in patients with MPS I, regardless of treatment status, in relation to diagnosis and symptom onset.
METHODS Patient information collected in the MPS I Registry is submitted voluntarily by physicians after obtaining approval from their institutional investigational review board or ethics committee and written consent from patients or their parents/ guardians. All patient data are de-identified and entered by participating sites in accordance with applicable privacy regulations. At enrollment, detailed medical histories and baseline data are collected and physicians are encouraged to follow a recommended schedule of clinical assessments and to report regularly the results of those assessments.7 Because the MPS I Registry is an observational database, the time frame of observation for each patient varies and can encompass any interval from birth until the most recent data entry. Surgical procedures can be entered as free text and documented both in the patient’s medical history at enrollment and subsequently in specific Clinical Event forms. For this analysis, the data download from October 2006 was used. All surgical data were collected from a free text field. Related terms and procedures were classified by a team of physicians into 21 categories from a starting list of 1133 different descriptions of 1694 recorded interventions (Table I; available at www.jpeds.com). To restrict the dataset to surgeries that were most likely to be related to underlying disease, procedures directly related to stem cell transplantation or laronidase treatment (eg, bone marrow harvest or port-a-cath placement) were excluded. Also excluded were exam procedures (eg, biopsies, bronchoscopy). To capture the surgical burden of MPS I, the number of patients from the Registry who reported at least 1 surgery were determined overall, by reported phenotype, and for the following surgical categories: myringotomies and related procedures, adenoidectomy and tonsillectomy, tracheostomy, nasal and sinus procedures, upper airway interventions, corneal transplant procedures, eye interventions, cardiac valve procedures, hernia repair, genitourinary procedures, gastric inter860
Arn, Wraith, and Underhill
ventions and feeding tubes, tendon release and trigger fingers, orthopedic surgery, carpal tunnel, spinal procedures, ventriculoperitoneal shunt, oral surgical interventions, removal/ revision of inserted material, and other (Table I). Among the subset of patients enrolled in the Registry who reported at least 1 surgery, the following demographic data were collected: age at last data entry, reported phenotype, race, sex, and treatment status. When a patient is enrolled in the registry, the enrolling physician enters all pertinent data collected prior to enrollment retrospectively; going forward, data are entered. For each surgical category, the following data were collected: number of procedures reported overall, number and proportion of procedures by phenotype, patient’s age at first surgery (overall and for each specific procedure), age at procedure versus age at diagnosis, number of procedures of each type by patient, and the frequency of repeated procedures overall for each surgical category and among individual patients.
RESULTS Overall Surgical Burden As of October 2006, the MPS I Registry contained data on 544 patients, of whom 391 (72%) had reported a total of 1694 surgical procedures (Table I). Surgical burden was spread evenly across phenotypes; over 70% of patients in each phenotypic group reported at least 1 surgery (Figure 1; available at www.jpeds.com). Table II lists the demographic characteristics of the 391 patients who reported at least 1 surgery. Overall and by phenotype, patients with surgeries reported a mean of 3 to 4 surgeries apiece (median: 4; range: 1 to 23). By age 4, almost half of all patients had reported 2 or more surgeries (Figure 2). Types of Surgery Figure 3 shows the most frequent categories of surgeries performed in patients with MPS I overall and by disease phenotype in the total Registry population. Ear, nose, and throat surgeries were the most frequent (43% of total), followed by abdominal/genitourinary surgery (21%) and orthopedic surgeries (19% of total) (Figure 4; available at www.jpeds.com). The Journal of Pediatrics • June 2009
Figure 2. Most frequently reported surgeries. The percentage of patients reporting surgeries in each category is shown by phenotype. Also shown is the percentage of patients overall who reported any type of surgery. Shown are the surgical categories for which at least 10% of patients overall or in any phenotypic group reported surgeries. “Other” denotes all surgeries not represented in any other category and includes appendectomy, cholecystectomy, pacemaker placement, and patent ductus arteriosus (Table I).
In patients with Hurler, the most common surgeries were myringotomies and related procedures (Table I), hernia repair, adenoidectomy and tonsillectomy, and ventriculoperitoneal shunt, each reported for 57%, 45%, 37%, and 11% of patients, respectively. In patients with Hurler-Scheie, myringotomies and related procedures and hernia repair were both reported in 40% of patients, adenoidectomy and tonsillectomy in 37% of patients, and spinal procedures in 14% of patients. In patients with Scheie, the most common surgical category was carpal tunnel (in 43% of patients), followed by hernia repair (36% of patients), adenoidectomy and tonsillectomy (31% of patients), and orthopedic surgeries of the hip, knee, and foot (20% of patients).
Relation Between Symptom Onset, Diagnosis, and First Surgery Thirty-six percent of patients with Hurler, 46% of patients with Hurler-Scheie, 63% of patients with Scheie, and
41% of patients overall had at least one surgery before they were diagnosed with MPS I (Figure 5; available at www. jpeds.com). Among patients with surgery before diagnosis, the gap between the first surgery and the diagnosis of MPS I was 6 months for patients with Hurler, 2 years for patients with Hurler-Scheie, and 6.6 years for patients with Scheie (Figure 6; available at www.jpeds.com). Figure 2 shows the median age of first surgery among the most common surgical categories. For patients with Hurler, most first surgeries in a given surgical category occurred before age 5. For patients with Hurler Scheie and Scheie, only hernia repair, myringotomies and related procedures, and adenoidectomy/tonsillectomies commonly first occurred before age 5.
Type of Surgery in Relation to Diagnosis Surgeries sometimes occurred before diagnosis in all but 4 surgical categories (oral surgical interventions, nasal and
Characterization of Surgical Procedures in Patients with Mucopolysaccharidosis Type I: Findings from the MPS I Registry
861
Figure 3. Proportion of patients with 2 or more surgeries by age. Shown are the proportion of patients by reported phenotype and overall who reported 2 or more surgeries by the ages. Percentages are determined based on the number of patients who survived to at least the age specified.
sinus procedures, tracheostomy, and upper airway interventions). The surgeries that most frequently were performed before diagnosis are shown in Figure 7. Over one third (39%) of all patients who had hernia repair surgery, 22% of patients who had ventriculoperitoneal shunts, 21% of patients who had adenoidectomy and tonsillectomies, and 19% of patients who had myringotomies and related procedures first had these procedures before they were diagnosed with MPS I. In addition, for the following less commonly performed surgeries, a high proportion of the patients who had these procedures had them before diagnosis: genital and urinary procedures (52%); eye interventions (39%); others (Table I) (25%); tendon release and trigger fingers (22%); ventriculoperitoneal shunt (23%) and cardiac valve procedures (21%).
DISCUSSION This analysis confirms that patients with MPS I across the phenotypic spectrum frequently require surgical interventions for a range of disease manifestations. Children with MPS I have a very high frequency of common childhood surgeries, such as ear tube procedures, hernia repair, and adenoidectomy and tonsillectomy and also have surgeries that are uncommon in childhood, such as carpal tunnel surgery. Most children with MPS I have several apparently unrelated surgeries in early childhood. Often, surgeries precede diagnosis, especially among patients with Hurler-Scheie and Scheie. Because all data collected in the MPS I Registry are collected voluntarily, the actual surgical burden associated with MPS I may be underestimated. This supposition is supported by higher rates of surgery among the patients with MPS I who participated in a recent clinical trial of enzyme replacement therapy with laronidase. These 45 patients all had Hurler-Scheie or Scheie phenotypes and ranged in age from 6 to 43 (mean age, 15.5 years). At baseline, hernia repair was reported in 74% of patients, adenoidectomy-tonsillectomy in 67% of patients, myringotomies in 47% of patients, carpal tunnel surgery in 20%, and ventriculoperitoneal shut 862
Arn, Wraith, and Underhill
placement in 11% of patients (Genzyme data on file). Except for carpal tunnel surgery, these prospectively reported surgery rates are all higher than what we found among patients with Hurler-Scheie and Scheie in the MPS I Registry. The surgical disease burden we identify does not take into account examination procedures, many of which require anesthesia and are recommended on a regular basis to assess disease progression and/or response to treatment. Similarly, we excluded surgical procedures related to treatment, such as port-a-cath placement for enzyme replacement infusions and bone marrow harvesting for hematopoietic stem cell transplantation. Although these procedures are not directly related to clinical manifestations of MPS I, they do also contribute very significantly to the overall burden of surgery experienced by most patients with MPS I. Myringotomies and related procedures, adenoidectomy and tonsillectomy, and hernia repair are the three most common surgeries in children with MPS I and are the 3 most common surgeries among the general pediatric population.8 However, among our MPS I Registry cohort, each of these surgeries is reported in at least one third of patients overall— obviously, a greatly increased frequency compared with that of the general population. In addition, the age at which these surgeries typically occur may differ from the general pediatric population. The mean age of adenoidectomy/ tonsillectomy in the United States is 7 years,8 whereas among the MPS I Registry population, the median age is 2.8 years (Hurler: 2.2; Hurler-Scheie: 4.1, and Scheie: 4). The earlier age for adenoidectomy and tonsillectomy presumably reflects diseaserelated upper airway obstruction. Conversely, hernia surgery, and especially inguinal hernia surgery, often occurs at a later age in patients with MPS I than is typical in the general population. Most inguinal hernia surgeries in children occur before 1 year of age,9 whereas in MPS I, hernia surgery (all types as well as inguinal hernia specifically) is most common in toddlers and older children; the median overall age at hernia surgery is 2.5 years (Hurler: 1.8; Hurler-Scheie: 4.2; and Scheie: 6.2). With respect to inguinal hernia surgery alone, 52% of these procedures occurred in children age 1 year and older. The broader age range of children undergoing hernia surgery, as well as the overall high frequency of hernia surgery (and of repeat procedures), presumably reflects the high incidence of acquired rather than congenital hernia due to progressive hepatosplenomegaly, increased intra-abdominal pressure, and weakened abdominal muscles and connective tissue, all common early manifestations of MPS I disease. Carpal tunnel surgery is unusually common among children with MPS I. In fact, MPS disorders are one of the most common causes of carpal tunnel syndrome in children and adolescents.10,11 In our Registry population, carpal tunnel surgery was among the top 5 surgeries reported by all phenotypes, and was the most frequent surgery reported among patients with Scheie, occurring in 43% of patients with Scheie overall. The Journal of Pediatrics • June 2009
Figure 7. Surgeries most frequently performed before diagnosis. Shown are the surgeries most frequently performed before diagnosis by the number of surgeries overall. “Other” denotes all surgeries not represented in any other category and includes appendectomy, cholecystectomy, pacemaker placement, and patent ductus arteriosus (Table I).
Our present data delineates the scope of surgeries and confirm that a significant number of surgeries are reported before diagnosis (Figure 5), as noted in an earlier report from the MPS I Registry7 as well as in the recent analysis of Vieira et al12 exploring the path to diagnosis among patients with MPS in Brazil. Of the 18 patients with MPS I included in the Brazil study, 13 patients (72%) had a total of 25 surgeries (inguinal herniorrhaphy, umbilical herniorrhaphy, adenoidectomy, tonsillectomy, ear tube placement, orthopedic surgery, and other) before biochemical diagnosis of MPS I. Our data show that surgeries sometimes precede even the recognition of the earliest symptoms of MPS I. Delayed diagnosis is usually due to lack of disease awareness and/or the nature of early symptoms, which can be subtle and/or nonspecific. This is particularly true of the Hurler-Scheie and Scheie forms of the disease, which can elude diagnosis for years or decades; not surprisingly, the proportion of surgeries performed prior to diagnosis increased as the phenotype became more attenuated. Thus, physicians have an important opportunity to recognize the disease symptoms when a surgery is scheduled. Earlier disease recognition not only enables intervention before irreversible disease manifestations occur but also alerts surgeons and anesthesiologists to the anesthetic risk posed by most patients with MPS I due to the possibility of compromised airways.13-16 To increase the likelihood of prompt diagnosis of MPS I, we recommend that surgeons and pediatricians check for early signs and symptoms that may suggest a lysosomal storage disorder (Table III; available at www.jpeds.com) in any child who has surgical procedures at a particularly young age (or inguinal hernia surgery beyond age 1 year), multiple surgical procedures, or procedures that are uncommon in
children. Symptoms such as progressively coarsening facial features, corneal clouding, tongue enlargement, joint stiffness, recurrent otitis media, and unexplained cardiomyopathy are suggestive of an MPS disorder.17 The presence of a gibbus deformity, enlarged tongue, and/or 2 or more surgeries before age 18 months should prompt investigations for mucopolysaccharidosis or other storage disorders. In older children, claw hand, cardiac problems, and/or 2 or more surgeries before age 10 should raise the suspicion of an attenuated form of MPS I. Any patient with a suspected lysosomal storage disorder should be referred to a geneticist for further evaluation and potential diagnosis based on deficient enzyme activity. It is unclear whether or not hematopoietic stem cell transplantation or treatment with laronidase will alter the pattern or frequency of surgical intervention in patients with MPS I. At present, the MPS I Registry does not have sufficient longitudinal data to evaluate the effects of treatment on rates of surgery, but this will be an important area of investigation going forward as the patient database matures. Surgical and anesthetic complications, particularly in light of the number of procedures performed prior to diagnosis, are also areas that merit future analyses. We thank Gregory Fagan, Jessica Kong, Lakshmi Rangachari, and Marisa Sidman (Biomedical Operations, MPS I Registry, Genzyme) for expert biostatistical analyses and Gerald Cox, MD, PhD (Genzyme Clinical Research, Harvard Medical School, Children’s Hospital, Boston), Catherine Koepper (Genzyme Global Registries), Katherine Lewis (Biomedical Operations, Genzyme), and Vinciane Pirard, MD (Genzyme Global Medical Affairs) for critical review of the manuscript. Finally, we are grateful to the patients with MPS I and their physicians who provide data to the MPS I Registry.
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REFERENCES 1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver C, Beaudet A, Sly W, Valle D, Childs B, Kinzler K, et al, editors. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw Hill; 2001. p. 3421-52. 2. Boelens JJ, Wynn RF, O’Meara A, Veys P, Bertrand Y, Souillet G, et al. Outcomes of hematopoietic stem cell transplantation for Hurler’s syndrome in Europe: a risk factor analysis for graft failure. Bone Marrow Transplant 2007;40:225-33. 3. Peters C, Steward CG. Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelines. Bone Marrow Transplant 2003;31:229-39. 4. Wraith JE. The first 5 years of clinical experience with laronidase enzyme replacement therapy for mucopolysaccharidosis I. Expert Opin Pharmacother 2005;6:489-506. 5. Wraith JE, Beck M, Lane R, Van der Ploeg AT, Shapiro E, Xue Y, et al. Enzyme replacement therapy in patients who have mucopolysaccharidosis I and are younger than 5 years: results of a multinational study of recombinant human alpha-L-iduronidase (laronidase). Pediatrics 2007;120:e37-e46. 6. Wraith JE, Clarke LA, Beck M, Kolodny EH, Pastores GM, Muenzer J, et al. Enzyme replacement therapy for mucopolysaccharidosis, I: a randomized, doubleblinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). J Pediatr 2004;144:581-8. 7. Pastores G, Arn P, Beck M, Clarke J, Guffon N, Kaplan P, et al. The MPS I registry: design, methodology, and early findings of a global disease registry for monitoring patients with mucopolysaccharidosis type I. Mol Genet Metab 2007;91:37-47.
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8. Russo C, Owens P, Steiner C, Josephsen J. Ambulatory Surgery in US Hospitals, 2003. HCUP Fact Book No. 9. Agency for Healthcare Research and Quality, 2007. AHRQ Publication No. 07-0007. ISBN 1-58763-228-4. 9. Primatesta P, Goldacre MJ. Inguinal hernia repair: incidence of elective and emergency surgery, readmission and mortality. Int J Epidemiol 1996;25:835-9. 10. Lamberti PM, Light TR. Carpal tunnel syndrome in children. Hand Clin 2002;18:331-7. 11. Van Meir N, De Smet L. Carpal tunnel syndrome in children. Acta Orthop Belg 2003;69:387-95. 12. Vieira T, Schwartz I, Munoz V, Pinto L, Steiner C, Ribeiro M, et al. Mucopolysaccharidoses in Brazil: what happens from birth to biochemical diagnosis? Am J Med Genet A 2008;146A:1741-7. 13. Baines D, Keneally J. Anaesthetic implications of the mucopolysaccharidoses: a fifteen-year experience in a children’s hospital. Anaesth Intensive Care 1983;11: 198-202. 14. Walker R, Darowski M, Morris P, Wraith J. Anaesthesia and mucopolysaccharidoses: a review of airway problems in children. Anaesthesia 1994;49:1078-84. 15. Moores C, Rogers JG, McKenzie IM, Brown TC. Anaesthesia for children with mucopolysaccharidoses. Anaesth Intensive Care 1996;24:459-63. 16. Brambrink AM, Braun U. Airway management in infants and children. Best Pract Res Clin Anaesthesiol 2005;19:675-97. 17. Wilcox WR. Lysosomal storage disorders: the need for better pediatric recognition and comprehensive care. J Pediatr 2004;144:S3-14.
The Journal of Pediatrics • June 2009
Table I. Description of surgical categories by organ system Organ system ENT
Eye Cardiac Abdominal and genitourinary
Category of surgery Myringotomies and related procedures Adenoidectomy and tonsillectomy Tracheostomy Nasal and sinus procedures Upper airway interventions Corneal transplant procedures Eye interventions Cardiac valve procedures Hernia repair Genitourinary procedures
Orthopedic
Gastric interventions and feeding tubes Tendon release and Trigger fingers Orthopedic surgery Carpal tunnel Spinal procedures
Neurologic
Ventriculoperitoneal shunt
Other
Oral surgical interventions Others Removal/revision of inserted material
Includes
n (%) (N ⴝ 1694)
PE, grommet, and T-tube placement and adjustment
415 (24.5)
Both or either procedure
261 (15.4) 24 (1.4) 19 (1.1) 13 (0.8)
Polyp removal, sinus drainage, and outfracture of inferior turbinates Pharyngeal surgery, laryngeal, tracheal, and soft palate surgery, epiglottoplasty, palatectomy, uvulectomy, vocal cord reduction Surgeries related to strabismus, cataract, glaucoma Aortic and mitral valve replacement and reconstruction Repair of umbilical hernia and bilateral, left, and right inguinal hernia Non-neonatal circumcisions, fixation of right testicle, hydrocele repair, hypospadias repair, hysterectomy, phimosis repair, posthetomy, testis ectopia Gastric fistula dilatation, hiatal hernia repair Achilles, hamstring, and flexor tendon release Hip, knee and foot surgery; osteotomy, stapling, derotation, joint replacement, epiphysiodesis Surgery for all peripheral nerve entrapment Orthopedic and neurologic interventions, cervical fusion and laminectomy, decompression Placement of subdural, peritoneal, ventriculoperitoneal, and lumboperitoneal shunts Tooth extraction, repair, and restoration, mandibular cyst removal Appendectomy, cholecystectomy, pacemaker placement, patent ductus arteriosus, etc Removal of grommets, pressure equalizer tubes, T-tubes, hip plates and pins, knee staples
Characterization of Surgical Procedures in Patients with Mucopolysaccharidosis Type I: Findings from the MPS I Registry
29 (1.7) 26 (1.5) 20 (1.2) 297 (17.5) 28 (1.7)
26 (1.5) 103 (6.1) 91 (5.4) 84 (5.0) 43 (2.5) 85 (5.0%) 51 (3.0) 44 (2.6) 35 (2.0)
864.e1
Table III. Physical signs and symptoms suggestive of an MPS I disorder* ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Macrocephaly Coarse facial features† Macroglossia Thick, coarse hair Hepatomegaly with umbilical or inguinal hernias and prominent abdomen Corneal clouding Recurrent otitis media Chronic rhinitis Upper airway obstruction with snoring and/or sleep apnea Cardiomyopathy Cardiac valve disease Kyphosis of lumbar spine (gibbus) Contractures and joint stiffness Spinal cord compression Short stature
*All signs and symptoms may be seen in both severe (Hurler) and attenuated (HurlerScheie and Scheie) forms of MPS I. Clinical presentation is heterogeneous and not all symptoms are seen in any given patient. †Facial features tend to be more subtle in more attenuated forms of MPS I and patients are more likely to present with other symptoms.
Figure 4. Proportion of surgeries by organ system. Shown is the distribution of all 1694 surgeries recorded in the study population (n ⫽ 391) by organ system (Table I).
Figure 5. Proportion of surgeries occurring before diagnosis. The percentage of patients who reported at least 1 surgery before diagnosis and the proportion of surgeries overall that were reported before diagnosis are shown by phenotype and overall. Figure 1. Patients in the MPS I Registry reporting surgery. Shown are the number and proportion of patients in the MPS I Registry by phenotype and overall who have reported at least 1 surgical procedure. The “Total” column includes 61 patients for whom the phenotype was unknown. All data are from the October 2006 Registry download (n ⫽ 544).
864.e2
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The Journal of Pediatrics • June 2009
Figure 6. Chronology of symptom onset, diagnosis, and surgery. The relation between the median age at which symptoms were first recorded, median age of diagnosis, median age at first surgery that occurred before diagnosis (among patients who had surgery before diagnosis), and the mean patient age at all reported surgeries are shown by reported phenotype. The gap between symptoms and diagnosis is 3 months for patients with Hurler, 1.6 years for patients with Hurler Scheie, and 4.3 years for patients with Scheie. The gap between surgery and diagnosis is 5 months for patients with Hurler, 2 years for patients with Hurler-Scheie, and 6.5 years for patients with Scheie.
Characterization of Surgical Procedures in Patients with Mucopolysaccharidosis Type I: Findings from the MPS I Registry
864.e3
AND
LISA UNDERHILL, MS
Objective
To clarify the extent and chronology of surgical burden in relation to symptom onset and diagnosis in patients with mucopolysaccharidosis I (MPS I) as reported in the MPS I Registry, an international observational database. Study design Analysis of surgical data from 544 patients enrolled in the MPS I Registry. Among all patients with at least 1 reported surgery, the number and frequency of procedures, and age at procedure, diagnosis, and symptom onset were collected overall, by patient, and by reported phenotype (Hurler, Hurler-Scheie, Scheie). Results Overall and by phenotype, ⬃75% of patients in the MPS I Registry reported at least 1 surgery. The most common were myringotomies and related procedures, hernia repair, adenoidectomy/tonsillectomy, and carpal-tunnel release. Median age at first surgery was <5 years. A median of 3 to 4 surgeries was reported per patient. By age 1.5, 4, and 10 years, respectively, 22%, 44%, and 54% of patients reported >2 surgeries. At least 1 surgery preceded diagnosis in 36%, 46%, and 63% of patients with Hurler, Hurler-Scheie, and Scheie, respectively. Conclusions Pediatricians and pediatric surgeons need to be aware of the surgical burden of MPS I and be alert to its presenting signs and symptoms in children scheduled for surgery. (J Pediatr 2009;154:859-64)
ucopolysaccharidosis type I (MPS I ) is caused by deficiency of the lysosomal enzyme ␣-L-iduronidase,1 causing accumulation of its major substrates, the glycosaminoglycans dermatan and heparan sulfate, in lysosomes, resulting in progressive multisystem tissue and organ dysfunction, including respiratory, cardiac, and musculoskeletal manifestations. MPS I encompasses a spectrum of disease with variable age of onset, progression, and organ involvement. Patients have been divided into 3 clinical phenotypes: Hurler, Hurler-Scheie, and Scheie syndromes. At one end of the spectrum, “Hurler” denotes patients with onset in infancy, rapid progression, mental retardation, and life expectancy of less than 10 years. “Hurler-Scheie” denotes patients with an intermediate phenotype consisting of onset in childhood, little or no cognitive impairment, and a life expectancy of approximately 25 years. “Scheie” denotes From The Nemours Children’s Clinic (P.A.), Jacksonville, FL; Willink Biochemical patients with onset in later in childhood, no cognitive impairment, and slower somatic Genetics Unit (J.W.), Royal Manchester progression. Alternatively, the term “severe MPS I” is used to describe patients with early Children’s Hospital, Manchester, United Kingdom; and Genzyme Corporation onset and rapidly progressive disease and “attenuated MPS I” is used to describe patients (L.U.), Global Medical Affairs, Cambridge, with a more variable and protracted disease course. MA. Diagnosis of MPS I is often delayed due to lack of recognition and the nonspecific Supported by Genzyme Corporation. P.A. receives honoraria for presentations and nature of some of the early manifestations. With improved protocols for hematopoietic board meetings, travel expenses to meetstem cell transplantation and the availability of enzyme replacement therapy with laroniings, and paid and unpaid consultancy work 2-6 dase (recombinant human ␣-L-iduronidase), prompt diagnosis of MPS I has assumed from Genzyme. J.W. receives honoraria for presentations and board meetings, travel new importance. expenses to meetings, and paid and unpaid The MPS I Registry (www.mpsiregistry.com) is an observational, voluntary disease consultancy work and has been a principal investigator in Genzyme-sponsored clinical registry program initiated in June 2003 by BioMarin/Genzyme LLC and currently trials. L.U. is an employee of Genzyme Corsupported by Genzyme Corporation. Its purpose is to track the clinical onset, symptoms, poration, Global Medical Affairs. and outcomes of confirmed patients with MPS I, regardless of disease severity or Submitted for publication Aug 19, 2008; last revision received Oct 23, 2008; actreatment status, by capturing information prospectively and retrospectively from routine cepted Dec 10, 2008. clinical and laboratory assessments.7 Information regarding surgical procedures is colReprint requests: Dr Pamela Arn, Departlected on all patients. Using data from the MPS I Registry, we sought to clarify the extent ment of Pediatrics, The Nemours Chil-
M
CNS ERT
Central nervous system Enzyme replacement therapy
HSCT MPS I
Hematopoietic stem cell transplantation Mucopolysaccharidosis type I
dren’s Clinic, 807 Children’s Way, Jacksonville, FL 32207. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright © 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2008.12.024
859
Table II. Characteristics of patients in the MPS I Registry who reported at least 1 surgical procedure Reported phenotype Hurler (n ⴝ 235)
Hurler-Scheie (n ⴝ 100)
Scheie (n ⴝ 45)
Overall* (n ⴝ 391)
7.7 (4.1, 11.5) 131:104 75, 32%
14.1 (8.5, 22.3) 52:48 9, 9%
21.0 (16.6, 33) 19:26 1, 2%
9.4 (5.8, 17.2) 209:182 85, 22%
85, 36% 72, 31% 30, 13% 48, 20%
3, 3% 82, 82% 1, 1% 14, 14%
1, 2% 37, 82% 0 7, 16%
91, 24% 198, 51% 31, 8% 71, 18%
Characteristic Median age in years at last data entry (25th, 75th percentiles) Male to female ratio Deceased (n, %) Treatment status HSCT (n, %) ERT (n, %) HSCT and ERT (n, %) No treatment (n, %) HSCT, hematopoietic stem cell transplantation; ERT, enzyme replacement therapy. *“Overall” includes 61 patients whose phenotype was undetermined or missing.
and chronology of surgical burden in patients with MPS I, regardless of treatment status, in relation to diagnosis and symptom onset.
METHODS Patient information collected in the MPS I Registry is submitted voluntarily by physicians after obtaining approval from their institutional investigational review board or ethics committee and written consent from patients or their parents/ guardians. All patient data are de-identified and entered by participating sites in accordance with applicable privacy regulations. At enrollment, detailed medical histories and baseline data are collected and physicians are encouraged to follow a recommended schedule of clinical assessments and to report regularly the results of those assessments.7 Because the MPS I Registry is an observational database, the time frame of observation for each patient varies and can encompass any interval from birth until the most recent data entry. Surgical procedures can be entered as free text and documented both in the patient’s medical history at enrollment and subsequently in specific Clinical Event forms. For this analysis, the data download from October 2006 was used. All surgical data were collected from a free text field. Related terms and procedures were classified by a team of physicians into 21 categories from a starting list of 1133 different descriptions of 1694 recorded interventions (Table I; available at www.jpeds.com). To restrict the dataset to surgeries that were most likely to be related to underlying disease, procedures directly related to stem cell transplantation or laronidase treatment (eg, bone marrow harvest or port-a-cath placement) were excluded. Also excluded were exam procedures (eg, biopsies, bronchoscopy). To capture the surgical burden of MPS I, the number of patients from the Registry who reported at least 1 surgery were determined overall, by reported phenotype, and for the following surgical categories: myringotomies and related procedures, adenoidectomy and tonsillectomy, tracheostomy, nasal and sinus procedures, upper airway interventions, corneal transplant procedures, eye interventions, cardiac valve procedures, hernia repair, genitourinary procedures, gastric inter860
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ventions and feeding tubes, tendon release and trigger fingers, orthopedic surgery, carpal tunnel, spinal procedures, ventriculoperitoneal shunt, oral surgical interventions, removal/ revision of inserted material, and other (Table I). Among the subset of patients enrolled in the Registry who reported at least 1 surgery, the following demographic data were collected: age at last data entry, reported phenotype, race, sex, and treatment status. When a patient is enrolled in the registry, the enrolling physician enters all pertinent data collected prior to enrollment retrospectively; going forward, data are entered. For each surgical category, the following data were collected: number of procedures reported overall, number and proportion of procedures by phenotype, patient’s age at first surgery (overall and for each specific procedure), age at procedure versus age at diagnosis, number of procedures of each type by patient, and the frequency of repeated procedures overall for each surgical category and among individual patients.
RESULTS Overall Surgical Burden As of October 2006, the MPS I Registry contained data on 544 patients, of whom 391 (72%) had reported a total of 1694 surgical procedures (Table I). Surgical burden was spread evenly across phenotypes; over 70% of patients in each phenotypic group reported at least 1 surgery (Figure 1; available at www.jpeds.com). Table II lists the demographic characteristics of the 391 patients who reported at least 1 surgery. Overall and by phenotype, patients with surgeries reported a mean of 3 to 4 surgeries apiece (median: 4; range: 1 to 23). By age 4, almost half of all patients had reported 2 or more surgeries (Figure 2). Types of Surgery Figure 3 shows the most frequent categories of surgeries performed in patients with MPS I overall and by disease phenotype in the total Registry population. Ear, nose, and throat surgeries were the most frequent (43% of total), followed by abdominal/genitourinary surgery (21%) and orthopedic surgeries (19% of total) (Figure 4; available at www.jpeds.com). The Journal of Pediatrics • June 2009
Figure 2. Most frequently reported surgeries. The percentage of patients reporting surgeries in each category is shown by phenotype. Also shown is the percentage of patients overall who reported any type of surgery. Shown are the surgical categories for which at least 10% of patients overall or in any phenotypic group reported surgeries. “Other” denotes all surgeries not represented in any other category and includes appendectomy, cholecystectomy, pacemaker placement, and patent ductus arteriosus (Table I).
In patients with Hurler, the most common surgeries were myringotomies and related procedures (Table I), hernia repair, adenoidectomy and tonsillectomy, and ventriculoperitoneal shunt, each reported for 57%, 45%, 37%, and 11% of patients, respectively. In patients with Hurler-Scheie, myringotomies and related procedures and hernia repair were both reported in 40% of patients, adenoidectomy and tonsillectomy in 37% of patients, and spinal procedures in 14% of patients. In patients with Scheie, the most common surgical category was carpal tunnel (in 43% of patients), followed by hernia repair (36% of patients), adenoidectomy and tonsillectomy (31% of patients), and orthopedic surgeries of the hip, knee, and foot (20% of patients).
Relation Between Symptom Onset, Diagnosis, and First Surgery Thirty-six percent of patients with Hurler, 46% of patients with Hurler-Scheie, 63% of patients with Scheie, and
41% of patients overall had at least one surgery before they were diagnosed with MPS I (Figure 5; available at www. jpeds.com). Among patients with surgery before diagnosis, the gap between the first surgery and the diagnosis of MPS I was 6 months for patients with Hurler, 2 years for patients with Hurler-Scheie, and 6.6 years for patients with Scheie (Figure 6; available at www.jpeds.com). Figure 2 shows the median age of first surgery among the most common surgical categories. For patients with Hurler, most first surgeries in a given surgical category occurred before age 5. For patients with Hurler Scheie and Scheie, only hernia repair, myringotomies and related procedures, and adenoidectomy/tonsillectomies commonly first occurred before age 5.
Type of Surgery in Relation to Diagnosis Surgeries sometimes occurred before diagnosis in all but 4 surgical categories (oral surgical interventions, nasal and
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Figure 3. Proportion of patients with 2 or more surgeries by age. Shown are the proportion of patients by reported phenotype and overall who reported 2 or more surgeries by the ages. Percentages are determined based on the number of patients who survived to at least the age specified.
sinus procedures, tracheostomy, and upper airway interventions). The surgeries that most frequently were performed before diagnosis are shown in Figure 7. Over one third (39%) of all patients who had hernia repair surgery, 22% of patients who had ventriculoperitoneal shunts, 21% of patients who had adenoidectomy and tonsillectomies, and 19% of patients who had myringotomies and related procedures first had these procedures before they were diagnosed with MPS I. In addition, for the following less commonly performed surgeries, a high proportion of the patients who had these procedures had them before diagnosis: genital and urinary procedures (52%); eye interventions (39%); others (Table I) (25%); tendon release and trigger fingers (22%); ventriculoperitoneal shunt (23%) and cardiac valve procedures (21%).
DISCUSSION This analysis confirms that patients with MPS I across the phenotypic spectrum frequently require surgical interventions for a range of disease manifestations. Children with MPS I have a very high frequency of common childhood surgeries, such as ear tube procedures, hernia repair, and adenoidectomy and tonsillectomy and also have surgeries that are uncommon in childhood, such as carpal tunnel surgery. Most children with MPS I have several apparently unrelated surgeries in early childhood. Often, surgeries precede diagnosis, especially among patients with Hurler-Scheie and Scheie. Because all data collected in the MPS I Registry are collected voluntarily, the actual surgical burden associated with MPS I may be underestimated. This supposition is supported by higher rates of surgery among the patients with MPS I who participated in a recent clinical trial of enzyme replacement therapy with laronidase. These 45 patients all had Hurler-Scheie or Scheie phenotypes and ranged in age from 6 to 43 (mean age, 15.5 years). At baseline, hernia repair was reported in 74% of patients, adenoidectomy-tonsillectomy in 67% of patients, myringotomies in 47% of patients, carpal tunnel surgery in 20%, and ventriculoperitoneal shut 862
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placement in 11% of patients (Genzyme data on file). Except for carpal tunnel surgery, these prospectively reported surgery rates are all higher than what we found among patients with Hurler-Scheie and Scheie in the MPS I Registry. The surgical disease burden we identify does not take into account examination procedures, many of which require anesthesia and are recommended on a regular basis to assess disease progression and/or response to treatment. Similarly, we excluded surgical procedures related to treatment, such as port-a-cath placement for enzyme replacement infusions and bone marrow harvesting for hematopoietic stem cell transplantation. Although these procedures are not directly related to clinical manifestations of MPS I, they do also contribute very significantly to the overall burden of surgery experienced by most patients with MPS I. Myringotomies and related procedures, adenoidectomy and tonsillectomy, and hernia repair are the three most common surgeries in children with MPS I and are the 3 most common surgeries among the general pediatric population.8 However, among our MPS I Registry cohort, each of these surgeries is reported in at least one third of patients overall— obviously, a greatly increased frequency compared with that of the general population. In addition, the age at which these surgeries typically occur may differ from the general pediatric population. The mean age of adenoidectomy/ tonsillectomy in the United States is 7 years,8 whereas among the MPS I Registry population, the median age is 2.8 years (Hurler: 2.2; Hurler-Scheie: 4.1, and Scheie: 4). The earlier age for adenoidectomy and tonsillectomy presumably reflects diseaserelated upper airway obstruction. Conversely, hernia surgery, and especially inguinal hernia surgery, often occurs at a later age in patients with MPS I than is typical in the general population. Most inguinal hernia surgeries in children occur before 1 year of age,9 whereas in MPS I, hernia surgery (all types as well as inguinal hernia specifically) is most common in toddlers and older children; the median overall age at hernia surgery is 2.5 years (Hurler: 1.8; Hurler-Scheie: 4.2; and Scheie: 6.2). With respect to inguinal hernia surgery alone, 52% of these procedures occurred in children age 1 year and older. The broader age range of children undergoing hernia surgery, as well as the overall high frequency of hernia surgery (and of repeat procedures), presumably reflects the high incidence of acquired rather than congenital hernia due to progressive hepatosplenomegaly, increased intra-abdominal pressure, and weakened abdominal muscles and connective tissue, all common early manifestations of MPS I disease. Carpal tunnel surgery is unusually common among children with MPS I. In fact, MPS disorders are one of the most common causes of carpal tunnel syndrome in children and adolescents.10,11 In our Registry population, carpal tunnel surgery was among the top 5 surgeries reported by all phenotypes, and was the most frequent surgery reported among patients with Scheie, occurring in 43% of patients with Scheie overall. The Journal of Pediatrics • June 2009
Figure 7. Surgeries most frequently performed before diagnosis. Shown are the surgeries most frequently performed before diagnosis by the number of surgeries overall. “Other” denotes all surgeries not represented in any other category and includes appendectomy, cholecystectomy, pacemaker placement, and patent ductus arteriosus (Table I).
Our present data delineates the scope of surgeries and confirm that a significant number of surgeries are reported before diagnosis (Figure 5), as noted in an earlier report from the MPS I Registry7 as well as in the recent analysis of Vieira et al12 exploring the path to diagnosis among patients with MPS in Brazil. Of the 18 patients with MPS I included in the Brazil study, 13 patients (72%) had a total of 25 surgeries (inguinal herniorrhaphy, umbilical herniorrhaphy, adenoidectomy, tonsillectomy, ear tube placement, orthopedic surgery, and other) before biochemical diagnosis of MPS I. Our data show that surgeries sometimes precede even the recognition of the earliest symptoms of MPS I. Delayed diagnosis is usually due to lack of disease awareness and/or the nature of early symptoms, which can be subtle and/or nonspecific. This is particularly true of the Hurler-Scheie and Scheie forms of the disease, which can elude diagnosis for years or decades; not surprisingly, the proportion of surgeries performed prior to diagnosis increased as the phenotype became more attenuated. Thus, physicians have an important opportunity to recognize the disease symptoms when a surgery is scheduled. Earlier disease recognition not only enables intervention before irreversible disease manifestations occur but also alerts surgeons and anesthesiologists to the anesthetic risk posed by most patients with MPS I due to the possibility of compromised airways.13-16 To increase the likelihood of prompt diagnosis of MPS I, we recommend that surgeons and pediatricians check for early signs and symptoms that may suggest a lysosomal storage disorder (Table III; available at www.jpeds.com) in any child who has surgical procedures at a particularly young age (or inguinal hernia surgery beyond age 1 year), multiple surgical procedures, or procedures that are uncommon in
children. Symptoms such as progressively coarsening facial features, corneal clouding, tongue enlargement, joint stiffness, recurrent otitis media, and unexplained cardiomyopathy are suggestive of an MPS disorder.17 The presence of a gibbus deformity, enlarged tongue, and/or 2 or more surgeries before age 18 months should prompt investigations for mucopolysaccharidosis or other storage disorders. In older children, claw hand, cardiac problems, and/or 2 or more surgeries before age 10 should raise the suspicion of an attenuated form of MPS I. Any patient with a suspected lysosomal storage disorder should be referred to a geneticist for further evaluation and potential diagnosis based on deficient enzyme activity. It is unclear whether or not hematopoietic stem cell transplantation or treatment with laronidase will alter the pattern or frequency of surgical intervention in patients with MPS I. At present, the MPS I Registry does not have sufficient longitudinal data to evaluate the effects of treatment on rates of surgery, but this will be an important area of investigation going forward as the patient database matures. Surgical and anesthetic complications, particularly in light of the number of procedures performed prior to diagnosis, are also areas that merit future analyses. We thank Gregory Fagan, Jessica Kong, Lakshmi Rangachari, and Marisa Sidman (Biomedical Operations, MPS I Registry, Genzyme) for expert biostatistical analyses and Gerald Cox, MD, PhD (Genzyme Clinical Research, Harvard Medical School, Children’s Hospital, Boston), Catherine Koepper (Genzyme Global Registries), Katherine Lewis (Biomedical Operations, Genzyme), and Vinciane Pirard, MD (Genzyme Global Medical Affairs) for critical review of the manuscript. Finally, we are grateful to the patients with MPS I and their physicians who provide data to the MPS I Registry.
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REFERENCES 1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver C, Beaudet A, Sly W, Valle D, Childs B, Kinzler K, et al, editors. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw Hill; 2001. p. 3421-52. 2. Boelens JJ, Wynn RF, O’Meara A, Veys P, Bertrand Y, Souillet G, et al. Outcomes of hematopoietic stem cell transplantation for Hurler’s syndrome in Europe: a risk factor analysis for graft failure. Bone Marrow Transplant 2007;40:225-33. 3. Peters C, Steward CG. Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelines. Bone Marrow Transplant 2003;31:229-39. 4. Wraith JE. The first 5 years of clinical experience with laronidase enzyme replacement therapy for mucopolysaccharidosis I. Expert Opin Pharmacother 2005;6:489-506. 5. Wraith JE, Beck M, Lane R, Van der Ploeg AT, Shapiro E, Xue Y, et al. Enzyme replacement therapy in patients who have mucopolysaccharidosis I and are younger than 5 years: results of a multinational study of recombinant human alpha-L-iduronidase (laronidase). Pediatrics 2007;120:e37-e46. 6. Wraith JE, Clarke LA, Beck M, Kolodny EH, Pastores GM, Muenzer J, et al. Enzyme replacement therapy for mucopolysaccharidosis, I: a randomized, doubleblinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). J Pediatr 2004;144:581-8. 7. Pastores G, Arn P, Beck M, Clarke J, Guffon N, Kaplan P, et al. The MPS I registry: design, methodology, and early findings of a global disease registry for monitoring patients with mucopolysaccharidosis type I. Mol Genet Metab 2007;91:37-47.
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8. Russo C, Owens P, Steiner C, Josephsen J. Ambulatory Surgery in US Hospitals, 2003. HCUP Fact Book No. 9. Agency for Healthcare Research and Quality, 2007. AHRQ Publication No. 07-0007. ISBN 1-58763-228-4. 9. Primatesta P, Goldacre MJ. Inguinal hernia repair: incidence of elective and emergency surgery, readmission and mortality. Int J Epidemiol 1996;25:835-9. 10. Lamberti PM, Light TR. Carpal tunnel syndrome in children. Hand Clin 2002;18:331-7. 11. Van Meir N, De Smet L. Carpal tunnel syndrome in children. Acta Orthop Belg 2003;69:387-95. 12. Vieira T, Schwartz I, Munoz V, Pinto L, Steiner C, Ribeiro M, et al. Mucopolysaccharidoses in Brazil: what happens from birth to biochemical diagnosis? Am J Med Genet A 2008;146A:1741-7. 13. Baines D, Keneally J. Anaesthetic implications of the mucopolysaccharidoses: a fifteen-year experience in a children’s hospital. Anaesth Intensive Care 1983;11: 198-202. 14. Walker R, Darowski M, Morris P, Wraith J. Anaesthesia and mucopolysaccharidoses: a review of airway problems in children. Anaesthesia 1994;49:1078-84. 15. Moores C, Rogers JG, McKenzie IM, Brown TC. Anaesthesia for children with mucopolysaccharidoses. Anaesth Intensive Care 1996;24:459-63. 16. Brambrink AM, Braun U. Airway management in infants and children. Best Pract Res Clin Anaesthesiol 2005;19:675-97. 17. Wilcox WR. Lysosomal storage disorders: the need for better pediatric recognition and comprehensive care. J Pediatr 2004;144:S3-14.
The Journal of Pediatrics • June 2009
Table I. Description of surgical categories by organ system Organ system ENT
Eye Cardiac Abdominal and genitourinary
Category of surgery Myringotomies and related procedures Adenoidectomy and tonsillectomy Tracheostomy Nasal and sinus procedures Upper airway interventions Corneal transplant procedures Eye interventions Cardiac valve procedures Hernia repair Genitourinary procedures
Orthopedic
Gastric interventions and feeding tubes Tendon release and Trigger fingers Orthopedic surgery Carpal tunnel Spinal procedures
Neurologic
Ventriculoperitoneal shunt
Other
Oral surgical interventions Others Removal/revision of inserted material
Includes
n (%) (N ⴝ 1694)
PE, grommet, and T-tube placement and adjustment
415 (24.5)
Both or either procedure
261 (15.4) 24 (1.4) 19 (1.1) 13 (0.8)
Polyp removal, sinus drainage, and outfracture of inferior turbinates Pharyngeal surgery, laryngeal, tracheal, and soft palate surgery, epiglottoplasty, palatectomy, uvulectomy, vocal cord reduction Surgeries related to strabismus, cataract, glaucoma Aortic and mitral valve replacement and reconstruction Repair of umbilical hernia and bilateral, left, and right inguinal hernia Non-neonatal circumcisions, fixation of right testicle, hydrocele repair, hypospadias repair, hysterectomy, phimosis repair, posthetomy, testis ectopia Gastric fistula dilatation, hiatal hernia repair Achilles, hamstring, and flexor tendon release Hip, knee and foot surgery; osteotomy, stapling, derotation, joint replacement, epiphysiodesis Surgery for all peripheral nerve entrapment Orthopedic and neurologic interventions, cervical fusion and laminectomy, decompression Placement of subdural, peritoneal, ventriculoperitoneal, and lumboperitoneal shunts Tooth extraction, repair, and restoration, mandibular cyst removal Appendectomy, cholecystectomy, pacemaker placement, patent ductus arteriosus, etc Removal of grommets, pressure equalizer tubes, T-tubes, hip plates and pins, knee staples
Characterization of Surgical Procedures in Patients with Mucopolysaccharidosis Type I: Findings from the MPS I Registry
29 (1.7) 26 (1.5) 20 (1.2) 297 (17.5) 28 (1.7)
26 (1.5) 103 (6.1) 91 (5.4) 84 (5.0) 43 (2.5) 85 (5.0%) 51 (3.0) 44 (2.6) 35 (2.0)
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Table III. Physical signs and symptoms suggestive of an MPS I disorder* ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Macrocephaly Coarse facial features† Macroglossia Thick, coarse hair Hepatomegaly with umbilical or inguinal hernias and prominent abdomen Corneal clouding Recurrent otitis media Chronic rhinitis Upper airway obstruction with snoring and/or sleep apnea Cardiomyopathy Cardiac valve disease Kyphosis of lumbar spine (gibbus) Contractures and joint stiffness Spinal cord compression Short stature
*All signs and symptoms may be seen in both severe (Hurler) and attenuated (HurlerScheie and Scheie) forms of MPS I. Clinical presentation is heterogeneous and not all symptoms are seen in any given patient. †Facial features tend to be more subtle in more attenuated forms of MPS I and patients are more likely to present with other symptoms.
Figure 4. Proportion of surgeries by organ system. Shown is the distribution of all 1694 surgeries recorded in the study population (n ⫽ 391) by organ system (Table I).
Figure 5. Proportion of surgeries occurring before diagnosis. The percentage of patients who reported at least 1 surgery before diagnosis and the proportion of surgeries overall that were reported before diagnosis are shown by phenotype and overall. Figure 1. Patients in the MPS I Registry reporting surgery. Shown are the number and proportion of patients in the MPS I Registry by phenotype and overall who have reported at least 1 surgical procedure. The “Total” column includes 61 patients for whom the phenotype was unknown. All data are from the October 2006 Registry download (n ⫽ 544).
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Figure 6. Chronology of symptom onset, diagnosis, and surgery. The relation between the median age at which symptoms were first recorded, median age of diagnosis, median age at first surgery that occurred before diagnosis (among patients who had surgery before diagnosis), and the mean patient age at all reported surgeries are shown by reported phenotype. The gap between symptoms and diagnosis is 3 months for patients with Hurler, 1.6 years for patients with Hurler Scheie, and 4.3 years for patients with Scheie. The gap between surgery and diagnosis is 5 months for patients with Hurler, 2 years for patients with Hurler-Scheie, and 6.5 years for patients with Scheie.
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