Canadian Paediatric Surveillance Program - 2003 Results

Prader-Willi syndrome

(January 2003 to December 2004)

Highlights

• Preliminary data results suggest a prevalence of 1:6,700 to 1:10,000.
• As a result of increased awareness in the paediatric community, older PWS patients are being confirmed.
• Diagnosis is now confirmed more often by improved genetic testing than by clinical evaluation.

Background

Prader-Willi syndrome (PWS), an abnormality of chromosome 15, is the most common monogenetic cause of obesity (estimated at 1:10,000 to 1:15,000) with hypothalamic dysfunction leading to hyperphagia and consequent obesity with secondary sequelae of diabetes, heart disease, stroke, sleep apnea, and potential death. Prevalence data in PWS is not well known in Canada, but is drawn from estimates on other geographical locales, or small population studies. Knowing the true Canadian PWS incidence and clinical status on diagnosis will allow for a better understanding of the challenge to be faced and will help with future health-care planning, both on an individual level (intervention strategies) and on a population basis (resource planning), regarding socio-economic support, design and obesity prevention strategy programming.

Objectives

1. To determine the incidence and the mean age of PWS diagnosis in Canada.
2. To ascertain the method of PWS diagnosis: clinical and/or genetic.
3. To create an awareness in the scientific community of PWS.

Case definition

Any child up to and including 18 years of age with newly diagnosed PWS confirmed clinically (PWS clinical score), and/or genetically (methylation and/or FISH [fluorescent in situ hybridisation] test). A clinical diagnosis of PWS relies on a score derived from major and minor criteria:

• < 3 years: 5 points (4 from major criteria)
• > 3 years: 8 points (5 from major criteria)

Discussion

The PWS incidence is predicted at 22 cases per year. Preliminary data results suggest that so far two-thirds of this predicted number are being identified. Interestingly, the study also identified 17 PWS cases from previous years, providing important comparative data needing further analysis. Additionally, two of the patients confirmed genetically in 2003 were 14 and 39 years of age. As a result, the average age of diagnosis (5.4 years) is high for the 2003 cohort, compared to 2.33 years for confirmed cases diagnosed prior to the initiation of the study. Now the trend in the paediatric community is toward a genetic diagnosis (54.5% in 2003 vs. 42.8% in previous years), which is reducing the age of confirmation of PWS diagnosis to 1.4 years compared to 2.33 years previously. In subsequent years, this average age of diagnosis will undoubtedly go down even further, as more and more children will be diagnosed genetically.

With new genetic testing, confirmation is now more readily available, allowing for earlier diagnosis and treatment. Early establishment of environmental control and behavioural management will make great strides in improving the health and well-being of children and youth affected with Prader-Willi syndrome.

TABLE 26 Prader-Willi syndrome reported cases
PWS 2003	PWS prior years	Duplicates	Discards	Pending	Total
14	17	14	3	8	56

Principal investigator

Glenn B. Berall, MD, Department of Paediatrics, North York General Hospital, 4001 Leslie St, Toronto ON M2K 1E1; tel: 416-756-6222; fax: 416-756-6853; e-mail: gberall@nygh.on.ca

Co-investigators

Judith Allanson, MD, Genetics Department, Children's Hospital of Eastern Ontario

Maria Virginia Desantadina, MD, Department of Nutritional Sciences, University of Toronto, The Hospital for Sick Children

Consultant

Nita Goldband, Ontario Prader-Willi Syndrome Association

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Vitamin D deficiency rickets

(July 2002 to June 2004)

Highlights

• From July 2002 until December 2003, 69 cases of vitamin D deficiency resulting in rickets were confirmed among children living in Canada.
• The vast majority of confirmed cases were infants and toddlers with intermediate and dark skin, who had been exclusively breast-fed without vitamin D supplementation.
• These results indicate that despite the current Canadian Paediatric Society recommendation that exclusively breast-fed infants receive vitamin D supplementation (400 IU/day; 800 IU/day for infants living north of the 55th latitude), rickets remains a major public health problem in Canada.

Background

Vitamin D is necessary for calcium homeostasis and for mineralization of the growing skeleton. A deficiency in vitamin D during childhood is associated with potentially significant clinical consequences, as it leads to a mineralization defect of the growth plates (rickets) and of bone tissue (osteomalacia). Poor linear growth and skeletal deformity are hallmarks of vitamin D deficiency during childhood, in addition to hypocalcemic seizures, abnormal dentition, and delayed developmental milestones. The disease is entirely preventable through such simple measures as ensuring adequate dietary intake of vitamin D or administration of a daily supplement.

Recent literature has proposed that the incidence of vitamin D deficiency rickets is rising in many countries worldwide, and clinical experiences suggest that Canada may be no exception. This is despite the regulated, Canadian public health policy that all fluid dairy products (excluding yogurt drinks) are fortified with vitamin D, as infants and children living in Canada cannot depend upon adequate skin exposure to sunlight for vitamin D synthesis. Furthermore, the Canadian Paediatric Society (CPS) has recommended that all exclusively breast-fed infants receive a daily supplement of oral vitamin D, since breast milk is not a rich source of this nutrient. Despite these preventive measures, vitamin D deficiency rickets appears all too frequently in Canada, with certain geo-ethnic groups continuing to be at heightened risk for developing the disease. The main purpose of this study has been to determine the incidence of vitamin D deficiency rickets among children living in Canada by seeking reports of all newly diagnosed cases between July 2002 and June 2004.

Objectives

1. To ascertain the incidence of simple vitamin D deficiency (nutritional rickets) among children living in Canada by identifying all newly diagnosed cases over a two-year period.
2. To obtain demographic and medical information to facilitate the identification of children at risk for developing the disease.
3. To evaluate the efficacy of current strategies to prevent the development of the disease in Canada.
4. To supply data that will assist with the development of novel public health policies to prevent nutritional rickets among children living in Canada.

Case definition

Children up to and including 18 years of age with calcipenic rickets secondary to simple vitamin D deficiency (also known as nutritional rickets).

 Inclusion criteria

1. Low serum 25-hydroxyvitamin D (25OHD)
2. Elevated serum alkaline phosphatase

Exclusion criteria

1. Vitamin D deficiency rickets associated with underlying disease, such as fat malabsorption, liver disease and renal insufficiency, and with illnesses necessitating total parenteral nutrition.
2. Vitamin D deficiency secondary to heritable disorders of vitamin D metabolism, including:
   • 1a-hydroxylase deficiency (pseudo-vitamin D deficiency rickets, PDDR)
   • vitamin D receptor defects (hypocalcemic vitamin D resistant rickets, HVDRR).
3. Phosphopenic rickets of any etiology (where hypophosphatemia is the primary cause of the rickets, and not due to calcipenic rickets with secondary hyperparathyroidism).

Results

Between July 2002 and December 2003, there were 111 reports of vitamin D deficiency rickets among children living in Canada, of which 69 were confirmed cases, 21 were duplicates, ten were discarded because of failure to meet the inclusion criteria and 11 are still under review. Summaries of the results for 2003 and the cumulative data are presented in Tables 27 and 28.

Demographic data
The majority of confirmed vitamin D deficiency cases (49%, 34/69) were from Ontario, with an additional 16% from Alberta, 13% from Quebec, and the remaining 22% divided among British Columbia, Manitoba, Northwest Territories, Nunavut, Saskatchewan and Nova Scotia. There were no reported cases of rickets from the Yukon, New Brunswick or Prince Edward Island. The gender was indicated for 97% of the cases, with 45% being female and 52% male. The mean age at diagnosis was 1.46 years (0.95 standard deviations, SD; range 0.10-6.34). Sixteen percent (16%) of the cases had immigrated to Canada in the months preceding diagnosis. Thirty-three percent (33%) of the confirmed cases were Black, 14% were First Nations, 13% were Middle Eastern, 10% were Inuit, 9% were Caucasian, and 1% were Asian, while the ancestry was not indicated in the remaining 20% of cases. The mean maternal age at the time of delivery was 29 years (SD 6.3; range 18-39).

Risk factors for vitamin D deficiency
Eighty-six percent (86%) of the confirmed cases were classified as intermediate or dark-skinned. However, fair-skinned children living in Canada were not exempt from developing the disease, as they comprised 12% (8/69) of the confirmed cases. Skin colour was not indicated for 3% of the cases. Fourteen of 71 mothers were veiled during, and following, pregnancy. Physicians reported that 85% of the cases had been breast-fed, while the feeding status was not indicated in the remaining confirmed cases. As expected, the vast majority of the cases (86%, 59/69) had not received vitamin D supplementation prior to the development of the disease. In the remaining 14% of cases, supplementation with vitamin D was either not indicated on the case report form or was unreliably administered by caregivers prior to diagnosis. Only 16% of mothers were documented as having received vitamin D supplementation during pregnancy. Following delivery, this number fell to 6%, and the majority of mothers did not drink milk in the post-natal period. Milk allergies and sunscreen use did not appear to be significant risk factors for vitamin D deficiency among children in Canada, as only three of the confirmed cases manifested a milk allergy, while frequent sunscreen use was documented in only two of the cases.

TABLE 27 Vitamin D deficiency rickets results in 2003
Reported	Confirmed	Duplicates	Excluded	Under review
78	45	16	7	10

TABLE 28 Vitamin D deficiency rickets cumulative results: July 2002 to December 2003
Reported	Confirmed	Duplicates	Excluded	Under review
111	69	21	10	11

Clinical and biochemical features at diagnosis
The most frequent signs and symptoms at diagnosis included: skeletal deformity (46%), seizures (15%), failure to thrive (14%), fractures (10%) and delayed milestones (3%). The remaining 12% of cases presented with an incidental discovery of rickets (i.e., identification of a rachitic thoracic cage at the time of x-ray for a respiratory infection). Twenty-nine percent (29%) of patients presented with a combination of these signs and symptoms. Analysis of the serum biochemical parameters of bone and mineral metabolism prior to initiation of vitamin D therapy revealed a mean alkaline phosphatase level of 1,306 U/L (range 296 to 4,969). A 25-hydroxyvitamin D level prior to treatment was available in 48 of the 69 confirmed cases, giving a mean value of 21.0 nmol/L (SD 14.4; range 1-58).

Conclusions

Over 18 months of this two-year surveillance study, 69 cases of nutritional rickets were confirmed among children, predominantly infants and toddlers, residing in Canada. Intermediate- and dark-skinned children who were breast-fed without vitamin D supplementation were at greatest risk for developing the disease, although cases of rickets among fair-skinned children were also documented. A proportion of the mothers were veiled, and most did not receive vitamin D supplementation following delivery, nor did they ingest milk (thus eliminating a potential dietary source of vitamin D). Significant morbidity was present at diagnosis in all confirmed cases, including limb deformity, seizures, failure to thrive, fractures and delayed developmental milestones.

While breast milk should continue to be advocated as the ideal nutritional source for infants and children, it must be recognized that breast milk is not a rich source of vitamin D. This becomes particularly relevant for infants living in northern countries. In view of our northern latitude, the CPSP has recommended since 1998 that all exclusively breast-fed infants receive supplementation with vitamin D (400 IU/day; 800 IU/day for infants living north of the 55th latitude). However, these results suggest that the CPS position statement regarding vitamin D supplementation has not reached all of the general public and has not been universally implemented by health-care providers. Though it is not surprising that children with the greatest number of risk factors for vitamin D deficiency were the most frequently diagnosed, it is surprising that this condition is being detected in a country with ready access to vitamin D supplementation and a clear recommendation from the country's national paediatric organization for prevention of the disease. Evidently, there is an urgent need for heightened awareness of rickets prevention among health-care providers, and education of the general public is warranted. Studies to evaluate the success of educational interventions are a reasonable next step. Consideration should also be given to the role of financial barriers in ensuring that vitamin D is administered to all breast-fed infants. In addition, alternate modes of therapy, such as antenatal treatment of vitamin D-deficient mothers to ensure adequate stores during breast-feeding, are worthy of future investigation.

Principal investigator

Leanne M. Ward, MD, University of Ottawa, Division of Endocrinology and Metabolism, Children's Hospital of Eastern Ontario, 401 Smyth Rd, Ottawa ON K1H 8L1; tel.: 613-737-2253; fax: 613-738-4236; e-mail: ward_l@cheo.on.ca

Co-investigators

Moyez Ladhani, MD, McMaster University, Department of Paediatrics, McMaster Children's Hospital

Stanley Zlotkin, MD, Departments of Paediatrics and Nutritional Sciences, University of Toronto, Research Institute, The Hospital for Sick Children

Acknowledgement

The assistance of Colleen White and Isabelle Gaboury is greatly appreciated for data management and analyses.

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New Studies in 2004

Acquired demyelinating syndromes of the central nervous system

(April 2004 to March 2007)

"Children experiencing acquired demyelinating syndromes are at risk for the development of multiple sclerosis."

Acquired inflammatory demyelination of the central nervous system (CNS) in childhood is a serious illness characterized by acute loss of vision (optic neuritis), loss of function of the spinal cord (transverse myelitis), encephalopathy and multifocal symptomatology (acute disseminated encephalomyelitis), or varied symptoms dependent on the site of demyelination. Advancing our understanding of acute CNS demyelination in children is of utmost importance given that these children may suffer significant acute and long-term morbidity, and are at risk for the subsequent development of the chronic autoimmune disease, multiple sclerosis (MS).

The study proposes to use the CPSP to gather case-specific data to document the clinical features, epidemiological characteristics, familial autoimmune profile, and the current medical care practices provided to children with acquired demyelinating syndromes. This initiative will provide a measure of the impact of CNS demyelination on Canadian children and aims to enhance care of affected children by increasing awareness among Canadian paediatricians of CNS demyelination, and of MS in particular, facilitating prompt and specialized care for children with this disease.

Principal investigator

Brenda Banwell*, MD, Pediatric Multiple Sclerosis Clinic, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto ON M5G 1X8; tel.: 416-813-6660; fax: 416-813-6334; e-mail: brenda.banwell@sickkids.ca

• Representing the Pediatric Demyelinating Disease Network (22 paediatric care facilities across Canada)
  

Acute rheumatic fever

(April 2004 to March 2007)

"In the current era of evidence-based, judicious use of antibiotics, ongoing surveillance of this now rare but serious condition is crucial."

Acute rheumatic fever is a post-infectious collagen vascular disease affecting the heart, joints and central nervous system. It follows untreated group A streptococcal (GAS) pharyngitis after a latent period of approximately three weeks, but does not occur after other GAS infections, such as skin infection (impetigo). Worldwide, acute rheumatic fever remains the commonest cause of acquired heart disease in children, yet the incidence varies widely from region to region, with the vast majority of cases now occurring in developing countries.

The incidence of acute rheumatic fever in developed countries has decreased dramatically since its last peak in the 1970s, but it has not disappeared and remains an important public health issue. The reason for its decrease is not fully understood. The decline in incidence in the early 20th century had already begun prior to the introduction of effective antimicrobial agents, but common use of penicillin to treat symptomatic sore throat, may have contributed somewhat to the decline. Socioeconomic factors, such as overcrowding and low income are known to be significant risk factors. The majority of cases of rheumatic fever follow cases of pharyngitis due to specific M serotypes of GAS, most commonly 1, 3, 5, 6, 18, 19 and 24, and spontaneous fluctuation of the prevalence of these serotypes is known to occur.

Rheumatic fever is not a reportable condition in Canada, and in the current era of evidence-based, judicious use of antibiotics, ongoing surveillance of this now rare but serious condition is crucial. Rheumatic heart disease is a lifelong complication of the condition, which can lead to ongoing medical and surgical needs and can interfere with employment, causing significant socioeconomic impact. However, the risk of developing rheumatic fever must be balanced against the risk of encouraging microbial antibiotic resistance, which is a growing problem in all developed nations and carries its own impact. The study will gather Canadian data on the incidence of first-onset rheumatic fever in childhood and on current treatment practices from coast to coast.

Principal investigator

Christina G. Templeton, MD, Janeway Children's Health & Rehabilitation Centre, 300 Prince Philip Dr, St John's NL A1B 3V6; tel.: 709-777-4462; fax: 709-777-4747; e-mail: hcc.temc@hccsj.nf.ca

Co-investigators

Austin Rick Cooper, MD, Department of Paediatrics, Janeway Children's Health & Rehabilitation Centre

Derek G. Human, BM, Division of Cardiology, Department of Paediatrics, University of British Columbia

Proton Rhaman, MD, Memorial University of Newfoundland

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Adverse drug reactions - serious and life-threatening

(January 2004 to December 2005)

"Adverse drug reactions are responsible for 10% of all hospital admissions. Alarmingly, less than 5% are ever reported to regulators."

Adverse drug reactions (ADRs) are increasingly recognized in North America and Europe as an important cause of childhood morbidity and mortality, yet the true incidence of this problem is poorly defined due to the lack of reporting. In the past, health-care systems have relied steadfastly on the idea of voluntary surveillance systems for the identification and reporting of ADRs. The success of these voluntary systems has been poor, with an estimated 95% of all adverse drug reactions never being reported. In January 2004, the CPSP began active surveillance of ADRs with a goal of generating sufficient numbers of case reports to derive meaningful data for the study of serious and life-threatening ADRs in children.

For this project, a serious and life-threatening ADR to the use of prescription, non-prescription, biological (immunoglobulins) products, complementary medicine (including herbals), and radiopharmaceutical products has been defined as a noxious and unintended response to a drug which occurs at any dose and results in (1) patient hospitalization, (2) emergency department visit, (3) prolonged hospitalization, (4) persistent or significant disability or (5) death.

Principal investigator

Bruce Carleton, PharmD, Faculty of Pharmaceutical Sciences, University of British Columbia, Pharmaceutical Outcomes Programme, Children's & Women's Health Centre of British Columbia, 4480 Oak St, Vancouver BC V6H 3V4; tel.: 604-875-2179; fax: 604-875-2494; e-mail: bcrltn@interchange.ubc.ca

Co-investigators

Anne Smith, BSc (Pharm), MSc, Pharmaceutical Outcomes Programme, Children's & Women's Health Centre of British Columbia

Margaret Zimmerman, BSc, Paediatric Monitoring Project, Marketed Health Products Directorate, Health Canada

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Osteogenesis imperfecta

(January 2004 to December 2004)

"With the advent of bisphosphonate therapy for the treatment of children with osteogenesis imperfecta (OI), the prognosis for young OI patients has improved dramatically."

Osteogenesis imperfecta (OI) is a congenital disease of bone characterized by low bone mass and bone fragility. Four different types (OI types I-IV) are commonly distinguished on the basis of clinical features and disease severity, and are frequently due to mutations in type I collagen. Recently, three novel forms of OI with distinct clinical features have been identified and named OI types V-VII. The genetic basis of the novel OI forms has not been elucidated. In the past, OI has been associated with significant morbidity as patients frequently suffered tremendous physical limitations due to recurrent fractures. However, with the advent of bisphosphonate therapy for the treatment of children with OI, the prognosis for young OI patients has improved dramatically.

The current incidence of OI, including the novel OI forms, is presently unknown. The primary aim of this study is to identify the number of new cases of OI diagnosed over a one-year period through the Canadian Paediatric Surveillance Program. Additional study goals are to:
(1) identify patients in Canada with novel OI forms in order to obtain clinical and genetic information that may ultimately lead to mutation identification,
(2) determine whether a geographic distribution of OI in Canada exists, so that regions in need of a local OI intervention program can be identified, and
(3) raise physician awareness about OI in general, and the novel forms in particular, so that diagnoses of OI can be made in a timely fashion, and appropriate therapy can be initiated during the critical years of bone growth and development. Education of paediatricians regarding OI may also assist with the differentiation of an abused child from the child with bone fragility due to OI.

Principal investigator

Leanne M. Ward, MD, Division of Endocrinology and Metabolism, Children's Hospital of Eastern Ontario, 401 Smyth Rd, Ottawa ON K1H 8L1; tel.: 613-737-2253; fax: 613-738-4236; e-mail: ward_l@cheo.on.ca

Co-investigators

Francis H. Glorieux, MD, PhD, Genetics Unit, Shriners Hospital for Children

Frank Rauch, MD, Genetics Unit, Shriners Hospital for Children

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Severe combined immunodeficiency

(April 2004 to March 2006)

"Timely diagnosis of SCID is crucial as early treatment with bone marrow transplant, enzymatic replacement or gene therapy can be lifesaving."

Severe combined immunodeficiency (SCID) is a group of rare genetic disorders characterized by profound abnormalities in the development and function of the T and B lymphocytes and natural killer cells. Infants with SCID usually present in the first few months of life with a history of infections that are persistent, recurrent, difficult to treat, or caused by unusual infectious agents. Early diagnosis of SCID is critical because the chances for successful treatment by immune reconstitution are highest for infants who have not yet experienced severe opportunistic infections. Without prompt treatment, nearly all will die within the first year of life.

While no Canadian data on the incidence of SCID is available, it would appear that the rate is higher in the Aboriginal population. Information on the incidence of SCID is required to make an evidence-based decision about the risks (notably disseminated BCG infection) vs. the benefits of offering BCG vaccine to First Nations and Inuit children on reserves with endemic tuberculosis.

The objectives of this study are to estimate the incidence of SCID in the general population and in the Aboriginal population of Canada, and to describe the basic demographics, clinical features and outcomes of the Canadian SCID cases.

The CPSP is the best way to achieve these objectives for two main reasons. First, most cases of SCID in Canada will be captured through this active surveillance mechanism, as the majority will be referred to a paediatrician due to the severity of the disease, and second, because it is a prospective program, information such as Aboriginal ancestry, which is often not available through retrospective chart review, can be collected. Moreover, the study will raise the awareness of Canadian physicians regarding the importance of early diagnosis and prompt treatment of SCID cases.

Principal investigators

Louise Pelletier, MD, Office of Community Medicine, First Nations and Inuit Health Branch, Health

Canada, Jeanne Mance Bldg, 20th Floor, PL 1920B, Tunney's Pasture, Ottawa ON K1A 0K9; tel.: 613-948-2762; fax: 613-941-3170; e-mail: Louise_Pelletier@hc-sc.gc.ca

Rosemarie Ramsingh, MD, Office of Community Medicine, First Nations and Inuit Health Branch, Health Canada

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