Genetics and the Canadian Paediatric Surveillance Program

The mission of the Canadian Paediatric Surveillance Program (CPSP) is to “contribute to the improvement of the health of children and youth in Canada by national surveillance and research into uncommon paediatric diseases and conditions.” This mission strikes right to the heart of research into rare paediatric genetic disorders. Currently, there are two CPSP genetic projects: one project is underway, and the other one was recently approved and is expected to start in the summer of 2001. The objective of the first project is to determine the incidence of Smith-Lemli-Opitz syndrome (SLOS) in Canada (principal investigator, Dr M Nowaczyk), and the objective of the second project (principal investigator, Dr K Blake) is to identify cases of CHARGE association (coloboma, heart defects, atresia choanae, retardation of growth and development and/or central nervous system anomalies, genital anomalies and/or hypogonadism, and ear anomalies and/or hearing loss) (1). SLOS is an autosomal recessive disorder of cholesterol metabolism due to mutations in the DHCR7 gene. These mutations result in a deficiency of the 7-dehydrocholesterol reductase that causes abnormally low plasma cholesterol levels and elevated 7-dehydrocholesterol levels (2). People with SLOS have moderately short stature, with failure to thrive; moderate to severe mental retardation; microcephaly; facial dysmorphism, including anteverted nostrils, ptosis, low set ears and micrognathia; syndactyly of the second and third toes; and urogenital abnormalities that may present as sex reversal in males (3). Evidence suggests that early treatment with cholesterol (30 to 40 mg/kg/day in infants and 10 mg/kg/day in adults) may improve growth and some of the behavioural features associated with SLOS (4). The CPSP/SLOS project is expected to have a number of benefits. The main thrust of the project is to determine the incidence of SLOS, which is currently estimated to be between 1/10,000 and 1/100,000 population (4); knowing the incidence rate will allow estimates to be made of the need for and the development of appropriate intervention programs. In addition, there is evidence to suggest that this disorder may be detected in utero using the estriol component of maternal serum screening (5). In this type of prenatal screening, it is critical to know the incidence of the disorder in the population to set parameters such as cut-offs and false positive rates, and to estimate the detection rate of the screen. Anecdotally, the project appears to have had the effect of increasing physician awareness of the disorder, thus, allowing earlier intervention and/or prevention through genetic counselling and prenatal diagnosis. In the first year of the SLOS study, 14 cases were confirmed, and confirmation is pending for six more cases. CHARGE association is a nonrandom association of abnormalities that can occur alone or as a part of a syndrome. A person with CHARGE association may have some or all of these features. The incidence of this disorder is unknown (6), as is the etiology; however, a few people with CHARGE have been found to have deletions of chromosome region 22q11 (7,8). The investigators in the CPSP/CHARGE association project want to determine the incidence of this disorder, but are also interested in finding out whether early identification and treatment improve the general health and behaviour profile of patients with CHARGE. In addition, they are interested in answering a number of questions related to the natural history and etiology: What are the morbidity and mortality rates of CHARGE? Can a prognosis be based on the features of CHARGE? What effect does CHARGE have on development? What was paternal age at the time of conception? What is the effect of teratogen exposure? The two projects show how the CPSP can be helpful to researchers who are looking at rare paediatric genetic disorders and of benefit to patients. Since the implementation of the SLOS project, both geneticists and paediatricians across the country have been on the alert for cases. By bringing the disorder to the attention of so many practitioners, the awareness of the disorder has increased, potentially improving the care of patients. Questions about etiology, natural history and other queries can be asked at the time of ascertainment, but collaborative research relationships can also be formed with the physicians and families of patients. Because the surveillance program relies on voluntary participation and response, the CPSP cannot guarantee complete ascertainment, and, thus, incidence estimates may be very good but not perfect. Nevertheless, year-end study results confirm that the program has been very successful in capturing the high-end estimate of expected SLOS cases. As the Canadian College of Medical Geneticists representative to the CPSP, I have heard a little grumbling from my colleagues over filling out the monthly form and the occasional follow-up detailed questionnaire when cases are seen. I agree that this is a minor irritant, but I believe that the benefits far outweigh the inconvenience and strongly encourage active participation from all.

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