Reply to letter to the editor by Lowry et al.: An epidemiological analysis of CHARGE syndrome: Preliminary results from a Canadian study [Issekutz et al., 2005]

Dr. Brian Lowry and colleagues, in their letter to the journal have included important discussion points concerning our recent publication [Issekutz et al., 2005]. We agree with Dr. Lowry that for rare conditions such as CHARGE syndrome, longitudinal ascertainment over many years is necessary. Our study details only the preliminary findings from a 3-year surveillance, and Dr Lowry will be assured of the ongoing collection of data through multiple venues that continues across Canada including otolaryngologists, ophthalmologists, and geneticists. We feel strongly that the incidence of CHARGE syndrome is more in keeping with our Atlantic province data (1:8,500 live births) than the figure from Dr. Lowry’s team through the Alberta birth defect surveillance (1:51,000). As Dr. Lowry acknowledges, we have great interest and experience in CHARGE syndrome from many research perspectives [Dobbelsteyn et al., 2005; Doyle and Blake, 2005; Searle et al., 2005; Smith et al., 2005], including gene testing in the near future. This creates a situation of identifying an affected population that may not have been diagnosed with CHARGE in their early years because the classical features were either not present or subtle. The problem with registries is that they only record those anomalies that can be detected shortly after birth. Hence, they may miss the most characteristic findings of CHARGE syndrome due to lack of adequate descriptive terms or the presence of occult pathognomonic anomalies (distinctive ears, retinal colobomata, cranial nerve defects, and temporal bone anomalies) resulting in incomplete ascertainment. It is also possible that there is a genetic and casual heterogeneity that explains the marked variability in findings, possibly justifying retention of the term CHARGE association for some cases [Pagon et al., 1981]. Data from three Congenital Malformation Registries involving 5.43 million births in three countries varied in their rates of choanal atresia and subsequently, in their ascertainment of CHARGE syndrome, and this is not the most frequent feature inCHARGEsyndrome.Thefigure for choanal atresiawas 0.82/ 10,000 births in all three samples: SWEDEN: 0.54/10,000; mandatory report at birth; 0 ‘‘CHARGE’’ per 1.95 million births. FRANCE: 0.78/10,000; voluntary reports by trained pediatricians through age 1 year, with 12 ‘‘CHARGE’’ per 1.95 million births. However in CALIFORNIA: 1.13/10,000; staff reviews hospital and genetics clinic records through age 1 year, with 46 ‘‘CHARGE’’ per 1.9 million births. This illustrates howdifferentmodes of ascertainment canmarkedly influence estimates of incidence. An attempt to compare birth defects surveillance registry data with the epidemiological data from the Canadian Pediatric Surveillance Program data would be extremely useful. However, not all Canadian provinces have birth registries and that was one of the reasons we used the CPSP (Canadian Pediatric Surveillance Program) to do the incidence estimates for CHARGE syndrome in Canada. Wehave also observed a distinct pattern of characteristics in the older individuals with CHARGE syndrome, which need to be considered in the clinical diagnosis ofCHARGE [Blake et al., 2005; Searle et al., 2005]. As a result, we have detailed criteria for this older population [Issekutz et al., 2005], which include pubertal delay, hypogonadotropic hypogonadism, and osteoporosis [Forward et al., 2005]. With the recent gene findings in CHARGE syndrome, we are now aware of CHARGE individuals that do not have either coloboma or choanal atresia, which have previously been the mainstay for the clinical diagnosis. The criteria defined by Blake et al. [1998], with the addition of temporal bone findings as suggested by Graham [2001], have been found to be highly specific for detecting mutations in CHD7 [Jongmans et al., 2005] but there may be some individuals who did not meet the clinical diagnostic criteria for our study thatmaybepositive for mutations in the CHD7 gene. We did not address the issue of where the individuals were born, and as we continue to collect the epidemiological data, this will be amended. We agree with Dr. Lowry, not all geneticistswere included in theCPSPsurveyandweare trying to rectify thiswith continued interest inCHARGEsyndrome in Canada.