Canadian Paediatric Surveillance Program - 2003 Results

Conclusions

The 42 AFP cases identified to date for 2003 are below the expected rate in Canada, according to the World Health Organization criteria. For the corresponding period for 2002, a total of 39 cases were initially reported, although the final number has since increased to 43 with the inclusion of four additional ‘late' reports.

The decline in the number of AFP cases documented by the CPSP over the past three years might be due to under-reporting of cases or epidemiological peculiarities: both need to be further investigated. However, the high number of duplicate case reports, and the continued involvement of IMPACT, may in fact indicate this to be a true reflection of the changing trend.

It is still encouraging to note that the AFP reporting rate has improved since the introduction of pediatrician-based reporting through the CPSP from 0.5 per 100,000 children less than 15 years of age in 1996 (30 cases) to 1.04 per 100,000 in 2000 (61 cases). For unknown reasons, the rate has decreased since then. Undoubtedly, the expansion of AFP surveillance to the CPSP has improved the completeness of surveillance by ensuring that AFP cases seen at non-tertiary hospitals are reported in addition to those cases admitted to pediatric tertiary care hospitals that are reported through IMPACT.

A major area in which the AFP surveillance could be improved is the performance of polio-specific investigations and timely reporting of results. The proportion of cases where polio-specific laboratory investigations were reported remained low in 2003, with only 48% of cases having had an adequate stool investigation during this period. This compares with the 33% to 51% reported for the period 1996-2002. These rates of adequate stool investigation remain significantly lower than the WHO target of 80%. While neurological investigations provide supporting evidence for the final diagnosis in the majority of reported AFP cases, polio-specific laboratory investigations remain vital for the evaluation of all cases, including those in which poliomyelitis is not being considered as a possible diagnosis. Negative results of appropriate polio-specific investigations are as important as a positive result would be in AFP case evaluations. The single most important laboratory investigation, recommended by the National Working Group on Polio Eradication, to confirm or to rule out a diagnosis of paralytic poliomyelitis, is a stool specimen collected within two weeks of onset of paralysis for isolation of wild or vaccine strain poliovirus. Specimens may be collected up to six weeks after the onset of paralysis, although after two weeks, the sensitivity of virus isolation decreases. The examination of paired serum samples for evidence of a fourfold or greater rise in poliovirus antibody titre in paired sera and/or the presence of poliovirus-specific IgM antibody in a single serological specimen further enhance the evaluation of cases.

Principal investigator

Paul Varughese, DVM, MSc, Immunization and Respiratory Infections Division, Centre for Infectious Disease Prevention and Control,
Public Health Agency of Canada,
Health Canada,
Tunney's Pasture
PL 0603E1,
Ottawa ON
K1A 0K9
; tel.: 613-957-1344
fax: 613-998-6413
e-mail: paul_varughese@hc-sc.gc.ca

Acknowledgement

The assistance of Ms. Nadia Martinova is greatly appreciated for the analysis of the results.

CHARGE association/ syndrome

(September 2001 to August 2004)

Highlights

• Between 2001 and 2003, eight to ten patients per year were identified with CHARGE A/S.
  
• Significant causes of morbidity and presumed mortality were severe feeding difficulties (often requiring surgical interventions), cardiovascular and CNS anomalies.
  
• Preliminary cohort data (13 individuals) suggest evidence of autism spectrum disorder in the majority.
  

Background

CHARGE association/syndrome (CHARGE A/S) is a constellation of a number of congenital anomalies that was first given the acronym CHARGE (Coloboma, Heart Defect, Choanal Atresia, Retarded Growth and Development, Genital Hypoplasia, Ear Anomalies/Deafness) in 1981.

Over the past 15 years, the specificity of this pattern of malformations has reached the level that many clinicians now consider it to be a discrete recognizable syndrome (Graham JM. Am J Med Gen 2001;99:120-3). With increasing expertise, it became clear that the criteria originally proposed needed further refinement. The revised consensus diagnostic criteria by Blake et al. incorporated both major and minor features for CHARGE A/S and have been documented to enhance clinical diagnosis and facilitate research efforts. These criteria consist of four major characteristics: coloboma, choanal atresia, characteristic ear anomalies, cranial nerve dysfunction (facial palsy, vestibular dysfunction, and swallowing difficulties) and seven minor criteria: heart defect, orofacial cleft, genital hypoplasia, growth deficiency, developmental delay, tracheoesophageal fistula and a distinctive facial appearance. The diagnosis is firmly established when all four major or three major and three minor criteria are present. Some of the criteria are difficult to detect in infants, and as the major characteristics are rare in other conditions, the CHARGE A/S diagnosis needs to be considered in any individual who has one or two major criteria and several minor characteristics. To define CHARGE A/S in these individuals, a cranial CT or MRI scan may show hypoplasia of the semicircular canals and/or cochlea and/or choanal atresia or stenosis. High resolution chromosome studies, fluorescence in situ hybridization (FISH) for 22q11 deletion and the subtelomeric deletion FISH testing help to rule out any chromosomal abnormalities accounting for the multiple congenital anomalies. An increase in paternal age of CHARGE A/S children has been recognized as a risk factor and needs to be confirmed.

The purpose of this study is to determine the incidence and prevalence of CHARGE A/S in Canada, as the true incidence is unknown. As CHARGE A/S presents with a wide spectrum of clinical severity, mildly affected patients may also be diagnosed and can be followed prospectively. The review article, entitled "CHARGE association: An update and review for the primary pediatrician" (Clin Pediatr 1998;37:159-74), summarizes current understanding of the management of this complex and chronic multiple congenital anomaly, giving physicians a guide to the management of CHARGE A/S.

Objectives

1) To determine the incidence and prevalence of CHARGE A/S in Canada by ascertaining all identified cases of CHARGE A/S (old and new).

2) To obtain demographic and medical information on patients with CHARGE A/S, and assemble a database to answer research questions.

3) To follow developmentally and behaviourally an identified group of CHARGE A/S infants who have been diagnosed at an early age and have obtained early intervention services. Will early recognition and treatment of these infants improve their clinical and behavioural well being?

Case definitions

Infant/child/adult with four major criteria or three major and three minor criteria.

• Major inclusion criteria: coloboma, choanal atresia, characteristic ear abnormalities, cranial nerve dysfunction.
  
• Minor inclusion criteria: genital hypoplasia, developmental delay, cardiovascular malformations, growth deficiencies, orofacial cleft, tracheoesophageal (TE) fistula, characteristic face.
  

Exclusion criteria
Exclude other conditions such as velocardiofacial syndrome and DiGeorge Sequence using FISH test (fluorescent in situ hybridization) to exclude 22q11 deletion.

Results

Incidence
In 28 months of surveillance, 90 confirmed individuals, 48 males and 42 females, were reported with CHARGE A/S. Forty-three percent of the families agreed to be contacted for further follow-up studies. Table 8 not only provides current and cumulative data on case reports, but also demonstrates the high rate of duplicate reporting of CHARGE A/S cases.

Calculations of the estimated regional incidence for CHARGE A/S continued to demonstrate a provincial variation. The highest incidence was from provinces where the awareness of CHARGE A/S is particularly high, the Atlantic Provinces, Manitoba and Saskatchewan; averaging 1:9,300 live births with

TABLE 8 CHARGE association/syndrome cases
	Reported	Confirmed	Duplicates	Discards	Pending
2003 (12 mths)	37	12	12	11	2
2001-03 (28 mths)	174	90*	51	31	2
In the 28 months of surveillance, the Canadian estimated incidence of CHARGE A/S is 1:26,700.

CHARGE A/S. The global Canadian incidence is estimated at 1:23,000 live births.

Figure 4 demonstrates that a higher proportion of individuals with CHARGE A/S were identified within the younger population. There is still a paucity of adolescents being identified through the surveillance.

Morbidity and mortality
Feeding problems were present in 83% (75/90) of cases; gastrostomy and/or jejunostomy tubes were required in 77% (61/79). Among deceased

individuals, gastroesophageal reflux (GER) was present in 100% (6/6) of individuals older than one month at the time of death. See Table 9 for further mortality details. Major cardiovascular anomalies were present in 70% of the deceased population compared to 35% of the surviving cohort, with conotruncal anomalies and atrioventricular septal defects (AVSD) being significantly more common in the deceased compared to the surviving CHARGE A/S population.

Structural anomalies of the central nervous system, as diagnosed by computed tomography or magnetic resonance imaging, were more prevalent in the deceased compared to the surviving population (70% vs. 51%).

Behaviour and development
Results of standardized parent questionnaires on development/behaviour and a structured telephone interview are reported on the first 13 individuals (eight males, five females). This population has relatively low adaptive behaviour skills, motor impairment being particularly significant (Table 10).

TABLE 9 Deceased patients with CHARGE association/syndrome
	Age at time of death	Sex	Choanal atresia	Feeding difficulties	Cardiovascular defects	Other anomalies
1	<1 week	F	BPCA	GER, G-tube	TOF	H, A, N
2	7 weeks	M	—	GER, G-tube	PDA, ASD, TR	R, H, N
3	6.5 months	F	BPCA	GER, G-tube	PDA, ASD	—
4	8 months	F	—	GER, vomiting	TOF, AVSD	TEF, R
5	1 week	F	BPCA	—	PDA, abn TV & PV, RVH	F
6	4.5 months	F	CS	GER, aspiration, G-tube	AVSD, absent PV	F
7	2.5 months	M	CS	GER, partial nasal obstruction	—	CP, R, H, N
8	1 week	F	BPCA	TEF, G-tube	PS	TEF, R
9	9 years	M	CA	GER, G-tube	DORV, sub aortic stenosis	CL, CP, F, R, N, T
10	2 weeks	M	—	—	DORV, AVSD, PS	F, N

A: abdominal defects; A(V)SD: atria (ventricular) septal defect; BPCA: bilateral posterior choanal atresia; CL/P: cleft lip/palate; CS(A): choanal stenosis (atresia); DORV: double outlet right ventricle; F: characteristic facial features; GER: gastroesophageal reflux; H: hand anomalies; N: neck/shoulder anomalies; PDA: patent ductus arteriosus; PV(S): pulmonary valve (stenosis); R: renal anomalies; RVH: right ventricular hypertrophy; T: teeth anomalies; TEF: tracheoesophageal fistula; TOF: tetralogy of Fallot; TV(R): tricuspid valve (regurgitation).

TABLE 10 Vineland Adaptive Behavior Scales standard scores of CHARGE A/S individuals
Case #	Age at interview (yr-mo)	Communication	Daily living skills	Socialization	Motor skills*	Adaptive behaviour composite
1	3-2	60	56	59	50	52
2	3-5	82	62	89	56	67
3	4-4	79	80	84	51	68
4	5-7	48	50	56	45	46
5	4-6	68	56	80	50	58
6	4-4	53	53	66	56	52
7	5-4	57	59	67	58	55
8	5-10	43	38	52	—	41
9	9-1	26	43	50	n/a	37
10	12-1	<20	<20	<20	n/a	<20
11	17-3	111	88	46	n/a	56
12	23-7	†	†	†	n/a	†
13‡	24-2	16-6	18-0	12-8	n/a	15-8
Mean§	6-10	59.8	55.4	61.2	52.3	50-5
SD	(4-4)	(27.3)	(19.8)	(20.9)	(4.6)	(14.7)

*	Motor skills administered only for children less than 8 years of age.
†	Missing data
‡	Above age range of standardization sample; age-equivalent scores are shown.
§	Expected mean = 100, SD = 15

TABLE 11 Social-Communication Questionnaire (SCQ) scores* and clinical judgments of evidence for autism spectrum disorder (ASD) for CHARGE A/S individuals
Case #	Verbal†	SCQ score‡	Evidence of ASD
1	no	10	some, but <4 years
2	yes	10	some, but <4 years
3	yes	6	little
4	no	8	some
5	yes	10	moderate
6	no	12	some
7	no	8	some
8	no	16	moderate
9	no	13	strong
10§	no	23	n/a
11	yes	12	moderate
12	no	29	moderate
13	yes	14	strong

*	Berument et al., 1999
†	Refers to whether child is able to talk using short phrases and sentences.
‡	In verbal individuals, scores of 15 and higher are associated with an increased probability of autism, whereas in non-verbal individuals a lower SCQ cutoff may be accepted.
§	Severe-profound hearing/visual impairments, mental retardation - unable to assess for ASD.

TABLE 12 Confirmed cases of CHARGE association/ syndrome born between 1995-2003
Reporting province	1995	1996	1997	1998	1999	2000	2001	2002	2003
Alberta	1	0	0	0	0	0	0	0	0
British Columbia	1	0	1	0	3	1	3	1	0
Manitoba	0	0	0	2	2	0	0	1	1
Maritimes*	1	0	0	5	1	2	0	0	0
Newfoundland/ Labrador	0	0	0	0	0	0	0	2	0
Ontario	0	1	4	5	1	2	3	3	4
Quebec	0	1	3	2	1	2	1	3	0
Saskatchewan	0	0	0	0	1	0	2	0	3
Total cases per year	3	2	8	14	9	7	9	10	8
* Maritime provinces include New Brunswick, Nova Scotia and Prince Edward Island.

The majority showed evidence of autism spectrum disorder (ASD) although it is important to recognize the inherent challenges in diagnosing autism in individuals with sensory impairments.

Figures in Table 12 represent confirmed cases of CHARGE A/S born within the last nine years; not included in these figures are cases that are still pending confirmation of diagnosis, or the many duplicate reports that were received. If clinicians are unsure if their case has been reported, they can use this as a guide. Duplication is always better than to allow the chance of missing a report. Nine or ten cases per year yields an incidence of 1:30,000.

Conclusions

Ninety individuals represent the largest CHARGE A/S cohort in the literature. In several provinces where the awareness of CHARGE A/S is particularly well developed, an estimated incidence approaches 1:9,000 live births. As this study has identified a high prevalence of feeding difficulties that contribute significantly to the mortality and morbidity issues for CHARGE A/S individuals, investigation and intervention for GER and associated feeding difficulties are recommended. It will be important

to compare both rates and presentation of autism spectrum disorder in individuals with CHARGE A/S to those seen in other congenital anomaly syndromes, as well as in persons with sensory impairments.

Principal investigator

Kim Blake, MB,
Division of Medical Education,
IWK Health Centre,
Halifax NS B3J 3G9;
tel.: 902-470-6499;
fax: 902-470-7216;
e-mail: kblake@dal.ca

Co-investigators

John M. Graham, Jr, MD,
Clinical Genetics and Dysmorphology,
Cedars-Sinai Medical Center

Chitra Prasad, MD,
Department of Medical Genetics and Pediatrics,
London Health Sciences Centre,
University of Western Ontario

Isabel M. Smith, PhD,
Departments of Pediatrics and Psychology,
IWK Health Centre and Dalhousie University

CHARGE parents (for families of CHARGERS in Canada)

Lisa Weir,
tel.: 506-633-8445; 1-866-874-2474 (families);
e-mail: gweir@nbnet.nb.ca

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