Targeting under-diagnosis in hereditary hemorrhagic telangiectasia: a model approach for rare diseases?

Abstract

Background: Hereditary hemorrhagic telangiectasia (HHT), a rare autosomal dominant disease, is considered under-diagnosed. Our primary objective was to provide evidence of under-diagnosis of HHT in a North American population. We hypothesized that variation would exist in the diagnosed prevalence (D-prevalence) across regions in the province of Ontario, Canada and across age groups, due to under-diagnosis in certain groups. Our secondary objective was to collect data regarding contact and local access to consult specialists by HHT patients to help guide potential future diagnostic programs.

Methods: Primary objective- 556 adult patients with a definite HHT diagnosis seen at the Toronto HHT Centre were identified and geocoded with postal codes. Prevalence rates were calculated using Canadian census data. Secondary objective- A driving network model was developed in ArcGIS. Service area buffers around ear, nose and throat (ENT) clinics in Ontario were generated to evaluate the proportion of the Ontario population with access to these clinics. A survey was also sent to the email contact list of HHT Foundation International, targeting people with diagnosed HHT, regarding consultation with ENT physicians for epistaxis and timing of HHT diagnosis.

Results: Primary objective- D-prevalence rates varied among regions, from no cases to 1.1 cases per 5000 in large Ontario cities. There were no significant differences between urban and rural prevalence rates. Variation in prevalence was seen across age groups, with greater prevalence in older adults (≥50 years-old) compared with adults 20-49 years-old (0.36 versus 0.26 per 5000, p < 0.0005). Secondary objective- Most Ontarians had access to ENT clinics within a 30, 60 and 90 minute modeled drive time (92.7%, 97.8% and 98.6%, respectively). Nearly 40% of surveyed patients consulted an ENT physician for their epistaxis, on average 13.9 ± 12.2 years prior to being diagnosed with HHT.

Conclusions: The prevalence of HHT in Ontario is highly variable across regions and age-groups, suggesting under-diagnosis. Given that patients with HHT frequently consult ENT physicians for epistaxis prior to HHT diagnosis, and that there is almost universal access to ENTs in Ontario, we propose targeting ENT clinics as a province-wide approach to detect undiagnosed HHT patients and families.

Figure 1

Clinical manifestations of HHT, including pulmonary arteriovenous malformations (left) and mucocutaneous telangiectases (right). According to the Curaçao criteria, a confirmed clinical diagnosis of HHT requires 3 or more of epistaxis, mucocutaneous telangiectasia, visceral AVMs, and a positive family history of HHT. Recurrent epistaxis is the most common symptom of HHT and is present in more than 90 % of adults ≥50 years of age. HHT may also be diagnosed genetically based on known disease-causing mutations.

Figure 2

Variation in D-prevalence across all cities in Ontario, Canada. Each circle represents a given D-prevalence from one or more Ontario cities. There were 59 cities with no reported cases of HHT. The D-prevalence of HHT varied significantly across included regions and ranged from no cases to 9.4 per 5000 adults.

Figure 3

City size versus D-prevalence in large cities in Ontario, Canada. In order to eliminate overestimation biases due to large families with HHT living in small cities, the D-prevalence of HHT was compared in large cities, defined as those centers with a population ≥50,000. Even amongst these cities, there was still significant variation in the D-prevalence across regions, which ranged from no cases to 1.1 cases per 5000 adults. There was no correlation between the population size and the D-prevalence (R² = 0.0005).

Figure 4

Variation in D-prevalence across age-groups in all cities in Ontario, Canada. D-prevalence rates were significantly higher in older adults (0.36 ± 0.32 per 5000) compared to younger adults (0.26 ± 0.22 per 5000).

Figure 5

Access to ENT clinics in Ontario, Canada. The vast majority of adult Ontarians have access to an ENT clinic within a 30, 60 and 90 minute modeled drive time (92.7 %, 97.8 % and 98.6 %, respectively. While the majority of Northern Ontario appears outside the access zones (grey), only a very small proportion (<10 %) of the population inhabits this region of the province.