Orphan Genetic Disease Believed To Affect Ten Times More Children Than Previously Thought

Main Category: Pediatrics / Children's Health
Also Included In: Respiratory / Asthma;  Pharmacy / Pharmacist
Article Date: 07 Oct 2008 - 3:00 PDT

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Twenty-four European countries have just participated in the largest-ever epidemiological study on primary ciliary dyskinesia, led by a European Respiratory Society (ERS) Task Force.

The figures announced at the 18th Congress indicate that this genetic disease could affect up to one in 3,000 children, ten times more than previously believed.

Given the major divergences in how European countries diagnose and treat the condition, the Task Force recommends setting up an international register to develop research into the disease and harmonise its management across Europe.

Formerly believed to be a rare disease, Primary Ciliary Dyskinesia (PCD) involves an immobility of the motile cilia, which are found mainly on the surface of the airways (nose, sinus and trachea) and in the ears. Through beating movements, the cilia normally work to eliminate particles trapped in mucus. Indeed, sperm too owe their motility to a similar system of cilia.

PCD is transmitted as an autosomal recessive trait, meaning that both parents carry the defective gene, but do not necessarily suffer from the disease.

Most frequently, the disease is suspected in children suffering from repeated bronchitis and rhinosinusitis, with bronchial dilation seen on X-ray. In almost half of cases, the disease is associated with situs inversus (a mirroring of major organs from their usual position, where the heart, for example, is located on the right-hand side) and is rapidly identified.

More rarely, PCD is only diagnosed when the subject reaches adulthood, in particular where a male is suffering from sterility.

In practice, the condition shares many features with cystic fibrosis, and the treatments proposed are often comparable.

Unprecedented international study

Despite a gradual increase in understanding of PCD, there is still a crucial lack of data. As emphasised at the Congress by Claudia Kuehni (Institute of Social and Preventive Medicine, Bern, Switzerland), "there were no representative international data on the condition's prevalence, its outlook and sufferers' quality of life".

She explained that the rare epidemiological studies that had taken place described small, isolated series; the most significant ones (in the UK and the USA) include only 55 and 78 patients respectively.

Likewise, there is very little information on diagnosis and treatment across Europe. This is all the more regrettable, according to Kuehni, since early diagnosis and appropriate treatment could be expected to improve the long-term outlook for affected children.

Consequently, an international ERS Task Force took up the challenge of producing a maximally comprehensive inventory of primary ciliary dyskinesia in Europe.

The results of this unprecedented study of both diagnosis and treatment were revealed at the ERS Congress in Berlin, through several communications and a "Hot Topic" symposium.

Many cases remain undiagnosed

Having identified the Centres, of varying levels of specialisation, which treat children with PCD in Europe, the Task Force sent them a detailed questionnaire on their patients.

In total, the analysis covered 210 questionnaires from 24 countries. In the two years preceding the study, the various medical facilities had seen 1352 patients, of whom 1071 had files sufficiently detailed to be used in the study.

Once 162 patients aged over 20 had been eliminated from the study, there remained 909 children aged 0 to 19, who were subdivided into age groups as follows: 137 (15%) aged 0-4, 278 (31%) aged 5-9, 294 (32%) aged 10-14 and 200 (22%) aged 15-19.

The researchers then calculated PCD prevalence for each country as the number of cases reported per million children within each age group. Due to the study design, this prevalence estimate relates only to diagnosed and reported cases of PCD.

Which gave some very varied results, as the authors emphasised in Berlin. Cyprus is in the lead in terms of notified cases (90 per million inhabitants aged 0-19), far ahead of Denmark (38 per million), which is followed by Switzerland (36). Then come Sweden (23), Austria (21), Hungary (16), Spain (13) and Italy (12). Other European countries had fewer than ten cases per million.

Kuehni pointed out that the highest rates were seen in the 5-14 age group, which suggests that many children are diagnosed with a significant delay. Indeed, the prevalence of PCD is probably heavily underestimated, with a large number of sufferers having minor symptoms that evade diagnosis.

She believes the real prevalence to be between 1/3,000 and 1/10,000, far exceeding the generally accepted figure of 1/30,000.

Diagnosis at age five

On average, sufferers are diagnosed at age five (or at about age three where there is associated situs inversus). Here, again, there are striking disparities from one country to another. On average, the condition is diagnosed at age 5.5 in western and northern Europe, age seven in southern Europe, and age 8.5 in eastern Europe.

Furthermore, there is great variation in the examinations used to reach the diagnosis. Most specialised centres take nasal or bronchial biopsies to confirm diagnosis of the condition, but less than half of centres have an electronic microscope. In terms of non-invasive tests, only 37% of centres are equipped to measure nasal NO (which is abnormally low in subjects with PCD), and 34% are still using a version of the saccharin test.

Furthermore, genetic testing is only carried out systematically in 18% of facilities treating these patients.

"These disparities can also be seen in the management of child patients," the researchers told the Congress. "While most centres provide close monitoring (72% see patients at 3-4 month intervals and 21% every six months), some (4%) only offer an annual appointment, while others (2%) do so at the parents' request".

"And treatment standards, including use of appropriate drugs, also vary among centres and countries," add Kuehni and her colleagues.

"There is an urgent need to obtain rigorous scientific data on the effectiveness of these treatments and standardise management of the condition across Europe", the ERS Task Force concluded in Berlin.

European Respiratory Society

European Respiratory Society Annual Congress