CAIRN-INT.INFO : International Edition

1We have already explained the form of epidemiological investigation as well as the discovery of the geographical area in which the disease was concentrated in a previous paper [1] in this journal in 1984. In that paper 14 départements were studied. "The area of concentration" of the disease was specifically investigated (in the départements of Ain and Jura) as well as adjoining areas ; also included were the two "control" départements of Meurthe-et-Moselle and Deux-Sèvres. The probability of there being a concentration of this disease in the last département encouraged us to carry out further geographical exploration in order to study the geographical distribution of this inherited disease.

2An epidemiological investigation in 52 départements enables us to approach the study of the prevalence of this inherited disease.

I – Mail survey procedures

1 – An empirical approach

3The method used was naturally adapted to the clinical profile of Rendu-Osler disease, as in all suggested procedures in the epidemiological investigations of genetic diseases. For example, J. Sutter’s work on the dysplasia of the hip and the agenesis of upper lateral incisors [2], J. Feingold on cystic fibrosis [3], E. Dubois on cystinosis [4], C. Bonaiti on glaucoma [5], and E. Shields on cleft palate [6], as well as a number of investigations conducted by Unit 155 of INSERM (epidemiological genetics).

2 – Practical procedures

Mailing

4All physicians likely to come across cases of Rendu-Osler disease in their practices were contacted. A questionnaire was sent to them together with a circular which showed how to diagnose the disease. The circular stressed that even negative answers would be useful for analysis. A self-addressed stamped envelope was enclosed to encourage physicians to participate.

5For each département, lists of practitioners were provided either by the Direction Départementale de l’Action Sanitaire et Sociale (DDASS) or by the départment ’s medical association or failing that, Rosenwald’s directory of the medical profession was used. The telephone directory was also used to complete the lists. Eventually, specialists who had no reasons for seeing patients suffering from Rendu-Osler disease were excluded from this list (for example, paediatricians, psychiatrists, or orthopaedic surgeons), as were some who were eliminated because of the nature of their practice : junior medical staff, retired or non-practising physicians.

6Lastly, those whose contact with patients suffering from Rendu-Osler disease was very limited were also excluded, for example anaesthetists, surgeons, except those specializing in cardio-pulmonary and neuro-surgery who might diagnose Rendu-Osler symptoms while treating arterio-veinous complications [7]. Unfortunately, it is only in hospitals that surgeons’ specialization is officially recorded.

7Altogether nearly 60 % of practitioners were contacted. Some 23,435 circulars were mailed in the 52 départements studied.

Processing of replies

8The replies were analyzed on the basis of their contents, those giving information on one or several patients were processed in a specific manner. With the help of multiple-entry lists (patronymic, geographical location of family) efforts were made to see whether the patient mentioned was related to a family previously identified as containing sufferers from the disease. Among the patients identified in the mail survey, cross-checking of initial data helped avoid starting new files on patients whose families were already known to us through other members.

9In fact one member in each family was selected. His case notes included his personal data, as well as data on those related to him who had been identified in the epidemiological study, and by the different procedures used. Thus a family genealogy was established, indicating the numbers of both live and deceased patients as well as the degree of seriousness of their illness. A report on the patient’s disease-related experiences was also enclosed.

10If the physician replying to our questionnaire had obtained the consent of one or several of his patients, we wrote to him or them to ask for additional information about his/their family tree. In fact, the detail provided by different patients differed, and so did the value of information collected from them.

3 – The choice of départments

11Analysis carried out in 14 départements had revealed the likelihood of a second concentration of Rendu-Osler disease in the département of Deux-Sèvres.

12To verify this hypothesis, we investigated adjoining départements and tried to determine whether there existed a "transmission line" linking the two concentrations, whilst completing our investigation of North-Eastern France, which has been traditionally linked with the Ain-Jura concentration. Poitou-Charentes, Centre, Limousin, Auvergne, Bourgogne, Rhône-Alpes, Franche-Comté, Alsace, Lorraine, Champagne-Ardenne and Picardie were totally covered. Our investigation also included the départements of Eure, Manche, Maine-et-Loire and Vendée. Ile-de-France was omitted because of problems specific to the area (population density and medical organization chart). The investigation in the South-West began with two départements, Ariège and Aude.

13The départements under investigation cover a surface area of 313,026 sq.km or 57 % of metropolitan France with a population of 23,074,000 or 42 % of the total population (see Map 1). The population in these départements varies from 132,000 inhabitants (in the Territoire de Belfort) to 1,445,000 (in Rhône) and between these two départements, the number of physicians contacted varies between 150 and 1,023. The population density shows great contrasts, from 450 inhabitants per sq.km in Rhône to 25 in Creuse. On the other hand, the ratio between the number of physicians contacted and the population in a département is less variable, one doctor for every 435 inhabitants in Bas-Rhin to one for every 1,648 in Haute-Savoie.

Map 1

Extension of the survey to 52 départements

Map 1

Extension of the survey to 52 départements

II – The replies

1 – Percentage of replies received

1423,435 circulars were sent out in 52 départements, 5,745 of them in the 14 départements investigated in 1984, and 17,690 in the 38 new ones. The response ratio has fallen slightly from 15.7 % in 1984 to 14.2 % today. If we were to take into account only those physicians who were actually contacted, i.e. excluding those who had moved away or died, the response ratio would come to 14.7 % (see Table 1).

15The ratio differed considerably in different départements. In the first part of the investigation, it varied between 24.7 % in Haute-Savoie and 9.0 % in Doubs. In the 38 new départements, it varied between 21.6 % in Loir-et-Cher and 5.5 % in Cantal. It would be tempting to conclude that the physicians in the départements that were most affected would be more likely to participate in the investigation than others. In fact, no correlation was observed between the number of those who replied and the fact that they had had patients suffering from the disease. Out of 3,331 replies received 84.6 % came from those who had never had such patients (1,761 + 1,103, Table 1).

16There was also no relation between the reponse ratio and the availability of medical facilities, the density of physicians or the existence of a teaching hospital in the département. However, the response ratio was lowest in those départements in which information about specialists and the conduct of medical practice was least precise.

2 – Practitioners who responded

17An earlier investigation based on 324 individuals showed that Rendu-Osler disease often went untreated [8]. The families knew that the disease was hereditary, and therefore inevitable, and that there was no real cure. Provided the symptoms were not serious, which was true of the majority of cases, patients consulted a general practitioner who prescribed long-term palliative treatment, and showed the family simple ways of stopping nose bleeding, the most troublesome symptom of this condition.

18A fraction of the patients with more severe symptoms, depending on the nature of the complications, saw the specialist most suitable for them : a dermatologist for those with telangiectasia problems, an ear, nose and throat (ENT) specialist for nasal haemorrhage and angioma of the mucous membranes of the nose and mouth, a gastro-enterologist for angioma in the digestive system.

Table 1

Statistics of the mail survey

Table 1
Département Questionnaires sent Mail return Responses Category of respondent Number % 1 2 3 Ain 255 7 41 16.1 17 18 6 Aisne 454 14 78 17.7 9 45 24 Allier 485 8 38 7.8 5 21 12 Ardèche 177 6 29 16.4 7 15 7 Ardennes 320 5 54 17.5 9 28 17 Ariège 195 0 37 19.0 4 22 11 Aube 290 3 45 15.7 5 22 18 Aude 437 10 71 16.6 6 43 22 Cantal 220 10 12 5.5 1 3 8 Charente 532 5 67 12.6 13 36 18 Charente-Maritime 616 4 88 14.3 14 36 38 Cher 349 12 55 15.8 7 30 18 Corrèze 328 0 41 12.5 10 19 12 Côte-d’Or 369 1 77 20.9 12 39 26 Creuse 164 0 25 15.2 4 12 9 Doubs 345 23 31 9.0 8 18 5 Drôme 300 13 54 18.0 5 27 22 Eure 410 43 55 15.0 6 30 19 Eure-et-Loir 304 10 54 18.4 13 28 13 Indre 231 18 32 13.9 2 18 12 Indre-et-Loire 454 22 69 15.2 7 36 26 Isère 750 58 113 15.1 18 67 28 Jura 155 10 28 18.1 11 9 8 Loir-et-Cher 287 9 60 21.6 16 23 21 Loire 802 9 93 11.6 14 48 31 Haute-Loire 204 33 27 13.2 7 12 8 Loiret 545 12 68 12.8 5 47 16 Maine-et-Loire 745 15 105 14.1 20 48 37 Manche 442 9 81 18.7 11 48 22 Marne 570 12 81 14.5 16 41 24 Haute-Marne 212 3 33 15.6 2 20 11 Meurthe-et-Moselle 800 33 126 15.8 17 60 49 Meuse 185 2 22 11.9 3 12 7 Moselle 1 012 13 152 15.0 19 80 53 Nièvre 255 2 34 13.3 3 20 11 Oise 534 15 73 14.1 11 39 23 Puy-de-Dôme 648 49 72 11.1 8 33 31 Bas-Rhin 2 105 92 190 9.0 14 80 96 Haut-Rhin 595 14 104 17.5 19 39 46 Rhône 1 023 79 149 14.6 32 92 25 Haute-Saône 230 1 45 19.6 3 26 16 Saône-et-Loire 460 8 74 16.1 7 44 23 Savoie 500 4 69 13.8 13 34 22 Haute-Savoie 300 14 74 24.7 13 44 17 Deux-Sèvres 300 14 41 13.7 17 15 9 Somme 441 11 60 14.0 6 27 27 Vendée 493 7 88 17.9 7 45 36 Vienne 269 11 34 12.6 11 12 11 Haute-Vienne 475 4 41 8.6 7 19 15 Vosges 396 6 73 18.4 15 36 22 Yonne 317 5 40 12.6 3 28 9 Territoire de Belfort 150 7 28 18.7 0 22 6 Total 23 435 775 3 331 14.2 512 1 716 1 103

Statistics of the mail survey

N.B. :
  • Category 1 : Practitioners having already treated such patients.
  • Category 2 : Practitioners ready to participate in the survey in the future.
  • Category 3 : Other respondents.

19An analysis of the replies by practitioners who had treated such patients confirmed this approach. 512 replied that they had treated patients suffering from Rendu-Osler disease (see Table 2). The majority were general practitioners : they numbered 331, or nearly 65 % of all responding practitioners. Among the specialists, dermatologists (43) most frequently treated such patients, followed by ENT specialists (43), while those who treat digestive complications were next on the list (gastro-enterologists, specialists of the digestive system and internal organs).

Table 2

Distribution of responses by category of practitioners (answers of type 1)

Table 2
Speciality Crude No. Speciality Crude No. General practitioners 331 Angiologists 4 ENT specialists 43 Cardiologists 3 Dermatologists 43 Rheumatologists 3 Internal organs 25 Nephrologists 3 Gastro-enterologists 22 Haematologists 3 Pneumologists 10 Others 17 Specialists in occupational medicine 5 Total (Answers of type 1) 512

Distribution of responses by category of practitioners (answers of type 1)

20Some patients were reported several times : the same name was often reported by a general practitioner and a specialist. Dermatologists and ENT specialists often saw several patients during the course of their practice. This is especially true of well-known specialized units in teaching hospitals which often have up to ten patients on their files.

21Replies from practitioners of occupational medicine play a major role in investigations of this type. They screen patients systematically and negative replies from them can be significant ; five such doctors had seen Rendu-Osler patients.

3 – Reported cases of Rendu-Osler disease

The size of the mail survey

22Up to now 627 cases have been identified throughout France. Mail surveys in 52 départements showed 392 individuals residing in 62 départements[9]. Some practitioners, particularly those attached to hospitals, often see patients who have travelled a long way for a consultation.

Table 3

Place of residence and place of reporting in the mail survey

Table 3
Département Of residence Of report Département Of residence Of report Ain 31 30 Lot 1 0 Aisne 5 5 Maine-et-Loire 16 25 Allier 3 2 Manche 6 5 Ardèche 8 9 Marne 11 9 Ardennes 6 6 Haute-Marne 1 2 Ariège 1 3 Mayenne 3 Aube 4 6 Meurthe-et-Moselle 7 12 Aude 6 6 Meuse 3 3 Cantal 1 1 Moselle 9 7 Charente 5 5 Nièvre 3 3 Charente-Maritime 10 10 Oise 4 5 Cher 6 7 Puy-de-Dôme 4 5 Corrèze 6 5 Bas-Rhin 8 8 Côte-d’Or 8 8 Haut-Rhin 17 15 Creuse 4 4 Rhône 20 20 Doubs 6 8 Haute-Saône 2 1 Drôme 5 4 Saône-et-Loire 7 7 Eure 5 6 Savoie 15 12 Eure-et-Loir 8 8 Haute-Savoie 8 7 Hérault 1 Paris 2 Indre 2 0 Deux-Sèvres 20 15 Indre-et-Loire 4 6 Somme 5 5 Isère 8 13 Vendée 4 3 Jura 12 12 Vienne 7 7 Loir-et-Cher 12 11 Haute-Vienne 7 11 Loire 10 11 Vosges 13 10 Haute-Loire 4 3 Yonne 4 4 Loire-Atlantique 1 0 Territoire de Belfort 0 0 Loiret 2 2 Val-d’Oise 1

Place of residence and place of reporting in the mail survey

Individuals’ place of residence

23There is often a disparity between the number of Rendu-Osler patients residing in an area and the number reported by practitioners from that area. This is true of Maine-et-Loire (16 compared with 25) and Isère (8 compared with 13). The reverse is true for rural départements (20 compared with 15) in Deux-Sèvres. It was thought preferable to base the analysis on the individuals’ place of residence.

24The numbers of individuals reported in the epidemiogical surveys were highest in the départements of Ain with 31, and Rhone and Deux-Sèvres with 20 each. They were followed by Haut-Rhin, Maine-et-Loire and Savoie. The geographical distribution is rather irregular. But the Ain-Jura concentration with its extension into Rhône, remains preponderant with 63 individuals, and the existence of the disease in the Deux-Sèvres, Maine-et-Loire axis extending into Vienne and Charente, is confirmed with its 58 individuals.

Survey results

25Besides the total number of known cases, two indicators help us to assess the results of the epidemiological investigation.

26• The ratio between the number of practitioners treating sufferers from Rendu-Osler disease and the population of the département is the first (Table 4, left third).

27This ratio varies between 1/18,500 in Loir-et-Cher and 0 in the Territoire de Belfort. In six départements, the ratio is higher than 1/25,000 : Loir-et-Cher has already been mentioned, Deux-Sèvres (1/20,000), Jura (1/22,000), Corrèze (1/24,000), Ain (1/24,600) and Savoie (1/24,800).

28• The ratio between the number of practitioners treating Rendu-Osler disease and the total number of practitioners contacted has also been computed (central part of Table 4).

29This ratio ranges from 7.1 % in Jura to 0 in the Territoire de Belfort. In only four départements is the ratio higher than 5 % : in Jura (7.1 %), Ain (6.7 %), Loir-et-Cher (5.8 %) and Deux-Sèvres (5.7 %).

30None of the three parameters shown in the table is ideal, but by using them together it is seen that the same départements always seem to be at the top of the list : Ain, Jura, Deux-Sèvres, Maine-et-Loire. These are followed by Savoie, Haute-Savoie and Rhône for the Rhône-Alpes region, Maine-et-Loire and Eure-et-Loir in the west, and other "high-risk" départements such as Haut-Rhin and Vosges for the North-East and Corrèze for Limousin.

III – Prevalence estimates

31• Prevalence ratios may be compared by using different results from the epidemiological study. For the 52 départements covered by the mail survey, "minimum levels of prevalence" could be obtained from the survey alone.

Table 4

The 17 highest response rates in the survey

Table 4
Rank Département Ratio : number of practitioners reporting cases/population Département Ratio : number of practitioners reporting cases/all contacted Département Number of reported cases 1 Loir-et-Cher 1/18 500 Jura 7.1 % Ain 31 2 Deux-Sèvres 1/20 000 Ain 6.7 % Deux-Sèvres 20 3 Jura 1/22 000 Loir-et-Cher 5.8 % Rhône 20 4 Corrèze 1/24 100 Deux-Sèvres 5.7 % Haut-Rhin 17 5 Ain 1/24 600 Haute-Savoie 4.3 % Maine-et-Loire 16 6 Savoie 1/24 800 Eure-et-Loir 4.3 % Savoie 15 7 Charente 1/26 200 Vienne 4.1 % Vosges 13 8 Vosges 1/26 400 Ardèche 4.0 % Jura 12 9 Eure-et-Loir 1/27 900 Vosges 3.8 % Loir-et-Cher 11 10 Haute-Loire 1/29 400 Haute-Loire 3.4 % Charente-Maritime 10 11 Ardennes 1/33 600 Côte-d’Or 3.3 % Loire 10 12 Vienne 1/33 700 Haut-Rhin 3.2 % Moselle 9 13 Maine-et-Loire 1/33 700 Rhône 3.1 % Marne 9 14 Marne 1/34 200 Corrèze 3.0 % Ardèche 8 15 Haut-Rhin 1/34 200 Marne 2.9 % Haute-Savoie 8 16 Creuse 1/35 000 Ardennes 2.8 % Eure-et-Loir 8 17 Charente-Maritime 1/36 600 Maine-et-Loire 2.7 %

The 17 highest response rates in the survey

32• In Rhône-Alpes and Deux-Sèvres, "minimum prevalence" could be computed after taking account of the number of patients identified by the mail survey, as well as those obtained by the procedures mentioned below :

  • from consulting nosological indexes of the different departments of regional hospitals treating Rendu-Osler patients, regional university hospital centres in Lyons, Besançon, Poitiers and Geneva, and regional hospital centres in Oyonnax, Saint-Claude, Lons-Le-Saunier, Saint Julien, Annemasse and Annecy ;
  • from local family history surveys among families whose members were already known to be suffering from this disease ;
  • by contacting local practitioners directly ;
  • by presenting this research project to associations (like the Lyons ENT Specialists Association or to the French Society of Haematologists) and during postgraduate training sessions ;
  • by conducting "door-to-door" medical surveys among all the families living in villages in the heart of the geographical concentrations ;
  • by special surveys in two Paris hospitals to find out the exact geographical origin of patients treated in the establishments in the capital ;
  • by writing to all families living at a distance that could not be contacted in person ;
  • by organizing the prospective recruitment of all new patients coming for treatment or hospitalization in the Lyons area.

33L. Venturini has shown that on an average there were four living patients for every reported case [10]. If all these related patients were residents of the same département, the prevalence ratio could be obtained thus :

1 – Minimum prevalence

35Three départements stand out very clearly with prevalence ratios of 1/3,375 for Ain, 1/4,287 for Deux-Sèvres and 1/5,062 for Jura. In ten others, prevalence ratios vary between 1/6,000 and 1/13,000.

36Three regions which might in the future become areas known for Rendu-Osler disease are singled out : Limousin (Creuse, Corrèze, Haute-Vienne), the eastern slope of the Massif Central (Haute-Loire, Ardèche) and the Massif Vosgien (Vosges, Haut-Rhin, Map 2, Table 5).

Table 5

Minimum prevalence of Rendu-Osler disease in 52 départements

Table 5
Place of residence Number of reported cases Minimum prevalence Place of residence Number of reported cases Minimum prevalence Ain 124 1/ 3 375 Loiret 8 1/66 900 Aisne 20 1/26 700 Maine-et-Loire 64 1/10 554 Allier 12 1/30 791 Manche 20 1/23 300 Ardèche 32 1/ 8 375 Marne 44 1/12 300 Ardennes 24 1/12 600 Haute-Marne 4 1/52 625 Ariège 4 1/33 900 Meurthe-et-Moselle 28 1/25 607 Aube 16 1/18 600 Meuse 12 1/16 666 Aude 24 1/11 700 Moselle 36 1/27 972 Cantal 4 1/40 750 Nièvre 12 1/49 541 Charente 20 1/17 050 Oise 16 1/41 300 Charente-Maritime 40 1/12 825 Puy-de-Dôme 16 1/37 156 Cher 24 1/13 333 Bas-Rhin 28 1/32 696 Corrèze 24 1/10 062 Haut-Rhin 60 1/10 841 Côte-d’Or 32 1/14 796 Rhône 80 1/18 062 Creuse 16 1/ 8 750 Haute-Saône 8 1/29 000 Doubs 24 1/19 875 Saône-et-Loire 28 1/20 428 Drôme 20 1/19 500 Savoie 48 1/ 6 739 Eure 20 1/23 100 Haute-Savoie 32 1/15 453 Eure-et-Loir 32 1/11 300 Deux-Sèvres 80 1/ 4 287 Indre 8 1/30 375 Somme 20 1/27 200 Indre-et-Loire 17 1/31 625 Vendée 16 1/30 187 Isère 32 1/29 281 Vienne 28 1/13 267 Jura 48 1/ 5 062 Haute-Vienne 28 1/12 714 Loir-et-Cher 44 1/ 6 700 Vosges 40 1/ 9 900 Loire 40 1/18 487 Yonne 16 1/19 437 Haute-Loire 16 1/12 875

Minimum prevalence of Rendu-Osler disease in 52 départements

37Both concentrations found in Ain-Jura and Deux-Sèvres are surrounded by départements with low prevalence ratios of between 1/13,000 and 1/21,000. This fall is accentuated by the low prevalence ratio in Haute-Marne, Haute-Saône and in the Territoire de Belfort which separates Vosges from Jura. The same phenomenon is observed between Jura and Limousin. Finally at the département level, we observe what seems to be a break rather than a progressive tapering off as the disease spreads from one or two original areas of geographical concentration.

38The salient point is the identification of a large concentration of patients in Ain-Jura and Deux-Sèvres and the emergence of three areas characterized by a greater number of patients in Limousin, Vosges and the eastern Massif Central.

Map 2

Minimum prevalence of Rendu-Osler disease by département

Map 2

Minimum prevalence of Rendu-Osler disease by département

39Naturally, mobility interferes with the analysis of the geographical distribution of patients by place of residence. A number of patients from rural areas have become assimilated in Paris and Bordeaux. The case of Limousin is especially ambiguous. The lowest prevalence noted was in Creuse : 1/8,750 and in Corrèze : 1/10,062, rather high for the "postal epidemiological survey". These two départements have been particularly hard-hit by the rural exodus. It is difficult to estimate the prevalence ratio a century ago. Could it be an old focus of infection which is about to disappear owing to the rural exodus ? Or, does the higher proportion of old people among whom the chances of the disease being diagnosed are higher suggest an exaggerated view of the situation ?

40Obviously we are trying to trace inter-regional links that would help us follow the spread of genes from a suspected focus. Only a systematic genealogical approach would make it possible to confirm or reject the theory of families’ regional roots [11]. Moreover, an analysis of the distribution of patients by age should be carried out.

Table 6

Minimum and approximate prevalence in 8 départements

Table 6
Département Number of cases reported in the mail survey Minimum prevalence Total number of known cases Approximate prevalence Ratio : approximate/minimum Ain 124 1/ 3 375 420 1/ 996 3.4 Doubs 24 1/19 875 44 1/10 840 1.8 Isère 32 1/29 281 88 1/10 647 2.8 Jura 48 1/ 5 062 176 1/ 1 380 3.7 Rhône 80 1/18 062 288 1/ 5 017 3.6 Saône-et-Loire 28 1/20 428 52 1/11 000 1.9 Haute-Savoie 32 1/15 453 84 1/ 5 886 2.6 Deux-Sèvres 80 1/ 4 287 144 1/ 2 381 1.8

Minimum and approximate prevalence in 8 départements

41Since there is no evidence to show the progressive spread of the disease from one focus to another, we must admit that several mutations have occurred in different places at different times. However, recent mutations cannot be held responsible for a significant number of cases.

2 – Approximate prevalence

42The Rhône-Alpes region in which the original concentration of the disease was discovered and the region of Deux-Sèvres have been particularly well surveyed and all possible methods of investigation were used to account for all sufferers from Rendu-Osler disease [12]. In the départements of Ain, Jura and Rhône, the number of cases reported in the mail survey was multiplied by three and in five other départements by a factor varying between 1.8 and 2.8.

43The next stage in our epidemiological research would be to use our different procedures for Limousin, the Massif Vosgien and the eastern Massif Central.

44We stress that there have also been considerable variations within départements. Thus in the département of Ain, the arrondissements of Bourg and Belley were relatively little affected by the disease with a prevalence ratio of 1/3,506, whereas in the arrondissements of Nantua and Gex, prevalence ratios are very high at 1/327. For regions with high ratios, an analysis at the arrondissement or even at the canton level is needed.

Map 3

Prevalence of Rendu-Osler disease by arrondissement

Map 3

Prevalence of Rendu-Osler disease by arrondissement

Table 7

Prevalence by arrondissement in 7 départements

Table 7
Département and arrondissement Population Number of families Number of cases Prevalence Ain Belley 70 500 6 24 1/ 2 938 Bourg 238 000 15 60 1/ 3 967 Gex 40 800 34 136 1/ 300 Nantua 69 200 50 200 1/ 346 Jura Dole 74 200 2 8 1/ 9 275 Lons 122 100 20 80 1/ 1 526 Saint-Claude 46 600 22 88 1/ 530 Haute-Savoie Annecy 180 600 1 4 1/45 150 Bonneville 126 500 6 24 1/ 5 279 St-Julien-en-Genevois 102 800 14 56 1/ 1 836 Thonon 84 600 0 0 – Saône-et-Loire Autun 105 400 0 0 – Chalon 193 200 4 16 1/12 075 Charolles 115 900 2 8 1/14 488 Louhans 51 000 5 20 1/ 2 550 Mâcon 106 300 4 16 1/ 6 644 Deux-Sèvres Bressuire 92 200 10 40 1/ 2 430 Niort 184 100 12 48 1/ 3 835 Parthenay 66 800 14 56 1/ 1 193 Maine-et-Loire Angers 316 200 8 32 1/ 9 881 Cholet 176 800 3 12 1/14 733 Saumur 128 800 5 20 1/ 6 440 Sègre 53 400 0 0 – Loir-et-Cher Blois 162 900 6 24 1/ 6 787 Romorantin 67 100 4 16 1/ 4 183 Vendôme 66 300 4 16 1/ 4 144

Prevalence by arrondissement in 7 départements

45Both the concentrations become apparent when we look at the situation beyond départements. The original focus covers the north-eastern part of Ain (arrondissements of Gex and Nantua) and southern Jura (arrondissements of Saint-Claude and Lons) ; it extends east into the arrondissement of Saint-Julien-en-Genevois (in the département of Haute-Savoie) and north-east into the arrondissement of Louhans (in the département of Saône-et-Loire).

46Thus the arrondissements with the highest prevalence ratios (Gex 1/300, Nantua 1/346, Saint Claude 1/530) are surrounded by a zone in which there is a steeply declining trend of the disease. Beyond a 50 km radius from the epicentre, the prevalence ratios come to 1/10,000, a very considerable change from the outlying départements.

47The arrondissements affected by the Deux-Sèvres concentration show several different elements. Nowhere is the concentration as strong as in the previous case : the maximum prevalence ratio is of 1/1,193 in the Pathenay arrondissement ; in two other arrondissements in Deux-Sèvres prevalence rates are rather high : Bressuire (1/2,430) in the north and Niort (1/3,835) in the south. The concentration seems to extend north-east into the département of Maine-et-Loire (in Saumur arrondissement the prevalence ratio is 1/6,440). In the outlying départements the ratios are very small, especially in Vendée to the west (1/30,187). Hence, the effects of concentration and spread are lower here than those observed for the Ain-Jura concentration. But it leads us to speculate whether this can be considered as a more recent form of the mutation.

48As regards the département of Loir-et-Cher which seems to occupy the highest position (Table 4), the prevalence ratio varies from 1/4,144 (for the Vendôme arrondissement) to 1/6,787 (for that of Blois). Prevalence ratios are lower in the surrounding départements, especially the département of Indre-et-Loire which separates Loir-et-Cher from Maine-et-Loire and Deux-Sèvres, with only a very low prevalence rate of 1/31,625.

Conclusion

49It should not be forgotten that the prevalence ratio of 1/80,000 computed by McKusick is still largely accepted. The minimum figure we obtain for all 52 départements is 1/8,345. The method used and the results of the surveys on the spot lead us to suppose that this prevalence ratio could be two or three times higher.

50We now intend to extend the postal survey to cover the whole country. It is presently being extended to 21 new départements, and the national survey could be completed in 1989. We know that in the areas which have not yet been surveyed, cases of Rendu-Osler disease are found. Some family histories have been published in Lille, Bordeaux and Toulouse. We hope to be able to present a map with the prevalence ratios for the whole of France.

51If there are other geographical concentrations we shall be able to spot them more clearly and note the degree of concentration attained in each. We shall then be able to study how defective genes spread out from each of these concentrations, while keeping track of the demographic structure and population migrations in each département[13].

This work was published thanks to INSERM (external contracts 86.8.031 and 87.8.021).
Annex 1
tableau im12
Département Population Area Density Nb. pract. contacted Ratio pract./popul. Ain 418 500 5 756 72.7 255 1/1 641 Aisne 534 000 7 378 72.4 454 1/1 176 Allier 369 500 7 327 50.4 485 1/ 762 Ardèche 268 000 5 523 48.5 177 1/1 514 Ardennes 302 500 5 219 58.0 320 1/ 945 Ariège 135 700 4 890 27.8 195 1/ 696 Aube 289 300 6 002 48.2 290 1/ 998 Aude 280 700 6 232 45.0 437 1/ 642 Cantal 163 000 5 741 28.4 220 1/ 741 Charente 341 000 5 952 57.3 532 1/ 641 Charente-Maritime 513 000 6 848 74.9 616 1/ 833 Cher 320 000 7 228 44.3 349 1/ 917 Corrèze 241 500 5 860 41.2 328 1/ 736 Côte-d’Or 473 500 8 765 54.0 369 1/1 283 Creuse 140 000 5 559 25.2 164 1/ 854 Doubs 477 000 5 228 91.2 345 1/1 383 Drôme 390 000 6 525 59.8 300 1/1 300 Eure 462 300 6 004 77.0 410 1/1 128 Eure-et-Loir 362 800 5 876 61.7 304 1/1 193 Indre 243 000 6 778 35.9 231 1/1 052 Indre-et-Loire 506 000 6 124 82.6 454 1/1 115 Isère 937 000 7 474 125.4 750 1/1 249 Jura 243 000 5 008 48.5 155 1/1 568 Loir-et-Cher 296 200 6 314 46.9 287 1/1 032 Loire 739 500 4 774 154.9 802 1/ 922 Haute-Loire 206 000 4 965 41.5 204 1/1 010 Loiret 535 600 6 742 79.4 545 1/ 983 Maine-et-Loire 675 500 7 131 94.7 745 1/ 907 Manche 465 900 5 947 78.3 442 1/1 054 Marne 543 600 8 163 66.6 570 1/ 954 Haute-Marne 210 500 6 216 33.9 213 1/ 993 Meurthe-et-Moselle 717 000 5 235 137.0 800 1/ 896 Meuse 200 000 6 220 32.2 185 1/1 081 Moselle 1 007 000 6 214 162.1 1 012 1/ 995 Nièvre 239 500 6 837 35.0 255 1/ 939 Oise 661 800 5 857 113.0 534 1/1 239 Puy-de-Dôme 594 500 7 955 74.7 648 1/ 917 Bas-Rhin 915 500 4 787 191.2 2 105 1/ 435 Haut-Rhin 650 500 3 523 184.6 595 1/1 093 Rhône 1 445 000 3 215 449.5 1 023 1/1 412 Haute-Saône 232 000 5 343 43.4 230 1/1 009 Saône-et-Loire 572 000 8 565 66.8 460 1/1 243 Savoie 323 500 6 036 53.6 500 1/ 647 Haute-Savoie 494 500 4 391 112.6 300 1/1 648 Deux-Sèvres 343 000 6 004 57.1 300 1/1 143 Somme 544 600 6 175 88.2 441 1/1 235 Vendée 483 000 6 721 71.9 493 1/ 980 Vienne 371 500 6 985 53.2 269 1/1 381 Haute-Vienne 356 000 5 512 64.6 475 1/ 749 Vosges 396 000 5 871 67.5 396 1/1 000 Yonne 311 000 7 425 41.9 317 1/ 981 Territoire de Belfort 132 000 610 216.4 150 1/ 880
Annex 2
tableau im13
Département Nb. of responses Nb. of cases reported Cases already known from other sources New cases Ain 41 30 18 12 Aisne 78 6 1 5 Allier 38 2 2 0 Ardèche 29 9 6 3 Ardennes 54 7 1 6 Ariège 87 4 1 3 Aube 45 7 1 6 Aude 71 6 0 6 Cantal 12 1 0 1 Charente 67 5 0 5 Charente-Maritime 88 10 2 8 Cher 55 7 0 7 Corrèze 41 5 0 5 Côte-d’Or 77 8 4 4 Creuse 25 4 0 4 Doubs 31 8 3 5 Drôme 54 4 1 3 Eure 55 6 0 6 Eure-et-Loir 54 9 1 8 Indre 32 0 0 0 Indre-et-Loire 69 6 2 4 Isère 113 13 3 10 Jura 28 12 9 3 Loir-et-Cher 60 14 3 11 Loire 93 11 2 9 Haute-Loire 27 3 0 3 Loiret 68 3 1 2 Maine-et-Loire 105 25 7 18 Manche 81 6 1 5 Marne 81 12 3 9 Haute-Marne 33 2 0 2 Meurthe-et-Moselle 126 12 0 12 Meuse 22 3 0 3 Moselle 152 7 2 5 Nièvre 34 3 0 3 Oise 73 6 1 5 Puy-de-Dôme 72 5 1 4 Bas-Rhin 190 8 2 6 Haut-Rhin 104 15 0 15 Rhône 149 20 10 10 Haute-Saône 46 1 0 1 Saône-et-Loire 74 7 4 3 Savoie 69 12 3 9 Haute-Savoie 74 7 4 3 Deux-Sèvres 41 15 3 12 Somme 60 5 0 5 Vendée 88 3 2 1 Vienne 34 7 2 5 Haute-Vienne 41 11 0 11 Vosges 73 10 2 8 Yonne 40 4 1 3 Territoire de Belfort 28 0 0 0

Notes

  • [*]
    Translated by Nita Lery.
  • [**]
    Jean Sutter : La Luxation congénitale de la hanche, Paris, INED-PUF 1972, 240 p. (Travaux et Documents, Cahier n° 62).
  • [***]
    Alain Bideau : Centre P. Léon, UA 223 CNRS ; Henri Plauchu and Guy Brunet : Institut Européen des génomutations, 86 rue F. Locard, 69005 Lyon ; Jacques-Michel Robert : Université de Lyon II.
  • [1]
    Henri Plauchu and Alain Bideau, "Epidemiologie et constitution d’un registre de population à propos d’une concentration géographique d’une maladie héréditaire rare", Population, 4-5, 1984, pp. 765-786.
  • [2]
    J. Sutter, L’atteinte des incisives latérales supérieures. Paris, INED-PUF, 1966, 148 p. (Travaux et Documents, Cahier n° 46). La luxation congénitale de la hanche. Paris, INED-PUF, 1972, 242 p. (Travaux et Documents, Cahier n° 62).
  • [3]
    J. Feingold, A. Hennequet, M. Jehanne, J. Feigelson, L. Toudic, O. Quiniou, M.L. Briard, "Fréquence de la fibrose kystique du pancréas en France", Annales de Génétique, 17, n° 4, 1974, pp. 257-259.
  • [4]
    E. Bois, J. Feingold, P. Frenay, M.L. Briard, "Infantile cystinosis in France : genetics, incidence, geographic distribution", Journal of Medical Genetics, 13, 1976, pp. 434-438.
  • [5]
    C. Bonaiti, F. Demenais, M.L. Briard, J. Feingold, J. Frezal, "Congenital glaucoma : genetic models", Human Genetics, 46, 1979, pp. 305-317.
  • [6]
    E.D. Shields, D. Bixler, P. Fogh-Andersen, "Cleft palate : a genetic and epidemiologic investigation", Clinical Genetics, 20, 1981, pp. 13-34.
  • [7]
    A. Petrequin : La maladie de Rendu-Osler. II – Profil clinique et vécu de la maladie : à propos de 324 observations, Medical thesis, Lyon, 1983, 110 p. typed.
  • [8]
    See ref. in fn. 7.
  • [9]
    These are individuals reported as suffering from the disease ; starting with them, a genealogical history is established with, on an average, 6 Rendu-Osler patients in the family, four of whom are still alive (the average is based on more than 500 individual histories).
  • [10]
    L. Venturini : La Maladie de Rendu-Osler. I – Etude épidémiologique et étude génétique : à propos de 324 observations, Medical thesis, Lyon, 1983, 75 p. typed.
  • [11]
    M.J. Wehrlen : Utilisation de la mutation Rendu-Osler comme marqueur génétique dans le suivi des populations, Medical thesis, Lyon, 1984, 168 p. typed.
  • [12]
    J.Y. Lehy : L’angiomatose de Rendu-Osler : étude démographique et génétique dans le département des Deux-Sèvres, Medical thesis, Nantes, 1983, 164 p. typed.
  • [13]
    McKusick, Mendelian inheritance in man, Baltimore and London, The Johns Hopkins University Press, seventh edition, 1986.
English

The geographical dimension of epidemiology is as useful in demography as in medicine. By following the progress of a disease on a map, demographers can trace migration waves and in particular, matrimonial migrations if they carry genetic disorders with them. Thus J. Sutter’s [**] research on the incidence of the congenital dislocation of the hip threw light on endogamy in the Bigouden area.
By determining the area in which the disease is prevalent, physicians can locate one or more areas of geographical concentration undoubtedly caused by genetic mutations which would permit them to organize an efficient system of detection and cure. In the article, the two advantages of an epidemiological investigation of Rendu-Osler disease, a rare illness to which the reader’s attention has already been drawn by Alain Bideau, Henri Plauchu, Guy Brunet and Jacques-Michel Robert[***] in Population1, are clearly outlined.

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