Management of neurofibromatosis.

WHO News and activities Management of neurofibromatosisa Neurofibromatosis (NF) is a serious, genetically determined neurological disorder that affects both sexes and all races and ethnic groups. There are at least two forms of neurofibromatosis: NFl, which is commoner (affecting 1 in 4000 births) and can affect the ectodermal, mesodermal, and neural tube systems; and NF2 (affecting 1 in 100000 births), which ap- pears only to affect tissues in the ectodermal system. The Second Joint WHO/NNFF (National Neuro- fibromatosis Foundation) Meeting on the Control of Neurofibromatosis was held in Vienna, Austria, on 28 June 1992. Below are summarized the discussions and recommendations made by the participants. Educational materials Leaflets covering the clinical, genetic, and manage- ment aspects of NFl and NF2, which are available as educational materials to the general public, were reviewed at the meeting; the majority were written in English. Selected texts are also available in Dutch, French, and Spanish upon request from NNFF. Although the information in each brochure was simi- lar, the participants agreed that slight modifications should be made to adapt to the local health care structures in different countries. It would be helpful if a selection of brochures could be made available to those countries in the process of developing lay organizations for the condition and setting up NF clinics for the first time, so that they could design specific leaflets best-suited to their own needs. Resources available for the management of NF There is no uniform pattern of organizing health care for NF patients and the participants at the meeting had themselves been responsible for setting up NF clinics because of their own personal interest. A consensus for the management of patients with NFl was issued by the National Institutes of Health in 1987. It was agreed at the meeting that affected individuals should undergo annual medical reviews to determine whether they have any symp- toms or signs of complications. Bearing in mind the age of the patient, the examining physician should estimate the extent of any complications that may present, e.g., learning difficulties in school-age chil- dren. Whether or not an investigation is required to screen for complications is equivocal. A few centres recommend routine cranial imaging to monitor the development of optic gliomas, while most believe a Based on a contribution by V. Boulyjenkov. Reprint No. 5498 that the very low frequency of symptomatic optic gliomas and lack of proven evidence as to the benefit of detecting presymptomatic lesions does not justify this approach. Under the auspices of WHO it may be possible to target key clinicians in different countries to encourage them to develop a service for the care of NF patients. Clinicians with an interest in developing expertise in NF could be encouraged by the provi- sion of international visiting fellowships which could be sponsored by lay organizations. When it is decided to set up an NF clinic, it would be useful if the organizers inform the Interna- tional Neurofibromatosis Association (INFA), which would provide an information package to facilitate the establishment of the planned clinic. Such an information package could include the National In- stitutes of Health Consensus Statements on NF and Acoustic Neuroma, a variety of non-technical leaf- lets, copies of reports from WHO meetings, and an invitation to become a contributing centre to the NNFF International Database. The NNFF International Database is now in op- eration and any NF centre can contribute to it. The collection of standardized data that are thus produced was applauded at the meeting and it was suggested that information gathered by the database in certain key areas could be highlighted for future study; for example, learning disabilities, the natural history of optic glioma, and the natural history of plexiform neurofibromatosis, with particular respect to their predilection for malignant degeneration. Opportunities for international research collaboration The longest-running research collaboration in the world is the NNFF International Consortium on Gene Function in NFI and NF2, which is managed by the NNFF in the USA. The consortium, which meets approximately every nine months, includes all the major laboratories in the world that are currently working on NFl and NF2. Its purpose is for scien- tists to share new data regularly and thus to acceler- ate the pace of progress in NF research. The NNFF recently formed the International NFl Genetic Analysis Consortium, with both clini- cians and molecular biologists represented. The aim of the consortium is to encourage laboratories to sub- mit clinical data on all patients identified as having mutations within the NFI gene. In this way, it is hoped to identify genotype/phenotype correlations. Treatment for specific complications is particu- larly relevant to NF1. There is still controversy as to the ideal approach to investigating and managing certain aspects of NFl, such as learning disabilities, Bulletin of the World Health Organization, 1994, 72 (3): 511-516 © World Health Organization 1994 511 WHO News and activities presymptomatic detection and treatment of optic gliomas, and the identification of patients at risk for developing malignant nerve tumours. In contrast, the investigations used for assessing and treating patients with NF2 are much more uniform. However, since this condition is much rarer, it is important that liai- son between centres is encouraged so that new devel- opments in management can be compared for large numbers of patients. International research collaboration on these issues could be further encouraged by convening workshops/symposia of experts to consider specifi- cally such matters. Funding for such meetings would need to be provided by the lay NF organizations, but the INFA could play a coordinating role. Although no curative treatment is yet available for any of the disease manifestations of NFl or NF2, it is likely that further understanding of the function of the disease genes may lead to preventative treat- ments. These would need to be assessed in well- organized trials, and a number of centres would need to collaborate to ensure maximum participation. How such treatments could be quantatively measured could be the subject for discussion within the frame- work of a workshop in the near future. Conclusions and recommendations The INFA and WHO should collaborate on the issues outlined below. * Available literature on NFl and NF2 for the general public should be compiled for review by the NNFF so that the most appropriate information on every aspect of the two disorders can be assembled for distribution to centres starting up new NF clinics as well as to indi- viduals setting up new lay organizations. * Clinicians in different countries should be encour- aged to develop an expertise in neurofibromatosis. An information package should be made available to such individuals and the opportunities should be created for visiting fellowships to enable them to attend recognized NF clinics. * International research collaboration on the mol- ecular genetics of NF is well established and encour- aged by the regular meetings of the NNFF Inter- national Consortium on Gene Function in NFl and NF2. The recently formed International NFl Genetic Analysis Consortium is a move towards international collaboration at the clinical level, but there are speci- fic aspects of both NFI and NF2 where such collabo- ration could be further encouraged. * Future joint meetings of the INFA and WHO should be encouraged; these could be convened as satellite meetings at either major international gen- etics or neurofibromatosis meetings. Human plague in 1992b During 1992, nine countries notified a total of 1758 cases of human plague (including 198 deaths) to WHO. In 1991, plague was reported by 10 countries with human cases totalling 1966, of which 133 were fatal (Table 1).c In 1992, the global case-fatality rate was 11.3%, compared with an average of 10.1% per year in the previous 10 years. Table 1 shows the global incidence and distribu- tion of plague from 1978 to 1992. During this period 15 032 cases with 1511 deaths were notified in 21 countries, six of which (Brazil, Madagascar, Myan- mar, the United Republic of Tanzania, the USA, and Viet Nam) reported human plague practically every year. The highest numbers of plague cases were recorded in 1984, 1988 and 1990-92. Over the peri- od 1983-92, 62.5% of the cases (7466) and 81.8% of the deaths (1021) were reported from Africa. Africa In Africa, human plague was reported in Madagascar and Zaire, giving a total of 588 cases (166 deaths). As in previous years, plague in Madagascar (198 cases, 26 deaths) was recorded in the following four provinces: Antananarivo, Fianarantsoa, Mahajanga and Toamasina. A tendency for the incidence of plague to increase in Madagascar has been observed since 1988. As in 1991, the majority of cases were recorded in Antananarivo Province (61 cases, 19 deaths) and Fianarantsoa Province (99 cases, 5 deaths). Peaks in plague incidence were observed in January-May and November-December. The total number of plague cases reported from Zaire was 390, with 140 deaths. Human plague con- tinued to be recorded in the Ituri Sub-region (Upper Zaire Province) affecting five rural health zones: Logo, Rimba, Nyarembe, Rethy, and Bunia. The three major clinical forms of the disease - bubonic, septicaemic and pulmonary - were registered in 1992. Cases were reported from January until September, with a major incidence noted during May-July (nearly 60% of the annual total). The Americas In the Americas, a total of 158 plague cases (6 deaths) were reported by three countries: Brazil (25 cases), Peru (120 cases, 4 deaths) and the USA (13 cases, 2 deaths). b Based on: Human plague in 1992. Weekly epidemiological record, 1994, 69(2): 8-10. c See: Human plague in 1991. Weekly epidemiological record, 1993, 68(4): 21-23. 512 WHO Bulletin OMS. Vol 721994 Notes et activites OMS Prise en charge de la neurofibromatosea La neurofibromatose (NF) est une affection neurolo- gique grave, d'origine genetique, qui touche indiff&- remment les deux sexes, toutes les races et tous les groupes ethniques. I1 existe au moins deux formes de neurofibromatose: la forme NFl, la plus fr6quente (1 naissance sur 4000), peut affecter les tissus d'origine ectodermique, mesodermique et nerveuse; la forme NF2 (1 naissance sur 100 000) semble ne toucher que les tissus d'origine ectodermique. La deuxieme reunion conjointe OMS/NNFF (National Neurofibromatosis Foundation) sur la lutte contre la neurofibromatose s'est tenue a Vienne, (Autriche) le 28 juin 1992. On trouvera ci-dessous un resume des discussions et des recommandations des participants. Materiel didactique Lors de la reunion, les participants ont examine des brochures destinees au grand public et couvrant les aspects cliniques et genetiques de la NFl et de la NF2 ainsi que leur prise en charge. La plupart de ces brochures etaient redigees en anglais. Certaines bro- chures sont egalement disponibles en espagnol, en francais et en neerlandais sur demande adressee a la NNFF. Meme si leur contenu ne differait guere, les participants sont convenus qu'elles devaient etre legerement modifiees pour etre mieux adaptees aux structures locales des soins de sante dans les diff& rents pays. Il serait utile de mettre quelques-unes de ces brochures 'a la disposition des pays qui mettent actuellement sur pied des organisations non profes- sionnelles pour la prise en charge de la maladie et qui creent des centres de soins pour les neurofibro- mateux, afin que ces pays puissent elaborer leurs propres brochures, adaptees a leurs besoins. Ressources disponibles pour la prise en charge de la NF L'organisation des soins aux neurofibromateux ne repond pas a un schema uniforme. Les participants a la reunion ont par exemple ete eux-memes impliques dans la creation de centres antineurofibromateux pour des motifs personnels. Un consensus sur la prise en charge des sujets atteints de NFl a ete publie par les National Insti- a D'aprbs un article de V. Boulyjenkov. Tire a part No 5499 tutes of Health en 1987. I1 a ete convenu que ces sujets devaient se soumettre 'a un examen medical annuel afin de rechercher des signes de complica- tions. Compte tenu de l'age du sujet, le medecin devra evaluer l'etendue des eventuelles complica- tions, par exemple des difficultes d'apprentissage chez les enfants d'age scolaire. La question de savoir s'il faut proceder a des investigations plus poussees pour rechercher les complications est ouverte. Quelques centres recommandent de proc6der periodi- quement a des imageries craniennes afin de sur- veiller l'apparition de gliomes optiques, alors que la plupart des autres estiment que la tres faible frequen- ce des gliomes optiques symptomatiques et I'absence de preuves de l'interet de la detection de lesions pre- symptomatiques ne plaident pas en faveur de cette approche. Sous les auspices de l'OMS, il peut etre possible de reperer dans differents pays les cliniciens particu- lierement interesses et de les encourager 'a creer un service de soins aux neurofibromateux. Les medecins qui s'interessent 'a cette maladie pourraient etre encourages grace at 1'attribution de bourses d'echan- ge intemationales, qui pourraient etre parrainees par les organisations non professionnelles. Lorsqu'il a ete decide de creer un centre anti- neurofibromateux, il serait utile d'en informer l'Intemational Neurofibromatosis Association (INFA), laquelle pourrait foumir aux organisateurs toute l'information necessaire pour faciliter la creation du centre prevu. Cette information pourrait comprendre les declarations de consensus des National Institutes of Health sur la neurofibromatose et le neurinome de l'acoustique, diverses brochures grand public, des exemplaires de rapports de reunions de l'OMS, et une invitation a collaborer a la base de donnees intemationale de la NNFF. La base de donnees intemationale de la NNFF est maintenant operationnelle et tout centre NF peut y contribuer. Le recueil de donnees standardisees a ete applaudi par les participants, qui ont suggere que les informations recueillies dans certains domaines cles soient mises en avant pour de futures etudes, par exemple sur les difficultes d'apprentissage, sur l'his- toire naturelle des gliomes optiques et celle de la neurofibromatose plexiforme, en insistant particulie- rement sur la tendance marquee de ces demiers a la degenerescence maligne. Possibilites de collaboration en recherche internationale Le NNFF International Consortium on Gene Func- tion in NFl and NF2, gere par la NNFF aux Etats- Bulletin de l'Organisation mondiale de la Sant6, 1994, 72 (3): 517-523 © Organisation mondiale de la Sante 517 Notes et activit6s OMS Unis d'Amerique, represente la plus longue collabo- ration au monde en matiere de recherche. Le Consor- tium, qui se reunit tous les neuf mois environ, inclut tous les grands laboratoires qui travaillent actuelle- ment sur la NFI et la NF2, et permet aux chercheurs du monde entier d'echanger regulierement leurs nou- veaux resultats, dans le but d'accelerer les progres de la recherche sur la neurofibromatose. La NNFF a recemment constitue l'Intemational NFI Genetic Analysis Consortium, constitue de cli- niciens et de biologistes moleculaires et consacre a l'analyse genetique de la NFI. Ce Consortium est destine 'a encourager les laboratoires 'a soumettre des donnees cliniques sur tous les sujets chez lesquels on a identifie des mutations du gene NFI. On espere ainsi trouver des correlations entre genotype et phe- notype. Le traitement des complications specifiques est particulierement important en ce qui conceme la NFl. La meilleure approche pour 1'etude et la prise en charge de certains aspects de la NFl est encore au centre des debats, notamment en ce qui concerne les difficultes d'apprentissage, la detection presympto- matique et le traitement des gliomes du nerf optique, et l'identification des sujets pour lesquels il y a un risque d'apparition de tumeurs malignes du systeme nerveux. Les investigations applicables 'a la NF2 sont en revanche plus uniformement reconnues. Toute- fois, comme cette deuxieme forme est beaucoup plus rare, il importe d'encourager les liaisons intercentres de facon 'a pouvoir comparer les nouvelles approches de la prise en charge sur un plus grand nombre de malades. La collaboration intemationale en matiere de recherche sur ces questions pourrait etre encore davantage encouragee par l'organisation d'ateliers et de seminaires specifiques. Le financement de telles reunions devrait etre assure par les organisations non professionnelles de la NF, mais la coordination pour- rait etre assuree par l'INFA. Bien qu'il n'existe 'a l'heure actuelle aucun trai- tement curatif pour les manifestations de la NFI ou de la NF2, il est probable que la connaissance de la fonction des genes de la maladie pourra conduire a la mise au point d'un traitement preventif. Celui-ci devra etre evalue lors d'essais bien concus, et la col- laboration d'un certain nombre de centres sera neces- saire pour assurer une participation maximale. L'evaluation quantitative de tels traitements pourrait faire l'objet de discussions dans le cadre d'un pro- chain atelier. Conclusions et recommandations L'INFA et l'OMS devraient collaborer dans les domaines suivants: * Les publications sur la NFI et la NF2 destinees au grand public devraient etre collationnees en vue de leur examen par la NNFF de fa,on a rassembler les informations les plus adaptdes sur les differents aspects des deux formes de la maladie, pour les dis- tribuer aux centres qui mettent sur pied de nouveaux services antineurofibromateux, ainsi qu'aux particu- liers interesses par la fondation de nouvelles organi- sations non professionnelles. * Les cliniciens des divers pays devront etre encou- rages a developper leurs competences dans le domai- ne de la neurofibromatose. Un module d'information devra etre mis a la disposition de ces personnes ainsi que des possibilites de bourses leur permettant d'effectuer des stages dans des centres NF reconnus. * La collaboration intemationale en matiere de recherche sur la genetique moleculaire de la NF est deja bien etablie et est encouragee grace a des reunions periodiques du NNFF International Consor- tium on Gene Function in NFI and NF2. L'Intema- tional NFl Genetic Analysis Consortium, recemment constitue, est un pas de plus vers la collaboration internationale au niveau clinique, mais il existe enco- re des domaines de la NFI et de la NF2 dans les- quels une telle collaboration devra etre encore davantage encouragee. * I1 faudra encourager l'organisation de futures rdunions conjointes de l'INFA et de l'OMS; il pour- rait s'agir de reunions annexes dans le cadre de grandes reunions intemationales consacrees a la genetique ou a la neurofibromatose. La peste humaine en 1992b En 1992, neuf pays ont notifie a l'OMS un total de 1758 cas de peste humaine (dont 198 deces). En 1991, dix pays avaient notifie des cas de peste, avec 1966 cas humains dont 133 mortels (Tableau 1).c En 1992, le taux de letalite dans le monde a ete de 11,3% contre une moyenne de 10,1% par an au cours des 10 annees precedentes. Le tableau 1 montre l'incidence et la distribution mondiales de la peste de 1978 a 1992. Pendant cette pdriode, 15 032 cas et 1511 d6ces ont ete notifies dans 21 pays, dont 6 (Bresil, Etats-Unis d'Amerique, Madagascar, Myanmar, Republique-Unie de Tanza- nie et Viet Nam) ont signale des cas de peste humai- ne pratiquement chaque annee. Les nombres les plus b D'apres: La peste humaine en 1992. Relev6 6pid6miologique hebdomadaire, 1994, 69(2): 8-10. c Voir: La peste humaine en 1991. Relev6 6pid6miologique heb- domadaire, 1993, 68(4): 21-23. 518 WHO Bulletin OMS. Vol 72 1994