Human Genomics in Global Health

International collaborative research on craniofacial anomalies project

The International Collaborative Research on Craniofacial Anomalies project supported by the World Health Organization (WHO) is to establish an international network for the purpose of encouraging research in craniofacial anomalies (CFA) under four main areas:

  • genetic basis of craniofacial anomalies
  • hereditary and environmental interactions involved in craniofacial anomalies
  • prevention of craniofacial anomalies
  • optimal treatment of craniofacial anomalies

Current status of research in craniofacial anomalies
Main objectives
Project consensus meetings
Team members

Current status of research in craniofacial anomalies

Current research in craniofacial anomalies falls into three related spheres: etiology, prevention, and treatment. Unfortunately, much of this research is being conducted independently, with little evidence of a coherent global strategy.

Craniofacial anomaly

Research on the genetic basis of craniofacial anomalies has benefited dramatically over the last decade from the development of recombinant DNA technology. In over 50 craniofacial syndromes, genes involved have either been mapped to a chromosome location or actively isolated and their structure identified. However, this achievement represents only a fraction of the total number of craniofacial syndromes defined. The pathogenesis of the most common forms of CFA (non-syndromic) are especially challenging because they appear to arise from complex polygenic interactions with environmental influences. A co-ordinated international approach to this work will not only provide effective means of sharing data, samples and resources, but strategic exploitation of geographic and ethnic variation in the incidence and pathogenesis of CFA may hold the answer to vital questions.

Research on the prevention of craniofacial anomalies has been based primarily on isolated case control studies in Europe, Asia, USA and Latin America. These projects have occurred independently of each other, and consistent conclusions about viable interventions such as dietary supplementation in the preconceptional period have yet to emerge. Once again, international standardization of research protocols, consensus on preventive interventions suitable for clinical trials, and the performance of trials in an international framework, will enhance both their validity and consistency.

Craniofacial anomaly

The treatment of craniofacial anomalies has, so far, escaped the rigours of contemporary health technology assessment causing great confusion around what constitutes optimal management for even the most common conditions. For each of the many subgroups of CFA, the attainment of homogeneous samples of adequate size for randomized trials and long-term follow-up represents a significant challenge. Multisite cooperation is a prerequisite. In the developing world, the cost of rehabilitation and problem of access, puts treatment beyond the reach of vast numbers of affected individuals. Research is urgently required on systems of delivering care in different geographic and economic circumstances.

Main objectives

The main objectives of this project are:

  • to develop an international network for consensus building, planning and development for international collaborative biomedical, epidemiological and behavioural studies in the core areas of craniofacial anomalies research, namely the genetic basis, gene/environment interaction, prevention and treatment.
  • to create a directory of research resources in craniofacial anomalies.
  • to create the International Database on Craniofacial Anomalies (CFA)- a publicly accessible internet-based database composed of common data elements from the various global birth defect registries.

Project consensus meetings

International collaborative research on craniofacial anomalies

Four consensus meetings have taken place in order to review current research work and to establish international networks of health professionals for the purpose of defining craniofacial research in each of the four topic areas.

  • genetic basis of CFA
  • gene-environment interactions involved in CFA
  • prevention of CFA
  • optimal treatment of CFA

Three consensus meetings were held in Geneva, Switzerland from 5-8 November 2000, and included concurrent workshops on research concerning the genetic basis of CFA, gene/environment interactions, and the treatment of craniofacial anomalies.The fourth consensus meeting was held in Utah from 24-26 May 2001 and considered the prevention of craniofacial anomalies.

The aims and objectives of these consensus meetings were to:

  • seek counsel from experts involved in craniofacial research around the world.
  • describe the “state-of-the-science” with regard to treatment, genetics, gene/environment interaction and prevention, and highlight recent relevant research.
  • discuss requirements for future research in all areas of craniofacial anomalies.
  • arrive at a consensus on approaches to address data gaps, strategies, methodologies and protocols to advance knowledge.

Meeting report

International Database on Craniofacial Anomalies (IDCFA)

A meeting of experts was held to address the development of the international database of craniofacial anomalies (IDCFA) in Bauru, Brazil, 4-6 December 2001.

The objectives of the meeting were to

  • perform a critical analysis of comparability and compatibility of craniofacial birth defect registries
  • identify the essential global data needs, and to propose corresponding common set of data to be collected
  • design a framework for a global database composed of all the chosen elements

Meeting report


The successful completion of the project is an important step toward concerted international action aimed at achieving a number of long-term outcomes in future CFA research.

  • an integrated, international database of clinical descriptors, genetic locations, gene sequences and biochemical pathways involved in CFA
  • enhanced understanding of gene functions and the environmental influences, and the identification of factors governing variations across populations, thus targeting ‘at risk’ individuals, families and communities for prevention efforts
  • precise recommendations on dietary supplements (micronutrients and vitamin supplements), screening and other interventions to establish effective public programs aimed at reducing the risk for CFA
  • recommendations on optional treatments and delivery models for CFA care over a wide range of preventive and reconstructive needs

Team members

Drawing on its multinational experience and fifty years of contact with world leaders in genetics, nutrition, prevention and treatment, WHO cooperated with four team leaders to execute this project.

Dr Victor Boulyjenkov

Victor Boulyjenkov, PhD, DSc
Human Genetics Programme, World Health Organization

Dr. Boulyjenkov is responsible for the overall implementation and coordination of the project and for contacts on technical aspects of the project. He has more than 10 years of experience in supporting international collaborations between WHO and non-governmental organizations, including those on genetics and monitoring birth defects. WHO assists countries in the development of their national programmes on the control of birth defects in cooperation with the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS) and the European Registration of Congenital Anomalies (EUROCAT). At present, 26 various programmes of the ICBDMS in 22 different countries perform monitoring of 22 major congenital malformations, including clefting, covering about 3 million births annually. The EUROCAT data are based on 34 registers from 16 countries. He is the author of more than 100 publications in periodicals, and over 90 documents/reports related to WHO human genetics programme have been prepared under his direct responsibility.

Jeffery Murray

Jeffrey Murray, PhD, MD
Project team leader: genetic basis of CFA

Currently a Professor of Paediatrics at the University of Iowa, Department of Paediatrics, University of Iowa, USA, Dr. Murray is an expert in clinical and molecular genetics, especially in the field of gene and gene-environment interactions, resulting in clefts. He and his collaborators have identified the genetic association of clefting with TGFA and MSX1 and the gene (IRF6) for van der Woude syndrome. He has over 10 years experience with Operation Smile in a variety of international settings in the Philippines, Brazi and Japan on clefts. He collaborates closely with projects in Denmark and Norway as well.

Peter Mossey

Peter Mossey, PhD
Project team leader: genetic-environment interactions in CFA

Dr Peter Mossey is currently Professor of Craniofacial Development & Consultant in Orthodontics, Unit of Dental and Oral Health, University of Dundee Dental School, UK. He is presently involved in a number of research projects on aspects of etiology and pathogenesis of orofacial clefting, and has a particular interest in gene-environment interaction. His research team is in active collaboration on a number of multicentre research projects, particularly in Europe, the USA, and Brazil. He has also established links with countries where there is an unmet need, such as India and Nepal, where surveillance of craniofacial birth defects is being combined with research on etiology.

Ronald Munger

Ronald Munger, PhD, MPH
Project team leader: prevention of CFA

Dr. Munger is currently Professor at the Department of Nutrition and Food Sciences and Director of the Center for Epidemiologic Studies at Utah State University, Logan, Utah, USA. He has more than 15 years of experience in epidemiology, nutrition, and public health. He has participated in international research projects on maternal nutritional and risk of oral cleft birth defects.

William Shaw

William Shaw, PhD
Project team leader: treatment for patients with CFA

Professor Shaw is Professor of Orthodontics and Dentofacial Development at the Department of Dental Medicine and Surgery, University of Manchester. He is the Director of the Greater Manchester Cleft Lip and Palate Service, and co-ordinator of the EUROCRAN Project, an international Research consortium funded by the European Union. Since 1996 he has also been joint co-ordinating editor of the Cochrane Collaboration Oral Health Group.

Pierpaolo Mastroiacovo

Pierpaolo Mastroiacovo, PhD
Principal investigator, International Database on Craniofacial Anomalies (IDCFA)

Prof. Mastroiacovo is currently the Director of the International Centre for Birth Defects (ICBD). Until October 2002 he was Full Professor in Pediatrics and Chief of the Institute of Clinical Pediatrics of the Catholic University of Sacred Heart in Rome. He is professor in pediatrics with a wide experience in epidemiology and monitoring of birth defects. He published more than 120 papers on international journals in the field of birth defects prevention, epidemiology and clinics and in public health promotion. He is responsible for the Research Projects performed at ICBD and he is member of several medical and research associations and societies.

Elisabeth Robert-Gnansia

Elisabeth Robert-Gnansia, MD, PhD
Principal investigator, International Database on Craniofacial Anomalies (IDCFA)

Elisabeth Robert-Gnansia is the head of the Institut Européen des Génomutations, Lyon, France, where epidemiologic and advisory work is performed through registry of congenital malformations and teratogen information services. She acts as a 'liaison' between both organizations. She was President of the European Teratology Society in 1998-99, and has been a member of the Teratology Society since 1988. She serves on the editorial board of Reproductive Toxicology and as a consultant in Teratology for several medical journals. In 1998 she created a course of Teratology at the University of Lyon, France. Elisabeth has been involved in epidemiologic studies of a number of different malformations, including 3 different studies on facial clefts, and has been working on environmental exposures with respect to their potential effect on human reproduction. She is at the origin of the discovery of valproic acid as a teratogen in 1982 and since then has published several papers/book chapters on the reproductive risks of anticonvulsants, and also of other drugs like topical drugs, antineoplastics, vaccines, sex hormones, anorectics, antithyroids, corticosteroids, antidepressants (invited editorial for the New England Journal of Medicine). She is interested in the concepts of risk evaluation and risk communication.