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Report on Research on Rare Diseases in Children: FY 2000 to FY 2005

National Institute of Dental and Craniofacial Research (NIDCR)

Overview of NIDCR Rare Diseases in Children Research Activities, FY 2000–FY 2005

The mission of NIDCR is to improve and promote dental, oral, and craniofacial health through research and research training. NIDCR's programs encompass basic and clinical studies of a broad range of rare diseases, disorders, and syndromes involving the oral cavity and craniofacial structures of children (younger than age 21); related developmental biology studies; applied research on biologically compatible and biomimetic materials and methods to re-engineer damaged or dysfunctional tissues; and behavioral and epidemiological studies to better assess the scope of the problem, identify risk factors for and biomarkers of disease, understand health disparities, and provide the knowledge base for improved preventive and health care.

Most craniofacial anomalies are associated with abnormal developmental events and are apparent in pediatric populations. Rare diseases and syndromes affecting children compose a significant portion of NIDCR's program activities and include clefting syndromes; craniosynostosis syndromes; hemifacial microsomia and other congenital craniofacial anomalies; early-onset periodontitis; storage diseases; ectodermal dysplasias; chondrodysplasias; disorders of tooth and bone formation such as osteogenesis, amelogenesis, and dentinogenesis imperfecta; and noma.

Recent Scientific Advances in Rare Diseases in Children Research

Papillon-Lefevre Syndrome (PLS)

NIDCR-supported researchers identified mutations in the cathepsin C gene as the primary cause of PLS. PLS is a rare and devastating condition that affects the skin and teeth, causing an early-onset periodontitis that is unresponsive to traditional treatment. Affected individuals lose their primary teeth during their pre-school years and all their permanent teeth by the time they are young adults. The periodontitis infection results in severe destruction of bone tissue in the jaws that support the teeth. Twenty-five different mutations in cathepsin C have been identified, all of which render the enzyme non-functional as a lysosomal protease. Discovery of the gene for PLS may provide the means for early diagnosis and future therapies to prevent or slow the associated tooth loss. (FY 2000 through FY 2002)

Cleft Lip and Palate Syndrome

While clefts of the lip with or without cleft palate (CL/P) are one of the most common birth defects, there are different syndromes that include oral clefting and wide variations in types of oral clefts that are individually rare. Most cases of CL/P are non-syndromic; however, in approximately 30% of cases, CL/P occurs as part of a single-gene syndrome. Scientists recently announced the discovery of the gene responsible for autosomal recessive CL/P-ectodermal dysplasia syndrome type 1 (CLPED1). This syndrome is characterized by cleft lip/palate, hidrotic ectodermal dysplasia, and developmental defects of the hands. CLPED1 is generally a rare syndrome, but it occurs with a high frequency of 1 per 2,000 among the population of Margarita Island. The gene responsible, PVRL1 on chromosome 11, encodes the protein nectin-1, an immunoglobulin-related cell-cell adhesion molecule that plays a role in the development of the palate, teeth, and skin. The mutations identified in PVRL1 produce truncated proteins that are thought to interfere with cell-cell adhesion. (FY 2000 through FY 2003)

Ectodermal Dysplasia

Hypohidrotic ectodermal dysplasia results in abnormal development of the teeth, hair, and eccrine sweat glands. Affected children are hyperthermic and have sparse hair, misshapen or absent teeth, and dry skin. Scientists recently identified the gene responsible for the autosomal form of hypohidrotic ectodermal dysplasia. The discovery of the gene, DL, located on chromosome 2, was accelerated by the identification of a mutation in a mouse gene ("downless") that resulted in animals with sparse hair and other features that mimic the human disorder. The protein encoded by this gene acts as a receptor and, in fact, may be serving as the receptor for ED1, the gene previously identified for X-linked hypohidrotic ectodermal dysplasia. (FY 2000 through FY 2003)

Tooth Agenesis

Congenital anomalies involving missing teeth range in severity from mild hypodontia, to oligodontia (six or more missing teeth), to anodontia (the absence of teeth). The incidence of tooth agenesis disorders varies with each class of tooth, with third molars being the most commonly affected. Oligodontia involving the first and second molars is extremely rare. A recent study has identified a frameshift mutation in the PAX9 gene that results in an autosomal dominant form of oligodontia. Affected family members have normal primary dentition but lack most permanent molars. Some individuals also lack premolars as well as incisors. PAX9 is a member of a transcription factor family of genes involved in the formation of the eyes, teeth, palate, and thyroid gland. PAX9 is now the second developmental gene to be linked to the patterning of dentition. Previously, the homeobox gene MSX1 was linked to agenesis of the second premolars and third molars. (FY 2000 through FY 2003)

Ongoing, New, and Planned Research Initiatives in Rare Diseases in Children

Global Network for Women's and Children's Health Research

An RFA was published in March 2000, jointly sponsored by NIDCR and six other NIH Institutes, inviting applications to establish a flexible research network focused on critical global health problems of women and children. International, multidisciplinary teams of investigators will work collaboratively on research questions that are aimed at improving health and preventing premature disease and death among women and children in developing countries. In FY 2001, NIDCR plans to cosponsor one project focused on evaluating treatment interventions to reduce the prevalence of oral clefts in the Philippines.

Mouse Mutagenesis and Phenotyping: Developmental Defects

NIDCR is a participant in this multi-Institute-sponsored RFA that has established a facility in FY 2000 for large-scale mutagenesis and phenotyping of developmental defects in the laboratory mouse. The mouse models produced in this facility are expected to elucidate cellular, molecular, and genetic mechanisms that direct embryonic and post-embryonic growth and function and advance understanding of the mechanisms of human disease, including many rare diseases affecting children.

Center for Inherited Disease Research (CIDR)

NIDCR participation in the CIDR began in February 2000. CIDR is a centralized facility that provides genotyping and statistical genetics services for investigators seeking to identify genes that contribute to human disease. It is a joint effort supported by several NIH Institutes and the Johns Hopkins University. NIDCR-funded investigators seeking to identify gene mutations that contribute to inherited diseases, including many rare diseases that affect children, can now apply for use of the CIDR genotyping facility.

World Health Organization (WHO) Conference on International Collaborative Research on Craniofacial Anomalies

NIDCR supported an international consensus conference on craniofacial anomalies that was organized by the WHO and held in Geneva, Switzerland in November 2000. This three-day meeting brought together clinicians, epidemiologists, statisticians, and molecular and developmental biologists from around the world. Sessions focused on clinical treatment, genetics, gene/environment interactions, epidemiology, and bioethical issues in medical genetics. Experts described the state of the science and addressed guidelines for standardizing criteria, protocols, and methodologies that are needed to facilitate future global collaborative research efforts in the prevention and treatment of craniofacial anomalies.

Workshop on Strategies for Tooth Structure Regeneration

On May 12, 2000, NIDCR and ORD co-sponsored a workshop on "Strategies for Tooth Structure Regeneration." A variety of rare disorders that affect children are characterized by tooth abnormalities such as missing dentition, early tooth loss, and deformities in tooth structure. These disorders include the ectodermal dysplasias, Van der Woude syndrome, Williams syndrome (WMS), osteogenesis imperfecta (OI) type I, osteopetrosis, and many others. The specific purpose of the workshop was to provide a critical assessment of the state of knowledge in molecular genetics and bioengineering approaches that are essential for developing therapeutic strategies for tooth regeneration. The workshop provided a forum for biomedical researchers, clinicians, and engineers to discuss their vision for solving current obstacles to developing therapeutic strategies.

Workgroup on Genetics and Craniofacial and Dental Anomalies

In Novermber 1999, NIDCR held a workshop to assess the current status of dental, oral, and craniofacial genetics research. A committee of 60 scientists met to identify opportunities and obstacles for genetics research in the NIDCR research portfolio. The workgroup identified 47 heritable disease categories involving craniofacial, oral, and dental manifestations, the majority of which are rare disorders affecting children. The workgroup developed a set of prioritized recommendations for genetic and genomic research activities and resources to be developed during the next five years that will accelerate discoveries of causal gene products and facilitate prenatal diagnoses of these disorders.

Office of International Health Activities on Noma

NIDCR is a Collaborating Center of the International Action Network Against Noma that was launched by WHO in 1994. Noma is a devastating infection of severely protein-malnourished children in which extensive amounts of facial tissues are destroyed. The mortality rate exceeds 80%. The etiology and pathogenesis of the disease remains unknown. To enhance awareness of the disease and discuss research directions, NIDCR sponsored a seminar on international collaborative research on noma in June 1999. NIDCR is funding research on noma at the Forsyth Institute in Boston involving the use of new techniques to identify bacteria in the lesions that currently cannot be cultured. Through a supplement to a Fogarty International Training and Research in Emerging Infections grant to the University of Maryland, NIDCR is supporting clinical studies to characterize the earliest lesions in noma patients. The results will help identify ways to manage the infection while addressing the nutritional deprivation.

FY 2001 WHO Conference on the Prevention of Craniofacial Anomalies

NIDCR is supporting a consensus conference organized by the WHO entitled, "International Collaborative Studies on the Prevention of Craniofacial Anomalies," which will be held in Utah in May 2001. This WHO meeting will develop recommendations for global activities directed towards the prevention of craniofacial anomalies. The conference will focus on recent evidence that specific maternal vitamin deficiencies are associated with an increased risk of cleft lip and palate and will develop recommendations for the design of intervention trials to determine whether maternal vitamin supplementation will reduce the birth prevalence of clefts. The impact of environmental exposures during pregnancy such as maternal tobacco and alcohol use on the risk of craniofacial birth defects will also be discussed.

Activities with Voluntary Rare Diseases Organizations to Stimulate Research

Skeletal Disorders and Diseases

NIDCR is a participant in an NIH consortium that provides support for the NIH Osteoporosis and Related Bone Diseases National Resource Center. The Center is mandated to increase awareness and knowledge about osteoporosis and related bone diseases and is a partnership between the leading national nonprofit organizations in the field (the National Osteoporosis Foundation, the Paget Foundation, and the Osteogenesis Imperfecta Foundation) and NIH. Adolescent females represent a major at-risk population for future osteoporosis, and they are a key target of several of the Center's programs. Tasks of the Center include expanding the acquisition of research information; promoting the Center to physician and public audiences through exhibits and public service announcements; and disseminating information via electronic methods and print publications to medical and managed care organizations and at-risk populations. The Center also develops partnerships to evaluate model education programs to enhance bone health and reduce future risk of osteoporosis among at-risk populations. (FY 2000 through FY 2003)

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Last Reviewed: February 1, 2005
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