Biennial and Annual Report on the Rare Diseases Research Activities at the National Institutes of Health FY 2004

National Institute of Dental and Craniofacial Research (NIDCR)

Overview of NIDCR Rare Diseases Research Activities

The mission of the National Institute of Dental and Craniofacial Research is to improve oral, dental, and craniofacial health through research, research training, and the dissemination of health information. NIDCR’s programs encompass basic, translational, and clinical studies of the broad range of diseases, disorders, conditions, and syndromes involving the oral cavity and craniofacial structures. NIDCR’s section of this report highlights selected scientific advances within the Institute’s intramural and extramural programs and other related program activities relevant to rare diseases that fall within NIDCR’s mission.

Recent Scientific Advances in Rare Diseases Research:

Alzheimer’s Disease and Amyotrophic Lateral Sclerosis

Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases characterized by selective loss of motor neurons in the brain and spinal cord. Dysregulation of an enzyme known as cyclin-dependent kinase 5 (Cdk5) expression has been implicated as playing a critical role in processes underlying neurodegenerative diseases. In order to analyze the role of Cdk5 in such disorders, NIDCR scientists have developed many mouse models in which Cdk5 expression is genetically altered in one or more areas of the brain, during or after embryonic development. In one instance, studies of Cdk5-null mice revealed a neurodegenerative process typically seen in ALS. In another, specific elimination of Cdk5 in the frontal brain cortex resulted in drastic neurodegeneration similar to that observed in patients with advanced Alzheimer’s disease. Current studies are focused on further delineating the roles played by Cdk5.

Amelogenesis and Dentinogenesis Imperfecta

Amelogenesis imperfecta (AI) and dentinogenesis imperfecta (DI) are the most common hereditary diseases affecting tooth enamel and dentin, respectively.

  • AI is a heterogeneous group of rare inherited disorders that affect the formation of dental enamel and result in thin, malformed enamel that is easily abraded. As a tooth develops from its bud, an organic matrix forms that gradually crystallizes into tooth enamel. This process destroys nearly all traces of the matrix, along with clues to key information in understanding tooth formation. A team of NIDCR scientists report for the first time that the proteins amelogenin and ameloblastin interact in the matrix before mineralization proceeds. Understanding molecular interactions in the developing organic matrix of the tooth is necessary for understanding the causes of mineralization disorders such as AI and DI.
  • Mutations of enamelin and amelogenin are known to cause AI. Studies of human families have recently resulted in identification of additional genes (known as the kallikrein gene and the MMP20 gene) that, when mutated, cause AI. In addition, studies of human families with AI have shown that some enamelin gene mutations cause only enamel pitting when present as a single copy, while the same mutation present in two doses results in severe enamel defects and altered craniofacial structure, resulting in malocclusion. This is the first evidence for a gene dosage effect for enamelin mutations, which has important implications for understanding the variable clinical findings often reported for AI. These findings also suggest that the clinical phenotype of AI may need to be expanded beyond a simple tooth-related phenotype.
  • NIDCR scientists recently created mice deficient in the enamel matrix protein ameloblastin. The mutant mouse is characterized by severe enamel hypoplasia, a disease similar to AI in humans. In the mutant mice, ameloblasts, cells responsible for production of enamel matrix proteins, continue to proliferate. A significant number of mutant mice develop oral tumors in the maxilla with age. These tumors are likely derived from mutant ameloblasts defective in ameloblastin. Deficiency of ameloblastin is also likely one of the causes of ameloblastoma, the most common human odontogenic tumor.
  • DI is an inherited disorder that primarily affects dentin mineralization. It is classified into three subtypes: type I is the least severe, and type III is the most severe. Type I is also associated with osteogenesis imperfecta, while the more severe forms are restricted to dentin. Several mutations in the dentin sialophosphoprotein (DSPP) gene were recently identified in families with the type II disorder. In collaboration with extramural researchers, NIDCR scientists generated DSPP-deficient mice to characterize molecular roles of DSPP in tooth development. These mice develop tooth defects similar to DI in humans. NIDCR researchers now are analyzing the cooperation between DSPP and genes expressed in hard tissues. Along with NICHD investigators, they also have initiated an analysis of tooth defects in a mouse model for osteogenesis imperfecta.

Behçet's disease

Behçet's disease is a chronic condition that causes severe oral ulcers and ulcerations in other mucosal sites. The exact cause of Behçet's disease is unknown and currently there is no effective therapy. NIDCR scientists are using salivary gland gene transfer to produce proteins that will augment saliva and potentially promote healing of the oral ulcerations in Behçet's patients.

Dentin Dysplasia

Dentin dysplasia is a rare hereditary disorder resulting in dentin defects such as thin and broken dentin, resulting in chipped teeth susceptible to infection. In order to analyze the involvement of growth factors in tooth development, NIDCR scientists developed transgenic mice in which a growth factor (TGF-beta1) is overexpressed. Unexpectedly, these mice developed distinct tooth defects similar to those seen in dentin dysplasia. Currently, NIDCR researchers are characterizing multiple roles of the TGF-beta signaling pathway in tooth biology.

Cleft Lip/Cleft Palate

  • Scientists have gained new insight into the mechanism underlying cleft lip/cleft palate (CL/P) pathogenesis through the genetic mapping of Dancer mutant mice. Mice carrying a spontaneous mutation, Dancer (Dc), exhibit significantly increased susceptibility to CL/P. Researchers genetically mapped most of Dc chromosome 19. Analysis showed that one positional candidate gene, Tbx10, was ectopically expressed in Dc-mutant embryos; furthermore, they showed that ectopic expression of Tbx10 in transgenic mice can be passed to the next generation. Animal models are a valuable source of information in understanding the complex genetic mechanisms underlying CL/P disorders.
  • Researchers assessed the overall and cause of mortality of people from birth to 55 years with CL/P. This study used data from Danish registers to assess the long-term prognosis associated with CL/P, particularly overall mortality and cause-specific mortality. Investigators followed 5,331 people with CL/P. The expected number of deaths was 259, but 402 occurred. The increased risk of mortality was nearly constant for the three intervals at follow-up: first year of life, 1–17 years, and 18–55 years. The participants had an increased risk of all major causes of death. These findings suggest that children born with CL/P and possibly other congenital malformations may benefit from specific preventive health measures into and throughout adulthood.

Coffin-Lowry Syndrome

Coffin-Lowry syndrome (CLS) is an inherited, sex-linked disorder associated with craniofacial, dental, and skeletal abnormalities as well as mental retardation. It is caused by a mutation in RSK2, a gene that encodes a growth factor-regulated enzyme. Investigators supported by the NIDCR have accomplished the molecular dissection of an important signaling pathway and generated mouse models that will allow scientists to advance our understanding of this skeletal disorder and to design strategies for intervention. Specifically, they discovered that the transcription factor ATF4 is the substrate for RSK2 phosphorylation in osteoblasts. Therefore, mutation in RSK2 disrupts the signaling pathway to ATF4, which results in skeletal abnormalities seen in patients with CLS.


Growth and expansion of the brain continues well into postnatal life and requires growth of the overlying calvarial bones of the skull. Premature fusion of the cranial sutures, or craniosynostosis, impedes this growth and results in an abnormal shape of the skull and defects such as blindness and mental retardation. Cranial neural crest (CNC) cells are multipotent cells that contribute extensively to head and neck structures including the palate and calvaria. Molecular mechanisms that regulate the fate of CNC cells during development are not well understood. Previous studies have shown that members of the transforming growth factor β (TGFβ) family play an important role in palatal fusion and skull development. A research team supported by NIDCR recently reported that loss of TGFβIIR results in a complete cleft secondary palate and defects in the calvaria, dura matter, and jaw. The current study is significant in that it provides new information about the role of CNC-derived mesenchyme during development and the molecular mechanism and signaling pathways regulating CNC proliferation.

Dyssegmental Dysplasia

Dyssegmental dysplasia, Silverman-Handmaker type (DDSH) is a rare inherited skeletal disorder characterized by abnormally shaped vertebral bodies and short limbs. Individuals with DDSH also have a flat face, abnormally small jaws, cleft palate, and reduced joint mobility. Recently NIDCR scientists identified mutations of the perlecan gene (HSPG2) in three patients with DDSH. Investigation of the mutations indicates that DDSH is caused by mutations of the perlecan gene similar to perlecan gene-knockout mice. These results indicate that perlecan is essential for cartilage development. NIDCR researchers are studying the role of perlecan in cartilage development by identifying more mutations of DDSH through the creation of additional animal models.

Fabry Disease

Fabry disease is a familial sex-liked disorder of lipid metabolism in which glycolipid accumulates in many tissues. Major disease manifestations include pain in the extremities; angiokeratomas; corneal dystrophy; oral and dental abnormalities; and vascular disease of the heart, kidney, and brain, leading to premature death. Currently, patients are treated by systemic injections with the recombinant enzyme alpha-galactosidase. NIDCR scientists are collaborating with colleagues in NINDS to develop a gene transfer strategy employing salivary glands to treat this disease. Toward that goal, they have reported the generation and characterization of AGA-deficient mice with notable similarities to human patients with Fabry disease. NIDCR scientists are constructing recombinant viral vectors to deliver the enzyme alpha-galactosidase via the salivary glands of the mouse model of Fabry disease, and studies are in progress to analyze abnormalities in teeth and salivary glands of Fabry mice.

Giant-cell Arteritis

Giant-cell arteritis is a chronic granulomatous vasculitic disease primarily affecting elderly women. The typical presenting feature is a continuous, throbbing temporal headache. Other symptoms include pain during chewing, talking, or swallowing; ocular or orbital pain; transient loss of vision; blurred vision; or sudden, permanent blindness. Some patients respond to corticosteroid therapy while others do not; the reason for this difference is not known. NIDCR scientists analyzed vessel biopsy specimens from therapy-responding and nonresponding patients for genes that might account for this difference. They identified and validated several genes that were differentially expressed in the nonresponding patients. Their investigations identify CCL2 (MCP-1) as a relevant molecule in perpetuating inflammatory lesions in giant-cell arteritis and conclude that it may be a marker for the nonresponding patients and serve as a potential therapeutic target.

Growth Hormone Deficiency (Adult)

Growth hormone deficiency (GHD) is a disorder most commonly caused by frank pituitary disease, often the presence of nonfunctional pituitary adenomas, or as a result of surgery or radiotherapy for pituitary adenomas. NIDCR scientists, in collaboration with NICHD colleagues, continue to develop gene transfer strategies to treat adult GHD using salivary glands as the target tissue. Their recent focus has been on reengineering GH so that after gene transfer to a salivary gland, it will be efficiently secreted into the bloodstream. To enhance GH secretion into the bloodstream, they manipulate putative sorting signals in GH. Several GH mutations were tested and one biologically active mutant displayed a relative increase in proportion of GH secretion from rat salivary glands into the bloodstream. The results suggest that the final destination of a transgenic secretory protein may be controlled by reengineering sorting determinants.

Kaposi’s Sarcoma

Kaposi’s sarcoma (KS) is the most common cancer arising in HIV-infected patients and the most frequent oral neoplasm in immunosuppressed patients. KS has also emerged as one of the most prevalent cancers among children and adult men in the developing world. The Kaposi’s sarcoma-associated herpesvirus (KSHV; HHV-8) has been recently identified as the infectious cause of Kaposi’s sarcoma. Of interest, compelling evidence now supports a critical role for the oral cavity as the primary source of infectious HHV-8 in both immunocompetent and immunosuppressed patients. The sequencing of the full KSHV genome revealed a candidate gene, vGPCR, which promoted the development of visible dermal and internal vascular tumors that strikingly resemble human KS lesions. The results implicated vGPCR in both the initiation and promotion of Kaposi’s sarcoma. Subsequent studies examining the mechanism by which vGPCR acts are pointing to downstream targets, which may represent essential mediators of vGPCR-induced neoplasia.

McCune-Albright Syndrome and Fibrous Dysplasia of Bone

The McCune-Albright syndrome is defined by the triad of fibrous dysplasia of bone (FD), café-au-lait skin spots, and endocrine gland hyperfunction. Some patients may have only a single focus of bone affected, and others may have severe disease affecting multiple endocrine glands and virtually the entire skeleton. NIDCR scientists have five clinical research protocols under way studying various aspects of the disease, ranging from a study of the natural history of the disease to treatment studies for the bone and endocrine disorders. The natural history study is producing a number of findings resulting in better understanding of disease progression and patient care management. Clinical drug trials aimed to improve care for patients with this rare disease are ongoing. These findings, and those to come, have implications for the long-term prognosis and clinical management of patients with these rare disorders.


Mucolipidosis type IV (ML-IV) is a rare inherited metabolic disorder that leads to abnormal accumulation of certain fatty substances and complex carbohydrates in the cells of many tissues. It is generally characterized by mental retardation, impaired coordination of muscular and mental activities, and corneal opacity. Currently, there is no animal model available to develop effective therapies to treat this fatal disorder, but a recent advance by NIH scientists may change that situation for the better. In collaboration with NINDS investigators, NIDCR scientists have modified the ML-IV locus in mouse embryonic stem cells and have generated founder mice. These mice will be characterized in detail to identify whether they mimic ML-IV disease.

Schwartz-Jampel Syndrome

Schwartz-Jampel syndrome (SJS) is a rare inherited skeletal dysplasia associated with myotonia (muscle spasms or temporary rigidity). This disorder is characterized by short stature, abnormal development of the cartilage and bone, and a characteristic face with a “fixed” facial expression, narrowness of the fissure between the eyelids, pursed lips, and sometimes low-set ears and myopia. Skeletal abnormalities include spinal curvature, flattened vertebral bodies with coronal clefts, and joint contractures. NIDCR scientists and others have recently identified mutations of the perlecan gene (HSPG2) of patients with SJS. Based on clinical examinations, the SJS phenotype appears to encompass a wide spectrum of disorders. NIDCR researchers are now examining for possible mutations of the perlecan gene in other skeletal dysplasias that were previously identified as chondrodysplasia, such as micromelic chondrodysplasia and Burton’s disease. They have created a mouse model to study the mechanism of SJS myotonia by genetic manipulation. This mouse model will facilitate the development of strategies and reagents for therapy.

Squamous Cell Carcinomas of the Head and Neck

Squamous cell carcinomas of the head and neck result in approximately 11,000 deaths per year in the United States The majority involve neoplastic lesions in the oral cavity, lip, and pharynx. Although the incidence is rare compared to other cancers, these cancers remain among the most fatal and morbid of cancers at any anatomic site.

  • As part of NIDCR’s research program aimed at identifying the nature of those genes expressed during oral cancer development, a genome-wide analysis of nasopharyngeal carcinoma was recently conducted. This analysis enabled the identification of genes differentially expressed in normal, dysplastic, and cancerous cell populations and identified numerous genes whose overexpression can help explain the aggressive clinical nature of this tumor type as well as a decrease in genes involved in programmed cell death and tumor suppression.
  • The protein kinase Akt is a key regulator of normal and cancerous growth and cell fate decisions. Recently it was found that Akt activation correlates closely with the progression of squamous carcinomas in mice and that activation of Akt is a frequent event in human oral cancer. Evidence was obtained that the Akt signaling pathway may represent a biologically relevant target for the novel chemotherapeutic agent UCN-01 at concentrations safely achievable in clinically relevant situations.
  • Using transgenic mice, researchers have created an animal model that can promote the rapid (10–20 days) formation of malignant squamous carcinomas in the skin and oral tissues of animals treated with doxycycline. Current and future use of this animal model system may help to unravel the mechanisms responsible for squamous carcinomas and aid in the search for alternative oral cancer treatments.
  • Epstein-Barr virus (EBV) is the causative agent for several human ailments, including oral hairy leukoplakia, infectious mononucleosis, Burkitt’s lymphoma, and nasopharyngeal carcinoma. EBV infection of B lymphocytes is essential for infection in humans; however, the role of epithelial cell infection in the normal EBV life cycle remains controversial. Using an EBV-related herpesvirus that naturally infects rhesus macaques, researchers have shown that the virus can infect epithelial cells in immunosuppressed macaques and can induce epithelial cell lesions resembling oral hairy leukoplakia. These studies demonstrate a useful animal model for study of the pathogenesis of EBV infection in immunosuppressed hosts in which to perform controlled studies that are impossible to conduct in humans.
  • One of the most persistent problems in the treatment of head and neck cancers is the high incidence of local and regional recurrence, due partly to lack of sensitive techniques that can detect minimal residual disease after surgery or monitor patients for cancer recurrence. NIDCR-funded investigators developed a molecular technique named Gap Ligase Chain Reaction Assay that detects rare amounts of tumor/mutated DNA within a sample of primarily normal DNA. However, the application to clinical screening was hampered by the extended time required for preparation and analysis of the sample. Now they have described a modification termed Fluorescence Gap Ligase Chain Reaction. This assay can be performed in less than 5 hours, while the patient is undergoing surgery, providing crucial information on the spread and recurrence of head and neck tumors. The assay also can aid in molecular staging of head and neck cancers based on analysis of lymph nodes and/or serum.
  • Scientists discovered several years ago that interleukin-12 (IL-12), a protein secreted by immune cells, can alert disease-fighting T cells to recognize, attack, and remember tumor cells for months to come. However, they have found the protein or its gene is most effective when injected directly into tumors, not infused into the bloodstream. In a key first step in this direction, a team of scientists has identified four genes in oral squamous cell carcinoma cells that respond particularly well to direct administration of IL-12. Two of the genes—IRF7 and Wsb2—are little studied by cancer researchers and could provide excellent targets for further investigation. The Il-12 gene was delivered directly into squamous cell carcinoma cells with a technique called electroporation, in which pulses of electricity are used to open up small channels into the cell through which Il-12 can be delivered. Electroporation could have an important future role in treating oral cancer, particularly when combined with other therapies. The work was supported jointly by the NIDCR and the NCI.
  • Previous research has identified a link between the presence of human papillomavirus (HPV) and the risk for developing head and neck cancer. This finding opens a possibility of using HPV as an independent predictor of risk for this cancer. NIDCR-supported scientists used an oral rinse to recover cells that normally are shed in the mouth. They looked for the presence of high-risk HPV in the cells of head and neck cancer patients and compared them with persons of similar age and gender without the disease. They found that HPV high-risk types can be detected from oral exfoliated cells from an oral rinse. The finding may lead to the development of a screening test to prevent oral cancer or to detect it in the earliest stages.

Temporomandibular Muscle and Joint Disorders

Temporomandibular muscle and joint disorders (TMJDs) are a group of conditions causing pain and dysfunction in the temporomandibular joint and surrounding muscles. While there are no firm data on how many people are affected by TMJDs, orofacial pain is a major cause of poor quality of life. The prevalence of TMJDs is higher in women than men. Several recent studies have contributed new knowledge concerning associations between fluctuating levels of reproductive hormones and variations in both clinical TMJD pain and symptoms and responsiveness to experimentally induced pain. A prospective study of pregnant women with diagnosed TMJDs assessed variations in reported TMJD pain throughout pregnancy. A second study linked cyclic changes in levels of endogenous reproductive hormones with clinical pain levels reported by female TMJD patients. Findings from the studies suggest that clinical TMJD pain in women is highest when estrogen levels are at their lowest but that rapid estrogen change can also be associated with higher reported clinical pain levels. Results in rodents in a controlled laboratory setting also suggest that the differences in pain sensitivity found in humans are a real biological effect of sex hormones and not due entirely to the influence of environmental factors.

Rare Diseases Program Activities

Scientific Conferences

  • WHO International Collaboration to Reduce the Health-care Burden of Craniofacial Anomalies: For 5 years, NIDCR has supported a World Health Organization (WHO) global effort titled, "International Collaborative Research on Craniofacial Anomalies." The goal of the project is to reduce duplication of efforts and achieve broader coverage of priority research needs by bringing together international researchers through collaborative partnerships and to develop global consensus on craniofacial anomalies research directions and common research protocols. On December 2–4, 2004, participants met in Geneva to evaluate the project, identify next steps, and make recommendations for the future. Published reports from the project are available on NIDCR and WHO Web sites: and The WHO site also includes public access to the research resources and registry databases.
  • Gordon Research Conference on Craniofacial Morphogenesis and Tissue Regeneration: NIDCR and NICHD co-sponsored the newly established Gordon Research Conference on Craniofacial Morphogenesis and Tissue Regeneration. The international meeting, held in Ventura, CA, in January 2004, provided a forum for the exchange of information about the latest progress in craniofacial research. The conference focused on early events in craniofacial development that underlie human craniofacial defects. Future meetings will take place every 2 years.
  • Temporomandibular Joint Disorder: “The Third Scientific Meeting of the TMJ Association: Advancing Diagnostic Approaches for TMJ Diseases and Disorders” was held May 6–7, 2004, in Bethesda, MD. The meeting was stimulated by the critical need to establish improved research and diagnostic criteria for temporomandibular diseases and disorders. Clinicians and scientists interested in these conditions have been handicapped by an absence of standardized, accepted diagnostic criteria. The goal of the organizers was to bring together experts from many fields to assess and explore novel approaches to current challenges. The meeting was co-sponsored by NIDCR, NIBIB, NIAMS, Office of Rare Diseases, and the Office of Research on Women’s Health.


  • Craniosynostosis: NIDCR has funded a multi-site, 5-year longitudinal study in which infants with one of four types of single-suture craniosynostosis will be recruited: sagittal, metopic, right unilateral coronal, and left unilateral coronal. A case-matched "control" group of healthy, normal infants will also be followed. The long-term objectives are to chart the neurobehavioral course of single-suture fusions and to better understand how the developing cranium affects human brain growth and function. This research will take place in medical centers located in Seattle, Chicago, St. Louis, and Atlanta. Seattle's Children's Hospital and Regional Medical Center is the lead agency.
  • Squamous Cell Carcinoma of the Head and Neck: NIDCR recently funded three projects to develop state models for oral cancer prevention and early detection. The projects, located in Michigan, North Carolina, and Florida, use various methods to increase screening and detection of oral cancers while decreasing known risk factors.

Planned Activities

  • Research Conference: Sjögren’s Syndrome: Transition from Autoimmunity to Lymphoma: An international conference organized by the Sjögren’s Syndrome Foundation to explore the transition from Sjögren’s syndrome to lymphoma will occur in Baltimore, MD, in September 2005. Lymphoma is approximately 40-fold more prevalent in Sjögren’s syndrome patients than the general population, affecting 5–10 percent of patients. The conference will provide a forum for exchange of research findings by new and established investigators and provide opportunities to initiate or strengthen collaborations.


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Last Reviewed: July 22, 2005