What the future holds for ectodermal dysplasias: Future research and treatment directions†‡
Proceedings of the International Conference on Ectodermal Dysplasia Classification, Charleston, South Carolina March 9–12th, 2008 (for submission to The American Journal of Medical Genetics).
How to cite this article: Slavkin HC. 2009. What the future holds for ectodermal dysplasias: Future research and treatment directions. Am J Med Genet Part A 149A:2071–2074.
A contrarian view suggests that the ectodermal dysplasias, including more than 200 different disorders, represent clinical variability and molecular heterogeneity as well as complex multigene heritable conditions often characterized by dysmorphogenesis of derivatives of embryonic ectoderm and beyond. Controversy exists over which syndromes do or do not belong in the classification of the clinical features that characterize ectodermal dysplasias. For example, Ellis–van Creveld syndrome is characterized by abnormalities of the teeth and hair, as well as of the skeleton and the cardiovascular system. Precision in diagnosis often is a preamble for improved patient diagnosis, treatment and desired outcomes. In tandem, molecular studies of complex epithelial–mesenchymal interactions required for ectodermal derivatives (e.g., hair, nail, skin, teeth, and exocrine glands) continue to identify and explain many signal transduction pathways and networks related to ectodermal dysplasias. Meanwhile, major international investments in fundamental biomedical research continue to yield significant benefits to the larger society. The convergence of informatics, nanotechnology, genomics, and epigenetic studies with clinical medicine and dentistry promise major progress for special needs patients such as ectodermal dysplasias. For example, investments in the molecular biology of genes and their regulation and function now provide more than 30 candidates for specific biomarkers to improve diagnosis, prognosis, treatments, therapeutics, and biomaterials for ectodermal dysplasias. Innovations in high throughput genotyping, gene mapping, single nucleotide polymorphisms (SNPs), interference RNA treatments, bioimaging, tissue engineering and related biomimetic approaches to design and fabricate biomaterials, offer enormous promise for the future of ectodermal dysplasias. © 2009 Wiley-Liss, Inc.
Scientific inquiry can often lead to counterintuitive discoveries. It is also apparent that current dogma or so-called traditional thinking may not advance our collective understanding of the genesis of ectodermal dysplasias. Embracing new discoveries and new or alternative paradigms are crucial for the improvement of patient care as well as the advancement of science, technology and the health professions.
Classification of ectodermal dysplasia is changing and will continue to change. Historically, clinicians interested in treatment focused upon descriptions of structure and function (morphologic system). Clinicians addressing natural history and recurrence risk focused on the pathogenesis and cause of the disorder (clinical genetic system). With the recent advances from molecular biology elucidating the genes, patterns of mutations, epigenetic factors and signal transduction pathways that impact epidermal organ morphogenesis, a third system is emerging that is based on the specific mutation(s) in a specific gene accounting for the specific developmental disorder (molecular genetic system). Looking to the future, it is becoming increasingly evident that classification systems must evolve and reflect a much greater depth of understanding of the often complex ectodermal dysplasias.
A brief consideration of the changing nosology or classification of craniofacial dysmorphogenesis can be informative [Cohen and MacLean, 2000; Shum et al., 2000; Jones, 2002]. Human craniofacial morphology is a complex physical set of traits that is controlled by genetic, environmental, mechanical, and epigenetic factors. Mutations in single genes and multiple gene–gene, gene–environmental interactions have been identified [Shum et al., 2000]. Craniosynostosis can present as either non-syndromic or syndromic. In the late 1990s it was realized that clinical variability as well as molecular heterogeneity existed for many craniosynostosis disorders. Mutations in MSX2 (craniosynostosis type 2), FGFR1 (fibroblast growth factor receptor 1), FGFR2 (fibroblast growth factor receptor 2), FGFR3 (fibroblast growth factor receptor 3), TWIST (Saethre-Chotzen syndrome), and FBN2 (fibrillin 2) cause craniosynostosis [Jones, 2002]. It was further discovered that different or multiple mutations within the fibroblast growth factor receptor 2 gene causes different disorders (i.e., mutations in FGFR2 causes Apert, Baere-Stevenson, Crouzon, Jackson-Weiss, and Pfeiffer syndromes). It was also discovered that these FGF receptors have multiple alternative spliceforms or isoforms. Further, identical mutations in the same gene can lead to two different syndromes (i.e., mutations Cys278Phe in FGFR2 produces Crouzon syndrome in some patients and Pfeiffer syndrome in other patients). These provocative and often counterintuitive results challenge our ability to reconcile phenotypic versus molecular classifications [Jabs, 2002]. More recently, linkage disequilibrium analyses identified an FGFR1 haplotype-tag single nucleotide polymorphism (SNP) associated with normal variation in craniofacial shape and produced additional sets of SNPs to be used to discriminate with high resolution between normal and abnormal clinical phenotypes [Coussens and van Daal, 2005]. Therefore, the availability of SNPs and epigenetic investigations (acetylation, methylation, phosphorylation associated with transcriptional regulation) can and will significantly enhance specificity as well as resolution for classifications [Slavkin et al., 2008]. Complementary to the remarkable progress in the completion of the Human Genome and the advances in the identification of disease-causing genes in many human diseases and disorders, the advances in mapping and gene identification of human congenital malformations and syndromes is equally remarkable [Carey and Viskochil, 2007]. Curiously, clinical variability and molecular heterogeneity exists for many examples of ectodermal dysplasias; multiple genes map to different locations on different chromosomes [Cohen, 1997; Cohen and MacLean, 2000; Carey and Viskochil, 2007].
The purpose of this article is to provide recent highlights that provoke a paradigm shift as well as a framework that anticipates changes in the near future for the classification of ectodermal dysplasias. Rapid changes in health care for special needs patients are already occurring at an accelerating pace under the influence of the elucidation of the human genome. These changes also raise a set of critical questions. How can we better educate and train the next generation of health care professionals? How can we better educate existing health professions in the uses of modern genetics for Mendelian as well as for Complex Human Diseases? How can we advance evidence-based health care while controlling for escalating costs in health care? The answers to these and other related questions will profoundly influence the classification for ectodermal dysplasias in the 21st century.
THE EXAMPLE OF TRICHO-DENTO-OSSEOUS SYNDROME: DIFFERENT GENETIC BACKGROUNDS MODIFY A MUTANT GENE'S EFFECT AND PRODUCE VARIABLE CLINICAL EXPRESSION
Gene mutations can and do produce clinical phenotype variations that can confound classifications. One example is tricho-dento-osseous syndrome (TDO; OMIM 190320) which is an autosomal-dominant disorder characterized by curly hair at birth, enamel hypoplasia, taurodontism, and a thick cortical bone with mild nail involvement [Wright et al., 1997]. A common DLX3 gene mutation (distal-less is a transcription factor) has been identified for TDO in multiple families and is further associated with variable clinical phenotypes. Independently, an autosomal-dominant form of hypoplastic-hypomaturation-type amelogenesis imperfecta with taurodontism (AIHHT; OMIM 104510) presents only enamel defects with enlarged tooth pulp chambers that resemble taurodontic teeth; this disorder reflects another DLX3 gene mutation [Lee et al., 2008]. These DLX3 mutations are different, specific and yet are correlated with overlapping clinical phenotypes that complicate the establishment of genotype-phenotype correlations and precise diagnosis and classifications (e.g., ectodermal dysplasias vs. TDO vs. AIHHT).
DNA POLYMORPHISM, SNPS AND “DISEASOME”
This author asserts that the clinical phenotype and patterns of clinical phenotypes will be aligned with molecular underpinnings that will integrate “levels of knowing” that will profoundly influence classifications of ectodermal dysplasias and other diseases and disorders.
DNA polymorphisms such as SNPs are rapidly advancing our knowledge of diseases and disorders. Each person's genetic material contains a unique SNP pattern that is composed of a large number of genetic variations. Most of these variations are found in the non-coding regions of DNA and are not necessarily associated with disease; only 3–5% of the human genome encodes genes that are transcribed and then translated into proteins. SNPs can be informative in that they sometimes indicate candidate genes responsible for disease or disorders. SNPs can actually cause a disease and can be used to diagnose and classify diseases and disorders. SNPs occur frequently throughout the human genome and are considered genetically stable, diagnostic and valuable as biomarkers. The National Center for Biotechnology Information (NCBI) hosts public SNP databases and can be accessed at www.ncbi.nlm.nih.gov/snps.
The “diseasome” is a bold and innovative strategy designed to improve the classifications of diseases and disorders. To understand and advance diagnostics and classifications (as well as treatments and therapeutics) it is imperative to know more than a list of “disease or disorder” genes; rather, we need to map the specific molecular circuits or networks of the various intracellular processes to understand the pathogenesis of diseases or disorders. Creating disease-gene associations offers a platform to explore clinical phenotype and disease/disorder gene(s) associations, indicating the common molecular origins of diseases and disorders. Examples of this “human disease network” strategy to advance classifications and understanding of diseases and disorders offer enormous promise for the near future [Barabasi, 2007; Goh et al., 2007; Leitch et al., 2008].
BIOMIMETICS AND TISSUE ENGINEERING
In tandem, remarkable progress is being made to design and fabricate innovative biologically based solutions for tissue and organ repair and regeneration which can significantly improve treatments and biomaterials for patients with ectodermal dysplasias. Bone augmentation and regeneration using bone morphogenetic proteins is well-established [Urist, 1965; Hughes et al., 2006]. A number of very promising biomimetic approaches have established “proof-of-principle” for tissue engineering related to cartilage, bone, dentin, periodontal ligament, and tooth root design and fabrication [Baum and Tran, 2006; Duailibi et al., 2006; Slavkin and Bartold, 2006; Sonoyama et al., 2006].
INTERDISCIPLINARY HEALTH PROFESSIONAL EDUCATION: A CALL TO ACTION
The Institute of Medicine Committee on the Health Professions Education Summit's publication Health Professions Education: A Bridge to Quality [Greiner, 2003] asserts that major reform of the health professions education is critical to enhancing the quality of health care in the United States (and beyond) for all people. In this analysis one goal is an outcome-based education system that better prepares clinicians (medicine, dentistry, pharmacy, nursing, allied health professions) to address the needs of patients and communities and the changing requirements of a changing health care. The derivatives from the digital and biological revolutions are truly daunting. Bioinformatics as well as the completion of the human genome and numerous microbial, plant and animal genomes provide enormous opportunities for clinical health professionals. Major education revisions are required to integrate genomics, post-genomics, bioinformatics, and biomimetics into curriculum for preclinical and clinical phases of professional health education. In addition, shifting patient demographics and expectations, evolving clinical practice requirements and staffing arrangements, access and analysis to enormous databases are also challenging our educational programs.
A set of five core competencies for all health professions, regardless of disciplines, has been advanced to meet the needs of the 21st century health system [Greiner, 2003]. Competencies are defined here as the habitual and judicious use of communication, knowledge, technical skills, clinical reasoning, emotions, values and reflection in daily practice [Hundert et al., 1996]. The five core competencies are:
- (1)Provide patient-centered care;
- (2)Work in interdisciplinary teams;
- (3)Employ evidence-based practice;
- (4)Apply quality improvement;
- (5)Utilize informatics.
These five competencies are meant to be the core and should not be considered as definitive or exhaustive. Another evolving competency that will be required for the 21st century is related to the DNA-based transformation of health professional education that will understand not only the content of genomes but, even more importantly, the physiological consequences of variations in the genes and gene products that regulate cell, tissue, and organ physiology [Guttmacher et al., 2004; Varmus, 2004; Slavkin et al., 2008]. These competencies are enormously relevant towards the improvements for the diagnosis, treatments and outcomes related to ectodermal dysplasias.