2008 International Conference on Ectodermal Dysplasias Classification: Conference report


  • Carlos F. Salinas,

    Corresponding author
    1. Division of Craniofacial Genetics, Department of Pediatric Dentistry and Orthodontics, College of Dental Medicine, Medical University of South Carolina, Charleston, South Carolina
    • Division of Craniofacial Genetics, Department of Pediatric Dentistry and Orthodontics, College of Dental Medicine, Medical University of South Carolina, 173 Ashley Avenue, BSB 128, Charleston, SC 29425.
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  • Ronald J. Jorgenson,

    1. Scientific Advisory Board, National Foundation for Ectodermal Dysplasias, Austin, Texas
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    • Consultant in Medical Genetics.

  • J. Timothy Wright,

    1. Department of Pediatric Dentistry, University of North Carolina, Chapel Hill, North Carolina
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  • John J. DiGiovanna,

    1. Department of Dermatology, The Warren Alpent School of Medicine, Brown University, Providence, Rhode Island
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  • Mary D. Fete

    1. National Foundation for the Ectodermal Dysplasias, Mascoutah, Illinois
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  • How to cite this article: Salinas CF, Jorgenson RJ, Wright JT, DiGiovanna JJ, Fete MD. 2009. 2008 International Conference on Ectodermal Dysplasias Classification: Conference report. Am J Med Genet Part A 149A:1958–1969.


There are many ways to classify ectodermal dysplasia syndromes. Clinicians in practice use a list of syndromes from which to choose a potential diagnosis, paging through a volume, such as Freire-Maia and Pinheiro's corpus, matching their patient's findings to listed syndromes. Medical researchers may want a list of syndromes that share one (monothetic system) or several (polythetic system) traits in order to focus research on a narrowly defined group. Special interest groups may want a list from which they can choose constituencies, and insurance companies and government agencies may want a list to determine for whom to provide (or deny) health-care coverage. Furthermore, various molecular biologists are now promoting classification systems based on gene mutation (e.g., TP63-associated syndromes) or common molecular pathways. The challenge will be to balance comprehensiveness within the classification with usability and accessibility so that the benefits truly serve the needs of researchers, health-care providers, and ultimately the individuals and families directly affected by ectodermal dysplasias. It is also recognized that a new classification approach is an ongoing process and will require periodical reviews or updates. Whatever scheme is developed, however, will have far-reaching application for other groups of disorders for which classification is complicated by the number of interested parties and advances in diagnostic acumen. Consensus among interested parties is necessary for optimizing communication among the diverse groups whether it be for equitable distribution of funds, correctness of diagnosis and treatment, or focusing research efforts. © 2009 Wiley-Liss, Inc.


In the last decade, the study of the human genome has expanded the knowledge of the genes and molecular pathways causing the ectodermal dysplasias (EDs), a diverse group of inherited disorders that share developmental abnormalities of two or more of the following: hair, teeth, nails, sweat glands, and other ectodermal structures. The pace of discovery is truly staggering there being already over 70 scientific publications related to ED during 2008. The spectrum of topics, over the past couple of years, range from identification of mutations in the TP63 gene, the discovery of a gene causing Goltz syndrome, and the use of recombinant EDA protein in the treatment of X-linked hypohidrotic ED [Brunner et al., 2002; Gaide and Schneider, 2003; Casal et al., 2007; Clements et al., 2007]. In addition, a number of patient-oriented studies have provided insights into the cognitive abilities, growth and nutrition, allergies and asthma, and women's symptoms in patients affected with EDs. Studies of families with X-linked hypohidrotic ED continue to investigate the different types of mutations and the resulting severity and variability in the clinical manifestations.

The scientific community is using powerful new molecular approaches that allow them to explore the unique molecular pathways involved in the different EDs and advance our understanding on how specific molecular changes result in the developmental changes observed in the spectrum of ED conditions.

However, knowledge of the EDs is “a mile wide and an inch deep.” Beyond a few very well-described conditions (e.g., hypohidrotic ED) there remains a paucity of information on rare and uncommon disorders. More than 170 conditions under the umbrella term of “ectodermal dysplasia” have been described, but there are a number of challenges with the current scientific literature, including duplication and mischaracterizations of conditions and multiple and different eponymous nosologies. The sheer number of disorders makes it difficult to give order or structure to the ED conditions, which has led to the lack of one widely, accepted classification that could be useful for a variety of audiences.


Recognizing the need to integrate the multiple classification systems [Freire-Maia, 1977; Freire-Maia and Pinheiro, 1984; Priolo et al., 2000; Jimenez Sanchez et al., 2001; Lamartine, 2003; Itin and Fistarol, 2004] and the most recent clinical and molecular information available for the EDs, the National Foundation for Ectodermal Dysplasias (NFED) and the Medical University of South Carolina (P.I. Carlos F. Salinas NIH-NIDCR Grant) sponsored the International Conference on Ectodermal Dysplasias Classification, held in Charleston, South Carolina, on March 10–12, 2008. The conference, as it was planned, brought together experts from around the world, including a diverse group of health-care providers, researchers, patient advocate representatives, and administrators. The conference presented, discussed, and analyzed the various classification models of EDs and aimed to establish a consensus on the most appropriate classification model, based on current clinical knowledge and recent advances in molecular genetics. The challenge in the present case relates to the principle that any classification system needs to take account of the stakeholders and all subsequent end-users. The term “ectodermal dysplasia” encompasses an unusually wide range of diagnoses; the range of stakeholders is also diverse, ranging from affected individuals and their families to support groups, family doctors, general dentists and dental specialists, dermatologists, clinical geneticists, counselors, molecular diagnostic scientists, and research scientists. A classification system that is workable and readily accessible to all these diverse groups will be a significant achievement; it will represent a real advance in helping forge better care pathways for individuals affected by these conditions and, importantly, will better facilitate and focus new treatments and interventions in these conditions.


An international classification for ED could provide considerable and far ranging benefits. The EDs have proven to be a complex set of disorders, exhibiting extraordinary variation even within individual syndromes, let alone those that have not yet been fully described or are yet to be discovered. Without a better understanding and classification of EDs, it is very difficult for patients and families to make well-informed decisions regarding treatment, services, and prognosis, or to understand the genetic implications of their disorder and plan for the future. A widely accepted international classification that takes into account both clinical and molecular knowledge of EDs will:

  • Support the accurate diagnosis of individuals with an ED, offering patients an “answer” to explain their condition and a greater understanding of its genetic implications, as well as giving providers a path for counseling, testing, and treatment.

  • Move research forward, in particular, the overlay of molecular studies and clinical knowledge may result in genotype–phenotype correlations and the discovery of new mutations.

  • Lead to cures and hope for the future for patients and families.

  • Provide a common language around EDs for patients, families, researchers, and different types of health-care providers, ultimately enhancing communication among these diverse groups.

  • Help advocacy groups better serve their constituents and promote the effective use of limited resources.

This conference has presented the opportunity to move forward with the classification of the EDs, at a time when advances in molecular genetics have significantly expanded the understanding of the molecular pathways underlying the clinical presentation of the EDs.


Clinical Classification

Dr. Eleidi Freire-Maia and her team reviewed the most widely used clinical classification and were charged with discussing the pros and cons of this classification [Freire-Maia, 1971; Freire-Maia, 1977; Freire-Maia and Pinheiro, 1984; Freire-Maia et al., 2001]. A definition of the heterogeneous group of disorders, first characterized by Weech 1929 as EDs, was proposed by Freire-Maia 1971. Freire-Maia based his definition on the four “classical signs” associated with EDs: trichodysplasia, dental defects, onychodysplasia, and dyshidrosis. Group A includes those disorders with signs affecting at least two of the classical structures: (1) hair, (2) teeth, (3) nails, and (4) sweat glands. Group B includes disorders involving one of the classical signs associated with another ectodermal sign (subgroup 5). A “pure” ED is characterized by only ectodermal signs; an ED syndrome combines ectodermal signs and other malformations. This clinical definition is the foundation for the Freire-Maia classification, which follows a mnemonic procedure with the assignment of a number for each type of structure disturbance that are catalogued in 11 subgroups. This clinical classification is comprehensive, aids diagnosis, is useful for teaching, and remains a critical core resource. It is also important for the description of novel cases. The clinical classification also shows general patterns of signs that might be useful for stimulating research into functional pathways. However, a clinical approach to classification is not without its disadvantages. For example, it is difficult to measure some of the signs of ED (e.g., dry mouth and sweating activity). Some symptoms do not have clear “cutoffs.” Other less dramatic abnormalities might be missed entirely, and there is overlap in symptoms between what are considered distinct syndromes. These situations are not only observed in EDs but are common diagnostic problems of Mendelian inherited disorders. An update clinical classification review by Visinoni et al. is presented in this journal issue.

Molecular Classification

Drs. Manuela Priolo and Peter Itin described and discussed the molecular classification of the ED. More recently, the field of molecular genetics has shed new light on the genes and molecular pathways behind the development of EDs. For example, Priolo et al. 2000 and Priolo and Laganà 2001 have proposed a clinical–functional classification of EDs based on the assumption that the ED causative genes act through two different pathogenetic mechanisms, and all clinical findings observed in affected patients are highly specific for each of the two mechanisms identified.

Group 1 is characterized by defects in the epithelial–mesenchymal interaction, with localization of genes in the nucleus which are involved in differentiation and apoptosis. EDs in this group are clinically defined as “pure” EDs, with lone involvement of ectodermal derivatives and major skeletal involvement.

Group 2 includes disorders characterized by defects in the ectodermal structural proteins. The genes involved in this group encode proteins which are localized and highly specialized in the plasma membrane domains and cytoplasm, and are involved in the maintenance of the integrity and stability of cell membranes and underlying cytoskeleton. Clinically, this group includes “dermatologic” EDs, in which there is additional involvement of the ectoderm and highly differentiated epithelia. This classification is thought to be simple because it includes only primary involvement of ectodermal derivatives (thereby decreasing the total number of disorders under the “ectodermal dysplasia” umbrella); is homogeneous because it takes into account variable expression; and is accessible, involving only two major classification groups.

The advantages of a molecular approach include that it is objective, provides information on the pathogenesis of the EDs, offers clues as to the molecular basis of conditions sharing similar phenotypes, and contributes to the knowledge necessary for future molecular-based therapies and treatments. The molecular approach clarifies and enhances our understanding of the EDs and the interrelatedness of conditions. For example, Ankyloblepharon–Ectodermal Defects–Cleft Lip and/or Palate (AEC) and Rapp–Hodgkin syndrome were once thought to be two different syndromes, yet the molecular findings and biochemical evidence have now confirmed that they are part of the same spectrum of conditions caused by mutations in the same gene (TP63) [Rinne et al., 2007; Rinne et al., 2008]. The molecular approach also provides patients and families with an understanding of the genetic implications of their specific disorders.

There are disadvantages to the molecular approach to the classification of EDs. Analysis of individuals at the molecular level is not the way cases are initially identified and diagnosed. This approach can lead to decreased use of and decreased emphasis on the clinical judgment and deductive analysis of practitioners. These skills are especially important since phenotype is critical to the identification of an ED, and the signs can be subtle (a particular concern for educational programs and future practitioners). Also, the molecular approach is not readily understood by families and many clinicians, testing can be prohibitively expensive, and most EDs still cannot be delineated at the molecular level.

Additionally, the molecular pathways of EDs are complex, for a variety of reasons. First, the lack of a mutation does not rule out an ED diagnosis, given the incomplete knowledge of ED mutations. Secondly, a mutation in an ED-associated gene can result in a range of phenotypes (i.e., clinical variability). For example, a mutation in EDA can result in a phenotype ranging from hypodontia to “full-blown” hypohidrodic ED [Paakkonen et al., 2001]. Similar phenotypes often indicate that mutated genes function in the same pathway (i.e., genetic heterogeneity). For example, ectrodactyly can be caused by a mutation in the transcription factor coding gene TP63. However, mutations in target genes of TP63 (i.e., genes that are induced or repressed by the TP63 protein) may also cause this phenotype.

There are many factors involved in defining a phenotype, and the genotype–phenotype relationships for the EDs remain poorly understood. The genetics are further complicated by incomplete penetrance, variable expression, pseudodominant inheritance in rare diseases, and person-specific contiguous gene syndromes. It is questionable that one-to-one correlation between genotype and phenotype will ever be seen. An update paper from Priolo et al. is presented in this journal issue.

The conference participants also learned and discussed complementary information needed for a comprehensive approach to the EDs classification. The topics include the point of view of the largest advocacy group for ED, the NFED, the new International Classification of Functioning, Disabilities and Health, and a biostatistical approach for the validation of a classification criterion.

Patient Advocacy Point of View

In 1981, Mary Kaye Richter and a small group of families affected by EDs founded the NFED. Since that time, the mission of the NFED has grown from providing individuals and families affected by EDs with reliable information, support, and hope to educating professionals, maintaining a patient information database, advocating on behalf of patients, funding treatment for affected families, hosting an educational website, and supporting research. For a relatively small organization, NFED offers a wide range of services for affected families in more than 65 countries. The Foundation is recognized worldwide for being the leading clearinghouse of information on the ED syndromes.

The NFED's database currently contains information on 5,232 patients, and approximately 49 individual syndromes are represented. More than 50% of patients in the database have a disorder in which two or more ectodermal structures are clearly affected but do not yet have a diagnosis of a specific ED syndrome. This further illustrates the difficulties faced by clinicians in diagnosing EDs.

International Classification of Functioning, Disability, and Health

In 2001, the World Health Organization (WHO) published the International Classification of Functioning. Disability and Health (ICF), a classification of health states that involve functional impairment, activity limitation, or participation restriction among adult individuals or in populations. Drs. Rune J. Simeonsson and John F. Hough provided a general description of the ICF and provided insight as to how this approach had possible application to the EDs.

The comprehensive scope of the ICF/ICF-CY could have utility in documentation of the complex ED conditions both for the development of a classification system and as a separate, complementary taxonomy. In this regard, the ICF-CY can contribute to clinical work and research on ED by (a) providing a framework for interdisciplinary practice; (b) clarifying clinical diagnoses and co-morbidity; (c) yielding profiles of functioning; (d) offering codes for documenting change with development or treatment; and (e) standardizing documentation of variables in research. Application of the ICF/ICF-CY in terms of defining the specificity and severity of codes is based on evidence from assessment of ED characteristics of interest.

Methods for Revision and Validation of Classification Criteria

Decisions regarding how best to classify or subclassify a disease involve many considerations including clinical relevance, practicality, historical precedents, and effects on patients. While the trade offs of various options are best assessed by clinical and scientific experts, a computer-aided quantitative analysis of sets of patient scenarios can sometimes provide useful information to aid in these decisions. The presentation by Dr. Larry Magder provided a general description of the steps and options involved in performing such analyses.


A second block of sessions was devoted to the presentation of current research activities of the conference participants. Despite the complexity of the EDs, the field of molecular genetics has moved the state of the science far beyond where it stood when the disorders were first characterized and clinically classified. The following illustrates the type of paper presented at the conference that provided the participants an overview of relevant research efforts in the field of EDs.

Update on the Molecular Basis of Hypodontia

Rena N. D'Souza

The formation of mammalian dentition is one of the most remarkable processes in development and provides a powerful model for studying epithelial–mesenchymal interactions that control patterning and morphogenesis. The use of transgenesis, gene targeting, expression analyses, functional in vivo and in vitro tooth recombinations as well as bead implantation assays have advanced our knowledge about the patterning of missing teeth. What has emerged is the realization that tooth development involves a complex series of genetic interactions involving growth factors, transcription factors, signal receptors, and diffusible morphogens that interact within unique and interdependent signaling pathways. This presentation reviewed classic and current literature on tooth development and highlighted key questions that remain. Genes and their underlying mutations that lead to the congenital absence of teeth (hypodontia) were overviewed. New biochemical and molecular approaches used to elucidate the underlying mechanisms of hypodontia involving PAX9 and MSX1 genes were also discussed. The presentation concluded with a forecast of future strategies that can be used to better predict genotype–phenotype correlations for hypodontia.

Update on the Molecular Treatment of Ectodermal Dysplasia

Olivier F. Gaide

Identification of genetic mutations responsible for ED is paramount to our understanding of this family of diseases. It provides tools for diagnosis and genetic counseling, bringing an undisputable benefit to patients. This essential achievement may come with a bonus, the possibility to devise a cure for some of these diseases. The lecture provided a realistic view of the technologies (current and future) that allow the correction of genetic diseases, including gene therapy and “biologics,” and set in perspective the specificities of EDs. Finally, advances in the use of recombinant Ectodysplasin A to treat hypohidrotic ED was presented, an illustration of the technological, biological, regulatory, and financial challenges separating the bench from the bedside [Gaide and Schneider, 2003; Casal et al., 2007].

Focal Dermal Hypoplasia

Suzanne E. Clements

Focal dermal hypoplasia (FDH; Goltz syndrome) (OMIM 305600) is a rare X-linked dominant ectomesodermal dysplasia syndrome characterized by linear streaks of hypoplastic dermis and subcutaneous fat herniation occurring along the lines of Blaschko. FDH was first described by Goltz in 1962, but in 2007 mutations in the PORCN gene were identified as the molecular basis for this disorder. PORCN (human porcupine locus MG61/PORC) is a member of the porcupine (PORC) gene family and is located at chromosome band Xp11.23. The gene encodes a putative O-acyltransferase enzyme that catalyzes cysteine N-palmitoylation and serine O-acylation in the endoplasmic reticulum, which facilitates secretion of several Wnt proteins critical for embryonic tissue development. To date, ∼24 different pathogenic PORCN mutations have been reported, highlighting the role of PORCN and Wnt protein signaling in ectomesodermal embryonic development. It is possible that aberrant Wnt signaling in FDH skin suppresses fibroblast proliferation leading to a thin dermis with subsequent fat herniation. The combination of manifestations seen in Goltz syndrome illustrates the phenotypic consequences of defective modulation of Wnt signaling in utero and highlights the clinical importance of PORCN and Wnt signaling pathways in embryogenesis [Clements et al., 2007; Wang et al., 2007].

Ocular Findings Associated With Ectodermal Dysplasias

Thomas Kaercher

Ocular symptoms and signs are seen associated with numerous EDs, but at present they do not belong to the inclusion criteria of the disease group. Patients with confirmed ED syndromes have been investigated ophthalmologically. Dry eye symptoms were seen in 94% of the patients. Reduction of the eyebrows and lashes were detected in 94%. Changes of the Meibomian glands proved to be even more frequent, when investigated through transillumination. Corneal changes with loss of visual acuity occurred later on in life, leading occasionally to amaurosis. The alteration of the Meibomian glands proved to be a reliable sign in ED syndromes. It is seen in children and is present in carriers. As the Meibomian glands are easily accessible and the transillumination can be performed in all age groups, the ophthalmological test is a valuable screening method for the disease group. The morphology of the Meibomian glands additionally may have the importance of a staging of the disease group.

Function of the Ectodysplasin Pathway in Skin Appendage Development

Marja Mikkola

Mutations in the gene coding for Ectodysplasin (EDA) cause X-linked hypohidrotic (previously termed anhidrotic) EDs (HED), the most common form of all ED syndromes which is now known to involve deficient activation of the transcription factor NF-kB. Autosomal forms of HED are due to mutations in the EDA receptor EDAR, or the cytosolic EDAR-specific adapter protein EDARADD. Extensive recent progress has been made in understanding the biology of ED syndromes associated with the EDA signaling pathway, and, for example, the first transcriptional target genes of EDA have been identified. The author's group has used the mouse as a model to study pathogenesis of HED using both loss-and gain-of-function approaches. Studies by the author and others in the mouse reveal that Eda is involved in multiple steps of skin appendage development from initiation to differentiation. The presentation reviewed the current knowledge on the role of Eda pathway in hair, tooth, and mammary gland development, in particular, its role in initiation of organogenesis.

Oral and Dental Characteristics Associated With Ectodermal Dysplasias

Hilde Nordgarden

This presentation provided an overview of different findings craniofacial, dental, and salivary characteristics.


The conference was planned in such a way that all participants after receiving updated information on the pros and cons of current ED classifications and hearing the most relevant advances in research devoted the next day to discuss the steps towards a consensus classification.

Three consecutive panels of experts discussed the following issues:

  • (1)Clinical Delineation of EDsThe clinical characteristic of a disease plays a most important role for the proper diagnosis and its subsequent classification. In this session, the panelist and participants reviewed the major and minor signs described in the classical and more common EDs. The panelist discussed in general the definition of EDS and the best ways to elucidate the most significant clinical signs as well as the diagnostic criteria. They agreed that it should be based upon the classifications used today and the list of possible inclusion and exclusion criteria will be developed using consensus methodology. For the clinical signs the group of experts based the discussions on the EDs described in Online Mendelian Inheritance in Man (OMIM) and the Freire-Maia and Pinheiro review of 1994. They also defined what kind of ED syndromes will be analyzed and this process will begin with the most common disorders. The general goal is to minimize the number of signs and symptoms to the essential signs to be considered an ED. Accurate definition of “key signs” can aid researchers in an attempt to find new candidate ED genes.
  • (2)Genetic pathways associated with EDsThe task of the panelists were to review the main genetic pathways that are involved in the production of EDs and to review the conditions in which a gene has been identified associated with the production of the disorder.There are more than 50 EDs in which a gene has been identified. Increasing the knowledge of the genes associated with EDs will allow researchers to address more complicated issues including the relative contributions to disease of genes in the core biological set shared by all species and those encoding proteins specific to humans: how sequence features (such as conservation and polymorphism) relate to disease characteristics; and how protein function relates to outcome of clinical treatment. This approach was presented by J. Lamartine and also by G. Jimenez Sanchez, B. Childs, and D. Valle.This last group has found striking correlations between the function of the gene product and features of the disease such as age of onset and mode of inheritance. As knowledge of disease genes grows, including those contributing to complex traits, more sophisticated analyses will be possible. Their results will yield a deeper understanding of disease and enhance integration of medicine and biology. Learning about these mechanisms and placing them into perspective not only will facilitate the enunciation of a new classification, but also clearly opens new fields of research.
  • (3)Integration of the clinical with the molecular knowledge of EDsNew classification approaches have been reported in the literature such as the ones from J. Lamartine and M. Priolo. All are based on the new knowledge obtained with the advancement of molecular genetics. Knowledge continues to advance and based upon the information from the previous presentations and workshops a consensus approach to new classification for ED needs to be developed.The panelist and participants discussed how to integrate information regarding clinical signs, the specific gene, and associated mutations, and how those molecular defects affect specific molecular pathways that ultimately lead to the diverse clinical manifestations seen in affected individuals. This approach has been proposed by two different groups of authors that attended this conference. Such an approach suggests that both clinical and molecular data can help in defining each single patient. Molecular interactions and pathological mechanisms can explain many clinical signs, variability in severity, associated malformations, and overlap seen in some EDs cases.


Participants debated whether there should be two different classifications, one clinical and one molecular, or if the clinical and molecular should be combined to form a new, integrated system. Ultimately, participants agreed that the clinical and molecular approaches are both important and that they are interdependent. Thus, the more closely integrated the two are, the more robust and useful the resulting classification scheme. It will be the work of a group of experts in the field to determine the specific classification structure that results from these discussions. In preparation for that task, conference participants outlined a number of necessary characteristics of a new classification, potential issues and topics for further discussion, and a framework for moving forward.

A number of factors need to be considered in designing a new classification system for the EDs. First, it is important to consider the multiple ways in which the classification may be used: for purposes of diagnosis, counseling, teaching, treatment, research, or describing novel cases. Second, the classification must be useful to different users. Thus, families and patients need to feel that the description of their disorder is accurate. Health-care providers from diverse disciplines must feel that the classification is usable, fits within the language or “jargon” of their field, and is clinically relevant. For researchers, the classification needs to be useful regarding the development of hypotheses of causation, in the elucidation of molecular pathways, and in the development of molecular-based therapies.

Participants identified a number of necessary characteristics of a new classification, including:

  • Flexibility.

  • Being dynamic.

  • Objectivity.

  • Being nosologically sound.

  • Being adaptable to future clinical and gene advances.

  • Maintaining a balance between being inclusive and exclusivity.

  • Being clear and easy to use.

  • Intuitiveness.

  • Clinical relevance.

  • Online accessibility.

  • Being available free at point of use.

  • Being useful to patients while also robust enough to allow meaningful transfer of information between researchers and for potential therapeutic information.

Participants cautioned that even if all of these characteristics are met, the resulting classification still may not meet all the needs of potential end-users. In addition, they identified the need to be sensitive to the issue of individuals with conditions that have been considered an ED under current classifications but may not be under a new one. One suggested strategy would be to establish a classification of “ED-related” disorders to include those which no longer fall within the ED classification, yet share common clinical or molecular features with the EDs.


The consensus from the International Conference on Ectodermal Dysplasias Classification was to develop a classification model that integrates clinical and molecular information available for EDs. As a result, the last portion of the meeting was devoted to developing a plan for moving forward in creating a new classification.


The task of establishing a new classification must address two essential questions:

  • (1)What is the definition of EDs, and which conditions are included or excluded?
  • (2)How should the disorders that are included under the term EDs be classified, including which symptoms are criteria for each specific syndrome?

The recommended plan for establishing the new classification addresses these essential questions systematically, as described below.

Establishing a Definition of Ectodermal Dysplasias

In order to develop a new classification system that blends the clinical and molecular knowledge of EDs, several key terms must be defined and clarified. Clearly, there must be a consensus, to be established by a smaller workgroup, on the definition of the EDs. However, to achieve that consensus, there must be clarification regarding several key terms, including:

  • Appendages versus derivatives: When discussing ED, does the term refer to ectodermal appendages or derivatives or both? Derivative may be a broader term, but is that what is most accurate or useful?

  • Abnormalities versus dysplasias: The term “dysplasia” may or may not be the most accurate descriptor of the symptoms being considered. Consideration must be given to determine whether “disorder” or “abnormality” is a more appropriate term. A dysplasia is a defect of histogenesis, that is, of the establishment of cell lineages.

  • Syndromic versus nonsyndromic: Several questions arise regarding these terms. Should it be required that conditions have two or more derivatives to be considered an ED? Are the ED syndromes syndromic by definition? Should this change? Should only syndromes be considered or should the classification be expanded to include single organ system involvement? Inclusion of nonsyndromic conditions would greatly expand the number of EDs to include entities such as nonsyndromic hypodontia, enamel defects, and ocular abnormalities to name just a few. A syndrome is a casually defined entity.

  • Genetic versus acquired: It is important to clarify that “genetic” does not mean “inherited”—an ED can be the result of a de novo mutation. This raises the question: should EDs be restricted to genetic disorders? Additionally, should EDs, by definition, be strictly congenital or include conditions detected later in life as a developmental problem?Primary versus secondary characteristics: There are numerous conditions that are not considered an ED that have abnormalities of ectodermal appendages as secondary characteristics (e.g., Down syndrome and cleft lip/palate). This raises the question of how to classify a condition in which an ectodermal appendage is a secondary characteristic, along with the issue of how a secondary characteristic is defined. It is important to note that what is considered a defining characteristic may depend on who is making the characterization. Further questions include:

    • If features are to be prioritized and weighted, how should they be weighted?

    • Are there key clinical findings which suggest a complex syndrome, even if other signs of the disorder are not present?

    • Should only “pure” EDs, in which nothing but ectodermal appendages are involved, be considered EDs or should syndromes for which the defining characteristics go beyond ectodermal appendages also be included?

    • It is not uncommon to have mesenchymal defects in EDs. Do “pure” EDs even exist? There would be few pure EDs since so many genes are expressed in a variety of tissues, which is part of the body's way of creating complexity from a relatively scant genome. So most EDs have mesenchymal tissues affected to some degree.

These issues will serve as the starting point for the smaller workgroup's discussion. It was agreed that the final definition of EDs should have some “looseness around the edges” to account for the complexities involved in developing consensus around the terms that will help define and classify EDs. In addition, there was strong support for sustaining some degree of continuity with the existing terms and definitions, in order to retain a meaningful connection with past literature.

Develop Inclusion/Exclusion Criteria

The next step of the classification involves developing inclusion/exclusion criteria. These criteria can encompass both clinical features and molecular characteristics, though the exact balance and use of each remains to be determined. There are compelling arguments for the exclusive use of either clinical or molecular characteristics, as discussed above. Those in favor of clinically defined inclusion/exclusion criteria argue that clinical features should not be distorted to account for molecular evidence. Those in favor of a molecular-based set of criteria argue that molecular information should not be included as “just another sign” of ED, even for classification purposes. Considerable discussion was devoted to the question of whether clinical or molecular information should “drive” the classification. Ultimately, it was agreed that both should have a hand in driving the classification, and it will depend on the information available (and the use for which it is intended) to determine which is the dominant driver in any given situation.

There is clear consensus that the new classification should build upon previous work. It will be necessary:

  • 1.To review prior classifications, such as Freire-Maia and Pinheiro's, to determine which disorders fit in with the new criteria and which do not. Experts will have to make decisions regarding disorders that are technically EDs, according to previous definitions, but are rarely considered as such (e.g., Goltz syndrome), and others that are currently considered EDs but may not fit the established definition.
  • 2.To create a new list of diseases. Include OMIM number designations and cross reference with Freire-Maia classification.
  • 3.To identify clinical key features for all of the above.
  • 4.To identify the relationship of a disorder with a gene, a gene pathway or functional pathway. Experts also will need to take into account conditions in which molecular testing reveals a mutation in an ED causative gene but only one or two signs of ED are present.
  • 5.Once inclusion/exclusion criteria are established, a new list of diseases should then be developed and cross-referenced with OMIM, prior classifications, and other Web-based databases.

Establishing a New Classification for the Ectodermal Dysplasias

From the new list of disorders, experts should then determine whether or not each disease has a causative gene(s) identified. If a gene has been identified, an attempt can be made to cluster the genes by function or pathway. If there are common clinical features after clustering, functional pathways can then be examined for similarities in clusters. This step will also serve as a form of quality control—to confirm that certain disorders are linked functionally as well as clinically. However, it is important to note that if a given syndrome does not cluster with a particular group in terms of its molecular pathways, this does not disprove its classification. Conversely, if gene has not been identified for a set of disorders, experts can look to see whether key clinical features cluster, which may suggest a new gene or allele or a relation to already identified clinical feature clusters. If a new gene or allele is identified, it can then be related to genetic or functional interactions that have been described previously.

This clustering of clinical signs, genes, and molecular pathways is simple in theory, but challenging in practice. For example, clustering according to molecular pathways may be straightforward in a few cases (e.g., the EDA pathway and TP63 disorders), but is not as clear in most others. Experience demonstrates that there are not many “pure,” linear pathways. If a target gene of EDA is identified, there are several pathways that could be involved, since every gene is regulated by several pathways. A person with a mutation in this gene may have phenotypes related to HED, but also may have other defects. This raises the question of how to classify this situation. Does it belong in the EDA cluster, or a transcription factor cluster?

Experts agree that as knowledge of EDs evolves, changes will necessarily occur in the ways clinical features, genes, and molecular mechanisms are clustered and how well they fit together. There are a variety of ways EDs can be organized and subdivided: by phenotype, mode of inheritance, molecular basis, and pathogenesis or functional basis. Sometimes molecular information will group the phenotypic information (e.g., AEC and EEC would not be grouped together without the TP63 evidence) and in other instances it will be the reverse. In addition, conditions do not need to be categorized in one exclusive pathway. As a result, the new classification system will have to accommodate the fact that the nature of EDs is not linear, but three-dimensional.


A system capable of accommodating the complexities and demands of an ED classification system must be computer-based. In addition, to facilitate use by an international community, the system should make use of the Internet for accessibility and linkages to other databases and classifications. An online system is clearly the most useful and universally accessible approach. With appropriate and regular maintenance such a system could:

  • Characterize all that is known and published on all types of EDs.

  • Provide comprehensive clinical details.

  • Enable diagnosis through a robust search ability.

  • Link to clinical trials, basic research drives, and collaborative projects,

  • Provide molecular details, allelic variants, and genotype–phenotype correlation.

  • Give management advice.

  • Link to patient support.

The system could have different entry points to respond to user needs. The entry points could range from simple to complex to accommodate different levels of user needs and expertise. The system should also clearly present its “operating principles,” including any relevant assumptions or disclaimers. It can also have different “modules” or “axes” that give it the ability to accommodate future clinical, genetic, and functional advances. Other potential functions of an online classification system include links to algorithms for clinicians interested in diagnostic testing, and cross-references to PubMed, OMIM, the Human Proteins Database, the London Dysmorphology Database, GeneTests, and other databases for information related to the EDs, including mechanisms and testing algorithms. Ultimately, this system can also function as a dynamic interface connecting the new classification of EDs to key definitions and previous classifications.


It also was suggested that an international disease registry be established to collect the phenotype data necessary for a better understanding of the variability of expression in EDs and connecting those data to available molecular data. It is generally accepted that there is much variability in the phenotype of EDs, but that variability is not adequately quantified, even for the more common disorders. In addition, phenotype information that is currently collected through efforts such as the NFED's registry is not connected to molecular information on patients. Similarly, databases collected by molecular testing organizations are often not connected to phenotype information.


Another suggestion was to develop public–private partnerships that could advance the clinical knowledge necessary for informed molecular studies. Specifically, one suggested strategy was to develop interdisciplinary teams of academic and private sector clinicians (both medical and dental), researchers, and CLIA-certified laboratories. These teams would be similar to the practice-based research networks funded by the National Institute of Dental and Craniofacial Research, which are designed to bring together private sector dental clinicians and researchers to jointly solve commonly seen dental problems. It was also suggested that participants seek funding opportunities to pursue the ideas presented in this conference.


The expert workgroup established at this conference will move forward to address the issues and questions raised regarding the classification of EDs and to advance the process of developing a new classification. Such a classification holds the promise of providing clarity of diagnosis and stimulating research and discovery.

The challenge will be to balance comprehensiveness within the classification with usability and accessibility so that the benefits truly serve the needs of researchers, health-care providers, and ultimately the individuals and families directly affected by ectodermal EDs. It is also recognized that a new classification approach is an ongoing process and it can be expected that it will require periodical reviews or updates. This is a normal occurrence fact when there are dynamic factors involved and new findings are described continuously as we are experiencing today.


The Medical University of South Carolina and The National Foundation for Ectodermal Dysplasias (NFED) convened the “International Conference on Ectodermal Dysplasia Classification” on March 10–12, 2008, in Charleston, South Carolina. This conference was sponsored and funded by the National Foundation for Ectodermal Dysplasias (NFED). We greatly acknowledge the financial grant support from the following organizations who helped make this incredible conference a reality: National Institute of Dental and Craniofacial Research Grant Number 1R13DEO18845-01, Maternal and Child Health Bureau of the U.S. Department of Health and Human Services' Health Resources and Services Administration, the National Foundation for Ectodermal Dysplasias, the Medical University of South Carolina, Astra Tech, Straumann, and GeneDx. The authors acknowledge all of the participants listed in the Appendix of this document who donated their time, their expertise, and their enthusiasm to make this conference a success. In recognition of his outstanding contributions to the field of human and medical genetics and in particular for his always supportive role in the study of Ectodermal Dysplasias, The International Conference on Ectodermal Dysplasias Classification and the National Foundation for Ectodermal Dysplasias recognize and express their gratitude to Dr. John M. Opitz. Laura Sternesky McGovern, MPA, Senior Policy Associate, Evaluation and Research Methods Altarum Institute, recorded and documented the proceedings.


Conference participants (professional appointments listed at time of conference)

Carlos F. Salinas, DMD

PI and Conference Chairman

Professor and Director

Division of Craniofacial Genetics

Department of Pediatric Dentistry and Orthodontics

College of Dental Medicine

Medical University of South Carolina

Charleston, South Carolina, USA

Mary Fete, RN, MSN, CCM

Conference Co-Chair

Director of Research

National Foundation for the Ectodermal Dysplasias

Mascoutah, Illinois, USA

Sherri J. Bale, PhD, FACMG

President and Clinical Director

GeneDx, Inc.

Gaithersburg, Maryland, USA

Filippo Battelli, MD

Postdoctoral Fellow

University of Bologna

via Fra Luca Santini 5 47832

Coriano di Rimini (RN), Italy

Birgitta Bergendal, DDS

Head/LDS, Senior Consultant

National Oral Disability Centre

The Institute for Postgraduate Dental Education

Jönköping, Sweden

Alanna F. Bree, MD

NFED Scientific Advisory Board

Assistant Professor of Dermatology & Pediatrics

Baylor College of Medicine Pediatric Dermatology

Texas Children's Hospital

Houston, Texas, USA

Andrea Burk

Executive Director

Patient Support Group Ectoderma Dysplasias Patient, Registered Society

Aichtal, Germany

Margret L. Casal, DMV, PhD, DECAR

Assistant Professor of Medical Genetics

University of Pennsylvania

School of Veterinary Medicine

Philadelphia, Pennsylvania, USA

Silvia Castillo Taucher, MD


Hospital Clínico J J Aguirre

Universidad de Chile

Santiago, Chile

Eleidi A. Chautard-Freire-Maia, DSc


Federal University of Paraná

Department of Genetics

Curitiba, Paraná, Brazil

Angus Clarke, MD

Professor in Clinical Genetics

Department of Medical Genetics

School of Medicine

Cardiff University

Wales, United Kingdom

Suzanne E. Clements, MRCP

Genetic Skin Disease Group

St. John's Institute of Dermatology

The Guy's, King's College and St. Thomas' School of Medicine

Wales, United Kingdom

Rena N. D'Souza, DDS, PhD

Professor and Chair

Department of Biomedical Sciences

Baylor College of Dentistry

Texas A&M Health Science Center

Dallas, Texas, USA

John J. DiGiovanna, MD

Director, Division of Dermatopharmacology

Professor, Department of Dermatology

Brown Medical School

Rhode Island Hospital

Providence, Rhode Island, USA

Demetrio L. Domingo, DDS, MS

Deputy Clinical Director


Bethesda, Maryland, USA

Frank H. Farrington, DDS, MS

NFED Board of Directors

National Foundation for Ectodermal Dysplasia

William Fennis, DDS, PhD

Department of Oral Function and Prosthetic Dentistry and Centre for Special Dental Care

Radboud University Nijmegen Medical Centre

Nijmegen, The Netherlands

Timothy J. Fete, Sr., MD, MPH

NFED Scientific Advisory Board

Professor of Pediatrics

Saint Louis University School of Medicine

St. Louis, Missouri, USA

Olivier Gaide, MD, PhD

Geneva University Medical School


Geneva, Switzerland

Claudia Gil, DDS

Head, Division of Special Care Dentistry

Hospital del Niño Poblano

Puebla, Puebla, Mexico

Dorothy K. (Kathy) Grange, MD

NFED Scientific Advisory Board

Professor of Pediatrics

Division of Genetics and Genomic Medicine

Department of Pediatrics

Washington University School of Medicine

St. Louis, Missouri, USA

Encarna Guillén-Navarro, MD, PhD

Medical Genetics Unit

Department of Pediatrics

Hospital Universitario Virgen de la Arrixaca

El Palmar, Murcia, Spain

Bryan D. Hall, MD

Professor Emeritus of Pediatrics

Division of Clinical/Biochemical Genetics and Dysmorphology

Chandler Medical Center

Department of Pediatrics

University of Kentuky

Lexington, Kentucky, USA

Brody J. Hildebrand, DDS, MS

NFED Scientific Advisory Board

Baylor College of Dentistry

Practice: Preston Hollow Specialists

Dallas, Texas, USA

Ulrike Holzer

Executive Director

Patient Support Group Ectodermal Dysplasias

Vienna, Austria

John Hough, PhD


U.S. Department of Health and Human Services

Centers for Disease Control and Prevention

National Center for Health Statistics

Classifications and Public Health

Hyattsville, Maryland, USA

Alan Irvine, MD, FRCPI, MRCP

Consultant Paediatric Dermatologist

Our Lady's Hospital for Sick Children

Dublin, Ireland

Peter H. Itin, Dr Med

Professor and Head

Department of Dermatology

University Hospital of Basel

Basel, Switzerland

Ethylin Wang Jabs, MD

Chief, Division of Medical Genetics and Genomics

Professor and Vice Chair

Department of Genetics and Genomic Sciences

Professor, Departments of Pediatrics and Molecular, Cell, and Developmental Biology

New York, New York, USA

Ronald J. Jorgenson, DDS, PhD

Genetic Consultant

Scientific Advisory Board

National Foundation for Ectodermal Dysplasias

Austin, Texas, USA

Thomas Kaercher, Dr Med


Heidelberg, Germany

Helen Kenzle

Executive Director

Patient Advocacy Group

Kallered, Sweden

Michael J. Kern, PhD

Associate Professor

Department of Cell Biology and Anatomy

Medical University of South Carolina

Charleston, South Carolina, USA

Bjorn Knaudt

Dermatologie (Hautklinik)

der Eberhard-Karls-Universität Tübingen

Tubingen, Germany

Richard A. Lewis, MD, MS

NFED Scientific Advisory Board

Professor, Department of Ophthalmology, Medicine, Pediatrics and Molecular & Human Genetics

Baylor College of Medicine

Houston, Texas, USA

Larry Magder, PhD

Head, Division of Biostatistics and Bioinformatics

University of Maryland School of Medicine

Baltimore, Maryland, USA

Luc A.M. Marks, DDS, MSc, PhD

Coordinator Centre for Special Care in Dentistry,

Department of Paediatric Dentistry & Special Care,

Ghent University – Ghent University Hospital

Ghent, Belgium

Elizabeth A. Mauldin, DVM, DAVCP & DACVD

Assistant Professor, Dermatopathology

School of Veterinary Medicine

Philadelphia, Pennsylvania, USA

Marja Mikkola, PhD

Institute University of Helsinki

Institute of Biotechnology

Helsinki, Finland

Marco Montanari

PhD Student in Dentistry for Special Care

University of Bologna

Bologna, Italy

Olivia Niclas

Executive Director

Patient Organization for Ectodermal Dysplasias

Boulogne, France

Akiko Nishibu, MD

Department of Dermatology

Fukushima Medical University School of Medicine

Fukushima, Japan

Hilde Nordgarden, DDS, PhD


Lovisenberg Diakonale Hospital

Oslo, Norway

Raquel Oliva Sánchez, MD

Vice President

Asociación Española de Afectados con Displasia Ectodérmica

Murcia, Spain

John M. Opitz, MD, MD(hc), DSci(hc), MD(hc), MD(hc), DSci(hc)


Department of Pediatrics (Medical Genetics), Pathology, Human Genetics, Obstetrics and Gynecology

University of Utah Health Sciences Center

Salt Lake City, Utah, USA

Nina A.B. Pagnan, DSc

Associate Professor

Department of Genetics

Federal University of Paraná

Curitiba, Paraná, Brazil

Diana Perry

Executive Director

Ectodermal Dysplasia Society

Cheltenham, Glos, England

Jill K. Powell, MD

NFED Scientific Advisory Board

St. Louis University

Department of Obstetrics

St. Louis, Missouri, USA

Manuela Priolo, MD, PhD

Operative Unit of Medical Genetics

Az Ospedaliera Bianchi-Melacrino-Morelli

Reggio Calabria, Italy

Mary K. Richter

Executive Director

National Foundation for Ectodermal Dysplasias

Mascoutah, Illinois, USA

Gabriela Scagnet, DDS

Head of Special Care Dentistry Unit

Quinquela Martin Hospital of Pediatric Dentistry

National University of Buenos Aires

Buenos Aires, Argentina

Rhonda E. Schnur, MD

Head, Division of Genetics

Cooper University Hospital

Associate Professor of Pediatrics

Robert Wood Johnson Medical School in Camden

Camden, New Jersey, USA

Elaine C. Siegfried, MD

NFED Scientific Advisory Board

Professor of Pediatrics and Dermatology

Director, Pediatric Dermatology

Saint Louis University, St. Louis, Missouri, USA

Rune J. Simeonsson, PhD, MSPH

Professor of Education, Research Professor of Psychology

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, USA

Harold C. Slavkin, DDS


University of Southern California School of Dentistry

Los Angeles, California, USA

Anand K. Srivastava, PhD

Senior Research Scientist

J.C. Self Research Institute

Greenwood Genetic Center

Greenwood, South Carolina, USA

Clark Stanford, DDS, PhD

NFED Scientific Advisory Board Centennial Fund Professor

Director of Clinical Research

University of Iowa

Rapid Cedar, Iowa, USA

Laura Sternesky McGovern, MPA

Senior Policy Associate

Altarum Institute

Washington, District of Columbia, USA

Kari Storhaug, Director, PhD


Lovisenberg Diakonale Hospital

Oslo, Norway

Virginia P. Sybert, MD

Medical Genetics

University of Washington School of Medicine

Seattle, Washington, USA

Gianluca Tadini, MD

Institute of Dermatological Science

Istituto di Ricovero e Cura a Carattere Scientifico Policlinico

Milan, Italy

Barry A. Tanner, PhD

Detroit Receiving Hospital and University Health Center

Detroit, Michigan, USA

Sarah Tevis, DDS

NFED Board of Directors

Private Practice

Dallas, Texas, USA

Wieslaw H. Trzeciak, MD, PhD

Professor of Biochemistry

University of Medical Sciences

Poznan, Poland

Átila F. Visinoni, DDS, MSc

Department of Genetics

Federal University of Paraná

Curitiba, Paraná, Brazil

Andrew Williams

Executive Director

Australian Ectodermal Dysplasia

Support Group, Inc.

Rowville, Victoria, Australia

J. Timothy Wright, DDS, MS

NFED Scientific Advisory Board

Bawden Distinguished Professor & Chair Department of Pediatric Dentistry

School of Dentistry

Chapel Hill, North Carolina, USA

W. Jim Zheng, PhD

Assistant Professor

Department of Biostatistics, Bioinformatics & Epidemiology

Medical University of South Carolina

Charleston, South Carolina, USA

Jonathan Zonana, MD

Professor of Molecular and Medical Genetics, Pediatrics

Oregon Health & Sciences University

Portland, Oregon, USA