Approach towards a new classification for ectodermal dysplasias: Integration of the clinical and molecular knowledge

Authors

  • John J. DiGiovanna,

    Corresponding author
    1. Division of Dermatopharmacology, Department of Dermatology, The Warren Alpert School of Medicine of Brown University, Providence, Rhode Island
    • Division of Dermatopharmacology, Department of Dermatology, Rhode Island Hospital and Brown University, JBS-1, 593 Eddy Street, Providence, RI 02903.
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  • Manuela Priolo,

    1. Operative Unit of Medical Genetics, Bianchi-Melacrino-Morelli Hospital, Reggio Calabria, Italy
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  • Peter Itin

    1. Department of Dermatology, University of Basel, Basel, Switzerland
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  • How to cite this article: DiGiovanna JJ, Priolo M, Itin P. 2009. Approach towards a new classification for ectodermal dysplasias: Integration of the clinical and molecular knowledge. Am J Med Genet Part A 149A:2068–2070.

Abstract

Rapid advances in new basic knowledge have led to a greater understanding of the genetic, embryologic, molecular biologic, and functional mechanisms underlying the ectodermal dysplasias. Scientists, researchers, and clinicians from diverse fields desire a classification that meets the needs of these rapidly changing concepts which, in addition to being clinically useful, can help further advances in understanding the basic underlying mechanisms, and can also spur the development of new therapies. The currently used classification was designed for clinical utility and has not easily integrated with the new concepts. Various users have suggested that a new classification should be based on underlying genetic and molecular abnormality, functional mechanism, embryology, or clinical features. The goal of this conference was to advance towards a consensus and this manuscript is a summary of a workshop focused on an approach towards the development of a classification that integrates the clinical and molecular knowledge. © 2009 Wiley-Liss, Inc.

INTRODUCTION

The ectodermal dysplasias are complex clinical disorders. Freire-Maia and Pinheiro 1984 classification is based on only clinical findings and this approach has been useful for clinicians and patients. However, there is controversy concerning which diseases should be appropriately included as ectodermal dysplasias and the list has been expanding extensively in recent years. One level of complexity is that there are overlapping clinical phenotypes or symptom complexes where ectodermal malformations are a minor feature. Classification based on clinical phenotype can manage these clinical complexities and strives to include clinically related conditions. Advances in molecular biology are elucidating a framework of genetic and functional pathways, and this new knowledge has stimulated the desire to classify disorders based on their relatedness with respect to molecular and functional mechanism.

Recently there have been substantial advances in understanding the embryologic, genetic, and molecular basis of these disorders. It is fortunate that experts from diverse disciplines have focused their interest and expertise towards understanding these disorders and the pathways underlying ectodermal development. Clinicians from medical genetics, dentistry, oral surgery, dermatology, and others are interested in diagnosis, prognosis, and therapy. Basic researchers are interested in the pathways of ectodermal development in humans and animals. Knowledge of the genes underlying these disorders and progress in understanding the functional pathways have uncovered substantial limitations of a classification based on clinical manifestations alone. A need has emerged for a classification that better represents the underlying genetic abnormalities and molecular pathways recently elucidated. A classification based on the genetic abnormalities or one based on the underlying functional pathways could help to translate future scientific progress in genetics and basic biology into clinically utility. This would occur due to enhanced understanding of genotype/phenotype correlations, by better understanding functional aspects of the relevant mutations, genes and proteins, by facilitating the development of mechanism-based therapeutic approaches, and ultimately leading to a better understanding of the clinical disease. Recent proposals on classification have considered genetic and functional information, and data mining in large databases has been helpful in putting different symptom complexes together into genetic-related entities [Priolo and Lagana, 2001; Itin and Fistarol, 2004; Irvine, 2005].

The need for improving disease classification to incorporate new genetic and functional information is not limited to ectodermal dysplasias, but applies to much of medical genetics. Paradigms for integrating multiple classifications (e.g., clinical, underlying molecular, etc.), such as multiaxis nomenclature systems have been proposed [Robin and Biesecker, 2001].

How a disease is classified can have a direct effect on the resources that may be available to patients from insurance, government, or foundation resources. Changes to disease classification should consider impact on all users. The “2008 International Conference on Ectodermal Dysplasia Classification” was held in Charleston, South Carolina, March 9–12, 2008 in an effort to progress towards a new classification. The conference brought together experts with divergent views concerning classification. This manuscript is a summary of a Conference Workshop titled: “Approach Towards a New Classification for Ectodermal Dysplasias: Integration of the Clinical and Molecular Knowledge.”

CLASSIFICATION FRAMEWORKS

For recent knowledge to be most useful in helping to stimulate further advances, various users need to understand the relationships between the abnormalities of phenotype, genetics, and basic pathways (functions) affecting ectodermal dysplasias. Diverse approaches to classification emerged from the Workshop based primarily on (a) clinical phenotype, (b) underlying gene, or (c) functional pathways. Each of these levels attempt to organize the ectodermal dysplasias by finding patterns that can be puzzled (clustered) together by relatedness.

Clinical Phenotype: How can similar clinical manifestations be grouped (clustered) together to form patterns?

Clinicians have become familiar with the Freire-Maia–Pinheiro classification, and this approach has been well accepted and widely used for diagnosis. It is not surprising that clinicians strongly feel the need to continue to use a clinical classification in their efforts to formulate a diagnosis. However, there is substantial disagreement concerning which disorders should be included within the classification of ectodermal dysplasias. A uniformly accepted definition of ectodermal dysplasia has been elusive.

Gene Based: How can the molecular abnormalities in genes (mutations) be grouped (clustered) together to form patterns?

The discovery of the genes underlying several of the ectodermal dysplasias has raised interest in a classification based on the underlying mutations. This would be of value in molecular diagnosis. However there are complex relationships between the clinical phenotypes, mutations, and functional pathways. While a gene-based classification, such as OMIM, can be useful in understanding molecular abnormalities, clinicians are concerned that a pure gene-based classification might not facilitate clinical diagnosis.

Functional (Pathways): How can the functional pathways (protein abnormalities) be grouped (clustered) together to form patterns?

A classification based on underlying functional pathways could help clarify the relationship between the different clinical manifestations in the ectodermal dysplasias and facilitate progress in understanding how the disorders relate to each other, to animal models, and how to develop therapies to target relevant pathways. However, a functional-based classification may not be sufficiently useful for the diagnostic needs of clinicians and at the moment will not cover the whole spectrum.

APPROACH TO INTEGRATE THE CLINICAL AND MOLECULAR KNOWLEDGE

A classification system is needed for ectodermal dysplasias that will be used by clinicians, clinical, and basic scientists, and will also facilitate the development of effective therapies. In such a classification the terminology should be understandable and acceptable to all key players. It is clear that the diverse users with different needs will use a classification differently. A new classification should be flexible and extensively cross-reference other databases. To do this effectively, the classification should be web-based so that it could easily be linked to genetic databases (OMIM, 2008, etc.) and known pathways characterizing function.

In an effort to develop a classification system that serves the needs of these diverse users, a number of obstacles to moving forward towards a consensus classification have been identified. The following plan suggests an approach to move forward towards addressing these obstacles.

  • 1.Establish a definition of ectodermal dysplasia which is understandable and acceptable for diverse users. A consensus definition is the basis for developing further criteria.
  • 2.Develop inclusion/exclusion criteria based on clinical characteristics, in order to determine which disorders are to be classified. The primary use of a classification of diseases is for diagnosis and delivery of medical care.
  • 3.Review the Freire-Maia–Pinheiro classification to evaluate which disorders fit and which do not, and add additional conditions that fulfill the inclusion criteria developed.
  • 4.Create a new list of diseases. Include OMIM number and cross-reference with Freire-Maia–Pinheiro.
  • 5.Identify key clinical manifestations for all of the above.
  • 6.Figure 1 is a flow sheet which outlines the steps to look for relatedness (clustering or grouping) based on clinical features, clustering of genes, and similarities among steps within a pathway (function) in order to identify relationships. From the list of clinical disorders, determine if the disorder in question has a gene identified or not. If a gene has been identified as a cause of the clinical disorder, attempt to group this disorder with others by function/pathway. If there are common clinical findings of these disorders, this would validate a class of disorder (i.e., sharing a common genetic pathway and common clinical manifestations). If the causative gene has not been identified in a given disorder, seek key clinical traits and assess whether these occur in other disorders. If so, these could help direct studies towards a particular gene/allele based on key clinical manifestations. Alternatively, the similarity in key clinical traits may suggest involvement of a specific underlying functional pathway. Identifying these various relationships may also suggest directions for future research.
Figure 1.

Flow sheet outlining the steps to identify relationships between clinical features, underlying genes, and functional pathways. If a clinically defined disorder has a gene identified, determine if this gene is associated with other genes or pathways (clustering/grouping). If, in addition, other diseases caused by related genes or pathways have similar clinical features, this would validate a class of disorder. If the clinically defined disorder does not have a gene associated with it, look for key clinical features and if they cluster with other disorders. If so, this may suggest a new gene/allele based on key clinical features.

Patients, clinicians, and researchers would benefit from a classification with greater utility that addresses the complex needs of the diverse users. Optimally, a web-based system could be extensively integrated with other databases and have the flexibility to be amended to accommodate new discoveries.

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