Classifying ectodermal dysplasias: Incorporating the molecular basis and pathways (Workshop II)


  • How to cite this article: Wright JT, Morris C, Clements S, D'Souza R, Gaide O, Mikkola M, Zonana J. 2009. Classifying ectodermal dysplasias: Incorporating the molecular basis and pathways (Workshop II). Am J Med Genet Part A 149A:2062–2067.


Hereditary conditions are traditionally classified based either on physical/physiological attributes or using the names of the individuals credited with identifying the condition. For the 170 plus conditions classified as ectodermal dysplasias (EDs), both of these nosological systems are used, at times interchangeably. Over the past decade our knowledge of the human genome and the molecular basis of the EDs have greatly expanded providing the impetus to consider alternative classification systems. The incorporation of the molecular basis of hereditary conditions adds important information allowing effective transfer of objective genetic information that can be lacking from traditional classification systems. Molecular information can be added to the nosological system for the EDs through a hierarchical- and domain-based approach that encompasses the condition's name, mode of inheritance, molecular pathway affected, and specific molecular change. As new molecular information becomes available it can be effectively incorporated using this classification approach. Integrating molecular information into the ED classification system, while retaining well-recognized traditional syndrome names, facilitates communication at and between different groups of people including patients, families, health care providers, and researchers. © 2009 Wiley-Liss, Inc.


The ectodermal dysplasia (ED) syndromes are traditionally classified using phenotypic characteristics or the names of investigators that first described the condition [Freire-Maia and Pinheiro, 1984]. In the past, clinicians have been hampered in their ability to definitively classify individuals with ED partly due to the diverse and frequently overlapping phenotypes and a lack of knowledge of the molecular defects. Since identification of the first causal gene mutation in ED (EDA) in 1996 [Kere et al., 1996], there have been rapid advances toward the identification of genes that cause ED. Indeed, we now know that many of the conditions with virtually indistinguishable phenotypes involve different genes affecting closely related components of a common molecular pathway (e.g., EDA1, EDAR, and EDARADD in NF-κB pathway) [Kere et al., 1996; Monreal et al., 1999; Smahi et al., 2002]. Depending on how the conditions are classified there are now over 50 EDs with known molecular cause [Lamartine, 2003; OMIM, 2008]. There is little doubt that the molecular mechanisms responsible for many other EDs will be identified in the near future as we continue to extend our knowledge of the human genome. Classification of the diverse EDs by recognition of the causative molecular pathways would add critical information regarding the specific condition and the developmental mechanisms leading to the associated phenotype. At this time it seems that incorporation of molecular data into a consensus classification for EDs is certainly necessary and if properly applied, will advance our ability to classify effectively individuals affected with ED and transfer this information in a more meaningful way.

Consensus classification should provide language to optimize communication about ED phenotypes and their molecular basis that can be used effectively by families, patients, health care providers from diverse disciplines, and researchers. Inclusion of the molecular basis of EDs has a variety of advantages over a strictly phenotype-based nosology [Priolo and Lagana, 2001]. Molecular information is typically highly objective and can provide very specific data elucidating the pathogenesis of the condition. This knowledge can shed light on the pathogenesis of conditions with similar phenotypes as in the discovery of the EDAR gene and its role in autosomal dominant and recessive ED that causes identical phenotypes as seen in individuals with X-linked ED caused by EDA gene mutations [Monreal et al., 1999]. Understanding the molecular basis of the different EDs is tremendously important in advancing research of the EDs and paving the way for future molecular-based therapies [Srivastava et al., 2001; Gaide and Schneider, 2003; Casal et al., 2007].

Despite the many advantages of including the molecular basis of EDs into a classification system there are potential disadvantages. If specific genetic mutations or molecular pathways are used in the classification scheme, the information may not be readily understood by families and many clinicians. The data set of genes and pathways associated with the EDs is far from complete so the issue of classifying conditions with an unknown molecular basis must be dealt with. As we unravel the human genome and proteome it is abundantly clear that molecular pathways are extremely complex and genotype–phenotype relationships remain poorly understood for most conditions. There is also a concern that educational programs of the future could lack adequate clinical training by over-emphasizing the power of molecular diagnosis. Current molecular diagnostic approaches are typically predicated on careful clinical analysis that then allows a more efficient search for a specific gene and mutation. Therefore, the availability of individuals versed in the phenotyping and syndromology will continue to be essential for efficient diagnosis and classification of hereditary conditions for the foreseeable future.


Given that there is benefit derived from both clinical phenotype information and knowledge of the molecular basis of any specific ED, the ideal classification system should incorporate these different domains or “axes” to establish the most robust and useful nomenclature [Robin and Biesecker, 2001]. Indeed this approach is being used for other disorders such as skeletal dysplasias [Superti-Furga and Unger, 2007]. Not unexpectedly, the incorporation of molecular information tends to make classification systems more complex due to the diversity of allelic and non-allelic mutations associated with major and minor clinical manifestations of certain conditions such as the EDs. Phenotype information is critical for clinicians to make diagnoses and can be very useful in transferring information between clinicians and health care providers. For example, EDs named for specific phenotypic traits, such as tricho-dento-osseous syndrome, identifies the primarily affected tissues and thus is informative. The inclusion of mode of inheritance is not only critical for making an accurate diagnosis but also essential for genetic counseling. The addition of the molecular basis and/or pathways involved in a specific ED provides supporting evidence for the clinical diagnosis, can be helpful for predicting prognosis, can provide directions for further clinical evaluation, and typically provides definitive information concerning mode of transmission. Understanding the molecular pathways responsible for specific EDs is essential for developing novel therapies directed at ameliorating or even reversing the developmental defects and resulting pathoses of ED. Indeed several ED classification systems have been proposed that group the conditions based on their molecular defects and associated pathways [Priolo and Lagana, 2001; Lamartine, 2003]. This departure from a strictly phenotype-based classification clearly has certain advantages despite the many gaps in our knowledge of the molecular basis and pathogenesis of these diverse conditions.


Since discovery of the EDA gene's cause of X-linked hypohidrotic ED, multiple additional EDs have been identified that involve the NF-κB pathway as well as genes in a variety of other pathways (Table I). New ED-related [Grzeschik et al., 2007] genes and their associated pathways are being rapidly discovered as knowledge of the human genome is being advanced. In addition to the NF-κB pathway, ED can be caused by genes that are involved in cell adhesion, the Wnt pathway, transcription factors and gene expression regulation, and cell communication and signaling pathways [McGrath et al., 2001; Lamartine, 2003; Adaimy et al., 2007; Grzeschik et al., 2007]. The complex cellular pathways and specific pathogenetic mechanisms leading to the ED phenotypes remain poorly understood partially due to the diversity, complexity, and interrelatedness of many developmental pathways.

Table I. Ectodermal Dysplasias With Known Molecular Basis
OMIMSyndromeGene (OMIM gene #)Pathway
Autosomal dominant
 103285Acro-Dermato-Ungual-Lacrimal-Tooth Syndrome (ADULT Syndrome)Tumor Protein 63; TP63 (603273)p63 has the ability to transactivate p53, induce apoptosis and is an essential regulator of stem cell maintenance
 603543Limb-Mammary Syndrome (LMS)Tumor Protein 63; TP63 (603273)Some mutations cause loss of P63 transactivation inhibitory domain
 106260Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC; Hay–Wells Syndrome)Tumor Protein 63; TP63 (603273)Missense mutations give rise to amino acid substitutions in the sterile alpha motif (SAM) domain and were predicted to affect protein–protein interactions
 604292Ectrodactyly, Ectodermal Dysplasia, and Cleft Lip/Palate Syndrome 3; EEC3Tumor Protein 63; TP63 (603273)Mutations predicted to abolish the DNA binding capacity of p63
 115150Cardio-Facio-Cutaneous SyndromeK-V1-Ras2 Kirsten Rat Sarcoma Viral Oncogen Homolog , KRAS (190070); V-Raf Murine Homolog, BRAF (164757); Mitogen Activated Protein Kinase Kinase 1, MAP2K1 (176872); MAP2K2 (601236)Gain of function mutations for proteins that interact in a common RAS/ERK pathway that regulates cell differentiation, proliferation, and apoptosis
 125595Dermatopathia Pigmentosa Reticularis; DPRKeratin 14; KRT14 (148066)Mutations in non-helical head (E1/V1) domain were found to result in very early termination of translation thereby diminishing proapoptotic signals
 161000Naegeli SyndromeKeratin-14; KRT14 (148066)Increased apoptotic activity in basal cell layer where KRT14 is expressed. Suggesting apoptosis is an important mechanism in the pathogenesis of syndrome
 127550Dyskeratosis CongenitaTERC (602322), TERT (187270), TINF2 (604319)Three mutations: 1. Mutation in telomerase RNA component gene TERC. 2. Mutation in telomerase reverse transcriptase gene TERT. 3. Mutation in TRF1-interacting nuclear factor 2 gene TINF2
 129400Rapp–Hodgkin Syndromep63 (603273)Similar to AEC
 129490Hypodidrotic Ectodermal DysplasiaEDAR (604095), EDARADD (606603)Defects in both NF-kappa-B activation and LEF1/beta-catenin repression
 129500Hidrotic Ectodermal DysplasiaConnexin-30; GJB6 (604418)May affect connexin channels, gap junctions and cell–cell communication important in keratinocyte growth and differentiation
 148210Keratitis-Ichthyosis-Deafness Syndrome (KID Syndrome)Connexin 26, GJB2 (121011)Gap junctions provide dynamic adhesive contacts that interact with the internal cytoskeleton
 148350Palmarplantar Keratoderma with DeafnessConnexin 26, GJB2 (121011)Gap junctions provide dynamic adhesive contacts that interact with the internal cytoskeleton
 154780Marshall SyndromeType XI Alpha-1 Collagen; COLL11A1 (120280)Crucial in physiologic processes such as development, normal differentiation, and spatial organization of growth plate chondrocytes and wound healing
 158000MonilethrixKeratin 81; KRT 81 (602153), Keratin 83; KRT 83 (602765), Keratin 86; KRT 86 (601928)Important in hair differentiation and growth
 164200Ocuodentodigital Dysplasia; ODDDConnexin 43, GJA1 (121014)Misassembly of gap junction channels or altered channel conduction properties
 167200Pachyonichia Congenita Type 1Keratin 16 and 6A, KRT16 (148067); KRT6A (148042)Aberrant cytoskeletal networks leading to epithelial fragility
 167210Pachyonichia Congenita Type 2Kertain 17, KRT17 (148069)Regulates cell growth through binding to the adaptor protein 14-3-3-sigma
 181450Ulnar-Mammary SyndromeT Box 3, TBX3 (601621)Transcriptional regulation of cell lineage specification and topographical location
 189500Witkop SyndromeMuscle Segment Homeobox, MSX1 (142983)Hox family transcription factor involved in crosstalk between the Msx-Dlx pathways
 190320Tricho-Dento-Osseous SyndromeDistal-less 3, DLX3 (600525)Transcription factor involved in morphogenesis; cell differentiation; and cycling in hair, teeth, and bone
 190350Trichorhinophalangeal Syndrome, Type IZinc Finger Transcription Factor, TRPS1 (604386)Haploinsufficiency of transcription factor involved in morphogenesis; cell differentiation; and cycling in hair, teeth, and bone
 150230Trichorhinophalangeal Syndrome, Type IITRPS1 (604386); Exostosin EXT1 (608177)TRPS type II combines the clinical features of trichorhinophalangeal syndrome type I (190350) and multiple exostoses type I (133700), which are caused by mutations in the TRPS1 and EXT1 genes, respectively
 190351Trichorhinophalangeal Syndrome, Type IIITRPS1 (604386)Severe end of TRPS spectrum often caused by altering the GATA DNA binding zinc finger mutations
 193530Weyers Acrofacial DistosisEllis Von Creveld, EVC (604831); Limbin, EVC2 (607261)EVC is a component of the hedgehog signal transduction pathway
 601124Naxos DiseaseJunction Plakoglobin, JUP (173325)Component of the cadherin–catenin complex
 612132Hypohidrotic Ectodermal Dysplasia With T Cell ImmunodeficiencyNuclear Factor of Kappa Light Chain Enhancor in B Cells Inhibitor, NFKBIANFKB complex is inhibited by I-kappa-B proteins
Autosomal recessive
 209500Atrichia with Papular LesionsHairless Mouse Homolog, HR (602302)To function as a transcription factor may regulate one of the transitional parts of hair growth pathway
 224900Hypohidrotic Ectodermal DysplasiaEctodysplasin Anhidrotic Receptor, EDAR (604095) or EDARADD (606603)EDAR binds EDA signaling NF-kappa-B. These mutations cause impaired NF-kappa-B signaling
 225060Cleft Lip/Palate-Ectodermal Dysplasia Syndrome, Margarita Island TypePoliovirus receptor-like-1; PVRL1 (600644)PVRL1 codes for nectin-1, an immunoglobulin-related transmembrane cell–cell adhesion molecule that is part of the NAP cell adhesion system
 225280Ectodermal Dyplasia, Ectrodactyly, Muscular Dystrophy SyndromeCadherin-3, CDH3; (114021)An integral membrane glycoprotein responsible for calcium-dependent cell–cell adhesion
 601553Congenital Hypotrichosis with Juvenile Macular DystrophyCadherin-3; CDH3 (114021)CDH3 encodes P-cadherin
 225500Ellis–Van Creveld SyndromeEVC (604831); EVC2 (607261)EVC is a component of the hedgehog signal transduction pathway
 240300Autoimmune Polyendocrine SyndromeAutoimune Regulator, AIRE (707358)Involved in setting the threshold for self-tolerance versus autoimmunity
 245000Papillon–Lefevre SyndromeCathepsin C, CTSC (602365)Role in the activation of granule serine proteases expressed in bone marrow-derived effector cells of both myeloid and lymphoid series
 245010Haim–Munk SyndromeCathepsin C, CTSC (602365)Role in the activation of granule serine proteases expressed in bone marrow-derived effector cells of both myeloid and lymphoid series
 250250Cartilage-Hair HypoplasiaMitochondrial RNA-Processing Endoribonuclease, RMRP (157660)Cleaves mitochondrial RNA complementary to the light chain of the displacement loop at a unique site
 256800Insensitivity to Pain, Congenital, with AnhidrosisNeurotrophi Tyrosine Kinase Resceptor Type I, NTRK1 (191315)Nerve growth factor receptors whose ligands include neurotrophins
 257980Odontoonychodermal DysplasiaWingless Type MMTV Integration Site Family Member 10A, WNT10A (606268)WNT/beta-catenin pathway
 268400Rothmund–Thompson SyndromeRecQ Protein-like 4, RECQL4 (603780)Possibly involved in sister-chromatid cohesion or complexing with ubiquitin ligases of the N-end rule pathway
 256710Elejalede SyndromeMyosin VA, MYO5A (160777)Is a processive motor potentially important in organelle transport and neurite outgrowth
 602032Pure Hair-Nail Type Ectodermal DysplasiaKeratin 85, KRT855 (602767)Important hair keratin
 604536Ectodermal Dysplasia Skin Fragility SyndromePlakophilin 1, PKP1; 601975Important functions in cytoskeleton/cell membrane interactions
 604379HypotrichosisLipase H, LIPH (607365)Lipid mediator with diverse biologic properties including stimulation of cell proliferation
 300291Hypohidrotic Ectodermal Dysplasia with Immune DeficiencyNF-Kappa-B Essential Modulator, NEMO (300248)Required for activation of the IKK complex and NF-Kappa-B
 300301Anhidrotic Ectodermal Dysplasia with Immunodeficiency, Osteopetrosis, and LymphedemaNF-Kappa-B Essential Modulator, NEMO (300248)X420W mutation results in a 50–60% reduction of NF-kappa-B activation
 300606X-Linked HypodontiaEctodysplasin A; EDA (300451)Novel member of the TNF-related ligand family involved in the early epithelial–mesenchymal interaction that regulates ectodermal appendage formation
 305000Dyskeratosis Congenita, X-Linked; DKCDyskerin, DKC1 (300126)Protein that is responsible for some early steps in ribosomal RNA processing and seems to be a centromere or microtubule protein
 305100Hypohidrotic Ectodermal Dysplasia; ED1; Christ–Siemens–Touraine SyndromeEctodysplasin A; EDA (300451)Novel member of the TNF-related ligand family involved in the early epithelial–mesenchymal interaction that regulates ectodermal appendage formation
 305600Focal Dermal HypoplasiaPorcupine, PORCN (300651)Encodes an endoplasmic reticulum transmembrane protein involved in processing of wingless proteins (Wnt)
 308300Incontinentia Pigmenti; IPNF-Kappa-B Essential Modulator, NEMO (300248)Required for activation of the IKK complex and NF-Kappa-B
 311200Orofaciaodigital Syndrome IChromosome X Open Reading Frame 5, CXORF5 (300170)May contribute to the regulation of microtubule dynamics

The molecular pathways involved in regulating development of the ectoderm and its appendages frequently involve genes that are also important in the development of mesenchymal and endodermally derived tissues [Yamashiro et al., 2007; Rinne et al., 2008; Thomason et al., 2008]. Not surprisingly, the human DNA blueprint is employed in a highly efficient manner including the potential use of one gene's products in a variety of tissues and processes thereby allowing tremendous complexity at the proteomic level. Thus, the existence of hereditary conditions affecting exclusively ectodermally derived tissues is more the exception than the rule. Understanding the role of genes such as P63, DLX3, NEMO, EDA, WNT10A, and their associated molecular pathways during development is crucial for understanding the pathogenesis of the diverse ED conditions. It is critical to study the pathways involved to fully understand the pathogenesis of specific mutations and how the resulting mutant protein leads to abnormal or loss of function. This is well illustrated by the diverse mutations in NEMO and P63 that can result in markedly different phenotypes depending on the type and location of the mutation and resulting protein [McGrath et al., 2001; Smahi et al., 2002; Rinne et al., 2008; Thomason et al., 2008]. For example, NEMO mutations cause a variety of EDs with immunodeficiency while P63 mutations cause six different ED conditions (e.g., AEC syndrome-OMIM #106260, EEC syndrome-OMIM #12990, ADULT syndrome-OMIM #103285). Depending on the specific P63 mutation and altered function of the protein domain there can be changes in DNA binding, protein–protein interaction, gain of function, and dominant negative mechanisms [Rinne et al., 2008; Thomason et al., 2008]. Understanding the molecular mechanisms and specific alteration of the developmental pathway provides the foundation for establishing meaningful phenotype–genotype relationships.


Incorporating information from the clinical and genetic classification system with current molecular information clearly has merit. The approach should be logical in its construction and allow for ease of utility if wide acceptance is expected. One logical approach is to begin with the clinical information and mode of inheritance (as these are the initial presentation that will provide the basis for any subsequent molecular studies) followed by mutation and molecular pathway information (Fig. 1). Indeed, it is the careful clinical evaluation and phenotype characterization that provides the critical information necessary to consider pursuing a molecular diagnosis. Investigation of the molecular defect can lead to a more objective diagnosis if a specific and causative mutation is identified. This could result in changing the initial clinical classification and potentially the clinically perceived mode of inheritance. Figure 1 illustrates the interactive and dynamic nature of this process as one moves from clinical, to molecular, to pathway domains with each domain being at least partially elucidated or confirmed by other domains. Identification of a specific mutation can clarify the molecular pathway and will eventually lead to understanding the specific pathogenesis caused by the altered protein. Our knowledge of the molecular pathway and pathogenesis domain remains deficient and will continue to expand as new mutations and developmental mechanisms are discovered.

Figure 1.

Each domain or axis is used to classify or define the syndrome as illustrated for X-linked hypohidrotic ectodermal dysplasia. Interaction between the domains illustrates how knowledge in one domain supports and ultimately advances discovery; transfer of knowledge; and understanding in clinical, molecular etiology, and basic science domains.


Adoption of a classification system that incorporates clinical, genetic, and molecular information is critical for efficiently advancing our understanding of phenotype–genotype relationships of the EDs. Developing a new classification approach has significant social and scientific ramifications [Miller et al., 2006]. The development of national and international registries for the EDs would greatly facilitate meaningful phenotype–genotype studies of these relatively rare conditions. Toward this end, the development of public/private partnerships would help advance the establishment of accessible clinical data bases and material for molecular studies. One example of this would be to work with National Institutes of Health-Practice Based Research initiative to gather clinical phenotype data, recruit study participants, and gather materials for molecular studies. Adoption of a classification system that optimizes communication of hereditary, clinical, molecular, and pathogenesis information will help advance these initiatives and our efforts to better understand and manage the diverse ED syndromes.