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REVIEW ARTICLE
Year : 2021 | Volume
: 41
| Issue : 2 | Page : 55-66
Molecular basis of ectodermal dysplasia: a comprehensive review of the literature
Saeed Dorgaleleh1, Karim Naghipoor1, Zahra Hajimohammadi2, Morteza Oladnab3
1 Student Research Committee, Golestan University of Medical Sciences, Gorgan, Iran
2 Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
3 Department of Medical Genetics, School of Advanced Technologies in Medicine, Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
Correspondence Address:
PhD Morteza Oladnab
Department of Medical Genetics, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, 4934174516
Iran
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/ejdv.ejdv_54_20
Ectodermal dysplasia (ED) syndrome is a rare genetic disease that involves a heterogeneous group of hereditary disorders that occur as a result of mutations in genes that code for development of fetal ectoderm and lead to numerous disorders. Defects in the development of the ectoderm cause symptoms in tissues derived from the ectoderm layer, such as skin, nails, hair, and teeth. Because many pathways are involved in the development of the ectoderm, there are mutations in many genes that cause ED. Owing to the heterogeneity of ED, there are different types of the disease that have different symptoms. These symptoms include sparse hair, abnormal or missing teeth, nail dystrophy, lack of sweating owing to the absence of sweat glands, and cancer. In this review, in addition to discussing the role and pathway of each of the genes involved in ED, the incidence of cancer in these patients, diagnostic methods and differentiation from other similar diseases, and the treatments currently being performed for ED are discussed.
Keywords: cancer, diagnosis, ectodermal dysplasia, nuclear factor kappa B, tumor protein p-63, treatment
Ectodermal dysplasia (ED) is a rare genetic disease with a characteristic by sparse hair, lack of sweat glands, and abnormal teeth. The rate of the disease is one person per 100 000 live births [1]. ED affects both sexes and is seen in all ethnic groups. The disease is the result of mutations in the genes encoding the development of fetal ectoderm that leads to disorders of varying severity. The tissues that are primarily involved are the skin and its derivatives (including hair follicles, eccrine glands, sebaceous glands, and nails) and teeth. Clinical features include scattered hairs, abnormal or missing teeth, and lack of sweating owing to the absence of sweat glands [2]. It affects fetal organs that have an ectodermal structure such as teeth, nails, hair, sweat glands, lacrimal glands, and salivary glands. In this heterogeneous disorder, teeth turn to peg shaped. Therefore, missing teeth can have a negative effect on chewing, swallowing, speech, and malformed appearance ([Figure 1]). In severe form, affected people may have a violent appearance that can lead to psychological disorders [3]. Through sweating on the surface of the skin, the body heat reduction happens, and this is a clever mechanism for the body to regulate body temperature and prevent damage caused by increased body heat. Patients with ED have trouble adjusting their temperature, which is owing to reduced or no perspiration, leading to excessive heat storage and causing hyperthermia (body temperature above 39°C) and heat illness (including fatigue or heat) and eventually can cause death [4]. Approximately 200 different types of ED have been identified so far, of which only ∼30 have been identified at the molecular level [5] ([Figure 2]). The most common and most severe form of ED is the type of hypohidrotic ectodermal dysplasia (HED) or X-linked recessive Christ–Siemens–Touraine syndrome [6]. Approximately 20 mutations in the ectodysplasin A receptor (EDAR) gene have been identified in people with HED. The disorder accounts for 80% of ED, affecting one in 10 000. The overall mortality rate for HED is ∼30% in the first 2 years of life owing to fever, chest infection, and even brain damage in the affected because of transpiration decrease, which raises body temperature. The HED diagnostic triangle includes defects in hair glands, teeth, and sweat glands [7]. The second common form is hydrotic ED (Clouston syndrome), which usually has autosomal-dominant inheritance but is sometimes inherited as recessive autosomal recessive. The syndrome is characterized by a decrease in sweat glands and affects only teeth, hair, and nails. The clinical features are similar to the HED form but differ in severity in men and women. Diagnosis is usually made in infancy when tooth, hair, and nail defects are more evident. It can also be confirmed the diagnosis by genetically tests and having a positive family history, or clinical adaptation to a diagnostic triangle can confirm the diagnosis [8]. In some cases, ED is easily recognizable. In other cases, however, parents and doctors may diagnose ED when the tooth is abnormal (after 15 months). Diagnosis of ED will be possible by identifying the involved body parts and evaluating the function, growth, and development of those parts. Genetic tests are only available for a limited number of ED [1]. However, only 30% of the genes involved in ED have been identified, such as ED1, EDA, EDAR, GJB6, A88V EDARADD, and WNT10A [9] ([Figure 3]). Mutations in different genes (EDA, EDAR, and EDARADD), where mutations in one gene may lead to different phenotypes, and mutation in other downstream genes in the same signaling pathway may completely alter the phenotype [1]. The EDAR gene provides instructions for making a protein called the EDAR. This receptor is part of a signaling pathway that plays an important role in prenatal growth. In particular, it is crucial for the interaction between two layers of embryonic cells called the ectoderm and mesoderm. In the early embryo, these cell layers (ectoderm and mesoderm) are formed. Genes that mutate in this pathway are mostly involved in signaling, cell adhesion, and cellular regulation [10] ([Table 1]).
Figure 1 Classification of ectodermal dysplasia based on which tissue affects each disease.
Figure 2 Diseases associated with ectodermal dysplasia and their indicative symptoms.
Figure 3 Classification of ectodermal dysplasias based on molecular pathways. Each of these pathways somehow contribute to the development and morphogenesis of ectoderm-derived tissues. Mutations in the genes of these pathways give rise to diseases associated with ectodermal dysplasia.
Table 1 Statistical characteristics of individuals with uremia and healthy participants Ectodermal dysplasia genes Ectodysplasin A receptor
EDAR (it also has called ED1R, EDA3, HRM1, and EDA1R) is the abbreviation for ectodysplasin A receptor. It is located on 2q13 and has 12 exons. EDAR is expressed in esophagus, lymph node, skin, salivary gland, etc. This gene encodes a member of the tumor necrosis factor receptor (TNFR) family [11]. EDAR contains an extracellular TNFR domain and an intracellular death domain. Through extracellular domain, it binds to ligands such as EDA-A1 and activates signaling pathways within the cell [12] ([Figure 4]). These activated pathways lead to the development and morphogenesis of ectoderm-derived structures such as teeth, hair, nails, and glands, as well as the regulation of adipocytes [13]. The TNF pathway also plays a role in the morphogenesis of mammary glands, resulting in defects in this pathway, causing problems in the development of breast [12]. Mutations in this gene can cause hypohidrotic dysplasia, a predominant form of autosomal recessive and autosomal recessive [11].
Figure 4 The TNF-α signaling pathway is involved in cutaneous differentiation. EDA, expressed under the control of the Wnt/beta catenin pathway and Lef1, encodes two isoforms. These isoforms, which contain EDA-A1 and EDA-A2, are homologous to the TNF family. The extracellular domain of EDA has a furin cleavage site that is essential for its function. EDA-A1 with EDAR and EDA-A2 with XEDAR interact. While XEDAR interacts with and TRAF, the extracellular EDAR of the domain connects to the EDARADD adapter without an adapter. The use of the TRAF-6 adaptor activated the kinase complex and intermittent IKB degradation. Then, NFKB enters the nucleus and causes expression of certain genes. EDAR, ectodysplasin A receptor; NFKB, nuclear factor kappa B; TNF, tumor necrosis factor.Ectodysplasin A
EDA (it also has been called ED1, ODT1, XHED, ECTD1, and XLHED) is the abbreviation for ectodysplasin A. It is located on Xq13.1 and has 13 exons. EDA is expressed in adrenal, thyroid, heart, skin, salivary gland, etc. [14]. EDA has five different expressions as a result of alternative splicing, with EDA-A1 having the most expression with eight exons [15]. EDA belongs to the TNF-linked ligand family and has four important areas, including the following: (a) collagen-like domains that form a trimer structure with each other and activate signaling pathways; (b) several domains similar to TNF [16]; (c) the part that links between the extracellular domain and transmembrane; and (d) cleaves the furin fragment which is released by cleavage in this region of the soluble portion of the protein EDA. Binding of EDA to the receptor activates pathways involved in the morphogenesis and maintenance of the evolution of ectoderm-derived organs, as well as in the repair and regeneration of the skin and enhancing the regeneration capacity of bone marrow mesenchymal stem cells [17]. Defects in this gene are a cause of ED, anhidrotic, also known as X-linked HED [14].
Gap junction protein beta 6
GJB6 (it also has called ED2, EDH, HED, and CX30) is the abbreviation for gap junction protein beta 6. It is located on 13q12.11 and has six exons. GJB6 is expressed in esophagus, bone marrow, brain, and skin [18]. GJB6 encodes a protein called connexin 30 [19], which binds cells to adjacent cells via gap junctions [20]. Each connexin protein has four transmembrane segments, two extracellular loops, a cytoplasmic loop formed between the two inner transmembrane segments, and the N-terminus and C-terminus both being in the cytoplasm. The specificity of the gap junction is determined by which connexion proteins comprise the hemi channel [18]. This gap junction transmits nutrients, ions, and signaling molecules between cells [19] that coordinate activity between cells. The mutation in GJB6 is caused by a defect in gap junction and is associated with hidrotic ED (also called Clouston syndrome) disease that have clinical features such as nail dystrophy (micronychia or anonychia), hair loss and palmoplantar keratoderma (PPK) but have normal teeth, sweat, fat glands [20].
Tumor protein p-63
TP63 (it has also been called NBP, RHS, p40, and p51) is the abbreviation for tumor protein p-63. It is located on 3q28 and has 17 exons. TP63 is expressed in skin, esophagus, urinary bladder, prostate, and salivary gland. This gene encodes a member of the p53 family of transcription factors. Alternative splicing of this gene and the use of alternative promoters results in multiple transcript variants encoding different isoforms that vary in their functional properties [21]. TP63 has an important domain that binds to DNA and a domain named sterile alpha motif (SAM) and transactivation inhibition domain (TID) after SAM and creates a balance between the isoforms of TP63. Protein P-63 is expressed in embryogenesis and is involved in the differentiation and proliferation of the epidermal layer and the interaction between the epithelium and the mesenchyme and in the regulation of hair development [20]. Some isoforms have been found to protect the germline by eliminating oocytes or testicular germ cells that have suffered DNA damage [21]. The defect in TP63 is involved in at least six syndromes associated with ED, all of which have autosomal-dominant inheritance [20]. (a) Ectrodactyly-ectodermal-dysplasia-cleft/lip palate (EEC) syndrome is the most common form and has symptoms of malformation of limb, orofacial cleft, tear duct abnormalities, deafness, alopecia, dry skin, and hypodontia or anodontia. (b) Ankyloblepharon-ED-cleft/lip palate (AEC) syndrome is the result of a mutation in the SAM domain and the symptoms of skin erosion in the scalp, head, and neck, cleft palate, and hypopigmentation or hyperpigmentation. In childhood, owing to skin manifestations such as collodion membrane and ichthyosis scaling, it may be suspected of epidermolysis bullosa. (c) Limb-mammary syndrome occurs because of mutations in SAM and TID and is clinically overlapping with other types of TP63. Symptoms are cleft palate, ectrodactyly, hypoplasia of the mammary glands, and are present in the skin and hair without any problems. (d) Acro-dermato-ungual-lacrimal-tooth syndrome occurs as a result of mutation in TID and has clinical signs similar to EEC, but their differential diagnosis is the absence of orofacial palate in acro-dermato-ungual-lacrimal-tooth. (e) Rapp-Hodgkin syndrome occurs mutation in SAM domain and has the same symptoms as AEC. (f) Split-hand-foot malformation presents with syndactyly, split hand and foot, hypoplasia of the phalanges, and metacarpal signs [20],[22].
Inhibitor of nuclear factor kappa kinase regulatory subunit gamma B
IKBKG (it has also been called IPD2, NEMO, and IKK-gamma) is the abbreviation for inhibitor of nuclear factor kappa B (NFKB) kinase regulatory subunit gamma. It is located on Xq28 and has 12 exons. IKBKG is expressed in spleen, appendix, lymph node, skin, etc. [23]. The pathway of EDA and EDAR leads to the activation of NFKB pathway. If this pathway is not active, NFKB is inhibited by IKB. The kinase complex activates the NFKB pathway by phosphorylation of IKB. One of the components in the kinase complex is NEMO, which plays a regulatory role in this complex [24]. Posttranslational modifications occur in the NEMO protein, which is required for its function in this complex [25]. Mutations in this gene cause XL-HED-ID, which in addition to the symptoms of HED, indicates a lack of response to cytokines due to defects in inflammatory factors. In addition, in these patients, there is a defect in NK cells and decrease in TNF and interleukin (IL)-2 production. Therefore, we expect these individuals to be susceptible to bacterial infections in the respiratory and gastrointestinal tracts, skin, and bone [20].
Nectin cell adhesion molecule 1
NECTIN-1 (it has also been called ED4, PRR, PVRL1, and HV1S) is the abbreviation for nectin cell adhesion molecule 1. It is located on 11q23.3 and has 10 exons [26]. NECTIN-1 is expressed in skin, esophagus, brain, urinary bladder, etc. Poliovirus receptor like 1 (PVRL1) encodes nectin-1 protein [27]. Nectin-1 is expressed in the tissue of the ectoderm such as skin, teeth, and hair [20]. Nectin is a part of NAP cell adhesion system (nectin, afadin, and ponsin) that is very important in the stability and integrity of cell membranes and also plays a role in cell signaling [28]. This protein acts as a receptor for glycoprotein D of herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) and pseudorabies virus and mediates viral entry into epithelial and neuronal cells [26]. Mutation in this gene leads to cleft/lip palate-ectodermal dysplasia with autosomal recessive inheritance. Symptoms include syndactyly, tooth abnormalities, palmoplantar hyperkeratosis, and bilateral cleft/lip palate. The disease overlaps with EEC phenotype, which can be used for autosomal-dominant inheritance and limb malformation for differential diagnosis [20].
NFKB inhibitor alpha
NFKBIA (it has also been called IKBA, MAD-3, NFKBI, and EDAID2) is the abbreviation for NFKB inhibitor alpha. It is located on 14q13.2 and has six exons. NFKBIA is expressed in bone marrow, ovary, appendix, adrenal, etc. [29]. In the NFKB pathway, the NFKB transcription factor plays a significant role in extracellular signal transduction and intracellular response. This pathway plays a role in cell adhesion and the immune response and activation of expression of factors affecting immunity. In the absence of an NFKB activation signal, NFKB is inhibited in the cytoplasm by an NFKB inhibitor (IKB). The activation signal activates the kinase complex, which phosphorylates IKB, leading to ubiquitination and degradation. Mutation in IKBA (IKB has three components: IKBA, IKBB, and IKBE) leads to lack of phosphorylation and inactivation of the NFKB pathway and causes AD-HED-ID disease. Symptoms include anhidrosis, dental abnormalities, sparse hair [30], and T-cell immunodeficiency, but unlike XL-HED-ID, NK-cell are normal [20].
EDAR-associated death domain
EDARADD (it has also been called ED3, EDA3, ECTD11A, and ECTD11B) is the abbreviation for EDAR-associated death domain. It is located on 1q42.3-q43 and has seven exons. EDARADD is expressed in urinary bladder, placenta, kidney, esophagus, etc. The protein encoded by this gene is a death domain-containing protein and is found to interact with EDAR, a death domain receptor known to be required for the development of hair, teeth, and other ectodermal derivatives. This protein and EDAR are expressed in epithelial cells during the formation of hair follicles and teeth [31]. EDARADD in its N-terminal bind to a TRAF and in death domain in C-terminal bind to EDAR. EDAR is activated upon connection to EDA and by using the EDARADD adapter (which is connected to the complex TRAF-6) activates the NFKB pathway. This activation is important for skin differentiation. The defect in EDARADD causes a defect in the activation of the NFKB pathway and also the autosomal-dominant and recessive autosomal form of HED [32].
Keratin 74
KRT74 (it has also been called ADWH, HTSS2, and HYPT3) is the abbreviation for keratin 74. It is located on 12q13.13 and has seven exons. KRT74 is expressed in testis, skin, esophagus, etc. [33]. KRT74 is a member of the keratin 2 gene cluster [34]. Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins [33]. Keratins have the role of protecting the skin, hair, and nails against trauma and chemical agents. The keratin and proteins that attach to them form cross-links in the hair stem and nail that play a role in strength. A mutation in this gene causes autosomal recessive pure hair and nail ectodermal dysplasia. Symptoms include sparse brittle hair, hypotrichosis, micronychia, onychodystrophy, and spoon-shape nails [34].
Protein kinase D1
PRKD1 (it has also been called PKD, PKCM, and CHDED) is the abbreviation for protein kinase D1. It is located on 14q12 and has 23 exons. PRKD1 is expressed in testis, prostate, kidney, ovary, etc. [35]. PRKD1 belongs to the serine/threonine kinase family. This protein is involved in the regulation of Golgi organization and in the process of epithelial cell transfer, preventing apoptosis and enhancing proliferation, and is involved in the regulation of myocardial contractions [36]. It also differentiates into keratocytes by expressing the factors involved in differentiation. Deficiency in this gene causes congenital heart defects and ectodermal dysplasia disease with autosomal-dominant inheritance. Symptoms of this disease can be noted to pulmonary valve abnormality, atrioventricular septal defect, dry skin, sparse hair, fragile nail, and depressed or prominent nasal bridge [37].
Gap junction protein beta 2
GJB2 (it has also been called KID, PPK, and CX26) is the abbreviation for gap junction protein beta 2. It is located on 13q12.11 and has three exons. GJB2 is expressed in esophagus, skin, liver, etc. These structures are shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells [38]. GJB2 encodes protein connexin 26 (CX26), which is produced by the assembly of two connexons from two different cells. CX26 is a part of gap junction that plays a key role in the development and stability of ectodermal tissues and the interactions between cells and in stria vascularis of the cochlea [39],[40]. Mutation in the GJB2 gene is responsible for as much as 50% of prelingual, recessive deafness [38] and keratitis-ichthyosis-deafness (KID) syndrome disease, which has the autosomal-dominant inheritance [41]. Symptoms include sensorineural hearing loss, erythrokeratoderma, dry skin, alopecia, and dystrophic nail [40].
TNFR-associated factor 6
TRAF-6 (it has also been called RNF85 and MGC) is the abbreviation for TNFR-associated factor 6. It is located on 11p12 and has 9 exons. TRAF-6 is expressed in bone marrow, thyroid, spleen, testis, and skin [42]. The TNF pathway, which contains EDA, EDAR, and EDARADD are important components of the TNF pathway that are involved in the activation of NFKB as well as in the growth of teeth, glands, hair, and skin. However, the TNF pathway requires TAK-2, TRAF-6, and TAB-2 adapters to activate the kinase complex (IKK) [43]. In the N-terminal of the TRAF-6 protein there is a zinc finger motif that activates the NFKB and JNK pathway and in C-terminal binds to EDARADD [44]. The interaction of this protein with UBE2N/UBC13, and UBE2V1/UEV1A, which are ubiquitin conjugating enzymes catalyzing the formation of polyubiquitin chains, has been found to be required for IKK activation by this protein [42]. On the contrary, the EDA-A2 and XEDAR pathway uses the TRAF-6 adapter to activate NFKB. Mutation in this gene causes HED disease [45].
Nectin cell adhesion molecule 4
NECTIN-4 (it has also been called LNIR, PRR4, EDSS1, and PVRL4) is the abbreviation for nectin cell adhesion molecule 4. NECTIN-4 is expressed in the skin and esophagus. It is located on 1q23.3 and has 9 exons. The NECTIN-4 gene encodes a member of the nectin family. The encoded protein contains two C2 domains such as immunoglobulin (such as Ig) and an Ig domain of type V. NECTIN-4 is involved in cell adhesion through homophilic and heterophilic interactions. The soluble form is produced by proteolytic cleavage at the cell surface by ADAM17/TACE matrix metalloproteinase. The secreted form is found in both breast tumor cell lines and patients with breast tumors. Mutations in this gene cause ectodermal syndrome-type 1 syndrome, an autosomal recessive disorder [46]. There is high expression of nectin-4 in hair follicle structures. In addition, in discrete hair follicle structures, localization changes have been found in the nectin–afadin and cadherin–catenin complexes, which are essential for the formation of junctions and their importance in reorganizing the actin cytoskeleton [47].
Grainyhead-like transcription factor 2
GRHL2 (it has also been called BOM, ECTDS, PPCD4, DFNA28, and TFCP2L3) is the abbreviation for grainyhead-like transcription factor 2. GRHL2 is expressed in skin, prostate, and 14 other tissues. It is located on 8q22.3 and has 18 exons. The protein encoded by this gene is a transcription factor that can act as a homodimer or as a heterodimer with GRHL1 or GRHL3 [48]. It plays an essential role during epithelial progression [49]. The defect in this gene causes nonsyndromic autosomal-dominant motor hearing loss of type 28 (DFNA28) [48], and clinical findings on autosomal recessive ED syndrome highlight the importance of the role of GRHL2 in skin development, homeostasis, and human disease [49].
Twist family BHLH transcription factor 2
TWIST2 is the abbreviation for twist family BHLH transcription factor 2. TWIST2 is expressed in fat and endometrial tissue. It is located on 2q37.3 and has three exons. The protein encoded by this gene is a helix-loop-helix-based transcription factor and has a high similarity to twist. This protein can inhibit osteoblast maturation and preserve cells in the preosteoblast form during osteoblast growth. This gene may have decreased regulation in some cancers [50]. The p. R31GfsX71 mutation identified in the BHLH domain study destroys the TWIST2 protein and plays an important role in this domain in the development of cutaneous and cartilage tissues [51]. A mutation in this gene causes focal skin dysplasia of type 3 [50].
Cystatin E/M
CST6 (it has also been called ECTD15) is the abbreviation for cystatin E/M. CST2 expression in the skin and lung. It is located on 11q13.1 and has three exons. The cystatin superfamily contains proteins that contain several sequences similar to cystatin. Some members are active inhibitors of cysteine proteinase, whereas others have lost or may never have this inhibitory activity. There are three families of inhibitors in the superfamily, including cystatin type 1, cystatin type 2, and quinogens. Cystatin type 2 proteins are a type of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to have protective functions. The gene encodes a cystatin from the type 2 family, which is downregulated in metastatic breast tumor cells compared with primary tumor cells [52]. Loss of expression is probably associated with the progression of a primary tumor to a metastatic phenotype, and ectodermal-15 dysplasia (ECTD15) is not characterized by a tuberculosis that occurs in childhood and lack of sweating, except with vigorous exercise. They have dry skin at birth and may develop eczematous lesions in adulthood. Other features of the disease include blepharitis and photophobia [53].
Homeobox C13
HOXC13 (it has also been called HOX3, ECTD9, and HOX3G) is the abbreviation for homeobox C13. It is located on 12q13.13 and has 2 exons. HOX13 is expressed in skin, testis, and placenta. The HOX13 gene is from the homeobox gene family. The homeobox gene, which plays an important role in morphogenesis, is a highly conserved family that encodes vital transcription factors that play a role in all multicellular organisms. Mammals have four similar homeobox gene clusters, including HOXA, HOXB, HOXC, and HOXD, which are located on different chromosomes and consist of 9–11 consecutive clustered genes. This gene is one of several HOXC homeobox genes located in a cluster on chromosome 12. The product of this gene may play a role in hair and nail growth [54]. HOXC13-deficient mice are known to develop hair and nail defects very similar to those seen in PHNED, which is a congenital disease characterized by hypotrichosis and nail dystrophy [55].
Desmoplakin
DSP is the abbreviation for desmoplakin. It is located on 6p24.3 and has 24 exons. DSP IS expressed in skin, esophagus, placenta, and colon [56]. Desmosomes are involved in cellular connections and cellular communication and signaling. Desmosomes are mainly found in the epidermis and cardiomyocytes, which provide flexibility and cellular endurance [57],[58]. Desmosomal components include plakophilin, desmoplakins, plakoglobins, desmoglobins, desmogleins, desmocollin, and corneodesmosomes, where mutations in these components includes a range of diseases involving the skin, hair, and heart. Desmoplakin is one of the many components of desmosomes that bind to intermediate filaments. Mutations in the desmoplakin gene cause dilated cardiomyopathy, woolly hair, and keratoderma (Carvajal syndrome) disease, which has an autosomal recessive inheritance. Symptoms of this disease are cardiomyopathy, decreased contractility, PPK, and abnormalities hair [59].
Ectodermal dysplasia and cancer
Owing to the fact that the genetic basis of HED is still unclear, the study of gene expression in epidermis and ectoderm has been suggested. Proteins are involved in epithelial–mesenchymal interactions. Therefore, this can affect any tissue or organ between the epithelium and mesenchyme, including the trachea, which has cartilage and muscle derived from mesoderm [60]. Reporting a case of HED in a young woman with squamous cell carcinoma that connects the skin and nails in two areas suggests a possible HED vulnerability to upper respiratory tract cancer [61]. One of the most common abnormalities in patients with ED is the absence or underdevelopment of the breasts. XEDAR is a receptor belonging to the TNF family with the ability to bind to EDA-A2. Analyses of the XEDAR expression, not EDA-A2, in breast epithelial cells have shown that this expression will be destroyed in breast cancer tumors. As the lack of TNFR family death receptors leads to the survival of tumor cells, it is thought that XEDAR will act as a tumor suppressor gene in the breast. Methylation of CPG promoter islands, gene light, and SPLISE site mutations are involved in the inactivation of suppressive genes and also in the progression of cancer and carcinogenic malignancies. Evidence suggests that XEDAR is unable to induce apoptosis, leading to the development of breast cancer. The association between XEDAR expression silencing and promoter mutilation cannot only be attributed to the breast cancer cell category but also to other cancers, including colorectal cancer and lung cancer. XEDAR targets two P53 junctions within its own intron via P53, leading to colorectal cancer. XEDAR lacks the ability of cell death, and despite the ambiguity in the role of XEDAR in evolution, it interacts with TRAF (with the ability to participate in different signaling pathways and carcinogens) and ultimately leads to increased cell proliferation [62]. XEDAR interaction with FAS also leads to increased apoptosis. Moreover, the negative regulation of FAK (involved in cell adhesion) by XEDAR has been shown to increase its expression in colorectal cancer. Therefore, inhibition of FAS and FAK activation owing to lack of XEDAR expression, P53 mutations, proliferative hyperthermia, and genetic mutations are associated with an increase in the presence of Anoikis in cancer cells. In general, XEDAR is a tumor suppressor that can play a role in preventing malignancy through FAK and FAS. The findings show poor EDA expression in malignant tumors such as basal cell carcinoma, squamous cell carcinoma, and melanoma. Recent findings have also shown a reduction in EDA mRNA expression in breast cancer samples [63].
Diagnosis
Overlapping phenotype and whole exome sequencing
Because ED comes in a variety of forms and includes a wide range of phenotypes, it may be overlapping with other diseases. For example, AEC is characterized by phenotypic symptoms of cleft lip/palate, ankyloblepharon, erythroderma, and scalp erosion. In one study, a case with symptoms of skin erosion, cleft palate, nail dystrophy, and erythroderma was first diagnosed with epidermolysis bullosa or congenital ichthyosiform erythroderma, which after genetic analysis revealed mutation in the P-63 gene, and AEC was diagnosed. Of course, the mutation in P-63 gives six different types of ED, which owing to the presence of scalp erosion leads to distinction of AEC from the rest. This study shows that the presence of overlapping phenotypes can lead to misdiagnosis, and genetic analysis such as whole exome sequencing and whole genome sequencing can help correctly diagnose the disease [64]. Because ED has 200 different types and symptoms, it can be difficult for physicians to diagnose. Today, whole exome sequencing and whole genome sequencing technologies can be used to find mutations, and it helps to properly diagnose and treatment [65].
Prenatal diagnosis
Early detection of this disease, especially for the HED type, which has a defect in thermoregulation due to lack of sweat gland, which causes serious complications such as hyperthermia, reduces the mortality rate. For HED, the probability of death in the first child is higher owing to the family’s lack of knowledge about the carrier of the disease. Prenatal diagnosis of Oligodontia, hypodontia, and anodontia, a prominent phenotype in ED patients, can be performed using dental ultrasound at 20–24 weeks of gestation. Three-dimensional ultrasound can also be used to assess mandibular hypoplasia, which is associated with oligodontia. In one study, Wünsche et al. [66] performed tooth germ sonography at 20–24 weeks of gestation in nine pregnant women with a family history of HED. To confirm the study, a molecular analysis was performed using the amniocentesis fluid, and the results confirmed tooth germ sonography findings. Another study was conducted in 2018 that looked at more people. In this study, 38 women were studied for the EDA mutant carrier during pregnancy. With tooth germ sonography at 18–28 weeks gestation, the number of tooth germs in the mandible and maxilla was assessed. Then all the cases underwent molecular analysis. The results showed that among 37 of 38 cases, sonography diagnosis results were correct, but in one case, the number of tooth germs was reported to be normal, which was after molecular analysis was detected as XLED (false-negative result). One of the disadvantages of tooth germ sonography is that the tooth germ evaluation depends on the position of the fetus, and it may be unsuitable for a careful examination [67]. Today, using chorionic villi sample and amniocentesis, amniocentesis methods can perform molecular analyses and find gene mutations can be found [68].
Treatment
Treatment of patients with ED requires several specialists, including dermatology, pediatrics, genetics, dentists, psychology, etc. [69]. One of the symptoms seen in patients with ED is congenital alopecia. Nowadays, minoxidil is used to treat alopecia. Minoxidil causes opening of the potassium channel, in order to allow more nutrients and blood entrance to hair follicles, which causes the follicles to move to the telogen phase [70]. Owing to the lack of sweat glands, patients with HED have difficulty regulating body temperature and experience hyperthermia, which is fatal. Therefore, it is better for the temperature of the living environment of these patients to be cool, to wear wet and thin clothes, and to refrain from physical activity constantly [71]. Dental treatment and early prosthetic rehabilitation are important for esthetics, normal speech, improved self-esteem, dirty pattern, and quality of life. Implants can be used for these patients [72].
Hematopoietic stem cell transplantation
There is a lot of research today on the use of the hematopoietic stem cell transplantation (HSCT) to treat ED with immune deficiency. In fact, HSCT involves the intravenous infusion of allogeneic stem cells in order to reestablish hematopoietic function in patients with bone marrow defect or immunodeficiency. The first successful HSCT in a child with EDA-ID was reported in 2006. Along with this success, repair both innate and adaptive immune responses, improve diarrhea and other gastrointestinal symptoms, without any GVHD, and no life-threatening infections for up to seven years. The success of this transplant led to normal immunological manifestations, including the production of cytokines such as IL-1, IL-6, and IL-10, and the immunologic phenotype was persisted for about 7 years after transplantation [73]. Despite the potential for significant mortality in transplantation of this type of patient, the first successful transplant in a patient with NEMO deficiency syndrome after Tersulfan as a high-immunity suppressor was reported. HSCT can repair fatal immunodeficiency and provides an opportunity for long-term survival. Further experience about HSCT for treatment of ED with NEMO mutation is essential to use this therapy [74].
Tumor necrosis factor pathway
TNF-α signaling pathway participates in the differentiation of skin appendages. As mentioned before, HED is a heterogeneous group of disorders owing to mutations of several genes that are engaged in TNF-α-related signaling pathway. Mutations of these genes, including ED1, EDAR, EDARADD, and NEMO, can disturb the interaction during embryonic development which causes problems in the process of initiation, formation, and differentiation of skin appendages. Owing to these mutations, some studies have been performed to treat the disease in mice and dogs, but unfortunately no gene therapy through TNF-α signaling pathway has been performed on human yet. Some of these mutations that happen in TNF-α-related signaling pathway are owing to the missense mutations which usually do not affect the structure of protein production. More investigations on the genes encoding components of the TNF-α-related signaling pathway are required [44],[75].
ConclusionED is a genetic heterogeneous disease. This rare disorder has different inherited patterns, and its prevalence is one in 10 000 live births. Owing to the heterogeneity of the ED, it is difficult to diagnose and treat. Although there are different ways to manage and diagnose, we still see the birth of children with this disorder. Patients with ED are also more likely to develop cancer, so screening for these patients is critical to prevent secondary infections and cancer. In this study, the genes involved in ED, signaling pathway, pathogenesis of the disease, communication with cancers, and treatment are discussed in detail to carefully examine the cellular translation of ED disease and the path of management and treatment of rare ED. Let us make it easier for future researchers and take a step toward introducing this disease further.
Acknowledgments
The authors would like to express gratitude toward the faculty members at Department of Medical Genetics, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences.
Source of funds: This study was supported by the Congenital Malformations Research Center, Research and Technology Department, Golestan University of Medical Sciences, Gorgan, Iran.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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