The human congenital syndromes ectrodactyly ectodermal dysplasia-cleft lip/palate syndrome, ankylobleph- aron ectodermal dysplasia clefting, and split-hand/foot malformation are all characterized by ectodermal dysplasia, limb malformations, and cleft lip/palate. These phenotypic features are a result of an imbalance between the proliferation and differentiation of precursor cells during development of ectoderm-derived structures. Mutations in the p63 and interferon regulatory factor 6 (IRF6) genes have been found in human patients with these syndromes, consistent with phenotypes. Here, we used human and mouse primary kera- tinocytes and mouse models to investigate the role of p63 and IRF6 in proliferation and differentiation. We report that the ΔNp63 isoform of p63 activated transcription of IRF6, and this, in turn, induced proteasome- mediated ΔNp63 degradation. This feedback regulatory loop allowed keratinocytes to exit the cell cycle, there- by limiting their ability to proliferate. Importantly, mutations in either p63 or IRF6 resulted in disruption of this regulatory loop: p63 mutations causing ectodermal dysplasias were unable to activate IRF6 transcription, and mice with mutated or null p63 showed reduced Irf6 expression in their palate and ectoderm. These results identify what we believe to be a novel mechanism that regulates the proliferation-differentiation balance of keratinocytes essential for palate fusion and skin differentiation and links the pathogenesis of 2 genetically different groups of ectodermal dysplasia syndromes into a common molecular pathway.
Ectodermal dysplasias (EDs) are a group of human pathological conditions characterized by anomalies in organs derived from epithelial-mesenchymal interactions during development. Dlx3 and p63 act as part of the transcriptional regulatory pathways relevant in ectoderm derivatives, and autosomal mutations in either of these genes are associated with human EDs. However, the functional relationship between both proteins is unknown. Here, we demonstrate that Dlx3 is a downstream target of p63. Moreover, we show that transcription of Dlx3 is abrogated by mutations in the sterile ␣ -motif (SAM) domain of p63 that are associated with ankyloblepharon-ectodermal dysplasia-clefting (AEC) dysplasias, but not by mutations found in ectrodactyly- ectodermal dysplasia-cleft lip/palate (EEC), Limb-mammary syndrome (LMS) and split hand-foot malformation (SHFM) dysplasias. Our results unravel aspects of the transcriptional cascade of events that contribute to ectoderm development and pathogenesis associated with p63 mutations.
The last decade has seen several important insights into the molecular basis of several of the ectodermal dysplasias. In some cases the molecular data have confirmed clinical impressions, for example Hay–Wells syndrome and ectrodactyly, ectodermal dysplasia, clefting (EEC) syndrome have ectodermal dysplasia and clefting of the palate and lip as common clinical findings and these conditions are now known to be allelic [McGrath et al., 2001]. Prompted by the great advances in molecular knowledge several authors have proposed new molecular-‐based approached [Priolo and Lagana, 2001; Lamartine, 2003; Itin and Fistarol, 2004]. These proposed approaches classify conditions based on the class of molecule responsible for the disorder, for example categorizing together those with mutations in structural or developmental molecules. This approach has many advantages, especially for characterization of defects in preparation for molecular diagnostics and, hopefully, molecular therapy. These systems, however, need to be integrated with clinical findings and need to be accessible to all clinicians involved in the care of these patients. Importantly, it has to be realized that currently it is not possible to provide a molecular diagnosis for all patients, even in those with classical clinical abnormalities of conditions well characterized at a molecular level. Molecular factors such as unusual mutation mechanisms can
Ectodermal Dysplasias comprise a large, heterogenous group of inherted disorders that are defined by primary defects in the development of two or more tissues derived from embryonic ectoderm. A multidisciplinary approach to dental treatment is required. This clinical report attempts to describe the prosthodontic management of a 13 year old girl affected by ectodermal dysplasia. Treatment included overdenture and a mandibular removable partial denture to improve
Ectodermal dysplasias (EDs) are a group of pathological conditions characterized by congenital defects that involve ectodermal structures and their appendages (hair, nails, teeth, and sweat glands) . EDs are rare syndromes and their incidence is estimated in about 7 cases in 10 000 births . More than 170 diﬀerent clinical conditions have been described as ectodermal dysplasias, with extremely varied manifestations and a large superimposition of clinical features, some of them observed more frequently (Table 1) [2–4].
Ectodermal dysplasias (EDs) are a heterogeneous group of disorders characterized by developmental Siemens-Touraine syndrome) males and is inherited through female and they become ichosis or hypotrichosis), abnormal and inability to sweat due to lack of sweat glands hypohidrosis).The lack of teeth and the special appearance were reported to be major from this disorder should therefore the genes and gene products are defined, hence identification ly will be beneficial. For the effects on growth and development of the jaws is often the most significant clinical and therapeutical problem. The course of the treatment normalise the vertical dimension and support dysplasia with review in this article for
Background: Odonto-onycho-dermal dysplasia (OODD) is a rare form of ectodermal dysplasia characterized by severe oligodontia, onychodysplasia, palmoplantar hyperkeratosis, dry skin, hypotrichosis, and hyperhidrosis of the palms and soles. The ectodermal dysplasias resulting from biallelic mutations in the WNT10A gene result in highly variable phenotypes, ranging from isolated tooth agenesis to OODD and Schöpf-Schulz-Passarge syndrome (SSPS). Case presentation: We identified a female patient, with consanguineous parents, who was clinically diagnosed with OODD. Genetic testing showed that she was homozygous for a previously reported pathogenic mutation in the WNT10A gene, c.321C > A, p.Cys107*. The skin and nail abnormalities were for many years interpreted as psoriasis and treated accordingly. A thorough clinical examination revealed hypotrichosis and hyperhidrosis of the soles and dental examination revealed agenesis of permanent teeth except the two maxillary central incisors. Skin biopsies from the hyperkeratotic palms and soles showed the characteristic changes of eccrine syringofibroadenomatosis, which has been described in patients with ectodermal dysplasias. Together with a family history of tooth anomalies, this lead to the clinical suspicion of a hereditary ectodermal dysplasia.
consciousness. The tongues from each mouse were removed and immediately fixed in 4% formalin for about 24 h. After this period, the tongues were cut transversely into five slices, routinely processed and embedded in paraffin. During this procedure, great care was taken by us when a lesion was observed on the tongue surface to avoid its omission in the microscopic view. In this case, the lesion was carefully cut to permit its representation on histological slide. Paraffin-embedded, 5- µ m thick tissue sections were stained using a standard hematoxylin and eosin method to detect dysplasias and carcinomas according to the criteria established by Lumerman et al.  and Cardesa et al. , respectively. All histological slides were independently examined by three well-trained pathologists (PRF, AML, and SVC) to diagnose of the lesions. Discrepancies were solved after achieve a consensus scoring by the three pathologists. When two or more epithelial alterations were seen in the same histological slide, the highest aggressive lesion was taken to define the pathologic condition of the mouse. Immunohistochemistry
Clinical examination of the 12 years old boy with Ectodermal dysplasia showed that he suffered from missing teeth, polydiestemia and conical teeth. It was observed that especially there were missing teeth in the maxilla and mandible. Extra-oral examination of the patient revealed dry skin, saddle nose, abnormal hair, protruding lips (Figure 9). It was learned that it was not a kin marriage and no problems existed in other members of the family. After prosthetic evaluation, it was decided to apply removable partial denture to the maxilla in order to meet functional and aesthetic expectations as the patient had not completed his growth and development. Detailed information was given to and approval was obtained from the parents of the patient (Figure 6-10).
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Ectodermal dysplasia (ED) is not a single disorder, it is a large and complex group of disorders defined by the abnormal development of two or more structures derived from the embryonic ectoderm layer [1,2]. These are congenital, diffuse and non progressive disorders. More than 192 distinct disorders have been described till date. Most common of them are X-linked recessive anhidrotic (Christ-Siemens-Touraine syndrome) and hidrotic ectodermal dysplasias (Clouston syndrome) . It is also rare and non progressive and presents a triad of partial or total absence of sweat glands, hypotrichosis, and hypodontia . In addition, there are other signs and symptoms that can be found depending on the involvement of the ectodermal tissue . The ectoderm, one of three germ layers present in the developing embryo, gives rise to the central nervous system, peripheral nervous system, sweat glands, hair, nails, and tooth enamel . As a result, patients of ED exhibit the following clinical sign: hypotrichosis, hypohidrosis, and cranial abnormalities. The patients often exhibit a smaller than normal face because of frontal bossing, a depressed nasal bridge, the absence of sweat glands results in very smooth, dry skin and/or hyperkeratosis of hands and feet. Oral traits may express themselves as anodontia, hypodontia, and conical teeth. Anodontia also manifests itself by a lack of alveolar ridge development [7, 8]. The earliest recorded cases of ED were described in 1792. Since then, nearly 200 different pathologic clinical conditions have been recognized and defined as ED. These disorders are considered relatively rare, 1 in 10,000 to 1 in 100,000 births [9, 10].
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Over the last two decades, dominant gain-of-function mutations of the specific site in fibroblast growth factor receptor 3 (FGFR3) have been shown implicated in human skeletal dysplasias, including achondroplasia (ACH), hypo- chondroplasia (HCH), thanatophoric dysplasia (TD) and severe achondroplasia, with developmental delay and acanthosis nigricans (SADDAN) [4, 10]. The FGFR3 is one of the four members of fibroblast growth factor recep- tor (FGFR) family, but differs from other FGFRs in its af- finity for ligands and tissue distribution as it is mainly expressed in cartilage and brain [11, 12].
We sorted out the GFP-positive cells derived from the small ectoderm fragments using fluorescence-activated cell sorting (FACS) and analyzed gene expression of various lineage markers. Three of the four fragments expressed similar levels of epidermal markers and neural markers when cultured with or without BMP4, respectively, with the exception of fragment 2, which expressed lower levels of epidermal markers (Fig. 6Bb,Bc). Consistent with the whole A/P explants (Fig. 5Cc), all four fragments expressed mesoderm/endoderm markers at much lower levels compared with the posterior explants (supplementary material Fig. S4). We conclude that, despite some heterogeneity in the differentiation efficiency of ectodermal derivatives, the entire A/P fragment can give rise to neural and surface ectoderm. By comparison, the small fragment of the A/D region co-cultured with large anterior ectoderm explant expressed very weak epidermal markers and relatively higher levels of mesoderm/endoderm markers when cultured with BMP4 (supplementary material Fig. S5). This result confirmed the difference between A/D and A/P regions. Moreover, it indicated that the large anterior fragment did not alter the differentiation potential of small fragments in an obvious manner.
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We thank the individuals and families who participated in this project, as well as the executive staff and past and present mem- bers of the Scientific Advisory Board of the National Foundation for Ectodermal Dysplasia, including Frank H. Farrington, DDS; Albert D. Guckes, DDS; Christopher J. Hartnick, MD; Ronald J. Jorgenson, DDS, PhD; Richard A. Lewis, MD; Charles M. Meyer, III, MD; Jill K. Powell, MD; Lynette L. Rosser, MSW; Laura J. Russell, MD; Elaine C. Siegfried, MD; Clark M. Stanford, DDS, PhD; and Barry Tanner, PhD, who generously volunteered their efforts during the research workshops.
Different kinds of recombination experiments have shown that the AER exerts a permissive function on the underlying mesoderm. The mesodermal component of a limb bud can be separated from its ectodermal hull and recombined with a limb ectoderm of different age, type (fore versus hind) or even a different species (chick versus mouse) and still it will give rise to a normal limb (Rubin and Saunders, 1972; Kuhlman and Niswander, 1997; Fernandez- Teran et al., 1999). These experiments highlight the equivalence between AERs of different developmental age and origin disre- garding the variations in morphology and gene expression (see below) that the AER normally undergoes. However, the above- mentioned experiments can also be taken as indicating that the AER is a very malleable structure that rapidly responds to the mesoderm; an AER transplanted over a non-matching mesoderm (because of developmental age, type of limb, specie, etc.) rapidly modifies its morphology and gene expression to adapt to the new situation (Zwilling, 1956; MR personal results). It should be noted here that recombination experiments mentioned above have only been successful when the mesoderm is of the same (or related e.g. chick/quail) species origin as the host in which it is going to be grafted. For example recombinant limbs with mouse mesoderm and chick ectoderm have not been shown to survive on a chick host.
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hidrotic, where sweat glands are normal and the condition is inherited as autosomal dominant (Clouston’s syndrome).1,5 The clinical manifestation of ectodermal dysplasia syndrome includes anomalies in the dentition and hair being affected similarly in both types of ED, but the hereditary patterns and nail and sweat gland manifestations tend to differ.9 Christ- Siemens-Touraine syndrome, with X-linked recessive inheritance, is the most common and frequently reported manifestation of ectodermal dysplasia.2,7,9based on the severity of clinical manifestations, Christ-Siemens-Touraine syndrome can further be classified into hypohidrotic or anhidrotic ectodermal dysplasia.8 Oral traits of ectodermal dysplasia (ED) may be expressed as anodontia or hypodontia, with or without a cleft lip and palate. Anodontia also manifests itself by a lack of alveolar ridge development; 7 as a result, the vertical dimension of the lower third of the face is reduced, the vermilion border disappears,existing teeth are malformed, the oral mucosa becomes dry, and the lips become prominent. The face of an affected child usually has the appearance of old age which is mainly due to the wasting of the jaw muscles and hypoplasia of the jaws and also loss of mechanical stress due to anodontia or hypodontia.7, 9 Gene studies regarding the etiology of ED reveal that the mutations in the ectodysplasin-A and ectodysplasin-A receptor genes are responsible for X- linked and autosomal hypohidrotic ectodermal dysplasia.The diagnosis is based on clinical ,structural and biochemical characteristics of hair, skin biopsy, and characteristics of Article History:
her and upon whom she was totally dependent for care. The patient had speech and cognitive impairment that limited the ability to obtain a direct history. The parents described a history of worsening hip pain from progres- sive, bilateral hip dysplasias. Whereas previously their daughter could ambulate with assistance, she was now incapacitated by relentless pain. As best as they were able to determine, the pain radiated from her hips laterally, down her thighs and provoked regular paroxysms of screaming, crying and guarding.
congenital skin disorder often grouped into three categories: chromosomal, Several of these disorders are isolated and also has oral phenomenon, oral genodermatoses. Among these Ectodermal dysplasia (EDs) is a large group of an inherited disorders represented by a primary defect in hair, teeth, nails or function of sweat gland, in derived tissue e.g. ears, eyes, lips, mucous membranes of an oral cavity or nose, central nervous system. The diverse forms of ectodermal dysplasia are caused by the mutation or deletion of specific genes located on different chromosomes. mptoms differ markedly among the different forms of the condition and rely on the structures that are affected. Presently there are about 150 different forms of ectodermal dysplasias. The commonest forms are Hypohidrotic (anhidrotic) Ectodermal Dysplasia and Hidrotic Ectodermal Dysplasia. The frequency of the different ectodermal dysplasias is highly variable in a given population. There is no particular treatment, only disease management is accessible.
Malformations of cortical development frequently result in varying combinations of intractable seizures, mental retardation, cerebral palsy, and focal neurological deficits . Although microdysgenesis could be important in the pathophysiology of epilepsy, the basic mechanisms involved remain unknown . Previous studies in autism have suggested a deficit in the inhibitory surround of minicolumns reflective of cellular networks prone to monotonically increasing avalanches of activity, i.e., a “rich-gets-richer” mechanism [30,51]. Furthermore, once an error enters such a system it will be propagated and amplified through downstream connections. It is thus unsurprising that cortical dysplasias are intrinsic epilepto- genic lesions that commonly provide for intractable sei- zures  of multiple types  with remissions occurring in only a small proportion of patients . Focal cortical dysplasia may thus serve as a causative factor or, in some instances, a propitiating factor for seizures. This cortical malformation may thus confer a susceptibility rendering the affected brain vulnerable to seizures after subsequent injuries such as febrile convulsions or head trauma [55,56].
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The cellular consequence of reduced FGF signaling in the facial processes in mice deficient of WNT/-catenin signaling remains unclear. BA1 ectoderm-specific Fgf8 deletion studies have shown that ectodermal FGF signaling is mainly required for mesenchymal cell survival in BA1 (Trumpp et al., 1999), whereas reduced cell proliferation is a major response affected by reduced FGF signaling in the NP and MxP of Lrp6 (Song et al., 2009) and Wnt9b (this study) mutant mice. There are several possible explanations for these seemingly contradictory results. One possibility is that ectoderm-derived FGF signaling plays roles in both the survival and proliferation of mesenchyme cells in the facial processes in a concentration-dependent manner. For instance, cell survival might require low-level FGF signaling, whereas cell proliferation might need higher levels of FGF signaling and be more sensitive to the reduced FGF signaling. It is noteworthy that FGF2 differentially regulates the behavior of cranial neural crest cells in a dose- dependent manner in vitro, enhancing proliferation at lower doses and inducing differentiation at higher doses (Sarkar et al., 2001). In embryos carrying an ectoderm-specific Ctnnb1 deletion, in which canonical WNT signaling is almost completely blocked, more severe downregulation of FGF gene expression and increased
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Anhidrotic ectodermal dysplasia with immunodeficiency is associated with multiple infections and a poor clinical outcome. Hypomorphic mutations in nuclear factor B essential modulator (NEMO)/I B kinase complex and a hypermorphic mutation in inhibitor ␣ of nuclear factor B (I B ␣ ) both result in impaired nuclear factor B acti- vation and are associated with X-recessive and autosomal- dominant forms of anhidrotic ectodermal dysplasia with immunodeficiency, respectively. Autosomal-dominant an- hidrotic ectodermal dysplasia with immunodeficiency is also associated with a severe T-cell phenotype. It is not known whether hematopoietic stem cell transplantation can cure immune deficiency in children with anhidrotic ectodermal dysplasia with immunodeficiency. A boy with autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency and a severe T-cell immunodeficiency underwent transplantation at 1 year of age with haploiden- tical T-cell– depleted bone marrow after myeloablative con- ditioning. Engraftment occurred, with full hematopoietic chimerism. Seven years after transplantation, clinical out- come is favorable, with normal T-cell development. As expected, the developmental features of the anhidrotic ectodermal dysplasia syndrome have appeared and per- sisted. This is the first report of successful hematopoietic stem cell transplantation in a child with anhidrotic ec- todermal dysplasia with immunodeficiency. Hematopoi- etic stem cell transplantation is well tolerated and effi- ciently cures the profound immunodeficiency associated with autosomal-dominant anhidrotic ectodermal dyspla- sia with immunodeficiency.