EEC Syndrome Research Articles

Association of generalized aggressive periodontitis and ectrodactyly-ectodermal dysplasia-cleft syndrome

Ectrodactyly-ectodermal dysplasia-cleft (EEC) syndrome is an autosomal dominant disorder characterized by the triad of ectrodactyly, ectodermal dysplasia, and facial clefting. Even though literature has documented the association of various genetic disorders with aggressive periodontitis, the periodontal manifestations in patients with EEC syndrome have never been addressed. This case report presents the periodontal status of three patients in a family with EEC syndrome. The presence of generalized aggressive periodontitis was noticed in these patients. EEC syndrome could be a new addition to the group of genetic disorders associated with aggressive periodontitis.

Ectrodactyly, ectodermal dysplasia, cleft lip, and palate (EEC syndrome)

The ectodermal dysplasias (EDs) are a large and complex group of diseases. More than 170 different clinical conditions have been recognized and defined as ectodermal dysplasias. Commonly involved ectodermal-derived structures are hair, teeth, nails, and sweat glands. In some conditions, it may be associated with mental retardation. We report a case of 10-year-old male child with ectrodactyly, syndactyly, ED, cleft lip/palate, hearing loss, and mental retardation.

A sporadic case of oligosymptomatic ectrodactyly-ectodermal dysplasia-clefting syndrome

A sporadic case of oligosymptomatic ectrodactyly-ectodermal dysplasia-clefting syndrome

Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome: A case report of "Incomplete syndrome"

Ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) is a rare syndrome having ectrodactyly, ectodermal dysplasia, and cleft lip/palate. So far, very few cases have been reported in literature. However, we report a case of incomplete EEC syndrome having ectrodactyly and cleft lip and palate with absence of signs of ectodermal dysplasia with no other systemic anomalies. Other feature noted is the syndactyly of toes which is reported rarely in this syndrome. A multidisciplinary approach for treatment is needed which is co-ordinated by pedodontist or pediatrician.

Ectrodactyly-Ectodermal Dysplasia – Cleft Syndrome (EEC)

The Ectrodactyly- Ectodermal dysplasia-Cleft syndrome EEC is an autosomal dominant disorder with cardinal signs of ectrodactyly ectodermal dysplasia and orofacial clefts. It has been linked to chromosome 3q27 and heterozygous p63 mutations 1.We report a case of EEC syndrome in an 8-month female infant who presented with these features

Ectrodactyly and Prenatal Diagnosis

Ectrodactyly is an autosomal dominant ectodermal dysplasia presenting as bilateral congenital malformed hands and feet [1]. It affects about 1 in 90,000 births with males and females equally as likely to be affected. It is characterized by transverse terminal aphalangia or partial to total absence of the distal segments of fingers. It may involve one or more digits or the full hand and even part of the upper arm. More severe manifestations are hemimelia or amelia. All these abnormalities are considered to represent various degrees of severity of the same anomaly and may be due to an intrauterine vascular occlusion or insufficiency [2]. These different forms are connected with a different genetic mutation. Type I, the most frequent form has been found to be a mutation on chromosome 7 in a region that contains two homeobox genes, DLX5 and DLX6. Usually this is characterized as the split hand/foot deformity due to the absence of the third digit, with clefting into the proximal portion of the hand or foot and syndactyly of remaining digits on each side of the cleft. The hand resembles a lobster claw [3]. The association of ectrodactyly with cleft lip and palate was originally described by Cockayne [4]. It was known as Ectrodactyly-Ectodermal Dysplasia-Cleft lip/palate syndrome (EEC syndrome) [5].

Development of an Allele-Specific Real-Time PCR Assay for Discrimination and Quantification of p63 R279H Mutation in EEC Syndrome

The ectrodactyly-ectodermal dysplasia-clefting syndrome is a rare autosomal dominant disorder caused by heterozygous mutations in the p63 gene, a transcription factor belonging to the p53 family. The majority of cases of ectrodactyly-ectodermal dysplasia syndrome are caused by de novo mutations and are therefore sporadic in approximately 60% of patients. The substitution of arginine to histidine (R279H), due to a c.836G>A mutation in exon 7 of the p63 gene, represents 55% of the identified mutations and is considered a mutational hot spot. A quantitative and sensitive real-time PCR was performed to quantify both wild-type and R279H alleles in DNA extracted from peripheral blood and RNA from cultured epithelial cells. Standard curves were constructed for both wild-type and mutant probes. The sensitivity of the assay was determined by generating serial dilutions of the DNA isolated from heterozygous patients (50% of alleles mutated) with wild-type DNA, thus obtaining decreasing percentages of p63 R279H mutant allele (50%, 37.5%, 25%, 12.5%, 10%, 7.5%, 5%, 2.5%, and 0.0%). The assay detected up to 1% of the mutant p63. The high sensitivity of the assay is of particular relevance to prenatal diagnosis and counseling and to detect therapeutic effects of drug treatment or gene therapy aimed at reducing the amount of mutated p63.

Limbal Stem Cell Deficiency and Ocular Phenotype in Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome Caused by p63 Mutations

To describe the ocular phenotype in patients with ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome (MIM#604292) and to determine the pathogenic basis of visual morbidity. Retrospective case series. Nineteen families (23 patients) affected by EEC syndrome from the United Kingdom, Ireland, and Italy. General medical examination to fulfill the diagnostic criteria for EEC syndrome and determine the phenotypic severity. Mutational analysis of p63 was performed by polymerase chain reaction-based bidirectional Sanger sequencing. All patients with EEC syndrome underwent a complete ophthalmic examination and ocular surface assessment. Limbal stem cell deficiency (LSCD) was diagnosed clinically on the basis of corneal conjunctivalization and anatomy of the limbal palisades of Vogt. Impression cytology using immunofluorescent antibodies was performed in 1 individual. Histologic and immunohistochemical analyses were performed on a corneal button and corneal pannus from 2 EEC patients. The EEC syndrome phenotypic severity (EEC score), best-corrected Snellen visual acuity (decimal fraction), slit-lamp biomicroscopy, tear function index, tear breakup time, LSCD, p63 DNA sequence variants, impression cytology, and corneal histopathology. Eleven heterozygous missense mutations in the DNA binding domain of p63 were identified in all patients with EEC syndrome. All patients had ocular involvement and the commonest was an anomaly of the meibomian glands and lacrimal drainage system defects. The major cause of visual morbidity was progressive LSCD, which was detected in 61% (14/23). Limbal stem cell deficiency was related to advancing age and caused a progressive keratopathy, resulting in a dense vascularized corneal pannus, and eventually leading to visual impairment. Histologic analysis and impression cytology confirmed LSCD. Heterozygous p63 mutations cause the EEC syndrome and result in visual impairment owing to progressive LSCD. There was no relationship of limbal stem cell failure with the severity of EEC syndrome, as classified by the EEC score, or the underlying molecular defect in p63. The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Familial Ectrodactyly Syndrome in a Nigerian Child: A Case Report

Ectrodactyly, also known as Split-Hand/Split-Foot Malformation (SHFM) is a rare genetic condition characterized by defects of the central elements of the autopod. It has a prevalence of 1:10,000-1:90,000 worldwide. The X-linked and autosomal dominant types have been described. It can occur as an isolated malformation or in combination with other anomalies, such as tibial aplasia, craniofacial defects, and genitourinary abnormalities. Ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC) is an example of ectrodactyly syndrome accompanied by multiple organ defects. Ectrodactyly has been reported in Africa, especially in several families in remote areas of central Africa but there has not been any published work on ectrodactyly in Nigeria. A baby was born in Ilorin, North Central Zone of Nigeria, with an uneventful prenatal and delivery history but was noticed to have malformation of the two hands and the two lower limbs at birth which are replica of the father's malformation. We present this case to highlight familial ectrodactyly in Nigeria and prepare us to improve upon simple prenatal diagnosis and management of the challenges associated with patients with congenital malformation in Nigeria and other developing countries.

Differential altered stability and transcriptional activity of ΔNp63 mutants in distinct ectodermal dysplasias

Heterozygous mutations of p63, a key transcription factor in epithelial development, are causative in a variety of human ectodermal dysplasia disorders. Although the mutation spectrum of these disorders displays a striking genotype-phenotype association, the molecular basis for this association is only superficially known. Here, we characterize the transcriptional activity and protein stability of ΔNp63 mutants (that is, mutants of a p63 isoform that lacks the N-terminal transactivation domain) that are found in ectrodactyly-ectodermal dysplasia-cleft syndrome (EEC), ankyloblepharon-ectodermal dysplasia-clefting syndrome (AEC) and nonsyndromic split-hand/split-foot malformation (SHFM). DNA-binding and sterile alpha motif (SAM) domain mutants accumulate in the skin of EEC and AEC syndrome patients, respectively, and show extended half lives in vitro. By contrast, C-terminal mutations found in SHFM patients have half-lives similar to that of the wild-type protein. The increased half-life of EEC and AEC mutant proteins was reverted by overexpression of wild-type ΔNp63. Interestingly, the mutant proteins exhibit normal binding to and degradation by the E3 ubiquitin ligase Itch. Finally, EEC and AEC mutant proteins have reduced transcriptional activity on several skin-specific gene promoters, whereas SHFM mutant proteins are transcriptionally active. Our results, therefore, provide evidence for a regulatory feedback mechanism for p63 that links transcriptional activity to regulation of protein homeostasis by an unknown mechanism. Disruption of this regulatory mechanism might contribute to the pathology of p63-related developmental disorders.

Ectrodactyly-ectodermal dysplasia-clefting syndrome causing blindness in a child

Ectrodactyly-ectodermal dysplasia-clefting syndrome, the result of a mutation in the gene encoding tumor protein p63, causes ocular surface disease. It is typically progressive, with vision loss in adulthood. We present a case of severe corneal disease, glaucoma, and blindness related to ectrodactyly-ectodermal dysplasia-clefting syndrome in a 3-year-old female patient.

Phenotypic analysis of Arg227 mutations of TP63 with emphasis on dental phenotype and micturition difficulties in EEC syndrome

Phenotypic analysis of Arg227 mutations of <i>TP63</i> with emphasis on dental phenotype and micturition difficulties in EEC syndrome

Heterozygous TP63 mutation in a Chinese patient with ectrodactyly-ectodermal dysplasia clefting syndrome without clefting

To determine if alteration in TP63 is responsible for a Chinese patient with ectrodactyly-ectodermal dysplasia clefting (EEC) syndrome, but without cleft palate/lip. Screening of TP63 gene was performed in the patient with EEC syndrome and his family members using PCR-single strand conformational polymorphism (SSCP) analysis, then performed by direct sequencing of the coding region. A C > T substitution at nucleotide position 838 in exon 7 was detected in the patient, and the change predicted a heterozygous missense mutation, Arg280Cys. His parents showed the wild type. The results indicate that the de novo mutation Arg280Cys of the TP63 gene observed in the patient maybe contribute to his EEC syndrome.

ADULT Syndrome Caused by a Mutation Previously Associated with EEC Syndrome

Acro-Dermato-Ungual-Lacrimal-Tooth (ADULT) syndrome is a rare autosomal dominant syndrome characterized by ectrodactyly or syndactyly, excessive freckling and dry skin, dysplastic nails, lacrimal duct atresia, primary hypodontia and early loss of permanent teeth. ADULT syndrome is one of five such syndromes that result from mutations in TP63, encoding the transcription factor p63. Until now, only four families and three individuals with ADULT syndrome have been reported in the English literature. We present a 14-year-old female patient with ADULT syndrome and discuss phenotype-genotype correlations in the p63 syndromes.

Ectrodactyly-ectodermal dysplasia-clefting syndrome: the oral hygiene management of a patient with EEC

Ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC) is a rare genetic disorder. EEC was first described in 1970 and occurs in 7 of 10,000 people. This paper discusses the effects of EEC and the dental complications typically associated with this syndrome. It is important for dental practitioners to be aware of EEC due to the number of dental conditions associated with it. A case report is presented to discuss the dental management, especially issues related to oral hygiene, of a patient who had EEC.

Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome-Plastic Surgeon's Considerations

Ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome is a rare autosomally dominant disorder phenotypically characterized by specific abnormalities of the hand, feet, and orofacial region coexisting with ectodermal dysplasia features. The purpose of this study was to describe the plastic surgeon's approach to EEC treatment by retrospective analysis of the course of surgical treatment. Medical documentation of 10 patients with EEC syndrome treated in the Department of Plastic Surgery in Polanica Zdroj in the years 1976-2008 was given retrospective analysis. In the analyzed group of patients, various levels of intensity of ectodermal dysplasia symptoms were confirmed, and in every case, severe forms of clefts were observed. Intensity of cleft malformation, but foremost belated and exacerbated healing, and coexistence of ectodermal dysplasia were the evident cause of more frequent complications and occurrence of greater postcleft deformations. Treatment of this hand and feet malformation is by its nature hampered, and procedures between subsequent stages of cleft surgery are performed. In patients with nasolacrimal duct atresia, dilatation or dacryocystorhinostomy was performed, which effectively improved patients' quality of life. In reference to plastic surgery point of view, treatment of coexistence with ectodermal dysplasia malformations in EEC syndrome demands more individual therapeutic approach. The presence of ectodermal dysplasia symptoms increases the risk of complications in cleft surgery and treatment of hand and foot deformities or orbital area malformations. Severity of cleft malformation requires surgery supported by experience and embracing the necessity of performing a greater number of more complex corrective procedures.

Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome Associated with p63 Mutation and an Uncommon Phenotype

Ectrodactyly-ectodermal dysplasia-clefting syndrome is an uncommon disorder that includes a clinical spectrum of limb, facial, ocular, internal ear, and urogenital malformations. The disease is caused by heterozygous mutations in the 3q27-29 located p63 gene. In this paper we describe a 17-year-old girl affected by ectrodactyly-ectodermal dysplasia-clefting syndrome with a de novo p63 mutation that predicts a heterozygous missense substitution (arginine to tryptophan substitution caused by a cytosine to thymine transition) at the amino acid 304 (R304W) of the p63 DNA-binding domain. Scattered freckles on face, legs, and abdominal region, an uncommon feature associated with this syndrome, were recognized in our patient. The clinical features and genotype-phenotype correlation with previous p63 mutations related to the syndrome are discussed and compared with those observed in our patient. This case expands the phenotypic spectrum of ectrodactyly-ectodermal dysplasia-clefting syndrome.

The retinal dehydrogenase/reductase retSDR1/DHRS3 gene is activated by p53 and p63 but not by mutants derived from tumors or EEC/ADULT malformation syndromes

Retinol and its metabolites have important roles in many processes including embryonic development, cellular differentiation, apoptosis and maintenance of epithelia. Retinal short-chain dehydrogenase/reductase retSDR1, also known as dehydrogenase/reductase member 3 (DHRS3), is involved in maintaining the cellular supply of retinol metabolites. We observe that retSDR1 expression is activated by members of the p53 family. Particularly p53 and TAp63γ regulate transcription through two separate response elements in the retSDR1 promoter. Both proteins bind the promoter in vitro and in vivo. Induction of DNA damage leads to recruitment of p53 and p63 to the retSDR1 promoter. A tumor-derived p53 mutant is unable to activate retSDR1 transcription. As mutants of p63 in humans exhibit phenotypes that cause several autosomal dominantly inherited syndromes leading to developmental malformations, we tested the transcriptional response of TAp63γ mutants derived from the EEC, SHFM and ADULT syndromes. EEC syndrome-specific mutations of TAp63γ fail to transactivate retSDR1 and an ADULT syndrome-derived mutant stimulates retSDR1 transcription significantly less than the wild-type variant of p63. Taken together, the results suggest a potential role of the p53/p63-mediated retSDR1 activation in tumor suppression as well as in developmental processes.

White sponge nevus in a patient with EEC syndrome

A 10-year-old boy, affected by cleft lip and palate and the Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) syndrome, presented with hypodontia, microdontia, enamel hypoplasia and caries, as well as white macules and plaques on the buccal mucosa bilaterally. Verrucous plaques were noted on the right side and a smooth diffuse white macule was present on the left side. Samples of each were taken by incisional biopsy. Microscopic analysis revealed oral mucosa comprised of hyperplastic stratified squamous epithelium with either hyperparakeratosis or lack of keratinization. There was extensive hydropic degeneration and sparse cells with perinuclear eosinophilic condensation were identified. The underlying fibrous connective tissue exhibited blood vessels with mild subepithelial mononuclear inflammatory infiltrate, bundles of skeletal striated muscle fibers, and areas of hemorrhage at deeper regions. White sponge nevus was diagnosed. To our knowledge, no other case of white sponge nevus has been reported in a patient with EEC syndrome. Considering the low prevalence of this disorder and also of the EEC syndrome, future studies on the etiology of the white sponge nevus might look at the common etiopathogenic aspects of both the white sponge nevus and the EEC syndrome.

TP63 Gene Mutations in Chinese P63 Syndrome Patients

TP63 plays an essential role in the development of epidermis and skin appendages. Mutations in TP63 can give rise to a series of syndromes characterized by various combinations of ectodermal dysplasia, limb malformations, and orofacial clefting in many populations. To test whether TP63 is the disease-causative gene for these phenotypes in Chinese, we recruited two Chinese Ectrodactyly-Ectodermal-dysplasia-Cleft lip/palate syndrome (EEC) cases and a Limb-Mammary-Syndrome (LMS) patient to carry out TP63 gene sequencing. Three missense mutation, c.812G>C (Ser271Thr), c.611G>A (Arg204Gln), and c.680G>A (Arg227Gln), which lead to the substitution of highly conserved amino acids in the DNA-binding domain of TP63, were identified. These mutations were predicted to disrupt DNA-binding specificity and affinity. To our knowledge, this is the first report of EEC and LMS syndromes in individuals of Chinese descent. Analysis of our data demonstrated that TP63 is critical for the development of ectoderm in humans.