EEC Syndrome Research Articles

Peripheral giant cell granuloma in a child with ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome: a case report

BackgroundEctrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) syndrome mainly affects ectodermal and mesodermal tissues. It is usually manifested as split hands and feet, ectodermal dysplasia, and orofacial clefting, along with other signs and symptoms. A multidisciplinary approach to treatment is required, in which dentists play an important role in identifying and treating various oral conditions that may be genetically linked to or may be the result of EEC syndrome.Case presentationThe present case describes the oral condition of a young child suffering from EEC syndrome and presenting with peripheral giant cell granuloma (PGCG) in the mandibular anterior region. After obtaining a thorough medical and family history and a clinical examination, the lesion was surgically excised under local anesthesia. The patient was followed up at periodic intervals for the next twenty four months, during which no recurrence of the lesion was observed.ConclusionThis report highlights the role of a dentist in the management of the oral conditions of patients suffering from EEC syndrome.

Ectrodactyly-ectodermal dysplasia-clefting syndrome. Prenatal prospective ultrasound diagnosis.

Prenatal diagnosis of the Ectrodactyly-Ectodermal dysplasia-clefting (EEC) syndrome has been based upon the detection of ectrodactyly, in association with facial clefting and/or positive family history. Our aim is to describe other ultrasonographic features indicating the presuntive diagnosis, regardless of genetic diagnosis, especially in cases of negative family history. A case report and a review of the literature was assessed. Our case report showed a singleton foetus "lobster claw" deformities of hands and feet. Paternal history revealed bilateral agenesia of two fingers. Through literature, 15 case reports of prenatal diagnosis of EEC syndrome were found, 14 of which were eligible for our systematic review. The 33% of cases (5/15) had a familiar history of EEC, thus, we found one case of consanguinity of parents. Anomalies EEC-related were recognized in the 40% of cases (6/15). An association with genitourinary anomalies was found in 30% (5/15) of them. A strong suspicion of final diagnosis of EEC may be done in the presence of ectrodactyly, facial clefting and urinary malformation especially in cases of negative family history. More attention should be given to a genetic counseling, especially to understand a possible relation to other genetic syndromes.

Ectrodactyly-Ectodermal Dysplasia-Cleft Syndrome: Ocular Findings and Surgical Treatment.

Ectrodactyly-ectodermal dysplasia-cleft (EEC) syndrome is a rare genetic disorder. We present ocular findings and their treatment in patients with EEC. We report on 3 female patients (aged 59, 45, and 11 years) suffering from EEC with varying extraocular and ocular severity of phenotypic expression of the disease. Slit-lamp biomicroscopy, visual acuity, and medical treatment were evaluated over 4 months to 4 years. All patients experienced visual impairment and foreign body sensation. Examination revealed bilateral chronic blepharitis, dry eye syndrome, and corneal vascularization and clouding due to limbal stem cell deficiency (LSCD). Patient #1 presented a corneal ulcer with severe stromal thinning on the right eye. Allogeneic simple limbal epithelial transplantation (allo SLET), penetrating keratoplasty combined with allo SLET, and in total 5 amniotic membrane transplantation were performed to preserve the integrity of the eye. In patients #2 and #3, conservative therapy with lubricant eye drops, topical steroids, and antibiotics was sufficient to stabilize LSCD. In all cases, corneal epithelialization and improvement of visual acuity were achieved. To the best of our knowledge, this is the first report of surgical treatment in a patient with EEC. Allo SLET may be a surgical option to treat LSCD associated with EEC.

Treatment and Management of Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome With Scleral Prosthetic Devices.

This case report highlights the unique application and long-term benefits of customized scleral devices in a patient with ocular complications from ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome over the span of 10 years. A 13-year-old girl with a history of EEC syndrome and ocular manifestations, including severe bilateral dry eye disease, corneal neovascularization and scarring, progressive fibrous pannus, and limbal stem cell deficiency, was examined and fitted with scleral devices. The goal of treatment was to stabilize the ocular surface, enhance vision, and improve ocular comfort. Throughout the course of treatment, there was minimal progression in ocular signs, despite interruptions in scleral device wear from application and removal challenges secondary to ectrodactyly. Customized scleral devices provided an optimal environment to support the ocular surface, improve comfort, and improve visual acuity. Further studies are required to demonstrate the benefits of scleral devices in larger populations of patients with EEC syndrome.

Anesthetic consideration for a patient with EEC syndrome and cardiac disease.

Anesthetic consideration for a patient with EEC syndrome and cardiac disease.

Innovative Therapeutic Approaches for the Treatment of the Ocular Morbidities in Patients with EEC Syndrome.

Ectrodactyly-Ectodermal dysplasia-Clefting (EEC) syndrome is caused by heterozygous missense point mutations in the p63 gene, an important transcription factor during embryogenesis and for stem cell differentiation in stratified epithelia. Most of the cases are sporadic, related to de novo mutations arising during early-stage development. Familial cases show an autosomic dominant inheritance. The major cause of visual morbidity is limbal stem cell failure, which develops in the second to third decade of life. Patients often show ocular surface alterations, such as recurrent blepharitis and conjunctivitis, superficial microlesions of the cornea, and spontaneous corneal perforation and ulceration, leading to progressive corneal clouding and eventually visual loss. No definitive cures are currently available, and treatments to alleviate symptoms are only palliative. In this review, we will discuss the proposed therapeutic strategies that have been tested or are under development for the management of the ocular defects in patients affected by EEC syndrome: (i) gene therapy-based approaches by means of Allele-Specific (AS) siRNAs to correct the p63 mutations; (ii) cell therapy-based approaches to replenish the pool of limbal stem cells; and (iii) drug therapy to correct/bypass the genetic defect. However, as the number of patients with EEC syndrome is too limited, further studies are still necessary to prove the effectiveness (and safety) of these innovative therapeutic approaches to counteract the premature differentiation of limbal stem cells.

Oral management of children/adolescents with ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome: A scoping review.

EEC is a rare syndrome characterized by the triad of ectrodactyly, ectodermal dysplasia, and orofacial clefting, along with other clinical manifestations mainly in hair, skin, and teeth. The present paper aimed to perform a scoping review to collect the most relevant studies and focused on the diagnosis and oral management of EEC syndrome in the pediatric dental setting. This review also pretended to make recommendations and map the gaps in this clinical topic. An exhaustive electronic and manual search was conducted in four databases (PubMed, EMBASE, Google Scholar, and Dentistry & Oral Sciences Source/EBSCO) according to previously established eligibility criteria, using different combinations of keywords, MeSH terms, and Boolean operators. Titles, abstracts, and full-text articles were screened and selected by precalibrated reviewers. A data charting was also accomplished for summarizing the overview of the evidence. A total of 37 references were identified, and 32 titles remained after removing duplicates; then, 25 potential full-text articles were carefully reviewed. Finally, 15 relevant and most informative studies were included. Most studies were single clinical case reports. Only one descriptive retrospective study was detected. None randomized clinical trials or comparative observational studies were found. A medical/dental multidisciplinary approach is needed for the management of EEC syndrome. Diverse dental specialists must be involved. Pediatric dentists must play a principal role in the prevention and treatment of oral diseases; particularly the preservation of the primary and mixed dentitions, trying to achieve normal orofacial growth.

Analysis and pharmacological modulation of senescence in human epithelial stem cells.

Human epithelial stem cells (ESCs) are characterized by long‐term regenerative properties, much dependent on the tissue of origin and varying during their lifespan. We analysed such variables in cultures of ESCs isolated from the skin, conjunctiva, limbus and oral mucosa of healthy donors and patients affected by ectrodactyly‐ectodermal dysplasia‐clefting syndrome, a rare genetic disorder caused by mutations in the p63 gene. We cultured cells until exhaustion in the presence or in the absence of DAPT (γ‐secretase inhibitor; N‐[N‐(3, 5‐difluorophenacetyl)‐L‐alanyl]‐S‐phenylglycine T‐butyl ester). All cells were able to differentiate in vitro but exhibited variable self‐renewal potential. In particular, cells carrying p63 mutations stopped prematurely, compared with controls. Importantly, administration of DAPT significantly extended the replicative properties of all stem cells under examination. RNA sequencing analysis revealed that distinct sets of genes were up‐ or down‐regulated during their lifetime, thus allowing to identify druggable gene networks and off‐the‐shelf compounds potentially dealing with epithelial stem cell senescence. These data will expand our knowledge on the genetic bases of senescence and potentially pave the way to the pharmacological modulation of ageing in epithelial stem cells.

P63 in corneal and epidermal differentiation

The transcription factor p63, belonging to the p53 family, is considered the master regulator of epidermal differentiation, skin, and in general of the differentiation of ectodermal tissues. Mutations in TP63 gene cause several rare ectodermal dysplasia disorders that refers to epidermal structural abnormalities and ocular surface disease, such as Ectrodactyly Ectodermal Dysplasia Clefting (EEC) syndrome. In this review, we discuss the key roles of p63 in keratinocytes and corneal epithelial differentiation, highlighting the function of the ΔNp63α isoform in driving limbal stem cell and epithelial stem cells commitment. We have summarized the specific ocular phenotypes observed in the TP63-mutation derived EEC syndrome, discussing the current and novel therapeutic strategies for the management of the ocular manifestations in EEC syndrome.

Reconstruction sequence and microsurgery in ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome: a case report

Ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome (EEC), is a rare entity characterized by alterations in the skin, hair, nails, apocrine glands and teeth, associated with dimorphisms in extremities and midface dysplasia. It is attributed to a mutation in the p63 gene. These patients require multiple surgical procedures to achieve functional goals. We present the surgical sequence of the interdisciplinary management performed on a patient diagnosed with this syndrome and the functional results obtained. A 5 months old female patient presented to our service with a suspected EEC syndrome. We present the case and the surgical procedures performed to achieve functional results. EEC syndrome is a low frequency patology which requires specialized surgical procedures of different kinds. Different surgical methods and techniques should be considered, due to the number and complexity of the malformations, which is why all human and technical resources must be available for its proper treatment.

Prenatal diagnosis of ectrodactyly-ectodermal dysplasia clefting syndrome ‒ a case report with literature review

Abstract Objectives The ectrodactyly-ectodermal dysplasia clefting (EEC) syndrome is a rare genetic anomaly described as ectrodactyly (hands and feet), ectodermal dysplasia, and facial cleft with an incidence of around 1 in 90,000 in the population. This syndrome belongs to the TP63 gene’s mutation family. Ectrodactyly is described as the absence of the central toes or fingers or parts of these appendages. Ectodermal dysplasia usually includes changes in the skin, teeth, hair, nails, endocrine glands, nasolacrimal ducts, genitourinary system, conductive hearing loss. Case presentation This is a unique case of a 40-year-old second gravida, suspected of having a sporadic form of EEC syndrome. Routine transabdominal ultrasound at 14 weeks of gestation revealed malformation of the limbs. The two-dimensional and three-dimensional ultrasound at 16 weeks showed a fetus with ectrodactyly of right hand and foot and cleft palate presence. Diagnostic amniocentesis was performed at 17 weeks of gestation. A molecular genetics test using the Sanger sequencing method from amniotic fluid was performed by scanning TP63 gene sequences and revealed a heterozygous pathogenic variant in TP63. The patient decided on feticide. Conclusions The heredity of the syndrome is autosomal dominant with high variable expression. More than 300 clinical cases of this syndrome are described in the literature, including both sexes, but the actual etiology is unknown.

EEC syndrome: A rare case management

EEC syndrome: A rare case management

A Case Series Outlining the Relationship between Dolichoectasia and Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome

Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome (EEC) is a rare heritable condition marked by ectodermal dysplasia with nails, teeth, sweat glands, and hair, eye and lacrimal duct malformations, midfacial hypoplasia, ectrodactyly (loss of fingers or toes), syndactyly, clinodactyly, auricular anomalies, short height, orofacial cleft palates, genitourinary anomalies, malformations within the central nervous system (CNS) leading to mental impairment or hearing loss, nevocellular nevi, flat noses, and hypopigmentation (National Foundation for Ectodermal Dysplasias 2021 and Cyriac & Lashpa 1980).

A Case Series Outlining the Relationship between Dolichoectasia and Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome

Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome (EEC) is a rare heritable condition marked by ectodermal dysplasia with nails, teeth, sweat glands, and hair, eye and lacrimal duct malformations, midfacial hypoplasia, ectrodactyly (loss of fingers or toes), syndactyly, clinodactyly, auricular anomalies, short height, orofacial cleft palates, genitourinary anomalies, malformations within the central nervous system (CNS) leading to mental impairment or hearing loss, nevocellular nevi, flat noses, and hypopigmentation

P63 Mutation Impacts the Structure of Cardiopharyngeal Field Derived Muscles in Mice

The cardiopharyngeal field (CPF) includes anterior lateral mesoderm of the first heart field and the contiguous pharyngeal mesoderm. The latter gives rise to second‐heart‐field‐derived heart regions and branchiomeric head muscles. Neural crest cells (NCCs) surround and infiltrate mesoderm cells, forming connective tissue of head and heart musculature. NCCs are also involved in the septation of the cardiac outflow tract, the patterning of pharyngeal arch arteries, and in the proper development of attachments of branchiomeric muscles to skull, jaw, hyoid bone, and laryngeal cartilages.The p63 (aka Trp63) transcription factor is essential for the differentiation of epithelial tissue (ectoderm and endoderm) during embryogenesis. To form the correct amount of mature ectodermal, mesodermal, and NCC populations and to control the differentiation of the CPF, p63 interacts with downstream transcription factors, such as Tbx1, Isl1, and nkx2.5. We analyzed how the loss of p63 expression in p63−/− mice affected the mesodermal derivatives of the CPF. We hypothesized that the loss of p63 decreases the number of mesodermal cells differentiating from the CPF, causing a smaller mesodermal cell population in the CPF. We expected to see smaller CPF derived muscles in the p63 mutant mice, as well as deficient connective tissue in head and heart musculature as well as weakened attachments of craniofacial muscles.To determine if and when certain muscular defects appear, we performed muscle antibody staining and dissected wildtype littermates and p63−/− mice (B6.129S7‐Trp63tm2Brd/J strain) aged embryonic day (E) 12–18. We have collected minimum of five specimens for each age. We studied craniofacial, laryngeal, as well as cardiac musculature by analyzing the antibody stained specimens under the microscope and by performing microdissections under a stereomicroscope. We used 3D computed tomography scan images (taken with a uCT scanner, Skyscan 1172) to compare the craniofacial skeletons between wildtype and mutant mice.In p63−/− mice, branchiomeric muscles such as the masseter, buccinator, and nasolabialis were properly attached to bony elements but were smaller than what was seen in the wildtype mice. The p63−/− head is flexed and the chin is closer to the chest than in the wildtype specimens: this posture could be caused by the shortened and less dense sternocleidomastoid muscle in the p63−/− mice. Corresponding with previous reports, our p63 −/− mice also showed several malformations (e.g., poorly developed limbs, cleft palate, cardiac abnormalities) stereotypical of this mouse mutant and which are also seen in humans with p63 mutations such as in ADULT (acro‐dermatoungual‐lacrimal‐tooth) and EEC (Ectrodactyly‐Ectodermal Dysplasia‐Cleft Lip /Palate) syndromes. Despite that p63 expression is restricted to epithelium, the described defects reveal that p63 expression is important to much earlier, and shared developmental processes, notably NCC proliferation and differentiation, that do impact tissues derived from mesoderm as well as from epithelium. Analyzing the influence of p63 on CPF differentiation will contribute to a better understanding of regulatory mechanisms during head and heart development including the role of these mechanisms in human congenital syndromes.

Improvement of epidermal covering on AEC patients with severe skin erosions by PRIMA-1MET/APR-246

P63 is a major transcription factor regulating skin development and homeostasis. It controls many genes involved in cell proliferation, adhesion, and early differentiation. P63 is mutated in several rare syndromes called p63-related ectodermal dysplasia syndromes (ED). The main forms are EEC and AEC syndromes due to p63 missense mutations on the DBD and SAM domains, respectively. ED patients display many developmental defects, including ectrodactyly, clef/lip palate, and ectodermal dysplasia, while AEC patients suffer from severe skin erosions that not always heal. We have previously showed that ED-derived iPSC display altered epidermal commitment. P63 belongs to the p53 gene family sharing similar structural domains. We found that ED-iPSC epidermal commitment can be rescued by a p53-reactivating compounds called PRIMA-1MET, also named APR-246 and currently used in anticancer clinical trials. Here, we established primary epidermal culture from two AEC children (S.F. and Y.M.) suffering from persistent skin erosions at age of 9 and 15, respectively. These patients carry missense mutations on the SAM domain (I576T and I537T). We found that primary keratinocytes (KCs) isolated from these AEC patients underwent altered epidermal differentiation that was rescued by PRIMA-1MET treatment. It prompted us to formulate the compound onto a cream that was topically applied on the right hand of one patient and on the scalp of the second patient. In both cases, the daily treatment allowed re-epithelialization of the eroded skin and a drastic loss of pain after few weeks, improving quality of life. Normally, mutant p63 exerts a dominant-negative effect, mainly through the formation of aggregate with WT p63 and p73. PRIMA-1MET did not reduce protein aggregation while enhancing cell differentiation, suggesting that PRIMA-1MET targets cell differentiation and not p63 activity directly. In conclusion, we propose that repurposing of the antitumoral PRIMA-1MET compound could become a general treatment of AEC skin erosions.

The case of prenatal ultrasound diagnosis of EEC syndrome (Ectrodactyly, Ectodermal dysplasia, Cleft lip/palate syndrome) at 14 weeks of gestation

Case of prenatal ultrasound diagnosis of EEC syndrome at 14 weeks of gestation is presented. A rare feature of the case was the ectrodactyly of all limbs.

Significance of foot length determination to enhance accuracy of fetal clubfoot diagnosis

Case of prenatal ultrasound diagnosis of EEC syndrome at 14 weeks of gestation is presented. A rare feature of the case was the ectrodactyly of all limbs. 29 women with fetal clubfoot have been examined. The principal sonographic sign of this pathology has been established to be the foot length shortening that varied between 1 week and 1 day in 13 weeks and 6 days of gestation and 4 weeks and 5 days in 37 weeks and 1 day of gestation. Some sort or other pathology was found in those fetuses in 86.2 % of follow-up cases, while combined with clubfoot in 48.3 %. In total, 30 various congenital abnormalities with the total number of 78 (which made 2.7 congenital abnormalities per one fetus) have been diagnosed in this group of fetuses

P63 cooperates with CTCF to modulate chromatin architecture in skin keratinocytes

The transcription factor p63 regulates epidermal genes and the enhancer landscape in skin keratinocytes. Its molecular function in controlling the chromatin structure is, however, not yet completely understood. Here, we integrated multi-omics profiles, including the transcriptome, transcription factor DNA-binding and chromatin accessibility, in skin keratinocytes isolated from EEC syndrome patients carrying p63 mutations, to examine the role of p63 in shaping the chromatin architecture. We found decreased chromatin accessibility in p63- and CTCF-bound open chromatin regions that potentially contributed to gene deregulation in mutant keratinocytes. Cooperation of p63 and CTCF seemed to assist chromatin interactions between p63-bound enhancers and gene promoters in skin keratinocytes. Our study suggests an intriguing model where cell type-specific transcription factors such as p63 cooperate with the genome organizer CTCF in the three-dimensional chromatin space to regulate the transcription program important for the proper cell identity.

Cover

The cover image based on Original Article Tooth defects of EEC and AEC syndrome caused by heterozygous TP63 mutations in three Chinese families and genotype-phenotype correlation analyses of TP63-related disorders by Jinglei Zheng et al., DOI: 10.1002/mgg3.704. Illustration Credit: Jinglei Zheng.