Ectrodactyly-ectodermal Dysplasia Research Articles

Case report: Artificial thymic organoids facilitate clinical decisions for a patient with a TP63 variant and severe persistent T cell lymphopenia

Pathogenic variants in the transcription factor TP63 are associated with clinically overlapping syndromes including ectrodactyly-ectodermal dysplasia clefting (EEC) and ankyloblepharon-ectodermal defects-cleft lip/palate (AEC). T cell lymphopenia has rarely been described in individuals with TP63 variants and the cause of the T cell defect is unclear. Here, we present a case of a female infant born with TP63-related syndrome and profound T cell lymphopenia, first uncovered through newborn screening. Flow cytometry analysis revealed low CD4+ naïve T cells and nearly absent CD8+ T cells with intact B and NK cell compartments. A de novo heterozygous pathogenic variant c.1040 G>A (C347Y) in exon 8 of TP63 was identified. An artificial thymic organoid system, to assess the intrinsic ability of the patient’s hematopoietic cells to develop into T cells, was performed twice using separate peripheral blood samples. Ex vivo T cell differentiation was evident with the artificial organoid system, suggesting that a thymic stromal cell defect may be the cause of the T cell lymphopenia. Consistent with this, interrogation of publicly available data indicated that TP63 expression in the human thymus is restricted to thymic epithelial cells. Based on these data, congenital athymia was suspected and the patient received an allogenic cultured thymus tissue implant (CTTI). This is the first report of suspected congenital athymia and attempted treatment with CTTI associated with TP63 variant. At 9 months post-implant, peripheral lymphocyte analysis revealed measurable T cell receptor excision circles and presence of CD4+ recent thymic emigrants suggestive of early thymopoiesis. She will continue regular monitoring to ensure restoration of T cell immunity.

Congenital hand anomalies and rare syndromes in children

Congenital hand anomalies and associated rare syndromes in children are commonly seen in clinical practice and require complete clinical, radiological and genetic evaluation. The purpose of this case series is to describe four rare syndromic children with varied hand anomalies and differences. Three of the children are female and one is a male. Distal limb defects from simple polydactyly, clinodactyly to cleft hand were identified including preaxial anomalies. Significant clinical problems noted were chiefly cosmetic and altered self-image was also noted in one child. The orofacial clefting noted in the child with ectrodactyly ectodermal dysplasia (EEC) syndrome required repeated surgery though the child had minimal feeding difficulty and significant speech delay. Multidisciplinary management is necessary with the early involvement of clinical geneticist.

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.

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.

Digital Transfer for Hand Reconstruction in Cleft Hand and Foot Differences.

Digital transfer for hand reconstruction in children with cleft hand and foot differences present unique challenges with anomalous anatomy and rare opportunities to dramatically improve function of one- or two-digit hands. Medical records were reviewed for patients with cleft hand and foot treated at two pediatric institutions between 1996 and 2018. Hospital records, clinical photographs, radiographs, and alginate molds were available on all patients. Patient characteristics, indications for transfer, associated syndromes, donor and recipient anatomy, and complications were examined. Twenty digital transfers were identified in 16 patients. The mean age at time of transfer was 6 years (range: 3-18 years). Associated syndromes in this study included ectrodactyly ectodermal dysplasia clefting (EEC) syndrome and Goltz's syndrome. Recipient sites included the thumb (n = 17) and index ray (n = 3) in 10 hands with monodactyly, 6 hands with a two-digit ulnar syndactyly, and 3 hands with central deficiency and associated polydactyly or other anomalies. Donor sites included the great toe (n = 7), fifth toe (n = 9), great toe polydactyly (n = 2), thumb polydactyly (n = 1), and second toe (n = 1). All transfers survived. Revisions included tenolysis (n = 2), repeat fixation for nonunion or malunion (n = 2), and fusion for instability (n = 3). Digital transfer in cleft hand and foot patients is a functional endeavor. The transferred digits provide sensation, mobility, and stability for opposition. Technically challenging due to small structures and atypical anatomy, these rare cases represent unique opportunities to improve function and appearance in the pediatric hand. This is a therapeutic study and reflects level of evidence IV.

Ectrodactyly–ectodermal dysplasia–clefting syndrome

Ectrodactyly–ectodermal dysplasia–clefting syndrome

Developmental glaucoma in a patient of ectrodactyly-ectodermal dysplasia.

A 23-year-old Indian female, already on intraocular pressure (IOP) lowering eye drops was referred for control of IOP. Systemic involvement was marked for coarse facial features [Fig. 1a], dental and skeletal abnormalities [Fig. 1c-g] suggestive of ectrodactyly-ectodermal dysplasia (EED). The right eye was in exotropia with no perception of light. The left eye had generalized nebular corneal opacification [Fig. 1b], wide-angle recess with numerous iris processes on gonioscopy, and visual acuity of 20/800. Applanation IOP was 28 mm Hg in the right eye and 46 mm Hg in left eye. Pachymetry and axial lengths were 523 μm and 24.32 mm, respectively in the left eye. Hazy view of fundus revealed glaucomatous optic disc changes.Figure 1: (a) Coarse facial features. (b) Dense corneal opacity in the right eye and the left eye with hazy cornea. (c) Oligodontia. (d) Orthopantomograph showing oligodontia with underdeveloped alveolar bone. (e and f) Ectrodactyly of hands. (g) Ectrodactyly and syndactyly of feetAfter lowering IOP with oral acetazolamide, Ahmed glaucoma valve FP7 (New World Medical, Inc CA) was implanted in superotemporal quadrant. The tube was placed in in the anterior chamber. At 4 months, full-thickness penetrating keratoplasty (PK) was done. In the early postoperative period vision was 20/1000 and IOP varied between 6 to 9 mm Hg [Fig. 2a]. At 7 months follow-up after PK, best-corrected visual acuity (BCVA) was 20/80 [Fig. 2b]. The corneal graft was clear but cataractous changes were noticed [Fig. 2c]. The IOP was 16 mm Hg, and the tube was well placed in the anterior chamber [Fig. 2d] with diffuse functional bleb [Fig. 2e]. The left eye fundus examination revealed average-sized disc with vertical cup-to-disc ratio of 0.75 and inferior rim thinning [Fig. 2f]. At 18-month follow-up, graft was clear, BCVA was 20/50, and IOP was 16 mmHg.Figure 2: (a) Some edema of the graft 1-week post-keratoplasty (b) Clear graft at 7-month follow-up (c) Clinically significant cataract. (d) Ahmed glaucoma valve FP7 tube in situ (white arrow) in the anterior chamber. (e) Bleb (red arrow). (f) Fundus photo depicting glaucomatous cupping in the left eyeDiscussion The reported ocular involvement in EED includes telecanthus, blepharophimosis, entropion, meibomian gland absence, atresia of lacrimal outflow tract components, ocular surface and tear film disorders, and keratopathy.[12] Infantile glaucoma has been reported with ectodermal dysplasia.[3] The absence of iris anomalies and presence of ectrodactyly differentiate this case from Axenfeld-Rieger syndrome.[4] Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

An Anatomical study of Cleft hand in North – East population of Assam

Introduction: Cleft hand or Ectrodactyly or Split Hand is a rare form of congenital hand disorder in which there is deficiancy of one or more central rays of the hand. The hand presents with a V-shaped gap situated in the centre of the palm. The condition may occur alone or maybe associated with anomalies of foot, syndactly, polydactyly, triphalangeal thumb, transverse bones in the hand or maybe part of Ectrodactyly Ectodermal dysplasia Cleft (ECC) Syndrome. Aims and Objectives: To find out the sex ratio and incidence of laterality (unilateral or bilateral) of cleft hand in North East population of Assam. Subjects and Methods: This study included 31 children between age group of 3 years to 8 years with hand deformities who were brought to the Plastic Surgery Department, Gauhati Medical College, Guwahati for aesthetic correction within a time span of 2 years. Only those cases who had central defects of hand were included & those with other syndromic anomalies were excluded. For this detailed clinical and radiological examination was done to evaluate the extent of bone or tissue involvement and to find out any syndromic association of the condition. Results: Out of 31 cases, 10 cases were had Unilateral and 21 cases had Bilateral Cleft Hands. It was seen that out of 31 cases, 22 were males and only 09 were females indicating that male to female ratio of the deformity is 2.44 .Thus, males were more affected than females. Conclusion: Most of the cases presented with absence of the middle finger and central tissue of the affected hand since birth. The embryological basis has been highlighted to throw light into such a catastrophe where both males and females were affected and showed unilateral or bilateral involvement of the hand leading to cosmetic and functional debility. Therefore, the study revealed that males were more affected than females and bilateral involvement of the hands were common than unilateral involvement.

Meibografía infrarroja y evaluación molecular de la mutación del gen p63 en un paciente mexicano con síndrome EEC

ObjectiveTo report the finding of infrared meibography in a Mexican patient with EEC syndrome (Ectrodactyly–ectodermal dysplasia–cleft syndrome) confirmed by molecular analysis of the p63 gene. Clinical caseA 31 year-old male patient was seen due to a history of progressive visual loss in both eyes associated with long-term photophobia. The patient was born with cleft lip and palate, ectrodactyly of right hand, and afterwards, displayed nail dysplasia, anodontia and alopecia, with which ectodermal dysplasia was diagnosed. The ophthalmological findings were limited to the adnexa and the ocular surface. In vivo infrared meibography showed total absence of Meibomian glands in the lower eyelids and severe deficiency in the upper eyelids. In addition, it was shown that the patient was a heterozygous carrier of a missense mutation R304W (C → T) in exon 8 of the p63 gene. DiscussionThe R304W mutation in the p63 gene region is definitely related to characteristics such as the absence of Meibomian glands.

Differentially Expressed Genes in EEC and LMS Syndromes.

ObjectivesEctrodactyly ectodermal dysplasia cleft lip/palate (EEC) syndrome and limb-mammary syndrome (LMS) share a similar phenotype and the same pathogenic gene, which complicates the ability to distinguish between these diagnoses. The current study aims to identify a potential and practical clinical biomarker to distinguish EEC from LMS.MethodsTwo EEC pedigrees and one LMS pedigree that have been previously reported were reanalyzed. After confirmation of the causative mutations for these new patients, whole-genome expression microarray analysis was performed to assess the molecular genetic changes in these families.ResultsFive new patients with classic symptoms were reported, and these individuals exhibited the same mutation as their relatives (c.812 G>C; c.611G>A; and c.680G>A). According to the whole genome expression results, the EEC patients exhibited different gene expression characteristics compared with the LMS patients. More than 5,000 genes were differentially expressed (changes >2 or <0.5-fold) among the EEC patients, LMS patients and healthy individuals. The top three altered pathways have been implicated in apoptosis, the hematopoietic cell lineage and the Toll-like receptor signaling pathway.ConclusionOur results provide additional clinical and molecular information regarding EEC and LMS and suggest that peripheral blood cytokines may represent a promising clinical biomarker for the diagnosis of these syndromes.

Ectrodactyly-ectodermal dysplasia clefting syndrome (EEC syndrome)

Ectrodactyly-ectodermal dysplasia- clefting syndrome (also k/a. split hand- split foot malformation <SHFM>/split hand-split foot ectodermal dysplasia- cleft syndrome/ectodermal dysplasia cleft lip/cleft palate syndrome) a rare form of ectodermal dysplasia, is an autosomal dominant disorder inherited as a genetic trait and characterized by a triad of (i) ectrodactyly, (ii) ectodermal dysplasia and, (iii) & facial clefts.

Retinal Tear Presenting in a Patient with Ectrodactyly Ectodermal Dysplasia

This article aims to report a case of known ectrodactyly ectodermal dysplasia in a young male patient who subsequently was found to have a retinal tear and localized retinal detachment. This is a case report of a 22-year-old white male patient with a history of ectrodactyly ectodermal dysplasia. Our patient initially presented with an acute exacerbation of bilateral, red, irritated eyes. No recent changes in vision were reported. The patient's ocular surface disease was consistent with ectrodermal dysplasia syndrome. However, a dilated fundus examination revealed an asymptomatic retinal tear with a surrounding localized retinal detachment. In this case, the patient presented with longstanding ocular surface disease known to be associated with this patient's inherited ectoderm disorder. In addition, this patient revealed a retinal tear, raising the possibility that patients with inherited congenital ectodermal dysplasia could be at risk for damaged structures originating from the neural ectoderm. In this heterogeneous disease, we are contributing to the existing literature a case of ectodermal dysplasia syndrome with obvious ectodermal complications that also had retinal findings leading us to speculate question if neural ectoderm could also be involved in this inherited disease.

A novel c.1037C > G (p.Ala346Gly) mutation in TP63 as cause of the ectrodactyly-ectodermal dysplasia and cleft lip/palate (EEC) syndrome.

Ectrodactyly – ectodermal dysplasia and cleft lip/palate (EEC) syndrome (OMIM 604292) is a rare disorder determined by mutations in the TP63 gene. Most cases of EEC syndrome are associated to mutations in the DNA binding domain (DBD) region of the p63 protein. Here we report on a three-generation Brazilian family with three individuals (mother, son and grandfather) affected by EEC syndrome, determined by a novel mutation c.1037C > G (p.Ala346Gly). The disorder in this family exhibits a broad spectrum of phenotypes: two individuals were personally examined, one presenting the complete constellation of EEC syndrome manifestations and the other presenting an intermediate phenotype; the third affected, a deceased individual not examined personally and referred to by his daughter, exhibited only the split-hand/foot malformation (SHFM). Our findings contribute to elucidate the complex phenotype-genotype correlations in EEC syndrome and other related TP63-mutation syndromes. The possibility of the mutation c.1037C > G being related both to acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome and SHFM is also raised by the findings here reported.

Novel mutation in TP63 associated with ectrodactyly ectodermal dysplasia and clefting syndrome and T cell lymphopenia

A male child with clinical features consistent with EEC/EECUT plus syndrome (ectrodactyly, ectodermal dysplasia, clefting, urinary tract abnormalities, and thymic abnormalities) including mild ectodermal abnormalities, ectrodactyly of hands and feet, cleft palate, bilateral hydronephrosis, and T cell lymphopenia is reported. He was noted to have T cell receptor excision circle (TREC) analysis below the cutoff for normal on newborn screening and T cell lymphopenia on further immunologic evaluation. A novel, presumably pathogenic de novo 3 bp deletion in exon 7 of TP63 (c.970_972delATT; NCBI Reference Sequence NM_003722.4) was identified. This observation provides supporting evidence for the association between TP63 mutations and EECUT plus syndrome. Clinicians caring for infants presenting with EEC spectrum disorders in the newborn period should also consider the possibility of T cell lymphopenia.

Endonasal Dacryocystorhinostomy in a Pediatric Patient With Ectrodactyly-ectodermal Dysplasia After Failure of External Dacryocystorhinostomy and as First Procedure

A 9-year-old patient affected by ectrodactyly-ectodermal dysplasia was referred to our clinic complaining of epiphora in both eyes. She had previous external dacryocystorhinostomy in her left eye. Ophthalmic examination revealed absence of the superior tear ducts and discharge in both eyes. Lacrimal irrigation through the inferior canaliculi revealed nasolacrimal duct obstruction on both sides. A bilateral endo-dacryocystorhinostomy was performed as a revision procedure in the left eye and as first procedure in the right eye. A monocanalicular silicone stent through the inferior tear duct was introduced on both sides at the end of the surgery. Follow up was 8 and 5 months for the left and the right eye, respectively. Epiphora was absent, and lacrimal irrigation showed a patent osteum at last follow-up. This case suggests that endo-dacryocystorhinostomy seems to be a safe and effective procedure, both as revision and as first procedure, even in children with ectrodactyly-ectodermal dysplasia.

Familial ectrodactyly–ectodermal dysplasia–clefting syndrome

Familial ectrodactyly–ectodermal dysplasia–clefting syndrome

Corneal changes in ectrodactyly–ectodermal dysplasia–cleft lip and palate syndrome: case series and literature review

The aim of this study is to describe the corneal changes in three unrelated patients with ectrodactyly-ectodermal dysplasia-cleft lip and palate (EEC) syndrome and review the literature on the possible etiology and clinical presentation of similar cases. Case 1 is an 18-year-old female with cleft lip and palate, syndactyly, and bilateral corneal pannus superiorly and inferiorly. She was initially diagnosed and treated as herpes simplex virus keratitis. Case 2 is a 3-year-old female born with cleft lip and palate, absent radial digits in both hands, and bilateral lacrimal stenosis. She developed progressive stromal scarring and neovascularization in both eyes. Her cornea perforated after developing infectious ulceration. Case 3 is a 49-year-old male with cleft palate, claw-hand deformities, absent meibomian glands and lacrimal duct, right ankyloblepharon, and a superior wedge-shaped opacity in the left cornea. The clinical findings demonstrated the different spectrum of keratopathy seen in patients with EEC. All patients were treated medically and without any surgical intervention. Limbal stem cell deficiency (LSCD) is presumed to be the cause in all three cases. Corneal changes in EEC can have variable presentation. LSCD seems to be the etiology of such keratopathy. Recurrent infection from lacrimal drainage obstruction and tear film instability are other risk factors for disease severity and progression.

Analysis of Large Phenotypic Variability of EEC and SHFM4 Syndromes Caused by K193E Mutation of the TP63 Gene

EEC (ectrodactyly, ectodermal dysplasia, clefting; OMIM 604292) is an autosomal dominant developmental disorder resulting mainly from pathogenic mutations of the DNA-binding domain (DBD) of the TP63 gene. In this study, we showed that K193E mutation in nine affected individuals of a four-generation kindred with a large degree of phenotypic variability causes four different syndromes or TP63-related disorders: EEC, Ectrodactyly-ectodermal dysplasia (EE), isolated ectodermal dysplasia, and isolated Split Hand/Foot Malformation type 4 (SHFM4). Genotype-phenotype and DBD structural modeling analysis showed that the K193-located loop L2-A is associated with R280 through hydrogen bonding interactions, while R280 mutations also often cause large phenotypic variability of EEC and SHFM4. Thus, we speculate that K193 and several other DBD mutation-associated syndromes may share similar pathogenic mechanisms, particularly in the case of the same mutation with different phenotypes. Our study and others also suggest that the phenotypic variability of EEC is attributed, at least partially, to genetic and/or epigenetic modifiers.

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.

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.