Prevalence rates for ectodermal dysplasia syndromes.

BACKGROUND: Ectodermal dysplasias (EDs) are a heterogeneous group of genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. There are currently 49 recognized EDs with molecularly confirmed etiology. The EDs are very rare disorders, individually and in aggregate. Very little is published regarding the prevalence of these rare disorders. As a result of the genomics revolution, rare diseases have emerged as a global health priority. The various disabilities arising from rare disorders, as well as diagnostic and treatment uncertainty, have been demonstrated to have detrimental effects on the health, psychosocial, and economic aspects of families affected by rare disorders. Contemporary research methodologies and databases can address what have been historic challenges encountered when conducting research on rare diseases. OBJECTIVE: In this study, we aim to ascertain period prevalence rates for several of the more common ectodermal dysplasia syndromes, by querying a large multicenter database of electronic health records, Oracle Real-World Data. METHODS: For each of the included ectodermal dysplasia syndromes a clinical definition was developed by a committee of international experts with interests in EDs. The clinical definitions were based upon a combination of clinical features and designated by ICD-9 and ICD-10 codes. The January 2023 version of the Oracle Real-World Data database was queried for medical records that coincided with the clinical definitions. For our study, there were 64,523,460 individual medical records queried. RESULTS: Period prevalence rates were calculated for the following ED disorders: hypohidrotic ectodermal dysplasia, found to be 2.99 per 100,000; ectodermal dysplasia and immunodeficiency 1, 0.23 per 100,000; Clouston syndrome, 0.15 per 100,000; ectrodactyly ectodermal dysplasia and cleft lip/palate syndrome, 0.61 per 100,000; ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, 0.36 per 100,000; focal dermal hypoplasia, 0.10 per 100,000; and incontinentia pigmenti, 0.88 per 100,000. CONCLUSION: This study established estimated period prevalence rates for several of the ectodermal dysplasia syndromes, and it demonstrated the feasibility of utilizing large multicenter databases of electronic health records, such as Oracle Real World Data.

Clinical and Molecular Genetic Analysis of Cases with Ectodermal Dysplasia.

INTRODUCTION: Ectodermal dysplasias are a group of >200 clinically and congenitally heterogeneous disorders characterized by abnormal development in the ectodermal structures, such as hair, nails, teeth, and sweat glands. We report here the clinical and molecular genetic analysis of five Greek families with different types of ectodermal dysplasia (ED). SUBJECTS: The study involved 15 individuals from 5 Greek families that included 8 ED patients, 5 carriers of recessive X-linked or autosomal ED, and 2 healthy relatives. After genetic counseling, the parents signed an informed consent form before subsequent genetic testing. METHODS: Genomic DNA was isolated from white blood cells of all studied individuals. The search for mutations was realized in patients' DNA samples using next-generation sequencing (NGS) gene panel, whole exome sequencing (WES), chromosomal microarray analysis (CMA), and multiplex ligation-dependent probe amplification (MLPA) technique. RESULTS: The clinical diagnosis of common X-linked recessive hypohidrotic ectodermal dysplasia (HED) was suspected in five male patients with partial anodontia of baby and permanent teeth, hypohidrosis, and thin hair from three families. All HED patients were hemizygous for deletions in the EDA1 gene (Xq13.1): three related patients had a 20 bp deletion, one had a 19 bp deletion, and one had a 180 bp deletion. A female patient had the rare autosomal dominant syndrome of ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) caused by heterozygous missense mutation in the TP63 gene (3q28) that appeared de novo. Two siblings with hypotrichosis and hypodontia, a female and a male, had two pathogenic mutations in compound heterozygosity in the TSPEAR gene (21q22.3); therefore they presented with ectodermal dysplasia type 14 (ECTD14). CONCLUSION: Clinical and molecular genetic analysis may set an accurate diagnosis of different types of ED. In the reported families, genetic diagnosis and genetic counselling assisted the parents to view their children's condition realistically and to cooperate with the specialists who will contribute to the best possible treatment for their children.

Simple surgical approach for treatment of ankyloblepharon filiforme adnatum: A case report.

Ankyloblepharon flliforme adnatum (AFA) is a rare congenital abnormality of the eyelids. Upper and lower eyelids are joined by single or multiple bands. It is usually isolated but can be associated with ophtalmic and systemic diseases. AFA is potentially amblyopic condition. Treatment is quick, safe, and minimizes the risk of amblyopia. We report a case of newborn with isolated AFA at birth, treated by surgical excision of the band tissue.

Ankyloblepharon-ectodermal Defects-cleft Lip-palate Syndrome Due to a Novel Missense Mutation in the SAM Domain of the TP63 Gene.

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a rare genetic disease with an autosomal dominant transmission, characterized by several congenital anomalies. Clinical features include ectodermal defects affecting the skin, hair, teeth, nails and sweat glands, associated with typical eyelid fusion in addition to a cleft lip and/or palate. The diagnosis is based on clinical criteria and molecular genetic testing of TP63 gene, the gene related to AEC syndrome. In this context, most reported mutations induce an amino acid change in the sterile alpha motif (SAM) domain, and are predicted to disrupt protein-protein interactions. We here describe the case of a 2-year-old Moroccan girl diagnosed with AEC syndrome on the basis of clinical features. The molecular studies and bioinformatics tools revealed a novel heterozygous missense mutation c.1798G>C (p.Gly600Arg) in exon 14 of the TP63 gene, that was not found in her parents. The molecular analysis and the early diagnosis of this syndrome are important to offer appropriate genetic counseling and management to patients and their families.

Amino-terminal residues of ΔNp63, mutated in ectodermal dysplasia, are required for its transcriptional activity.

p63, a member of the p53 family, is a crucial transcription factor for epithelial development and skin homeostasis. Heterozygous mutations in TP63 gene have been associated with human ectodermal dysplasia disorders. Most of these TP63 mutations are missense mutations causing amino acidic substitutions at p63 DNA binding or SAM domains that reduce or abolish the transcriptional activity of mutants p63. A significant number of mutants, however, resides in part of the p63 protein that apparently do not affect DNA binding and/or transcriptional activity, such as the N-terminal domain. Here, we characterize five p63 mutations at the 5' end of TP63 gene aiming to understand the pathogenesis of the diseases and to uncover the role of ΔNp63α N-terminus residues in determining its transactivation potential.

Congenital ankyloblepharon in a leopard gecko (Eublepharis macularius).

A 6-month-old leopard gecko with unilateral partially fused eyelids since birth was presented for examination. A diagnosis of congenital ankyloblepharon was made and surgical correction was performed successfully.

Clinical Variability in a Family with an Ectodermal Dysplasia Syndrome and a Nonsense Mutation in the TP63 Gene.

Mutations in the TP63 gene have been associated with a variety of ectodermal dysplasia syndromes, among which the clinically overlapping Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) and the Rapp-Hodgkin syndromes. We report a multiplex nonconsanguineous family of Ashkenazi-Jewish descent, in which the index patient presented with a persistent scalp skin lesion, dystrophic nails and light thin hair. Further evaluation revealed over 10 affected individuals in the kindred, over four generations, exhibiting varying degrees of ectodermal involvement. Analysis of the TP63 gene from four of the patients and from two healthy individuals of the same family was performed. Gene sequencing of the patients revealed a nonsense mutation leading to a premature termination codon (PTC) (p.Gln16X). The same mutation was found in all tested affected individuals in the family, but gave rise to marked phenotypic variability with minor clinical manifestations in some individuals, underscoring the clinical heterogeneity associated with the recently described PTC-causing mutations.

Modeling AEC-New approaches to study rare genetic disorders.

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a rare monogenetic disorder that is characterized by severe abnormalities in ectoderm-derived tissues, such as skin and its appendages. A major cause of morbidity among affected infants is severe and chronic skin erosions. Currently, supportive care is the only available treatment option for AEC patients. Mutations in TP63, a gene that encodes key regulators of epidermal development, are the genetic cause of AEC. However, it is currently not clear how mutations in TP63 lead to the various defects seen in the patients' skin. In this review, we will discuss current knowledge of the AEC disease mechanism obtained by studying patient tissue and genetically engineered mouse models designed to mimic aspects of the disorder. We will then focus on new approaches to model AEC, including the use of patient cells and stem cell technology to replicate the disease in a human tissue culture model. The latter approach will advance our understanding of the disease and will allow for the development of new in vitro systems to identify drugs for the treatment of skin erosions in AEC patients. Further, the use of stem cell technology, in particular induced pluripotent stem cells (iPSC), will enable researchers to develop new therapeutic approaches to treat the disease using the patient's own cells (autologous keratinocyte transplantation) after correction of the disease-causing mutations.

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.

Ankyloblepharon Filiforme Adnatum in a 3-day-old Neonate: A Case Report.

Ankyloblepharon filiforme adnatum (AFA) is a rare congenital anomaly consisting of partial or complete fusion of the eyelid margins. It is usually isolated and benign, but its presence should alert the neonatologist as it may rarely be associated with other disorders. We present a case of a 3-day-old newborn presenting with isolated AFA at birth.

[Clinical aspects of ocular mucosal pemphigoid]. / Klinik des okulären Schleimhautpemphigoids.

Mucosal pemphigoid is a rare chronic autoimmune disease that also affects the eyes in more than two thirds of all cases. Especially in the early phase of the ocular manifestation, the findings are subtle and the disease is often not recognized. The aim of this article is to provide the clinical aspects of ocular mucosal pemphigoid so that timely diagnostics can be initiated when this disease is suspected.

Peri-operative management of a patient with an ectodermal dysplasia (Rapp-Hodgkin) syndrome.

We present the case of a 41-year-old man with Rapp-Hodgkin syndrome who underwent nasal septum deviation surgery under general anaesthesia. This syndrome is rare, with approximately 70 cases reported worldwide. It is one of a group of ectodermal dysplasia syndromes and results from the aberrant development of ectoderm during fetal development. Some of the clinical features may affect anaesthetic management. The most important considerations are potentially difficult airway management, the need for meticulous temperature control, and the importance of skin protection. This case was uneventful, but as there are few case reports on the management of patients with ectodermal dysplasia syndromes undergoing anaesthesia this report contributes useful knowledge. The pathogenesis and clinical features of Rapp-Hodgkin syndrome and the anaesthetic management for this patient are described.

Ocular Manifestations in Patients Affected by p63-Associated Disorders: Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) and Ankyloblepharon-Ectodermal Defects-Cleft Lip Palate (AEC) Syndromes.

BACKGROUND/AIMS: The Ectrodactyly-Ectodermal dysplasia-Clefting (EEC) and Ankyloblepharon-ectodermal defect-cleft lip/palate (AEC) syndromes are rare autosomal dominant diseases caused by heterozygous mutations in the p63 gene. Patients are characterized by abnormalities of the skin, teeth, and hair and have limb defects, orofacial clefting and ectodermal dysplasia. In addition, they often show ocular surface alterations, leading to progressive corneal clouding and eventually blindness. Here, we present 8 cases describing patients affected by EEC (n = 6, with 5 sporadic and 1 familial cases) and AEC (n = 2, both sporadic cases) syndromes. We attempt to provide a description of the ocular disease progression over the years. METHODS: Clinical examinations and monitoring of ocular parameters for the assessment of limbal stem cell deficiency were constantly performed on patients between 2009 and 2023. Quantitative data and comparison with existing cases described in the literature are reported. RESULTS: The therapies supplied to patients were essential for the management of the symptoms, but unfortunately did not halt the progression of the pathology. CONCLUSIONS: A constant monitoring of the patients would help avoid the sudden worsening of symptoms. If the progression of the disease slows down, it would allow for the development of newer therapeutic strategies aimed at correcting the genetic defect.

Molecular Modeling Analysis Provides Genotype-Phenotype Correlation Insights in a Patient with Ankyloblepharon-Ectodermal Dysplasia-Clefting Syndrome.

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a rare autosomal dominant disorder. AEC is caused by mutations in the TP63 gene that encodes the tumor suppressor p63 protein, itself involved in the regulation of epidermal proliferation, development, and differentiation. We present here a typical AEC case of a four-year-old girl with extensive skin erosions and erythroderma of the scalp and the trunk, and to a lesser extent of the limbs, nail dystrophy on the fingers and toes, xerophthalmia, a high-arched palate, oligodontia, and hypohidrosis. Mutation analysis of the TP63 gene detected a de novo missense mutation in exon 14 (c.1799G>T; p.Gly600Val). We discuss the phenotype-genotype correlation by presenting the clinical features of AEC in the patient, and the effect of the detected mutation in p63 structure and function using protein structural modeling, in view of similar cases in the literature. We performed a molecular modeling study in order to link the effect on the protein structure level of the missense mutation G600V. We noted that the introduction of the bulkier Valine residue in place of the slim Glycine residue caused a significantly altered 3D conformational arrangement of that protein region, pushing away the adjacent antiparallel α helix. We propose that the introduced locally altered structure of the G600V mutant p63 has a significant functional effect on specific protein-protein interactions, thus affecting the clinical phenotype.

Congenital fusion of jaw and ankyloblepharon filiforme adnatum: malformation and multiple systems anomaly.

Congenital fusion of jaw and its association with ankyloblepharon filiforme adnatum is reported but is a quite rare congenital benign anomaly. It may be unilateral or bilateral and can present with a single system or multiple systems involvement. This report concentrates on describing the clinical features of above disease, likely aetiological causes, and embryogenesis with classification, diagnostic, and, treatment modality, anesthesia problems and review of literature.

Isolated Ankyloblepharon Filiforme Adnatum: A Case Report.

Ankyloblepharon filiforme adnatum (AFA) is a rare congenital anomaly consisting of partial or complete adhesion of the upper and lower eyelids, and it can be an isolated finding, or associated with other multisystemic anomalies. Its presence should alert the neonatologist of the need for a detailed systemic evaluation. We present a twenty day old baby who presented to our facility on the 8th of August 2019, with bilateral adhesions of the upper and lower eyelids, and had them excised with the use of McPherson's forceps and Vannas scissors, with no sedation or anesthesia. Timely separation of the lids is important to prevent the onset of stimulus deprivation amblyopia.

Irreversible Bilateral Cicatricial Keratoconjunctivitis after Dupilumab Therapy.

This report highlights a case of irreversible bilateral cicatricial keratoconjunctivitis related to dupilumab therapy for the treatment of severe atopic dermatitis (AD). After 38 years of AD, the patient began dupilumab therapy and achieved disease control. Two years into treatment, his ophthalmic examination was significant for bilateral cicatricial keratoconjunctivitis with severe foreshortening of the inferior conjunctival fornices, symblepharon, and ankyloblepharon, which persisted even after topical steroid eye drops and discontinuation of dupilumab. Treating dermatologists should be aware of this potential irreversible adverse effect, and we recommend that patients are monitored for ocular complications while on dupilumab therapy.

Symblepharon, Ankyloblepharon, and Salt Gland Dysfunction in a Loggerhead Sea Turtle (Caretta caretta).

Adhesions involving the bulbar and the palpebral conjunctiva (Symblepharon) may interfere with tear drainage, cause chronic conjunctivitis, and reduce ocular motility. This condition may be associated with adhesion of the edges of the upper and lower eyelids (ankyloblepharon). The present case describes bilateral symblepharon, ankyloblepharon and salt gland dysfunction in a juvenile Caretta caretta. The loggerhead presented both eyelids swollen, ulcerated, and not separable when rescued. Eye examination was not possible, but ultrasonography showed right bulbar integrity, while the left eye was smaller, with a thicker cornea that had lost its normal doubled lined structure. Surgical dissection of the fibrous adhesions between the palpebral and bulbar conjunctiva, cornea, and third eyelid was performed, and large dacryoliths were removed. The microscopic findings were consistent with chronic keratoconjunctivitis. Ultrastructurally, no virus-like particles were observed. In addition, tissue samples were negative for herpesvirus by qualitative PCR. The eyelids of both eyes and the corneal epithelium of the right eye healed; moreover, the vision was restored in the right eye. There were no recurrences after 12 months of follow-up, and the turtle was released 16 months after the end of treatments on the southern Tyrrhenian coast in the western Mediterranean Sea. To the authors' knowledge, this is the first report of symblepharon with ankyloblepharon and salt gland dysfunction in Caretta caretta turtle. Ocular ultrasonography was helpful in the preliminary diagnostic work-up.

Bilateral ankyloblepharon: more than a simple malformation. / Anquilobléfaron bilateral: Algo más que una simple malformación.

"Ankyloblepharon filiforme adnatum" is a congenital anomaly characterized by partial or complete adhesion of upper and lower eyelids. The lid margins remain fused until the end of the fifth month of gestational age. Complete separation usually is completed about the seventh fetal month. Ankyloblepharon may be an isolated manifestation or may be associated with abnormalities in other organs and / or systems. The case is presented on a newborn male with family history of hypohydrotic ectodermal dysplasia (mother and maternal grandfather). It revealed extensible bands of skin in right and in left eye. Apart from this, he presented cleft lip, complete absence of palate, nail and ungueal dysplasia and supernumerary nipples.

Ocular manifestations of ectodermal dysplasia.

PURPOSE: The ectodermal dysplasias (EDs) constitute a group of disorders characterized by abnormalities in two or more ectodermal derivatives, including skin, hair, teeth, and sweat glands. The purpose of the current study was to evaluate ocular manifestations in pediatric patients with ED. METHODS: Retrospective case series including consecutive ED subjects who were treated in the ophthalmology department at the Children's Hospital of Philadelphia over a 12-year period (2009-2020). Main Outcome Measures were ocular and ocular adnexal abnormalities. RESULTS: Thirty subjects were included: 20 males (67%), mean age of 4.5 years (range 0.3-18). Patients with different subtypes were included, with the hypohidrotic ED and ectrodactyly-ectodermal dysplasia-clefting variants being most prevalent. Most common findings were: lacrimal drainage obstruction in 12 (40%) including punctal agenesis in 10 (33%), refractive errors in 13 (43%) and amblyopia in 6 (20%). A new finding of eyelid ptosis or eyelash ptosis was demonstrated in 11 subjects (37%), mostly associated with TP63 or EDA1 genes variants. CONCLUSION: Ectodermal dysplasias are associated with various ocular pathologies and amblyopia in the pediatric population. We report a possible genetic association between lash ptosis and EDA1 gene, and eyelid ptosis and TP63 or EDA1 genes variants.