Ectodermal Dysplasia Research Articles

A Rare Case of TP63-Associated Lymphopenia Revealed by Newborn Screening Using TREC

The expanded newborn screening (NBS) program in the Russian Federation was initiated in 2023, among which severe combined immunodeficiency (SCID) is screened using TREC/KREC assays. Here, we report a rare case of a TP63-associated disease identified through this NBS program. Dried blood spots from newborns were initially screened for TREC/KREC levels, and those with values below the cut-off underwent confirmatory testing and further genetic analysis, including whole-exome sequencing (WES). A male newborn was identified with significantly reduced TREC values, indicative of T cell lymphopenia. Genetic analysis revealed a heterozygous NM_003722.5:c.1027C>T variant in TP63, leading to the p.(Arg343Trp) substitution within the DNA binding domain. This mutation has been previously associated with Ectrodactyly–Ectodermal Dysplasia–Cleft lip/palate syndrome (EEC) syndrome and shown to reduce the transactivation activity of TP63 in a dominant-negative manner. This case represents one of the few instances of immune system involvement in a patient with a TP63 mutation, highlighting the need for further investigation into the immunological aspects of TP63-associated disorders. Our findings suggest that comprehensive immunological evaluation should be considered for patients with TP63 mutations to better understand and manage potential immune dysfunctions.

Ocular and Systemic Abnormalities in Punctal Agenesis

Background: Punctal agenesis (PA) is a rare congenital anomaly that can occur in isolation or as part of an underlying syndrome. The benefit of genetic assessment in individuals with PA and clinical features that should prompt molecular workup has not been systematically studied. The aim of this study was to identify ocular and extraocular features associated with PA and determine its association with an underlying syndrome. Methods: A retrospective medical records review of ocular and extraocular medical histories in all patients diagnosed with PA at the Children’s Hospital of Philadelphia between 2009 and 2023 was conducted. Results: Forty-four patients were included, ages 3.3 ± 3.3 years. Our cohort was 31 males (70%). Twenty patients had isolated PA (45.5%), while 24 patients (54.5%) had other associated ocular or extraocular abnormalities. The most common ocular comorbidities were refractive disorders (n = 8, 33%), ptosis (n = 8, 33%), strabismus (n = 7, 29%), other eyelid disorders (n = 9, 38%), and amblyopia (n = 6, 25%). Nineteen (43%) individuals had systemic disorders and 18 (41%) underwent genetic testing. An associated genetic diagnosis was found in 17 (39%) individuals. The most common associated syndrome was ectodermal dysplasia. Systemic disorders were more prevalent in individuals with syndromic PA (4, 20% isolated PA vs. 15, 63%, PA-plus, p = 0.005). Conclusions: The presence of additional ocular abnormalities was associated with an increased rate of systemic disorders (63%). In individuals with PA who also exhibit additional ocular disorders, systemic evaluation and genetic workup should be considered.

CAD/CAM Manufactured PEEK framework for RPD in Ectodermal Dysplasia

CAD/CAM Manufactured PEEK framework for RPD in Ectodermal Dysplasia

'Living in the Present' mindfulness for parents of children with skin conditions: a single group case series.

Parents of children with skin conditions can experience stress from the additional responsibilities of care. However, there is a lack of psychological interventions for families affected by a dermatological diagnosis. To investigate (1) whether delivering the 'Living in the Present' mindfulness curriculum to parents of children with skin conditions reduced stress and increased both parental/child quality of life (QoL), and (2) determine intervention acceptability. Ten parents of children with eczema, ectodermal dysplasia, ichthyosis, and alopecia took part in a mindfulness-based intervention. Using mixed methods, a single-group experimental case design (SCED) was conducted and supplemented by thematic analysis of exit interviews. Parents completed idiographic measures of parenting stress, standardised measures of QoL, stress, mindfulness, and took part in exit interviews. Children also completed QoL measures. Tau-U analysis of idiographic measures revealed three parents showed some significant improvements in positive targets, and five parents showed some significant improvements in negative targets. Assessment of reliable change demonstrated that: one parent showed improvement in mindful parenting, three parents showed improvement in parenting stress, seven parents showed improvement in anxiety, three parents showed improvements in depression, six parents showed improvement in QoL, and four children showed improvement in QoL. However, two parents showed increased anxiety. Thematic analysis revealed positive changes to mood following mindfulness, although challenges were highlighted, including sustaining home practice. Findings suggest this specific form of mindfulness intervention could be effective for parents of children with skin conditions; however, further robust studies are needed.

Genotypic and phenotypic correlations in tooth agenesis: insights from WNT10A and EDA mutations in syndromic and non-syndromic forms.

Tooth agenesis (TA) occurs when tooth development is disrupted at the initiation stage. It can be classified into non-syndromic and syndromic forms (named NSTA and STA), depending on whether it is accompanied by abnormalities of other organs and systems. Genetic factors play a predominant role in the pathogenesis of tooth agenesis, with dozens of genes implicated in both forms. Several genes have been identified, mutations in which can lead to both forms of TA. Among these, WNT10A and EDA are frequently mutated genes in this context, representing extensively researched and documented genes in human non-syndromic selective agenesis of permanent teeth and their association with ectodermal dysplasia syndromes. In this review, we present an overview of the current knowledge regarding genes associated with NSTA and STA, focusing on the distribution and nature of WNT10A and EDA gene mutations. We also explore how these mutations relate to the condition's both forms, including their association with the number of missing permanent teeth.

Masticatory function in growing individuals with hypohidrotic ectodermal dysplasia: A longitudinal study.

Hypohidrotic ectodermal dysplasia (HED) is a hereditary disorder with agenesis of ectodermal derivatives, causing oligodontia or anodontia. Dentures are needed to improve the patients' mastication. This study aimed at preliminarily evaluating the masticatory function changes in Chinese individuals with HED after prosthetic rehabilitation from childhood to adolescence. This longitudinal study enrolled 10 HED patients. Data were collected during childhood and adolescence, respectively. The healthy children and adolescents were recruited as the control group. The surface electromyography (EMG) of masseter (MM) and anterior temporalis (TA) muscles during clenching and chewing were recorded. The EMG activity, asymmetry index (As), activity index (Ac), and chewing cycle were analyzed. The masticatory efficiency was measured by spectrophotometry with subjective masticatory ability assessed by a questionnaire. The EMG activities and masticatory efficiency of HED patients during childhood and adolescence were mostly lower with a higher As (p < .05). The chewing process enhanced the TA activity and balanced the As of HED adolescents (p > .05). The HED adolescents showed a more prevalent TA activity (p < .05). The masticatory function of the growing HED patients was functionally inferior to the dentate individuals with a narrowed gap from childhood to adolescence.

A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease.

Inositol 1,4,5-trisphosphate (IP3) receptor type 1 (ITPR1), 2 (ITPR2), and 3 (ITPR3) encode the IP3 receptor (IP3R), a key player in intracellular calcium release. In four unrelated patients, we report that an identical ITPR3 de novo variant-NM_002224.3:c.7570C>T, p.Arg2524Cys-causes, through a dominant-negative effect, a complex multisystemic disorder with immunodeficiency. This leads to defective calcium homeostasis, mitochondrial malfunction, CD4+ lymphopenia, a quasi-absence of naïve CD4+ and CD8+ cells, an increase in memory cells, and a distinct TCR repertoire. The calcium defect was recapitulated in Jurkat knock-in. Site-directed mutagenesis displayed the exquisite sensitivity of Arg2524 to any amino acid change. Despite the fact that all patients had severe immunodeficiency, they also displayed variable multisystemic involvements, including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. In conclusion, unlike previously reported ITPR1-3 deficiencies leading to narrow, mainly neurological phenotypes, a recurrent dominant ITPR3 variant leads to a multisystemic disease, defining a unique role for IP3R3 in the tetrameric IP3R complex.

Non-Skewed X-inactivation Results in NF-κB Essential Modulator (NEMO) Δ-exon 5-autoinflammatory Syndrome (NEMO-NDAS) in a Female with Incontinentia Pigmenti

PurposeGenetic hypomorphic defects in X chromosomal IKBKG coding for the NF-κB essential modulator (NEMO) lead to ectodermal dysplasia and immunodeficiency in males and the skin disorder incontinentia pigmenti (IP) in females, respectively. NF-κB essential modulator (NEMO) Δ-exon 5-autoinflammatory syndrome (NEMO-NDAS) is a systemic autoinflammatory disease caused by alternative splicing and increased proportion of NEMO-Δex5. We investigated a female carrier presenting with IP and NEMO-NDAS due to non-skewed X-inactivation.MethodsIKBKG transcripts were quantified in peripheral blood mononuclear cells isolated from the patient, her mother, and healthy controls using RT-PCR and nanopore sequencing. Corresponding proteins were analyzed by western blotting and flow cytometry. Besides toll-like receptor (TLR) and tumor necrosis factor (TNF) signaling, the interferon signature, cytokine production and X-inactivation status were investigated.ResultsIP and autoinflammation with recurrent fever, oral ulcers, hepatitis, and neutropenia, but no immunodeficiency was observed in a female patient. Besides moderately reduced NEMO signaling function, type I interferonopathy, and elevated IL-18 and CXCL10 were found. She and her mother both carried the heterozygous variant c.613 C > T p.(Gln205*) in exon 5 of IKBKG previously reported in NEMO-deficient patients. However, X-inactivation was skewed in the mother, but not in the patient. Alternative splicing led to increased ratios of NEMO-Dex5 over full-length protein in peripheral blood cell subsets causing autoinflammation. Clinical symptoms partially resolved under treatment with TNF inhibitors.ConclusionNon-skewed X-inactivation can lead to NEMO-NDAS in females with IP carrying hypomorphic IKBKG variants due to alternative splicing and increased proportions of NEMO-∆ex5.

Phenotypes, Genetics, and Estimated Prevalence of Focal Dermal Hypoplasia (Goltz Syndrome): A Single-Center Report.

Focal dermal hypoplasia (FDH), also known as Goltz syndrome, is a rare ectodermal dysplasia that primarily affects the skin, skeleton, and eyes. It is an X-linked dominant disorder, predominantly seen in females, caused by pathogenic variants in PORCN. We characterized a case series of four genetically confirmed FDH patients (three females, one male) at Aarhus University Hospital, Denmark. We estimated the FDH prevalence from our local cohort and nationwide registry data. Three patients had characteristic dermatological findings suspicious for FDH and confirmed by targeted PORCN analysis. One patient had an atypical presentation with several malformations but only subtle skin changes and was diagnosed following trio exome-sequencing analysis. Skin atrophy with fat herniations and telangiectasias were typical cutaneous findings. Limb malformations included oligodactyly (cleft foot), syndactyly, and polydactyly. Eye abnormalities included coloboma and microphthalmos. Facial dysmorphology was defined by asymmetry, thin upper lip, and malformed ears. One patient developed a giant cell bone tumor, which is a rare feature of FDH. Dental findings included enamel hypoplasia with vertical grooving and irregular crowns. Four PORCN variants were identified, including three not previously reported in the literature.We estimated a regional point prevalence in Western Denmark of 1.6 cases per million population (95% confidence intervals (CI): 0.7-3.7 per million) and a nationwide registry-based point prevalence of 1.2 cases per million population (95% CI: 0.6-2.4 per million). FDH is an extremely rare and complex multisystem disorder of variable presentation, which requires close multidisciplinary collaboration for diagnosis and patient care.

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.

Prevalence rates for ectodermal dysplasia syndromes.

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. 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. 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. 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. 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.

Hypohidrotic ectodermal dysplasia in a family: expanding spectrum of LEF-1 related disorders.

We report a novel heterozygous loss-of-function LEF1 variant in a 3-year-old girl and her mother, both diagnosed with hypohidrotic ectodermal dysplasia. The patients presented with sparse hair, dry skin, and oligodontia but lacked limb or mammary malformations, expanding the clinical spectrum of LEF1-related disorders. The study provides new insights into the variability and management of ectodermal dysplasias related to LEF1 gene.

Treatment strategy for patient with non-syndromic tooth agenesis: a case report and literature review

BackgroundNon-syndromic tooth agenesis (NSTA) is a type of ectodermal dysplasia (ED) in which patients with non-syndromic oligodontia may only affect teeth. No pathological findings were found in other tissues of the ectodermal. Herein, we report a case of a NSTA patient with severe dental anxiety and poor oral health.Case presentationA 5-year-old boy without systemic diseases presented as a patient with oligodontia, extensive caries, and periapical periodontitis. Molecular genetic analysis found a mutation in the Ectodysplasin A (EDA) gene, confirming the diagnosis of NSTA.ConclusionTooth agenesis (TA) is the most common ectodermal developmental abnormality in humans. Non-syndromic oligodontia patients often seek treatment in the department of stomatology. Because of their complex oral conditions, these patients should be provided with a systematic and personalized treatment plan.

Ectodermal dysplasia (DE) and its main characteristics

Ectodermal dysplasia (ED) is a rare genetic disorder that affects the development of ectodermal tissues and includes organs of the body such as: skin, hair, nails, teeth, and sweat glands. Therefore, this condition can be seen from birth and has different levels of severity. In addition, it is known that there is one case for every 10,000 to 100,000 children born, making it essential to diagnose the dentist for alteration problems in any of the identified areas. The method to be included is a case study in a 5-month-old male patient, after DNA diagnosis and prenatal type to the second semester with skin biopsy, ED characteristics were identified. The results identified a 5-month-old male, born at 39 weeks and 3 days, with 3150 grams, height 49 centimeters, scaly lesions are observed on the skin throughout the body, marbled skin, mild pyelocalyceal ectasia, in addition to the absence of of hair, eyebrows and eyelashes, after the DNA test with prior informed consent, the existence of ED was confirmed. Finally, it is concluded that ED is a genetic disorder, as presented in the case study, and that the most common is dyshidrotic ectodermal dysplasia.

Ectodermal dysplasia and cholesteatoma: A cross-sectional analysis of otologic issues

ObjectivesPrevious studies have also associated cleft palate with increased cholesteatoma risk. Despite this close relation, the incidence of cholesteatoma and associated otologic issues in patients with ectodermal dysplasia types highly associated with cleft palate (EDT-ACPs) has not been formally analyzed. This study provides insight to guide clinicians caring for patients with ED types associated with cleft palate. MethodsIndividuals with TP63 disorders and Goltz syndrome/Focal Dermal Hypoplasia in the National Foundation for Ectodermal Dysplasia database were contacted for participation in an online REDCap survey from Sept–Dec ‘22. Descriptive statistics were generated using SAS JMP Pro 17 statistical software. Results65 individuals participated in the survey (response rate approx. 18 %). The median [IQR] age was 22 [14, 43], 41 (63 %) were female, and Ectrodactyly-Ectodermal Dysplasia-Cleft Lip/Palate Syndrome (EEC) was most common (n = 26, 40 %). We found that, among our respondents with a history of cleft palate, the incidence of cholesteatoma was 39 %. Among respondents without a history of cleft palate, the incidence of cholesteatoma was 13 % ConclusionsOtologic issues, such as cholesteatoma, can have permanent implications including hearing loss that can be minimized by early identification and treatment. The estimated incidence of cholesteatoma among our participants is far above the estimated incidence of cholesteatoma in the general population with and without a history of cleft palate, suggesting an independent contribution of EDT-ACPs to the risk of cholesteatoma.

Clinical, Immunological, and Genetic Features in Patients with NFKB1 and NFKB2 Mutations: a Systematic Review.

Inborn errors of immunity (IEIs) encompass various diseases with diverse clinical and immunological symptoms. Determining the genotype-phenotype of different variants in IEI entity precisely is challenging, as manifestations can be heterogeneous even in patients with the same mutated gene. In the present study, we conducted a systematic review of patients recorded with NFKB1 and NFKB2 mutations, two of the most frequent monogenic IEIs. The search for relevant literature was conducted in databases including Web of Science, PubMed, and Scopus. Information encompassing demographic, clinical, immunological, and genetic data was extracted from cases reported with mutations in NFKB1 and NFKB2. The comprehensive features of manifestations in patients were described, and a comparative analysis of primary characteristics was conducted between individuals with NFKB1 loss of function (LOF) and NFKB2 (p52-LOF/IκBδ-gain of function (GOF)) variants. A total of 397 patients were included in this study, 257 had NFKB1 mutations and 140 had NFKB2 mutations.There were 175 LOF cases in NFKB1 and 122 p52LOF/IκBδGOF cases in NFKB2 pivotal groups with confirmed functional implications. NFKB1LOF and p52LOF/IκBδGOF predominant cases (81.8% and 62.5% respectively) initially presented with a CVID-like phenotype. Patients with NFKB1LOF variants often experienced hematologic autoimmune disorders, whereas p52LOF/IκBδGOF patients were more susceptible to other autoimmune diseases. Viral infections were markedly higher in p52LOF/IκBδGOF cases compared to NFKB1LOF (P-value < 0.001). NFKB2 (p52LOF/IκBδGOF) patients exhibited a greater prevalence of ectodermal dysplasia and pituitary gland involvement than NFKB1LOF patients. Most NFKB1LOF and p52LOF/IκBδGOF cases showed low CD19 + B cells, with p52LOF/IκBδGOF having more cases of this type. Low memory B cells were more common in p52LOF/IκBδGOF patients. Patients with NFKB2 mutations, particularly p52LOF/IκBδGOF, are at higher risk of viral infections, pituitary gland involvement, and ectodermal dysplasia compared to patients with NFKB1LOF mutations. Genetic testing is essential to resolve the initial complexity and confusion surrounding clinical and immunological features. Emphasizing the significance of functional assays in determining the probability of correlations between mutations and immunological and clinical characteristics of patients is crucial.

Current Evidence on the Rehabilitation of Ectodermal Dysplasia Patients with Dental Implants

Current Evidence on the Rehabilitation of Ectodermal Dysplasia Patients with Dental Implants

Skin GeneticsOral presentationsSG01 WNT10A-related ectodermal dysplasia: five cases demonstrating the phenotypic spectrum

Skin GeneticsOral presentationsSG01 WNT10A-related ectodermal dysplasia: five cases demonstrating the phenotypic spectrum

Medical and Social Aspects Affecting Disability Formation and Quality of Life in Children with Ectodermal Dysplasia

Medical and Social Aspects Affecting Disability Formation and Quality of Life in Children with Ectodermal Dysplasia

Novel homozygous frameshift insertion variant in the last exon of the EDARADD causing hypohidrotic ectodermal dysplasia in two siblings: case report and review of the literature

BackgroundHypohidrotic ectodermal dysplasia (HED) is a genetic disorder that results in the abnormal development of structures derived from ectodermal tissue. This rare condition predominantly affects the hair, nails, eccrine glands, and teeth. While HED can be caused by various genes, the EDA, EDAR, EDARADD, and WNT10A genes account for approximately 90% of cases. Notably, HED forms associated with variants in the EDA, EDAR, or EDARADD genes may exhibit similar phenotypes due to defects in a common signaling pathway. Proper interaction among the products of these genes is crucial for the activation of the nuclear factor (NF-κB) signaling pathway, which subsequently regulates the transcription of targeted genes. The EDARADD gene, in particular, harbors one of the rarest reported variants associated with HED.Case presentationFive-and two-years-old brothers born into consanguineous parents were examined at our outpatient medical genetics clinic at Sanliurfa Training and Research Hospital, Turkey. Both displayed the same classical phenotypic features of HED. The elder had a very sparse dark and brittle hair, sparse eyebrows and eyelashes, conical upper and lower premolar teeth with hypodontia, widely spaced teeth, very dry skin, mildly prominent forehead, and periorbital wrinkles. The younger one showed the same, but less severe, clinical features. After thorough examination and patient history evaluation, targeted next-generation sequencing analysis yielded the novel homozygous insertion variant c.322_323insCGGGC p.(Arg108ProfsTer7) in EDARADD. The mutation has not been reported to date in the literature.ConclusionsIn this report, we present two siblings exhibiting classical HED symptoms and a novel insertion variant of the EDARADD gene, which leads to a frameshift introducing a stop codon. Both brothers inherited such mutation from their parents, who were heterozygous carriers of the same variant. The present study may shed light about the pathogenic mechanisms underlying HED, and expand the spectrum of EDARADD gene variants associated with this condition.