Ectodermal Disorder Research Articles

Burden of congenital and hereditary anomalies and their epidemiological attributes in the pediatric and adult population of Peshawar valley, Pakistan

Objectives: To elucidate the burden and clinico-epidemiological attributes of congenital and hereditary anomalies (CA) in the extended Peshawar Valley of Pakistan. Method: This is a multicenter cross sectional study carried out in Buner, Charsadda, Mardan, Nowshera, Peshawar and Swabi districts, during 2017-2021. The pediatric and adult patients with CA were recruited from hospitals, public places and through door-to-door surveys. The anomalies were classified with the help of specialized clinicians. Descriptive statistics was employed. Results: In this study, 1065 independent subjects with certain types of CA from independent households were included. The index males were 71%; the majority of subjects originated from rural areas (72%), and spoke Pashto (96%). The CA were categorized into 10 major and at least 104 minor categories. There was highest representation of neurological disorders, n=375 (proportion.: 0.352; 95% CI: 0.323-0.381), followed by limb defects (n=281; prop.: 0.264), sensorineural defects (n=128; prop.: 0.120), musculoskeletal defects (n=84; prop.: 0.079), visual impairments (n=67; prop.: 0.063), hemoglobinopathies (n=40; prop.: 0.038), ectodermal disorders (n=34; prop.: 0.032), cardiovascular anomalies (n=19; prop.: 0.018), and orofacial anomalies (n=19; prop). Among the neurological disorder, intellectual disabilities and cerebral palsy were highly prevalent. The majority of the cases had a sporadic presentation (68%), and isolated occurrence (72%), whereas parental consanguinity was witnessed in 58% of cases. Conclusion: A wide range of CA were witnessed in this cohort with a preponderance of neurological disorders. The majority of the anomalies are of severe nature rendering a high morbidity burden in the population and requiring early detection, intervention and management. doi: https://doi.org/10.12669/pjms.40.10.9234 How to cite this: Naqvi SF, Ameena U, Qazi W, Ahmad S, Iqbal A, Malik S. Burden of congenital and hereditary anomalies and their epidemiological attributes in the pediatric and adult population of Peshawar valley, Pakistan. Pak J Med Sci. 2024;40(10):2181-2189. doi: https://doi.org/10.12669/pjms.40.10.9234 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Dermatopathia pigmentosa reticularis: a rare case report

Dermatopathia pigmentosa reticularis (DPR) is a very rare ectodermal disorder with autosomal dominant mode of inheritance. It is associated with a mutation in the keratin 14 gene on chromosome 17. It is characterized by a diagnostic triad of generalized reticulate hyperpigmentation, non-cicatricial alopecia, and onychodystrophy. We hereby report a case of a 26-year-old female who presented with reticulate hyperpigmentation all over the body, diffuse non-cicatricial alopecia, and onychodystrophy. Apart from this triad, she also had poorly developed dermatoglyphics.

O18 Precision genome editing for targeted correction of pathogenic D50N mutation in keratitis–ichthyosis–deafness syndrome using CRISPR/Cas9 and homology-directed repair

Abstract Introduction and aims Keratitis–ichthyosis–deafness (KID) syndrome is an ectodermal disorder that causes blindness, skin inflammation and deafness. It is caused by autosomal dominant mutations in the gap junction beta 2 (GJB2) gene with 86% being a hotspot mutation on c.148G>A, resulting in the amino acid replacement (D50N) in its coding protein connexin 26 (Cx26). There is currently no curative treatment for KID syndrome. We aim to correct the hotspot mutation D50N using a genome-editing approach. Methods Keratinocytes generated from the patient with KID who had a D50N mutation (KID-KCs) were genetically corrected by homologous-directed repair/CRISPR-Cas9 using an electroporation approach. The correction efficiency was determined and analysed using Sanger sequencing and Synthego Inference of CRISPR Edits analysis. The off-target effects were confirmed by whole-exome sequencing [exome next-generation sequencing (NGS)]. Furthermore, the functional recovery following genome editing was assessed by GJB2 mRNA production, Cx26 protein expression, and trafficking and hemichannel activity. Results The correction efficiencies ranged from 95% to 100% with different doses of CRISPR-Cas9 and 8µg CRISPR-Cas9 was the most optimal concentration with the efficiency of 100% and approximately 0% insertion-deletion (INDEL). Fifty days after gene editing, the INDEL increased to only 2%, indicating a minimum residual CRISPR-Cas9 effect in edited cells. The exome-NGS analysis also showed no off-target effects in the outside target area. Functional studies showed that there was a significant increase in wildtype GJB2 mRNA expression and a reduction of mutant GJB2 expression (n = 5, P < 0.01). Increased Cx26 membranous localization in KID-KCs was also observed (n = 3, P < 0.01). Additionally, Cx26 hemichannel activity assessment using the neurobiotin assay showed a significant decrease in ‘leaky’ hemichannel in gene-edited KID-KCs compared with unedited cells (n = 3, P < 0.05). Conclusions We can genome-correct KID keratinocytes harbouring the mutation D50N with 100% editing efficiency, 0–2% INDEL, and undetectable off-target effects. This result indicates a promising gene therapy for KID syndrome with the hotspot mutation D50N.

The EDA/EDAR/NF-κB pathway in non-syndromic tooth agenesis: A genetic perspective.

Non-syndromic tooth agenesis (NSTA) is one of the most common dental developmental malformations affected by genetic factors predominantly. Among all 36 candidate genes reported in NSTA individuals, EDA, EDAR, and EDARADD play essential roles in ectodermal organ development. As members of the EDA/EDAR/NF-κB signaling pathway, mutations in these genes have been implicated in the pathogenesis of NSTA, as well as hypohidrotic ectodermal dysplasia (HED), a rare genetic disorder that affects multiple ectodermal structures, including teeth. This review provides an overview of the current knowledge on the genetic basis of NSTA, with a focus on the pathogenic effects of the EDA/EDAR/NF-κB signaling pathway and the role of EDA, EDAR, and EDARADD mutations in developmental tooth defects. We also discuss the phenotypic overlap and genetic differences between NSTA and HED. Ultimately, this review highlights the importance of genetic analysis in diagnosing and managing NSTA and related ectodermal disorders, and the need for ongoing research to improve our understanding of these conditions.

Keratitis-Ichthyosis-Deafness Syndrome Caused by Missense Mutation in GJB2 Encoding Connexin 26 in a Chinese Patient

Introduction: Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital ectodermal disorder caused by a heterozygous missense mutation in GJB2 or GJB6, which encode connexin 26 and connexin 30, respectively. To date, three cases of KID syndrome caused by an N14Y mutation of GJB2 have been reported globally, but there is no relevant report in domestic literature. Case presentation: A 36-year-old man presented with scalp alopecia and absence of eyelashes, pubic hair, and axillary hair. Yellow-brown highly keratinized verrucous plaques were present on the perineum, palms, and soles. All 20 nails were severely abnormal. Keratitis, blepharitis, and profound sensorineural hearing loss were also observed. Foot biopsy revealed ichthyosis changes. Sequencing of GJB2 showed that the patient was heterozygous for a nucleotide change, c.40A > T, in exon 2, resulting in the substitution of asparagine for tyrosine at position 14 (N14Y) located in the N-terminal domain of connexin 26. Notably, the mutation site of KID syndrome has not been reported in domestic literature. The patient's father was heterozygous for the M195 V (c.583A > G) mutation, and his mother was heterozygous for the V37I (c.109G > A) mutation. The patient received oral retinoic acid, antibiotics and topical moisturizer packs, but was subsequently lost to follow-up. Discussion: KID syndrome manifests as the classic triad of chronic vascularizing keratitis, ichthyosiform erythroderma, and sensorineural hearing loss. Early and long-term multidisciplinary monitoring of affected individuals is essential. Genetic testing could help us detect the mutation site of connexin. Conclusion: These findings expand the mutation spectrum of KID syndrome in the Chinese population and provide a new understanding of the genotype–phenotype correlation. Functional studies on the N14Y mutation will help to reveal the underlying pathogenic mechanism.

A Novel Missense Mutation in the EDAR Gene and One Missense Mutation in EDA Gene in the Study of HED Patients in Iran

: Hypohidrotic ectodermal dysplasia (HED) is the most common type of ectodermal dysplasia that is the result of faulty ectodermal development leading to such ectodermal defects as hypotrichosis, anodontia or hypodontia, and hypohidrosis or anhidrosis. X-linked HED is caused by mutations in ectodysplasin A (EDA) gene and accounts for 90% of all HED cases. Autosomal HED is caused by mutations in other involved genes, such as EDA-receptor (EDAR) gene. In this study, we included two distinct families with three HED patients. We collected 5 mL of peripheral blood from the probands, associated parents, and 120 matched unrelated controls (from related ethnicity) without any ectodermal disorder. DNA was extracted using the routine salting-out protocol from blood leukocytes. Polymerase chain reaction (PCR) purification and bidirectional Sanger sequencing of the PCR products were performed. We identified p.R156H (c.467 G>A) mutation in EDA gene in two affected brothers and their carrier mother (family 1) and a novel missense mutation c.1210G>A (p.A404T) in EDAR gene in a 4-year-old affected boy and his heterogeneous parents (family 2). Clinical evaluation, genetic findings, and bioinformatic analysis supported deleterious effects of both identified mutations on the EDA and EDAR gene products, which should be considered in genetic assessment of HED cases in Southwest of Iran.

Expanding on the phenotypic spectrum of Woodhouse-Sakati syndrome due to founder pathogenic variant in DCAF17: Report of 58 additional patients from Qatar and literature review.

Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive neuroendocrine and ectodermal disorder caused by variants in the DCAF17 gene. In Qatar, the c.436delC variant has been reported as a possible founder pathogenic variant with striking phenotypic heterogeneity. In this retrospective study, we report on the clinical and molecular characteristics of additional 58 additional Qatari patients with WSS and compare them to international counterparts' findings. A total of 58 patients with WSS from 32 consanguineous families were identified. Ectodermal and endocrine (primary hypogonadism) manifestations were the most common presentations (100%), followed by diabetes mellitus (46%) and hypothyroidism (36%). Neurological manifestations were overlapping among patients with intellectual disability (ID) being the most common (75%), followed by sensorineural hearing loss (43%) and both ID and aggressive behavior (10%). Distinctive facial features were noted in all patients and extrapyramidal manifestations were uncommon (8.6%). This study is the largest to date on Qatari patients with WSS and highlights the high incidence and clinical heterogeneity of WSS in Qatar due to a founder variant c.436delC in the DCAF17 gene. Early suspicion of WSS among Qatari patients with hypogonadism and ID, even in the absence of other manifestations, would shorten the diagnostic odyssey, guide early and appropriate management, and avoid potential complications.

WNT10A, dermatology and dentistry.

WNTs (Wingless-related integration sites) are secreted glycoproteins that are involved in signalling pathways critical to organ development and tissue regeneration. Of the 19 known WNT ligands, one member of this family, WNT10A, appears to have specific relevance to skin, its appendages and teeth. This review focuses on how variants in the WNT10A gene have been associated with various ectodermal disorders and how such changes may have clinical relevance to dermatologists and dentists. Germline mutations in WNT10A underlie several forms of autosomal recessive ectodermal dysplasia in which heterozygous carriers may also display some lesser ectodermal anomalies. Within the general population, multiple heterozygous variants in WNT10A can cause skin, hair, sweat gland or dental alterations, also known as ectodermal derivative impairments. WNT10A variants have also been implicated in hair thickness, male androgenetic alopecia, hair curl, acne vulgaris, lipodystrophy, keloids, wound healing, tooth size, tooth agenesis, hypodontia, taurodontism and oral clefting. Beyond dermatology and dentistry, WNT10A abnormalities have also been identified in kidney fibrosis, keratoconus, certain malignancies (particularly gastrointestinal) and neuropathic pain pathways. In this review, we detail how WNT10A is implicated as a key physiological and pathological contributor to syndromic and nonsyndromic disorders, as well as population variants, affecting the skin and teeth, and document all reported mutations in WNT10A with genotype-phenotype correlation.

The Spread of Thyroid Diseases and the Algorithm for Diagnosing Thyroid Dysfunction

Diseases of the thyroid gland are considered one of the most common endocrinopathies. This is due to the influence of ecologically unfavorable environmental factors, bad habits, malnutrition, comorbid conditions and genetic predisposition. Determining an algorithm for diagnosing thyroid dysfunction for the timely detection of diseases is expedient and relevant. The objective: to analyze the state of the spread of thyroid diseases among the population of the Kiev region and to determine the diagnostic algorithm based on the identification of the main clinical syndromes of thyroid dysfunction. Materials and methods. Among the adult population of the Kiev region, a high level of morbidity and spread of thyroid diseases is recorded. The increase in the number of cases occurred, first of all, due to the newly diagnosed patients with hypothyroidism, thyroiditis. The manifestation of most diseases is associated with the development of thyroid dysfunction. Under the hypothyroidism one can observe and diagnose the following: a syndrome of neuropsychiatric disorders with slowing down of motor activity, decrease in cognitive functions; syndrome of vegetative-trophic disorders with cutaneous mucinosis, polyneuropathy; syndrome of cardiovascular changes with decreased myocardial contractility, slow blood flow, progressive development of atherosclerosis; anemic syndrome; digestive tract syndrome with impaired motor and secretory functions of the gastrointestinal tract; syndrome of hormonal disorders with decreased secretion of thyroid hormones, especially T4, increased levels of TSH (in primary hypothyroidism) or decreased TSH (in secondary and tertiary). Results. Thyrotoxicosis in patients is determined by an enlarged thyroid gland with the development of: thyrotoxic cardiomyopathy and systolic arterial hypertension; thyrotoxic encephalopathy, syndrome of neuropsychiatric disorders with a predominance of excitation processes, vascular dysfunction; thyrotoxic ophthalmopathy, ectodermal disorders syndrome along with a decrease in TSH production and an increase in the level of free fractions T4, T3. Conclusions. The algorithm for diagnosing hypofunction and hyperfunction of the thyroid gland provides for: clarification of complaints and anamnesis data, examination of the patient, additional laboratory and instrumental examination, which includes the study of the thyroid status, possible autoaggression, analysis of metabolic processes, assessment of pathomorphological changes in the thyroid gland.

Clinical, etiopathogenic, and therapeutic aspects of KID syndrome.

Keratitis-ichthyosis-deafness (KID syndrome) is a syndromes ichthyoses that is clinically and genetically heterogeneous requiring early and long-term multidisciplinary monitoring of affected individuals. A review of the clinical, etiopathogenic and therapeutic aspects is presented of this rare congenital ectodermal disorder.

Woodhouse-Sakati syndrome in a family is associated with a homozygous start loss mutation in the DCAF17 gene.

Woodhouse-Sakati syndrome (WSS) is a rare neuroendocrine and ectodermal disorder inherited in an autosomal recessive pattern. The syndrome presents prominent clinical features, including alopecia, neuroendocrine defects, neurological findings and progressive hearing loss. The condition results from mutations in the DCAF17 gene. To search for the underlying genetic defect in a Pakistani family with WSS phenotypes. Whole exome sequencing was used to search for the disease-causing variant. Analysis of the exome data revealed a start loss sequence variant (c.1A>G, p.M1?) in DCAF17. This variant is predicted to abolish translation of the DCAF17 polypeptide. To our knowledge, this is the first start loss variant identified in the DCAF17.

Novel contiguous gene deletion in peruvian girl with Trichothiodystrophy type 4 and glutaric aciduria type 3

Trichothiodystrophy type 4 is a rare autosomal recessive and ectodermal disorder, characterized by dry, brittle, sparse and sulfur-deficient hair and other features like intellectual disability, ichthyotic skin and short stature, caused by a homozygous mutation in MPLKIP gene. Glutaric aciduria type 3 is caused by a homozygous mutation in SUGCT gene with no distinctive phenotype. Both genes are localized on chromosome 7 (7p14).We report an 8-year-old female with short stature, microcephaly, development delay, intellectual disability and hair characterized for dark, short, coarse, sparse and brittle associated to classical trichorrhexis microscopy pattern. Chromosome microarray analysis showed a 125 kb homozygous pathogenic deletion, which includes genes MPLKIP and SUGCT, not described before. This is the first case described in Peru of a novel contiguous gene deletion of Trichothiodystrophy type 4 and Glutaric aciduria type 3 performed by chromosome microarray analysis, highlighting the contribution and importance of molecular technologies on diagnosis of rare genetic conditions.

Orodental manifestations of enamel renal syndrome in siblings: A rare case report

Amelogenesis imperfecta (AI) is a group of hereditary disorders that affect the quality and/or quantity of dental enamel. Hypoplastic AI can occur per se or in a variety of ectodermal syndromes and metabolic disorders. Enamel renal syndrome (ERS) is a very rare disorder associating hypoplastic AI with nephrocalcinosis. Since nephrocalcinosis is often asymptomatic, the orodental findings and dental radiographic features play a key role in the diagnosis of this extremely rare inherited disorder. This paper describes the orodental manifestations of ERS in siblings who were born of consanguineous parents.

The carboxy-terminus of p63 links cell cycle control and the proliferative potential of epidermal progenitor cells.

The transcription factor p63 (Trp63) plays a key role in homeostasis and regeneration of the skin. The p63 gene is transcribed from dual promoters, generating TAp63 isoforms with growth suppressive functions and dominant-negative ΔNp63 isoforms with opposing properties. p63 also encodes multiple carboxy (C)-terminal variants. Although mutations of C-terminal variants have been linked to the pathogenesis of p63-associated ectodermal disorders, the physiological role of the p63 C-terminus is poorly understood. We report here that deletion of the p63 C-terminus in mice leads to ectodermal malformation and hypoplasia, accompanied by a reduced proliferative capacity of epidermal progenitor cells. Notably, unlike the p63-null condition, we find that p63 C-terminus deficiency promotes expression of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1) (Cdkn1a), a factor associated with reduced proliferative capacity of both hematopoietic and neuronal stem cells. These data suggest that the p63 C-terminus plays a key role in the cell cycle progression required to maintain the proliferative potential of stem cells of many different lineages. Mechanistically, we show that loss of Cα, the predominant C-terminal p63 variant in epithelia, promotes the transcriptional activity of TAp63 and also impairs the dominant-negative activity of ΔNp63, thereby controlling p21(Waf1/Cip1) expression. We propose that the p63 C-terminus links cell cycle control and the proliferative potential of epidermal progenitor cells via mechanisms that equilibrate TAp63 and ΔNp63 isoform function.

Can Milk Teeth be Impacted? Why Not: A Case of Six Impacted Primary Teeth

ABSTRACT%The prevalence rate of impacted primary teeth is rare, still we can see impacted teeth in ectodermal dysplasia anhydrotic (EDA), endocrine deficiencies, metabolic disorders and local factors like cysts, tumors, trauma and thickened overlying bone or soft tissue. In cases of EDA, delayed tooth eruption is one of the characteristic finding.Present case report related to a rare case of primary teeth impaction of a 3 years old male child along with EDA. Intraoral examination and radiographs confirmed impacted primary maxillary and mandibular centrals and mandibular lateral incisors. Treatment carried out was surgical exposure of impacted primary teeth, then after patient was followed up for regular visits to check eruption status of the teeth.How to cite this article: Yadiki JV, Kategari YB, Chada P, Vallakatla V. Can Milk Teeth be Impacted? Why Not: A Case of Six Impacted Primary Teeth. Int J Clin Pediatr Dent 2014; 7(3):220-222.

Clouston's Syndrome—A Case Report

Clouston's syndrome or Hidrotic ectodermal dysplasia is an autosomal-dominant inherited rare ectodermal dysplastic disorder characterized by triad of nail dystrophy, palmoplantar keratoderma, and alopecia. Here we present a case report of clouston syndrome with classical triad along with hypodontia, microdontia and severe mental retardation. This is being reported because of it is rarity.

A Research of Pachyonychia Congenita Type 1 and Literature Analysis

Pachyonychia congenital (PC), consist of a group of rare autosomal-dominant ectodermal disorders. Symmetrically thickened, dystrophic fingernails and toenails are the defining characteristic of pachyonychia congenita. There are two main clinical subtypes of pachyonychia congenita: Pachyonychia congenita-1 and pachyonychia congenita-2. Pachyonychia congenita-U is another subtypes of pachyonychia congenita, where either a mutation has not been found or has not been investigated. Objectives: The present aim was to indentify the mutation of keratin 6a or keratin 16 gene in the pachyonychia congenita patient. Methods: The proband, her parents and 100 unrelated controls were subjected to mutation detection in keratin 6a or keratin 16 gene. Direct sequencing of all PCR products of the whole coding regions of keratin 6a or keratin 16 was performed to identify the mutation. Results: No mutation was found in keratin 6a or keratin 16 in the proband, her parents, and 100 unrelated and unaffected people. Conclusion: This study reported a Chinese female affected with pachyonychia congenita-1 without mutation in keratin gene.

Nadir Bir Genetik Hastalık: Pakionişya Konjenita Tip 2

Pachyonychia congenita (PC) is a rare inherited ectodermal disorder characterized mainly by hypertrophic nail dystrophy and focal palmoplantar keratoderma. Pachyonychia congenita can be divided into two main clinical subtypes, PC-1 and PC-2, which are correlated with mutations in keratins. Although the most prominent clinical feature of both PC subtypes is hypertrophic nail dystrophy, oral leukokeratosis is usually seen in PC-1 while PC-2 generally presents with nail dystrophy, widespread steatocystomas, natal teeth and hair abnormalities. We report a patient with PC type II presenting with the classical features of the disease that had been transmitted for four generations.

Ectodermal dysplasia-related disorders of the respiratory tract

Ectodermal dysplasia syndromes are frequently associated with manifestations of disease in the respiratory tract. Commonly, patients present with signs and symptoms of sinusitis, otitis media with effusion, bronchitis or pneumonia. The etiologic bases for these disorders are multi-factorial, including abnormal mucous production, anatomical variations, atopy and immune function abnormalities. This presentation reviews the current literature on the clinical manifestations and potential underlying causes for the noted increase in morbidity due to respiratory disease in the ectodermal dyplasia syndromes.

Photosensitive Trichothiodystrophy with Complex Cerebral Abnormalities

Aims: Trichothiodystrophy (TTD) is a rare ectodermal disorder with congenital hair dysplasia and autosomal recessive inheritance. Tiger tail banding under polarized light and low sulfur content of hair plus trichoschisis are pathognomic for this disorder. Most mutations are found in the ERCC2/XPD and ERCC/XPB gene in the long arm of chromosome 19. In the case of photosensitivity, the disease is typically associated with additional DNA repair defects which can be classified by distinct mutations.