Congenital nail abnormalities.

Congenital nail disorders are an uncommon presenting symptom which can be difficult to diagnose and manage. Nail diseases in the pediatric population differ from those in adults in terms of diagnosis, approach and management. In most cases, they do not require treatment and resolve with growth. Physicians need to be able to recognize them, to reassure the parents. The most frequently encountered pathologies associated with nail disorder are syndactyly, acrosyndactyly, symbrachydactyly, macrodactyly, Wassel I thumb duplication, Kirner's deformity and congenital onychodysplasia of the index finger. Treatment usually consists in surgical correction of the deformity. Nail malformation can also be an aspect of a systemic disease. It may provide a clue for screening, and should not be overlooked. Nail conditions can be the first sign of nail-patella syndrome, ectodermal dysplasia, dyskeratosis congenita, epidermolysis bullosa, pachyonychia congenita or lung disease. Medical treatment is therefore discussed on a case-by-case basis.

Like Father, Like Daughter - Ectodermal Dysplasia-Syndactyly Syndrome: A Case Report.

Ectodermal dysplasia-syndactyly syndrome 1 (EDSS1) is an exceedingly rare condition associated with mutations in the PVL4 gene. It is characterised by sparse, brittle hair, eyebrows and eyelashes, abnormal dentition and nails, along with bilateral cutaneous syndactyly involving the fingers and toes. We report a 2-year-old girl who presented to us with bilateral complete simple syndactyly of the third and fourth web spaces of the hands, along with bilateral syndactyly of both feet involving the second to fourth toes. Upon examination, sparse hair and eyebrows, along with abnormal dentition, were noted. Thorough clinical examination and genetic analysis were conducted on the affected child and her father, who exhibited similar clinical features. Genetic analysis revealed a homozygous nonsense mutation in the PVL4 gene in both individuals. According to the literature, EDSS1 has been reported in only 10 families worldwide, and there are no reported cases from India. Level of Evidence: Level V (Therapeutic).

Prevalence and Patient Characteristics of Ectodermal Dysplasias in Denmark.

Importance: Ectodermal dysplasias constitute a group of rare genetic disorders of the skin and skin appendages with hypodontia, hypotrichosis, and hypohidrosis as cardinal features. There is a lack of population-based research into the epidemiology of ectodermal dysplasias. Objective: To establish a validated population-based cohort of patients with ectodermal dysplasia in Denmark and to assess the disease prevalence and patient characteristics. Design, Setting, and Participants: This nationwide cohort study used individual-level registry data recorded across the Danish universal health care system to identify patients with ectodermal dysplasias from January 1, 1995, to August 25, 2021. A 3-level search of the Danish National Patient Registry and the Danish National Child Odontology Registry was conducted to identify patients with diagnosis codes indicative of ectodermal dysplasias; patients registered in the Danish RAREDIS Database, the Danish Database of Genodermatoses, and local databases were also added. The search results underwent diagnosis validation and review of clinical data using medical records. Of 844 patient records suggestive of ectodermal dysplasias, 791 patients (93.7%) had medical records available for review. Positive predictive values of the diagnosis coding were computed, birth prevalence was estimated, and patient characteristics were identified. Data analysis was performed from May 4 to December 22, 2023. Results: The identified and validated study cohort included 396 patients (median [IQR] age at diagnosis, 13 [4-30] years, 246 females [62.1%]), of whom 319 had confirmed ectodermal dysplasias and 77 were likely cases. The combined positive predictive value (PPV) for ectodermal dysplasia-specific diagnosis codes was 67.0% (95% CI, 62.7%-71.0%). From 1995 to 2011, the estimated minimum birth prevalence per 100 000 live births was 14.5 (95% CI, 12.2-16.7) for all ectodermal dysplasias and 2.8 (95% CI, 1.8-3.8) for X-linked hypohidrotic ectodermal dysplasias. A molecular genetic diagnosis was available for 241 patients (61%), including EDA (n = 100), IKBKG (n = 55), WNT10A (n = 21), TRPS1 (n = 18), EDAR (n = 10), P63 (n = 9), GJB6 (n = 9), PORCN (n = 7), and other rare genetic variants. Conclusions and Relevance: The findings of this nationwide cohort study indicate that the prevalence of ectodermal dysplasias was lower than previously reported. Furthermore, PPVs of the search algorithms emphasized the importance of diagnosis validation. The establishment of a large nationwide cohort of patients with ectodermal dysplasias, including detailed clinical and molecular data, is a unique resource for future research in ectodermal dysplasias.

A spectrum of TP63-related disorders with eight affected individuals in five unrelated families.

TP63-related disdorders broadly involve varying combinations of ectodermal dysplasia (sparse hair, hypohydrosis, tooth abnormalities, nail dysplasia), cleft lip/palate, acromelic malformation, split-hand/foot malformation/syndactyly, ankyloblepharon filiforme adnatum, lacrimal duct obstruction, hypopigmentation, and hypoplastic breasts and/or nipples. TP63-related disorders are associated with heterozygous pathogenic variants in TP63 and include seven overlapping phenotypes; Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC), Ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome 3 (EEC3), Limb-mammary syndrome (LMS), Acro-dermo-ungual-lacrimal-tooth syndrome (ADULT), Rapp-Hodgkin syndrome (RHS), Split-hand/foot malformation 4 (SHFM4), and Orofacial cleft 8. We report on five unrelated families with 8 affected individuals in which the probands presented with varying combinations of ectodermal dysplasia, cleft lip/palate, split-hand/foot malformation, lacrimal duct obstruction, and ankyloblepharon filiforme adnatum. The clinical diagnosis involved AEC syndrome (2 patients), EEC3 syndrome (2 patients), and a yet hitherto unclassified TP63-related disorder. Sanger sequence analysis of the TP63 gene was performed revealing five different variants among which four were novel and three were de novo. The identificated TP63 variants co-segregated with the other affected individuals in the families. The abnormalities of ectoderm derived structures including hair, nails, sweat glands, and teeth should alert the physician to the possibility of TP63-related disorders particularly in the presence of orofacial clefting.

Absent meibomian glands and cone dystrophy in ADULT syndrome: identification by whole exome sequencing of pathogenic variants in two causal genes TP63 and CNGB3.

BACKGROUND: Ectrodactyly is a rare congenital limb malformation characterized by a deep median cleft of the hand and/or foot due to the absence of central rays. It could be isolated or depicts a part of diverse syndromic forms. Heterozygous pathogenic variants in the TP63 gene are responsible for at least four rare syndromic human disorders associated with ectrodactyly. Among them, ADULT (Acro-Dermato-Ungual-Lacrimal-Tooth) syndrome is characterized by ectodermal dysplasia, excessive freckling, nail dysplasia, and lacrimal duct obstruction, in addition to ectrodactyly and/or syndactyly. Ophthalmic findings are very common in TP63-related disorders, consisting mainly of lacrimal duct hypoplasia. Absent meibomian glands have also been well documented in EEC3 (Ectrodactyly Ectodermal dysplasia Cleft lip/palate) syndrome but not in ADULT syndrome. METHODS: We report a case of syndromic ectrodactyly consistent with ADULT syndrome, with an additional ophthalmic manifestation of agenesis of meibomian glands. The proband, as well as her elder sister, presented with congenital cone dystrophy.The molecular investigation was performed in the proband using Whole Exome Sequencing. Family segregation of the identified variants was confirmed by Sanger sequencing. RESULTS: Two clinically relevant variants were found in the proband: the novel de novo heterozygous missense c.931A > G (p.Ser311Gly) in the TP63 gene classified as pathogenic, and the homozygous nonsense pathogenic c.1810C > T (p.Arg604Ter) in the CNGB3 gene. The same homozygous CNGB3 variation was also found in the sister, explaining the cone dystrophy in both cases. CONCLUSIONS: Whole Exome Sequencing allowed dual molecular diagnoses: de novo TP63-related syndromic ectrodactyly and familial CNGB3-related congenital cone dystrophy.

A case of MBTPS1-related disorder due to compound heterozygous variants in MBTPS1 gene: Genotype-phenotype expansion and the emergence of a novel syndrome.

MBTPS1 (NM_003791.4) encodes Site-1 protease, a serine protease that functions sequentially with Site-2 protease regulating cholesterol homeostasis and endoplasmic reticulum stress response. MBTPS1 pathogenic variants are associated with spondyloepiphyseal dysplasia, Kondo-Fu type (MIM:618392; cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome, and Silver-Russell-like syndrome). In this report, we describe a 14-year-old female with a complex medical history including white matter volume loss, early-onset cataracts, retrognathia, laryngomalacia, inguinal hernia, joint hypermobility, feeding dysfunction, and speech delay. Additionally, features of ectodermal dysplasia that she has include decreased sweating, heat intolerance, dysplastic nails, chronically dry skin, and abnormal hair growth issues. Exome sequencing analysis identified compound heterozygous variants in the MBTPS1 gene: c.2255G > T p.(Gly752Val) predicted to affect important function of the protein, which was inherited from the mother, and a splice site variant c.2831 + 5G > T, which was inherited from the father. The RNA-seq analysis of the splice variant showed skipping of exon 21, predicted to result in frameshifting p.(Ser901fs28*) leading to non-sense mediated decay. To our knowledge, only eight studies have been published that described the MBPTS1-related disorders. Interestingly, we observed the features of ectodermal dysplasia in our patient that further expands the phenotypic spectrum of MBTPS1 gene-related disorders.

The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic-Therapeutic Implications.

Cardiofaciocutaneous (CFC) syndrome is one of the rarest RASopathies characterized by multiple congenital ectodermal, cardiac and craniofacial abnormalities with a mild to severe ocular, gastrointestinal and neurological involvement. It is an autosomal dominant syndrome, with complete penetrance, caused by heterozygous pathogenic variants in the genes BRAF, MAP2K1/MEK1, MAP2K2/MEK2, KRAS or, rarely, YWHAZ, all part of the RAS-MAPK pathway. This pathway is a signal transduction cascade that plays a crucial role in normal cellular processes such as cell growth, proliferation, differentiation, survival, metabolism and migration. CFC syndrome overlaps with Noonan syndrome, Costello syndrome, neurofibromatosis type 1 and Legius syndrome, therefore making the diagnosis challenging. Neurological involvement in CFC is more severe than in other RASopathies. Phenotypic variability in CFC patients is related to the specific gene affected, without a recognized genotype-phenotype correlation for distinct pathogenic variants. Currently, there is no specific treatment for CFC syndrome. Encouraging zebrafish model system studies suggested that, in the future, MEK inhibitors could be a suitable treatment of progressive phenotypes of CFC in children. A multidisciplinary care is necessary for appropriate medical management.

[Ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome]. / Ectrodactylia, ectodermalis dysplasia, ajak- és szájpadhasadék szindróma.

The ectrodactyly-ectodermal dysplasia-clefting syndrome is an extremely rare genetic disorder that is inherited as an autosomal dominant trait, but can also occur sporadically. It is characterized by the triad of ectrodactyly (absence of fingers), ectodermal dysplasia and cleft lip and palate along with variable involvement of other organs. Both the ectodermal and mesodermal tissues may be affected resulting in a spectrum of phenotypes. Early diagnosis and treatment signify a unique challenge for those involved in the clinical management, while enable counseling and preparation of parents for the tasks ahead of them. In our report, we describe the case of a patient with sporadic EEC syndrome. In addition to the presentation of the complex phenotype along with the medical interventions, we summarize the most important characteristics of the disease, the diagnostic and therapeutic possibilities as well as the clinical significance of the accurate genetic verification. Using whole exome sequencing, we identified in the 3q28 chromosomal region a pathogenic mutation within the TP63 gene previously linked to the EEC3 phenotypes. The knowledge of pathogenic mutation provides the means to prenatal diagnostics or in vitro fertilization methods that allows us to minimize the possibility of inheriting the syndrome in the patient's offspring. By presenting our case, we aim to draw attention to this rare and disabling disease that requires the high quality works of a multidisciplinary team capable of ensuring good quality of life for the patient. Orv Hetil. 2023; 164(46): 1831-1837.

Aplasia Cutis Congenita of the Scalp with Bone Defect and Exposed Sagittal Sinus in Trisomy 13 Newborn - a Case Report.

Background: Aplasia cutis congenita is a heterogeneous disorders group with a rare reported incident of 0.5 to 1 in 10,000 births. ACC can be associated with physical defects or syndrome that may help in diagnosis, prognosis and further evaluation of the patient. Trisomy 13 is one of the most common fetal life limiting diagnosis which is associated with ACC of membranous type scalp. Objective: In this article, we report cases of aplasia cutis congenita of the scalp with dura and bone defect and exposed sagittal sinus in newborn diagnosed to have trisomy 13. It emphasizes the importance of ACC associated syndrome which is having high mortality prior to surgical intervention. Case presentation: The patient was born at 35 weeks of gestation. Her physical examination revealed a newborn girl with dysmorphic facial features including widely separated eyes, downward slanting of the palpebral fissure, microphthalmia, retrognathia, and low seat ears. She had area of loss of scalp skin and skull bone with seen brain tissue and sagittal sinus were exposed that was measure 6 by 5 cm in size. Additionally, she had a clenched fist and overlapping fingers and rocker bottom feet. Laboratory investigations include basic labs and the TORCH screen was negative. On the 9th day of life, a chromosomal analysis showed a female karyotype with three copies of chromosome number 13 in all 20 metaphase cells counts. Conclusion: The patient was managed conservatively. However, a multidisciplinary team agreed on do not resuscitate with no further surgical intervention as survival rate of trisomy 13 is poor.

Bullous Aplasia Cutis as a Presenting Sign of Encephalocele.

This case report describes a congenital cystic scalp nodule on a 2-week-old infant.

The Ectodermal Dysplasias-Burden of Disease Score: Development and Validation of an Ectodermal Dysplasia Family/Parental Burden Score.

Ectodermal dysplasias are genetic conditions affecting the development and/or homeostasis of 2 or more ectodermal derivatives, including hair, teeth, nails, and certain glands. No tool is available to assess the burden of ectodermal dysplasias and its multidimensional impact on patients and their families. This study developed and validated a familial/parental 19-item burden questionnaire designed specifically for ectodermal dysplasias. Each group of questions was linked to 1 of the following dimensions: (i) Impact of the disease on social life and hobbies; (ii) Future prospects; (iii) Restraint of the disease on outdoor activities; (iv) Financial burden of the disease; (v) Acceptance of the disease. Cronbach's alpha was 0.91 for the entire Ectodermal Dysplasias-Burden of Disease (ED-BD) scale, confirming excellent internal coherence. Intradimensional coherences all demonstrated excellent reliability (α > 0.76). The ED-BD questionnaire was highly correlated with the Short Form-12 and Psychological General Well Being Index validated questionnaires. Cultural and linguistic validation in US English was conducted. Development and validation of the questionnaire was based on data from patients with the 2 main ectodermal dysplasias subtypes. This ED-BD questionnaire represents the first specific assessment tool for evaluating the familial/parental burden of ectodermal dysplasias.

Acute Bacterial Meningitis and Petrous Apicitis in a Child with Aplasia Cutis Congenita: A Case Report.

Petrous apicitis and acute bacterial meningitis are uncommon in the present antibiotic era. The diagnosis of petrous apicitis is seldom considered unless there is cranial nerve palsy. A young child with aplasia cutis congenita presented with acute bacterial meningitis and an incidental opacified left mastoid in brain imaging. During the course, fever persisted, and high-resolution temporal bone imaging showed rapid progression to coalescent mastoiditis, petrous apicitis with erosions of tegmen tympani, and petrous apex. Other findings included bony dehiscences and thinning of left calvaria. Tympanomastoid exploration showed herniated brain and cerebrospinal fluid leak through tegmen tympani, which was closed with temporalis fascia graft. Herein, we report a rare presentation of petrous and tegmen erosion along with aplasia cutis congenita and discuss the challenges in diagnosis and management.

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.

Conservative Management of a Rare Entity-Aplasia Cutis Congenita: A Case Report.

Aplasia cutis congenita (ACC) is a rare entity characterized by a congenital localized absence of the skin, dermal appendages, and subcutaneous tissue. The cause of ACC is not clear, but inheritance is the most widely accepted cause. We report a rare case of a full-term (37 + 5 weeks) female newborn who showed complete absence of skin in localized areas of the upper and lower extremities. The patient was diagnosed with ACC associated with epidermolysis bullosa (EB; a disease that causes the skin to blister easily) and was initially treated using conservative measures. We applied mupirocin topical ointment and a nonocclusive polyester mesh impregnated with hydrocolloid and petroleum jelly daily. Complete healing of the affected areas occurred after 3 weeks. Managing patients with ACC is often challenging and based on the severity of the lesions, the approach may include both surgical and conservative treatment. Our case report suggests that a conservative approach can be effective for managing certain types of ACC and EB lesions. However, further research is warranted to better understand the pathogenesis and optimal management of this entity.

Novel insight into the ectodermal dysplasia 11A: Splicing variant of the EDARADD gene in a family with clinical variability and literature review.

Pathogenic variants in the EDARADD gene result in autosomal recessive and autosomal dominant ectodermal dysplasia. This article reports on the fourth family in the world with ectodermal dysplasia 11A (ECTD11A) cause from a novel splicing variant in the EDARADD gene, identified by whole exome sequencing and confirmed by Sanger sequencing. The proband and his mother were heterozygous for the detected variant (NM_145861.4:c.161-2A>T). The proband manifests unusual symptoms including hyperkeratotic plaques, slow-growing hair, recurrent infection, and pectus excavatum. His mother presents hypohidrosis, extensive tooth decay, fragile nails, and sparse hair. Further studies on ECTD11A patients could be useful to characterizing the phenotype features more precisely.

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.

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

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