Cutis Congenita Research Articles

Case Report: Alpha6 Integrin Disorder Presenting in Childhood with Nail Dysplasia and Onycholysis But No History of Fragile or Bullous Skin Changes

AbstractWe report a 7-year-old girl born with pyloric atresia but without congenital epidermolysis bullosa or skin fragility. Nail dysplasia developed at age 8 months and throughout childhood she suffered from onycholysis and mild nail hypertrophy. Whole-exome sequencing demonstrated biallelic mutations in alpha6 integrin (ITGA6): p. Q139* and R153W. ITGA6 normally forms a protein heterodimer with beta4 integrin (ITGB4), and this dimer participates in anchoring the basal skin cells to the extracellular matrix. Biallelic mutations in each gene are well known to cause epidermolysis bullosa and pyloric atresia. However, this child had ostensibly normal skin without any evidence of skin fragility. In a literature search, we identified 11 cases involving ITGA6 mutations, and all had epidermolysis skin changes. Thus, this case adds to the reported phenotype of ITGA6 disease since it is the first to show absence of an epidermolysis bullosa phenotype in the setting of pyloric atresia and nail dysplasia.

Bullous aplasia cutis congenita: A rare entity in the paradigm of congenital skin defect disorder

Bullous aplasia cutis congenita: A rare entity in the paradigm of congenital skin defect disorder

Highlights of Gene and Cell Therapy for Epidermolysis Bullosa and Ichthyosis.

Advancements in the molecular genetics of epidermolysis bullosa (EB) and ichthyosis, two rare inherited skin conditions, have enabled the identification of genetic variants that cause these diseases. Alongside technological advancements in genetic medicine, the identification of variants causal of these rare skin conditions has led to preclinical research and the clinical development of various in vivo and ex vivo gene and cell therapies for their treatment. Gene and cell therapies are considered to be the most advanced forms of personalized medicine, demonstrating safety and efficacy in numerous rare diseases. Although the orphan drug development boom has resulted in regulatory approval of multiple gene and cell therapies for various rare conditions, the application of these modalities to rare inherited skin conditions remains limited. Nonetheless, there are successful examples of both in vivo gene therapy- and ex vivo cell therapy-based approaches developed to treat EB and ichthyosis. This review highlights preclinical research and the clinical development of gene and cell therapies for multiple subtypes of these two devastating congenital skin conditions, including a gene therapy recently approved by the U.S. Food and Drug Administration for the treatment of recessive dystrophic EB.

Skin Development and Disease: A Molecular Perspective.

Skin, the largest organ in the human body, is a crucial protective barrier that plays essential roles in thermoregulation, sensation, and immune defence. This complex organ undergoes intricate processes of development. Skin development initiates during the embryonic stage, orchestrated by molecular cues that control epidermal specification, commitment, stratification, terminal differentiation, and appendage growth. Key signalling pathways are integral in coordinating the development of the epidermis, hair follicles, and sweat glands. The complex interplay among these pathways is vital for the appropriate formation and functionality of the skin. Disruptions in multiple molecular pathways can give rise to a spectrum of skin diseases, from congenital skin disorders to cancers. By delving into the molecular mechanisms implicated in developmental processes, as well as in the pathogenesis of diseases, this narrative review aims to present a comprehensive understanding of these aspects. Such knowledge paves the way for developing innovative targeted therapies and personalised treatment approaches for various skin conditions.

An update on the status of direct testing for Treponema pallidum subspecies pallidum for the laboratory diagnosis of syphilis in Canada

Background: In Canada, the recent resurgence of infectious syphilis and rising rates of congenital syphilis have renewed interest in direct detection methods for the laboratory diagnosis of syphilis. The Canadian Public Health Laboratory Network (CPHLN) has previously published a series of guidelines for the diagnosis of syphilis in Canada, including the use of direct tests. In the decade since those guidelines were published, laboratory practice has changed. Methods: This systematized review combined a literature search (MEDLINE) of methods for direct detection of Treponema pallidum with an informal survey of current testing practices in Canadian public health laboratories. Results: Direct testing methods have favourable performance characteristics for detection of early syphilis and congenital cases. Although no government licensed commercial nucleic acid amplification test (NAAT) for syphilis is available in Canada, laboratory-developed tests have been implemented in multiple Canadian jurisdictions. Clinical specimens with the highest yield of positive NAAT results for syphilis include genital ulcers, skin lesions, and oral swabs from primary and secondary syphilis patients. For investigation of congenital syphilis, nasopharyngeal, placenta, umbilical cord, blood, and skin lesions are specimens of choice for direct detection of T. pallidum by NAAT. Conclusions: This update on the status of direct testing highlights the importance of NAAT for the detection of T. pallidum, the reduced role of microscopy-based methods, and the emergence of DNA and genome sequencing as tools for phylogenetic analysis and molecular epidemiology.

PA08 Extensive congenital epidermal skin loss with sparing of the palms, soles and head: strikingly similar appearances in four patients with neonatal herpes simplex infection

PA08 Extensive congenital epidermal skin loss with sparing of the palms, soles and head: strikingly similar appearances in four patients with neonatal herpes simplex infection

O13 Benchmarking a human pluripotent stem cell-derived hair-bearing skin organoid model to prenatal skin

Abstract Introduction and aims Molecular regulation of mammalian skin development has been largely derived from murine studies. The lack of human studies stems primarily from the difficulties in prenatal human skin access. There is an important need to study human prenatal skin owing to the notable differences between human and mouse skin and the paucity of mechanistic understanding of congenital skin disorders. Methods We assembled the first comprehensive multiomic reference atlas of prenatal human skin (21 samples from 7 to 16 postconception weeks), combining single-cell (235 201 cells) and spatial transcriptomic data. We followed 84 skin organoids (SkOs) using single-cell analysis over a 5-month culture period and characterized the spatial organization of the skin in mature SkOs. Prenatal skin, SkO and any relevant pre-existing single-cell RNA-Seq datasets were integrated into the analysis. Cell–cell interactions and cell-lineage determination were explored using CellPhoneDB and trajectory inferences. We evaluated the differentiation trajectory alignment between prenatal skin and SkO using the Genes2Genes analysis. Results Our findings reveal predicted factors regulating the epithelial–mesenchymal crosstalk during human hair follicle formation; progressive expression of scar-promoting genes in later gestation, potentially contributing to scarless healing properties of human prenatal skin observed during the early stages of gestation and expression of genes causing genetic skin disorders in the same cell types in prenatal human skin and SkO. We also found that SkOs morphologically recapitulate human skin development from early (periderm formation and shedding) to late (cornification and hair follicle formation) stages. We also demonstrated that SkO and prenatal skin mesenchyme differentiation into hair follicle dermal condensate and dermal papilla is highly conserved at the cellular and molecular level. Conclusions SkOs faithfully recapitulate human prenatal skin development and are a valuable model for mechanistic studies on skin development including hair follicle biology and congenital skin disorders.

Congenital localized cutaneous Langerhans cell histiocytosis in a Holstein calf.

Distinct solitary dermal nodules, either covered by an alopecic, or sometimes ulcerated, epidermis, were noticed on the head of a stillborn Holstein calf. The head was submitted for autopsy, and the nodules were found to consist of homogeneous, diffuse pale-yellow, soft-tissue masses with distinct margins that elevated the epidermis above the adjacent skin. Histologically, the dermal nodules were well-delineated on the deep margin approaching the cutaneous muscle and consisted of perivascular neoplastic infiltrates of round cells that in some places coalesced into sheets that extended into the dermis and subcutis. Neoplastic cells separated adnexa and collagen. Immunohistochemistry revealed intense tumor cell expression of vimentin, Iba1, E-cadherin, and CD204; expression of CD18 was faint. The masses were diagnosed as Langerhans cell histiocytosis. Congenital cutaneous Langerhans cell histiocytosis has not been reported previously in cattle, to our knowledge, and should be included in the differential diagnosis of congenital nodular skin lesions.

Amniotic membrane dressings for treatment of aplasia cutis in newborns.

Aplasia cutis congenita (ACC) is a rare congenital skin defect characterized by a focal or extensive absence of the epidermis, dermis, and occasionally, subcutaneous tissue. When the wound caused by this defect is wide or deep, various treatments are used, including skin grafting. The amniotic membrane (AM) is a biological dressing that facilitates re-epithelialization as it contains mesenchymal cells and numerous growth factors. To report the efficacy of AM dressings in treating the skin defects of ACC. This study was conducted on five neonates diagnosed with ACC born between 2018 and 2022, referred to the Children's Medical Center in Tehran, Iran. AM dressings were applied on wounds larger than 1 cm2. The wounds were assessed weekly and, if required, an additional AM dressing was applied. The skin defects gradually re-epithelialized after application of the AM. The complete healing process took around 3.5 weeks on average. No hypertrophic scarring was observed. The application of AM dressing resulted in satisfactory cosmetic outcomes, with no hypertrophic scar formation. Complete healing occurred in all cases except one. The length of the hospital stay ranged from 2 to 6 weeks, depending on the size of the wound.

Term Neonate Born With Right Upper Extremity Skin Necrosis at Birth: A Case Report.

Congenital skin and soft tissue necrosis is a rare condition associated with significant morbidity and mortality in neonates. The authors treated a neonate born with significant skin necrosis of the right forearm. The case report is followed by a literature review and discussion of previously published reports of neonatal skin necrosis. A term female neonate was admitted to our hospital at 24 h of age for skin necrosis of the right forearm with sloughing and edema below the right elbow and contractures of her fingers. Topical treatment with cleansing and antibiotic application was initiated. The LUNA florescent microangiography showed superficial perfusion defects in the arm and dorsum of the hand along with overt ischemia over the dorsal aspect of the forearm. She was treated with intravenous antibiotics following a sepsis evaluation. Subsequently, she developed hypotension treated with fluid boluses, dopamine, and stress dose steroids. Concerns of wound infection and sepsis led to debridement of the necrotic area within the first 24 h post-admission. Wet-to-dry dressing changes using Vashe wound solution were begun postoperatively.; followed by placement of Integra on postoperative day-of-life (DOL) 7; dressing takedown on DOL 12; and autografting of the right hand and forearm with disarticulation of the 4th distal interphalangeal joints and right 5th distal interphalangeal transection on DOL 24. Postoperative dressing care was continued during the remainder of the hospital stay, she remained stable without any further complications and was discharged home on DOL 34 with outpatient clinic follow-up.

Understanding the effects of per- and polyfluoroalkyl substances on early skin development: Role of ciliogenesis inhibition and altered microtubule dynamics

Per- and polyfluoroalkyl substances (PFAS) are a class of highly stable chemicals, widely used in everyday products, and widespread in the environment, even in pregnant women. While epidemiological studies have linked prenatal exposure to PFAS with atopic dermatitis in children, little is known about their toxic effects on skin development, especially during the embryonic stage. In this study, we utilized human embryonic stem cells to generate non-neural ectoderm (NNE) cells and exposed them to six PFAS (perfluorooctanoic acid (PFOA), undecafluorohexanoic acid (PFHxA), heptafluorobutyric acid (PFBA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS) and perfluorobutyric acid (PFBS)) during the differentiation process to assess their toxicity to early skin development. Our results showed that PFOS altered the spindle-like morphology of NNE cells to a pebble-like morphology, and disrupted several NNE markers, including KRT16, SMYD1, and WISP1. The six PFAS had a high potential to cause hypohidrotic ectodermal dysplasia (HED) by disrupting the expression levels of HED-relevant genes. Transcriptomic analysis revealed that PFOS treatment produced the highest number (1156) of differentially expressed genes (DEGs) among the six PFAS, including the keratinocyte-related genes KRT6A, KRT17, KRT18, KRT24, KRT40, and KRT81. Additionally, we found that PFOS treatment disturbed several signaling pathways that are involved in regulating skin cell fate decisions and differentiation, including TGF-β, NOTCH, Hedgehog, and Hippo signaling pathways. Interestingly, we discovered that PFOS inhibited, by partially interfering with the expression of cytoskeleton-related genes, the ciliogenesis of NNE cells, which is crucial for the intercellular transduction of the above-mentioned signaling pathways. Overall, our study suggests that PFAS can inhibit ciliogenesis and hamper the transduction of important signaling pathways, leading potential congenital skin diseases. It sheds light on the underlying mechanisms of early embryonic skin developmental toxicity and provides an explanation for the epidemiological data on PFAS. Environmental implicationWe employed a model based on human embryonic stem cells to demonstrate that PFOS has the potential to elevate the risk of hypohidrotic ectodermal dysplasia. This is achieved by targeting cilia, inhibiting ciliogenesis, and subsequently disrupting crucial signaling pathways like TGF-β, NOTCH, Hedgehog, and Hippo, during the early phases of embryonic skin development. Our study highlights the dangers and potential impacts of six PFAS pollutants on human skin development. Additionally, we emphasize the importance of closely considering PFHxA, PFBA, PFHxS, and PFBS, as they have shown the capacity to modify gene expression levels, albeit to a lesser degree.

Gross motor development in children with epidermolysis bullosa.

Epidermolysis bullosa (EB) is a group of rare, congenital skin disorders, characterized by skin fragility and formation of blisters. The gross motor outcomes of children with EB are not known. The primary objective of the study was to measure the proportion of gross motor delay in children with EB. The secondary objectives were to measure the difference in gross motor outcomes between EB sub-types and change in gross motor outcomes over time. Children with EB, aged between one month and five and a half years of age, attending the Sydney Children's Hospital, Epidermolysis Bullosa Clinic, were eligible. Carers completed Ages and Stages Questionnaires, Third Edition, on behalf of their children. Questionnaires were scored, and outcomes were compared to age-expected norms. There were 24 participants to complete a questionnaire. Eleven participants completed additional questionnaires over the 24 month study duration. The proportion of children with EB with gross motor delay was greater than age-expected norms (29.17% vs. 2.5%). The delay occurred in children with recessive dystrophic (80%) and epidermolysis bullosa simplex (33.33%) sub-types, but not dominant dystrophic (0%). No children with Junctional EB or Kindler EB joined this study. This study demonstrates a difference in gross motor outcomes in children with EB. Children with recessive dystrophic and epidermolysis bullosa simplex should be prioritized for monitoring of, and intervention for, gross motor outcomes through multidisciplinary care. Further research investigating long-term outcomes for children with EB and the effectiveness of interventions would be beneficial.

Case report: Interleukin-17 targeted biological therapy in netherton syndrome

Netherton syndrome (NS) is rare and multisystemic congenital skin disorder classically distinguied as a triad of congenital ichthyosiform erythroderma, trichorrhexis invaginata (TI), and an atopic diathesis. Recent advances in pathogenesis have explored the role of IL-23/Th17 pathway in NS. Herein, we present a 17 years old girl harbouring homozygous four base pair deletion in exon 26 of the SPINK5 gene, presented with pruritus, scaling, dry skin and generalized eczematous lesions. She was administered anti IL17A (subcutaneous secukinumab) therapy. The treatment was well tolerated and resulted in a favourable clinical response, reduction of the IL17A gene expression and CD4 + Th17 cell population after 6 months which revealed an abrogation of Th17-skewing during therapy.

Characterization of Patient-Derived GNAQ Mutated Endothelial Cells from Capillary Malformations

Capillary malformations (CM) (port-wine stains) are congenital skin lesions that are characterized by dilated capillaries and postcapillary venules. CMs are caused by altered functioning of the vascular endothelium. Somatic genetic mutations have predominantly been identified in the endothelial cells of CMs, providing an opportunity for the development of targeted therapies. However, there is currently limited in-depth mechanistic insight into the pathophysiology and a lack of preclinical research approaches. In a monocenter exploratory study of 17 adult patients with CMs, we found somatic sequence variants in the GNAQ (p.R183Q, p.R183G, or p.Q209R) or GNA11 (p.R183C) genes. We applied an endothelial-selective cell isolation protocol to culture primary endothelial cells from skin biopsies from these patients. We successfully expanded patient-derived cells in culture in 3 of the 17 cases while maintaining endothelial specificity as demonstrated by vascular endothelial-cadherin immunostainings. In addition, we tested the angiogenic capacity of endothelial cells from a patient with a GNAQ (p.R183G) sequence substitution. These proof-of-principle results reveal that primary cells isolated from CMs may represent a functional research model to investigate the role of endothelial somatic mutations in the etiology of CMs, but improved isolation and culture methodologies are urgently needed to advance the field.

Sebaceous gland diseases: clinical picture risk factors and treatment

Sebaceous glands are present in almost every part of the skin or body except the palms and soles, and the primary function of these glands involves the generation of sebum. However, numerous diseases, both benign and malignant, have been linked to abnormal sebaceous gland activity. Sebaceous gland disorders are a class of widespread dermatological conditions with numerous aetiologies. Diseases in which the primary involvement is associated with sebaceous glands comprise conditions such as steatocystoma, sebaceous gland hyperplasia, sebaceoma, sebaceous adenoma, nevus sebaceous, and sebaceous carcinoma. Additionally, sebaceous glands play a secondary role in androgenic alopecia, acne vulgaris, and seborrheic dermatitis. Steatocystoma simplex or multiplex is a non-cancerous growth that arises either sporadically or through inheritance in an autosomal dominant manner, originating from mutations in the keratin 17 gene. Sebaceous gland hyperplasia refers to the non-malignant enlargement of sebaceous lobules, which presents as papules exhibiting a yellowish color and telangiectatic features. Common treatment methods for sebaceous gland hyperplasia include the application of topical retinoids, the administration of oral isotretinoin, and the surgical removal of the affected lesions. Nevus sebaceus also referred to as a nevus of Jadassohn or organoid nevus, represents a congenital skin hamartoma originating from mosaic mutations. While acne vulgaris is a highly prevalent and complex disorder influenced by various factors, one of which is the increased production of sebum. Acne can be managed using approaches like topical or systemic antibiotics, hormonal therapies, cautery-based lesion removal, and phototherapy techniques such as laser treatment. The purpose of this research is to review the sebaceous gland diseases: clinical picture, risk factors, and treatment.

Clinical characteristics of infants hospitalized with early congenital syphilitic nephropathy: a single-center retrospective cross-sectional study in China

BackgroundEarly studies claimed that early congenital syphilitic (CS) nephropathy was rare, and systematic studies about this disease are absent, which may lead to poor awareness of early CS nephropathy in clinicians and result in misdiagnosis and poor patient prognosis. The present study systematically and comprehensively analyzes the clinical characteristics of infants with early CS nephropathy hospitalized in Beijing Ditan Hospital, an infectious disease hospital in China in order to improve the understanding and management of this disorder.MethodsData of the children with early CS from July 1, 2008, to December 31, 2021, were collected from the electronic medical record system of the hospital. Each patient’s demographic characteristics, clinical history, mother’s history of syphilitic infection, and laboratory values were extracted. The patients were enrolled to either the nephropathy group or the non-nephropathy group depending on diagnosis. Descriptive statistics was used to report basic demographics, clinical and laboratory test values, and variables were compared between the two groups by nonparametric tests, t test or χ2 tests.ResultsOf the 122 children with early CS enrolled, 24(19.7%) were diagnosed with early CS nephropathy. All of the children with CS nephropathy were young infants < 6 months old. A majority of them showed typical congenital syphilitic skin lesions, but a quarter of them did not have skin lesions. Compared with non-nephropathic children with early CS, those with nephropathy had higher frequency of hepatosplenomegaly, fever, edema, gastrointestinal (GI) symptoms, and anemia, as well as decreased C3 levels. Urinalysis results showed hematuria in all patients with early CS nephropathy, with proteinuria and renal function impairment in 91.7% and 12.5% of the patients, respectively. Nephritic-type nephrotic syndrome and glomerulonephritis were diagnosed in 45.8% and 54.2% of these patients, respectively. All infants with CS nephropathy were cured or improved after appropriate treatments.ConclusionInfants with early CS nephropathy often presented with nephritic-type nephrotic syndrome or glomerulonephritis, and the typical skin lesions, fever, hepatosplenomegaly, and edema, etc., were its common clinical presentations, and these characteristics could help with the diagnosis. But for infants with nephropathy who did not have typical clinical presentations, CS should also be screened as an important etiology to avoid misdiagnosis.

Association of Congenital Cutaneous Aplasia and Congenital Bullous Epidermolysis Bart Syndrome: A Case Report

Background: Bart syndrome is a rare neonatal condition that combines congenital skin aplasia and congenital bullous epidermolysis. The clinical diagnosis is straightforward, but its management is intricate, and the extensive forms pose a true therapeutic challenge. We report a case of a newborn diagnosed in the pediatric intensive care unit at the Military Hospital of Rabat. Case Description: A female newborn from a well-followed pregnancy, delivered via cesarean section due to a narrow pelvis. The Apgar score was 10/10, and the birth weight was 2600g. The mother had been diagnosed with hypothyroidism during pregnancy and was taking synthetic antithyroid medication. The infant was admitted to the neonatal unit at 2 hours of life due to multiple skin ulcers noted at birth. Clinical examination revealed bilateral and symmetrical cutaneous aplasia affecting almost the entirety of both lower limbs. The vascular network was clearly visible. Other parts of the skin showed areas of skin fragility and some flaccid blisters. A clinical diagnosis of Bart syndrome associated with bullous epidermolysis was made. Hydration and antibiotic coverage were initiated, leading to good clinical improvement. Discussion: Bart syndrome represents clinical features of aplasia cutis congenita associated with congenital epidermolysis bullosa suspected by areas of fragility and sometimes by blisters. All types of congenital epidermolysis bullosa can be associated with this syndrome. Clinical diagnosis is usually easy, but the therapeutic management is difficult, and the prognosis is poor.

De Novo Mutation in KRT1 Leads to Epidermolytic Palmoplantar Keratoderma: from Chinese Traditional Treatment to Prenatal Diagnosis Using Whole-Exome Sequencing-Plus.

Congenital skin disorders are a class of complex genetic diseases that are difficult to diagnose and treat. We developed trio whole-exome sequencing-plus (WES-plus) for detecting de novo mutations and evaluated the use of traditional Chinese medicine (TCM) for treating congenital skin disorders. In this study, we successively performed panel-based next-generation sequencing (NGS) and Trio WES-plus in a child with frequent large blisters. Panel-based NGS revealed no pathogenic mutations. Trio WES-plus for resequencing based on cutaneous keratosis of the palms and feet detected a missense mutation (c.1436T>A, p.Ile479Asn) in the coding region of KRT1 in the child but not in his parents. Following prenatal diagnosis, a healthy second baby without the mutation was born. The disease symptoms of epidermolytic palmoplantar keratoderma (EPPK) application were improved by TCM and Western medicine. Our study revealed the pathogenicity of a de novo mutation in human KRT1, which expands the mutation spectrum of EPPK. Trio WES-plus is useful for diagnosing genetic diseases and providing genetic guidance from prenatal diagnosis to treatment.

CLINICAL AND MOLECULAR GENETIC ASPECTS OF STRÜMPEL'S HEREDITARY SPASTIC PARAPLEGIA IN UZBEKISTAN

The research work is based on a prospective and retrospective observation of 95 patients with hereditary spastic paraplegia (HSP), who constituted the main group. Among the examined patients of the main group, there were 58 (61%) boys and 37 (39%) girls. The average age in the main group was 7.8±0.48 years. All patients complained of limb weakness of varying degrees, gait disturbance. The age gradation of the patients ranged from 2 years to 15 years. When studying the pedigrees of patients with HSP, in 34 cases the marriage was related, which amounted to 35.7%. It was found that in 48% of cases (27 families) there were patients with a similar disease in families. During the clinical and neurological examination of patients with HSP, we revealed both pure spastic paraplegia, characterized only by motor disorders (82.1%), and spastic paraplegia with complications (17.8%) in the form of impaired craniocerebral insufficiency, dysfunction of the pelvic organs (7.3%), a history of seizures (5.2%), polyneuropathies (11.5%), extraneural symptoms were detected in 3 (3.1%) patients, i.e. congenital skin changes in the form of ichthyosis. In 2 patients with uncomplicated HSP, whole genome sequencing in the SPAST/SPG4 gene was performed; in both cases, homozygous carriage of pathogenic autosomal dominant mutations chr2:32369901CAT&gt;C and c.1617-105 T&gt;C in the coding region of the SPG4 gene in exon 15 responsible for for the synthesis of the protein spastin in the nervous system.

Congenital skin aplasia associated with unilateral focal dermal hypoplasia

Congenital skin aplasia associated with unilateral focal dermal hypoplasia