577 results on '"Skin Diseases, Genetic genetics"'
Search Results
2. Arterial Tortuosity Syndrome.
- Author
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Van Berkel B and Sneyers V
- Subjects
- Humans, Joint Instability diagnostic imaging, Female, Male, Computed Tomography Angiography methods, Vascular Malformations diagnostic imaging, Arteries abnormalities, Arteries diagnostic imaging, Skin Diseases, Genetic diagnostic imaging, Skin Diseases, Genetic genetics
- Published
- 2024
- Full Text
- View/download PDF
3. Sodium-Dependent Multivitamin Transporter Deficiency.
- Author
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Jiang X, Wang H, and Lin Z
- Subjects
- Female, Humans, Male, Sodium metabolism, Vitamins administration & dosage, Symporters genetics, Erythema genetics, Skin Diseases, Genetic genetics, Skin Diseases, Genetic pathology
- Published
- 2024
- Full Text
- View/download PDF
4. Total pulmonary arterial reconstruction in a patient with arterial tortuosity syndrome affecting the pulmonary artery: a case report and review of the literature.
- Author
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Alshair FM, Alsulami AS, Shihata MS, Alradi OO, Debis RS, Baghaffar AH, and Fatani MA
- Subjects
- Humans, Female, Child, Preschool, Vascular Surgical Procedures methods, Stenosis, Pulmonary Artery surgery, Joint Instability surgery, Joint Instability genetics, Plastic Surgery Procedures methods, Arteries abnormalities, Pulmonary Artery surgery, Pulmonary Artery abnormalities, Vascular Malformations surgery, Vascular Malformations complications, Skin Diseases, Genetic surgery, Skin Diseases, Genetic complications, Skin Diseases, Genetic genetics
- Abstract
Background: Arterial tortuosity syndrome is a rare Autosomal recessive disease that leads to a loss of function of the connective tissues of the body, this happens due to a mutation in the solute carrier family 2 member 10 (SLC2A10) gene. ATS is more likely to occur in Large and medium-sized arteries including the aorta and pulmonary arteries. This syndrome causes the arteries to be elongated and tortuous, This tortuosity disturbs the blood circulation resulting in stenosis and lack of blood flow to organs and this chronic turbulent flow increases the risk of aneurysm development, dissection and ischemic events., Case Presentation: A 2 years old Arabian female child was diagnosed with ATS affecting the pulmonary arteries as a newborn, underwent a pulmonary arterial surgical reconstruction at the age of 2 years old due to the development of pulmonary artery stenosis with left pulmonary artery having a peak gradient of 73 mmHg with a peak velocity of 4.3 m/s and the right pulmonary artery having a peak gradient of 46 mmHg with a peak velocity of 3.4 m/s causing right ventricular hypertension. After surgical repair the left pulmonary artery has a peak pressure gradient of 20 mmHg, with the right pulmonary artery having a peak pressure gradient of 20 mmHg., Conclusion: ATS is a rare genetic condition that affects the great arteries especially the pulmonary arteries causing stenotic and tortuous vessels that may be central branches or distal peripheral branches that leads to severe right ventricular dysfunction and hypertension. We believe that surgical treatment provides the optimum outcomes when compared to transcather approaches especially when the peripheral arteries are involved. Some challenges and hiccups might occur, especially lung reperfusion injury that needs to be diagnosed and treated accordingly., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
5. Validating a Curvature-Based Marker of Cervical Carotid Tortuosity for Risk Assessment in Heritable Aortopathies.
- Author
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Lee JV, Huguenard AL, Dacey RG, Braverman AC, and Osbun JW
- Subjects
- Humans, Female, Male, Risk Assessment, Adult, Middle Aged, Risk Factors, Young Adult, Predictive Value of Tests, Aortic Dissection diagnostic imaging, Aortic Dissection diagnosis, Aortic Dissection surgery, Vascular Malformations diagnostic imaging, Vascular Malformations diagnosis, Imaging, Three-Dimensional, Reproducibility of Results, Skin Diseases, Genetic genetics, Skin Diseases, Genetic diagnostic imaging, Skin Diseases, Genetic diagnosis, Magnetic Resonance Angiography, Computed Tomography Angiography, Loeys-Dietz Syndrome genetics, Loeys-Dietz Syndrome complications, Loeys-Dietz Syndrome diagnosis, Loeys-Dietz Syndrome diagnostic imaging, Carotid Arteries diagnostic imaging, Carotid Arteries pathology
- Abstract
Background: Cervical arterial tortuosity is associated with adverse outcomes in Loeys-Dietz syndrome and other heritable aortopathies., Methods and Results: A method to assess tortuosity based on curvature of the vessel centerline in 3-dimensional space was developed. We measured cervical carotid tortuosity in 65 patients with Loeys-Dietz syndrome from baseline computed tomography angiogram/magnetic resonance angiogram and all serial images during follow-up. Relations between baseline carotid tortuosity, age, aortic root diameter, and its change over time were compared. Patients with unoperated aortic roots were assessed for clinical end point (type A aortic dissection or aortic root surgery during 4 years of follow-up). Logistic regression was performed to assess the likelihood of clinical end point according to baseline carotid tortuosity. Total absolute curvature at baseline was 11.13±5.76 and was relatively unchanged at 8 to 10 years (fold change: 0.026±0.298, P =1.00), whereas tortuosity index at baseline was 0.262±0.131, with greater variability at 8 to 10 years (fold change: 0.302±0.656, P =0.818). Baseline total absolute curvature correlated with aortic root diameter ( r =0.456, P =0.004) and was independently associated with aortic events during the 4-year follow-up (adjusted odds ratio [OR], 2.64 [95% CI, 1.02-6.85]). Baseline tortuosity index correlated with age ( r =0.532, P <0.001) and was not associated with events (adjusted OR, 1.88 [95% CI, 0.79-4.51]). Finally, baseline total absolute curvature had good discrimination of 4-year outcomes (area under the curve=0.724, P =0.014), which may be prognostic or predictive., Conclusions: Here we introduce cervical carotid tortuosity as a promising quantitative biomarker with validated, standardized characteristics. Specifically, we recommend the adoption of a curvature-based measure, total absolute curvature, for early detection or monitoring of disease progression in Loeys-Dietz syndrome.
- Published
- 2024
- Full Text
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6. Biallelic novel variants in ZNF469 causing Brittle Cornea Syndrome 1: a detailed report of an Indian patient.
- Author
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Gupta S, Kumari A, Daniel R, Yangzes S, Srivastava P, and Kaur A
- Subjects
- Humans, Female, Young Adult, India, Skin Abnormalities genetics, Skin Abnormalities diagnosis, Arachnodactyly genetics, Arachnodactyly diagnosis, Connective Tissue Diseases genetics, Connective Tissue Diseases diagnosis, Eye Abnormalities genetics, Eye Abnormalities diagnosis, High-Throughput Nucleotide Sequencing, Pedigree, Mutation, Exons genetics, Abnormalities, Multiple genetics, Ehlers-Danlos Syndrome genetics, Ehlers-Danlos Syndrome diagnosis, Skin Diseases, Genetic genetics, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic pathology, Transcription Factors genetics, Joint Instability genetics, Joint Instability diagnosis, Joint Instability congenital, Alleles
- Abstract
Background: Variations in ZNF469 have been associated with Brittle Cornea Syndrome that presents with bluish sclera, loss of vision after trivial trauma, arachnodactyly, and joint laxity., Materials and Methods: Detailed medical and family history, physical examination, and molecular analysis., Results: A 21-year-old female presented with bluish discoloration of sclera, diminution of vision following trivial trauma in childhood along with hearing loss and systemic features of arachnodactyly and joint laxity. Clinical diagnosis of brittle cornea syndrome was made which was molecularly proven using next-generation sequencing which identified compound heterozygosity in ZNF469 for pathogenic and likely pathogenic nonsense variants. One variant namely NM_001367624.2:c.5882dup was identified in the exon 3 which was novel and classified as likely pathogenic according to American College of Medical Genetics (ACMG) criteria for variant classification. Another variant NM_001367624.2:c.8992C>T in the exon 2 was classified as pathogenic for Brittle Cornea Syndrome 1., Conclusions: The report adds to the allelic heterogeneity in ZNF469 causative of Brittle Cornea Syndrome 1 and shall acquaint the physicians about this potentially vision threatening, underdiagnosed, rare syndrome.
- Published
- 2024
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7. An Eye into the Aorta: The Role of Extracellular Matrix Regulatory Genes ZNF469 and PRDM5 , from Their Previous Association with Brittle Cornea Syndrome to Their Novel Association with Aortic and Arterial Aneurysmal Diseases.
- Author
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Moore P, Wolf A, and Sathyamoorthy M
- Subjects
- Humans, Joint Instability genetics, Joint Instability congenital, Histone-Lysine N-Methyltransferase genetics, Corneal Dystrophies, Hereditary genetics, Corneal Dystrophies, Hereditary pathology, Ehlers-Danlos Syndrome genetics, Ehlers-Danlos Syndrome pathology, Aortic Aneurysm genetics, Mutation, DNA-Binding Proteins genetics, Skin Diseases, Genetic genetics, Skin Diseases, Genetic pathology, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Eye Abnormalities, Skin Abnormalities, Transcription Factors genetics, Transcription Factors metabolism, Extracellular Matrix metabolism, Extracellular Matrix genetics
- Abstract
The extracellular matrix is a complex network of proteins and other molecules that are essential for the support, integrity, and structure of cells and tissues within the human body. The genes ZNF469 and PRDM5 each produce extracellular-matrix-related proteins that, when mutated, have been shown to result in the development of brittle cornea syndrome. This dysfunction results from aberrant protein function resulting in extracellular matrix disruption. Our group recently identified and published the first known associations between variants in these genes and aortic/arterial aneurysms and dissection diseases. This paper delineates the proposed effects of mutated ZNF469 and PRDM5 on various essential extracellular matrix components, including various collagens, TGF-B, clusterin, thrombospondin, and HAPLN-1, and reviews our recent reports associating single-nucleotide variants to these genes' development of aneurysmal and dissection diseases.
- Published
- 2024
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8. Topical gene editing therapeutics using lipid nanoparticles: 'gene creams' for genetic skin diseases?
- Author
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Guri-Lamce I, AlRokh Y, Kim Y, Maeshima R, Graham C, Hart SL, McGrath JA, and Jacków-Malinowska J
- Subjects
- Humans, Gene Editing, CRISPR-Cas Systems, Gene Transfer Techniques, Nanoparticles, Skin Diseases, Genetic genetics, Liposomes
- Abstract
Patients living with inherited skin diseases have benefited from recent advances in DNA sequencing technologies that provide new or improved diagnostics. However, developing and delivering new treatments for the 'genodermatoses' remains challenging. The goal of creating topical preparations that can recover the inherent gene pathology remains largely aspirational. However, recent progress in two fields - the chemistry of topical delivery formulations (lipid nanoparticles) and the molecular biology of gene repair (CRISPR-Cas9, base and prime editing) - presents new opportunities to address this unmet need. In this review, we discuss how lipid nanoparticle delivery vehicles could be used to deliver gene-editing tools to formulate topical 'gene creams' suitable for the treatment of genodermatoses. We summarize the historical landscape of topical therapeutics and advances in gene editing that may herald an era of new therapies for patients with inherited skin disorders., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)
- Published
- 2024
- Full Text
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9. Medulloblastoma in a child with osteoma cutis - a rare association due to loss of GNAS expression.
- Author
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Suntharesan J, Lyulcheva-Bennett E, Hart R, Pizer B, Hayden J, and Ramakrishnan R
- Subjects
- Humans, Male, Infant, Prognosis, Bone Diseases, Metabolic genetics, Bone Diseases, Metabolic pathology, Mutation, GTP-Binding Protein alpha Subunits, Gs genetics, Chromogranins genetics, Medulloblastoma genetics, Medulloblastoma pathology, Ossification, Heterotopic genetics, Ossification, Heterotopic pathology, Skin Diseases, Genetic genetics, Skin Diseases, Genetic pathology, Skin Diseases, Genetic complications, Cerebellar Neoplasms genetics, Cerebellar Neoplasms pathology, Cerebellar Neoplasms complications
- Abstract
Objectives: Inactivating GNAS mutations result in varied phenotypes depending on parental origin. Maternally inherited mutations typically lead to hormone resistance and Albright's hereditary osteodystrophy (AHO), characterised by short stature, round facies, brachydactyly and subcutaneous ossifications. Paternal inheritance presents with features of AHO or ectopic ossification without hormone resistance. This report describes the case of a child with osteoma cutis and medulloblastoma. The objective of this report is to highlight the emerging association between inactivating germline GNAS mutations and medulloblastoma, aiming to shed light on its implications for tumor biology and promote future development of targeted surveillance strategies to improve outcomes in paediatric patients with these mutations., Case Presentation: A 12-month-old boy presented with multiple plaque-like skin lesions. Biopsy confirmed osteoma cutis, prompting genetic testing which confirmed a heterozygous inactivating GNAS mutation. At 2.5 years of age, he developed neurological symptoms and was diagnosed with a desmoplastic nodular medulloblastoma, SHH molecular group, confirmed by MRI and histology. Further analysis indicated a biallelic loss of GNAS in the tumor., Conclusions: This case provides important insights into the role of GNAS as a tumor suppressor and the emerging association between inactivating GNAS variants and the development of medulloblastoma. The case underscores the importance of careful neurological assessment and ongoing vigilance in children with known inactivating GNAS variants or associated phenotypes. Further work to establish genotype-phenotype correlations is needed to inform optimal management of these patients., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)
- Published
- 2024
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10. Founder Variants in KRT5 and POGLUT1 Are Implicated in Dowling-Degos Disease.
- Author
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Kumar S, Borisov O, Maj C, Ralser DJ, Humbatova A, Hanneken S, Schmieder A, Groß J, Maintz L, Heineke A, Knuever J, Fagerberg C, Parmentier L, Anemüller W, Oji V, Tantcheva-Poór I, Fölster-Holst R, Wenzel J, Krawitz PM, Frank J, and Betz RC
- Subjects
- Humans, Keratin-5 genetics, Glucosyltransferases, Skin Diseases, Genetic genetics, Hyperpigmentation genetics, Skin Diseases, Papulosquamous diagnosis, Skin Diseases, Papulosquamous genetics
- Published
- 2024
- Full Text
- View/download PDF
11. Altered Notch signalling in Dowling-Degos disease: a transcriptomic insight into disease pathogenesis.
- Author
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Kumar S, Hausen J, Sivalingam S, Humbatova A, Buness A, Frank J, Ralser DJ, and Betz RC
- Subjects
- Humans, Transcriptome genetics, Hyperpigmentation genetics, Hyperpigmentation pathology, Skin Diseases, Papulosquamous diagnosis, Skin Diseases, Papulosquamous genetics, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic genetics, Skin Diseases, Genetic pathology
- Abstract
Competing Interests: Conflicts of interest the authors declare no conflicts of interest.
- Published
- 2023
- Full Text
- View/download PDF
12. X-linked genodermatoses from diagnosis to tailored therapy.
- Author
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Medori MC, Gisondi P, Bellinato F, Bonetti G, Micheletti C, Donato K, Dhuli K, Ergoren MC, Cristofoli F, Cecchin S, Marceddu G, and Bertelli M
- Subjects
- Male, Humans, Child, Ectodermal Dysplasia 1, Anhidrotic, Ichthyosis genetics, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic genetics, Skin Diseases, Genetic therapy, Genetic Diseases, X-Linked, Skin Neoplasms
- Abstract
Background: Genodermatoses are rare heterogeneous genetic skin diseases with multiorgan involvement. They severely impair an individual's well-being and can also lead to early death., Methods: During the progress of this review, we have implemented a targeted research approach, diligently choosing the most relevant and exemplary articles within the subject matter. Our method entailed a systematic exploration of the scientific literature to ensure a compre-hensive and accurate compilation of the available sources., Results: Among genodermatoses, X-linked ones are of particular importance and should always be considered when pediatric males are affected. Regardless of other syndromic forms without prevalence of skin symptoms, X-linked genodermatoses can be classified in three main groups: keratinization defects, pigmentation defects, and inflammatory skin diseases. Typical examples are dyskeratosis congenita, keratosis follicularis spinulosa decalvans, hypohidrotic ectodermal dysplasia, chondrodysplasia punctata, hypohidrotic ectodermal dysplasia, incontinentia pigmenti, chronic granulomatous disease, CHILD syndrome and ichthyosis. In this field, genetic diagnosis of the specific disease is important, also considering that numerous clinical trials of orphan drugs and genetic therapies are being proposed for these rare genetic diseases., Conclusions: Thus, this chapter starts from clinical to molecular testing and ends with a review of all clinical trials on orphan drugs and gene therapy for genodermatoses.
- Published
- 2023
- Full Text
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13. Dyschromatosis universalis hereditaria.
- Author
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Murthy AB, Palaniappan V, Karthikeyan K, and Anbarasan V
- Subjects
- Child, Preschool, Adolescent, Female, Humans, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic genetics, Hyperpigmentation diagnosis, Hyperpigmentation genetics, Liver Neoplasms
- Abstract
Reticulate pigmentary dyschromatoses primarily include dyschromatosis universalis hereditaria (DUH), dyschromatosis symmetrica hereditaria (DSH) (Reticulate acropigmentation of Dohi), and unilateral dermatomal pigmentary dermatosis, which differ in their patterns of distribution. The disease was initially described by Ichikawa and Hiraga in Germany in 1933. The prevalence of DUH is 0.3 per 100,000 with a female preponderance. The skin lesions usually appear in infancy or early childhood and cease to progress beyond adolescence. The subtypes DUH 1 and DUH 3 are found to have autosomal dominant inheritance, which is the most common inheritance pattern, while DUH 2 has an autosomal recessive pattern. The most common gene involved in DUH is ABCB6, while the other genes include SASH 1, PER 3, and KITLG (DUH type 2). DUH is characterized by multiple irregular hyperpigmented macules interspersed with hypopigmented macules in a mottled pattern over the trunk and extremities. The face is involved in 50% of individuals. Rarely, it can also involve hairs, nails, mucous membranes, palms, and soles. Other varied presentations include localized forms, localization of lesions to sun-exposed areas, large macules, uniform palmar hypopigmentation, diffuse hyperpigmentation with spotty depigmented macules, and unilateral involvement. DUH has been reported to be associated with various cutaneous and systemic diseases. The authors have observed cases of DUH associated with hepatocellular carcinoma, solitary keratoacanthoma, and dermoid cyst. The various diagnostic modalities include dermoscopy, histopathology, electron microscopy, and targeted gene sequencing. Though various treatment modalities like NBUVB and lasers have been tried, no treatment is promising., (© 2023 the International Society of Dermatology.)
- Published
- 2023
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14. Retyping and molecular pathology diagnosis of dyschromatosis universalis hereditaria.
- Author
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Zhou D, Yang P, and Chen H
- Subjects
- Humans, Pathology, Molecular, Melanins genetics, Pedigree, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic genetics, Skin Diseases, Genetic pathology, Hyperpigmentation diagnosis, Hyperpigmentation genetics
- Abstract
Dyschromatosis universalis hereditaria (DUH) is characterized by diffuse symmetrically distributed hypopigmented macules mixed with hyperpigmentation. DUH is divided into three types by Online Mendelian inheritance in man (OMIM) that is, DUH1 (OMIM 127500), DUH2 (OMIM 612715) and DUH3 (OMIM 615402) according to the different linkage regions. Although each condition possesses corresponding phenotypic characteristics and the prognosis for each is somewhat different, these disorders are highly overlapped and difficult to differentiate in the clinical setting. Our latest study reveals a novel DUH subtype that presents a mild phenotype of pigmentation anomalies and is named PER3
rs772027021 SNP related DUH or DUH4 by us, which make the DUH subtype can be further retyped. Heterozygous distribution or mosaic-like distribution of melanin is a newly discovered pathological features that is uniquely demonstrated in the affected layers of DUH1 and DUH4 patients. In this review, DUH is further divided into four subtypes according the causative genes and their mutational sites, and the mutation regions described in the previous reports. To make an accurate diagnosis, we suggest that Sanger sequencing or the target region sequencing (TRS) to the candidate causative genes related melanogenesis may be the most effective and convenient method of clinical diagnosis or/and prenatal diagnosis for DUH and DUH-like patients. More importantly, heterozygous distribution or mosaic-like distribution of melanin can be utilized for differential diagnosis of DUH. We also investigate the underlying molecular mechanism to form mosaic-like melanin in the affected layers of hyper- and/or hypo-pigmented macules from DUH1 and DUH4 patients. This review provides a molecular and pathological delineation of four types of DUH and aims to establish a concise diagnostic strategy to allow clinical dermatologists to make an accurate diagnosis., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)- Published
- 2023
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15. Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients.
- Author
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Esmel-Vilomara R, Valenzuela I, Riaza L, Rodríguez-Santiago B, Rosés-Noguer F, Boronat S, and Sabaté-Rotés A
- Subjects
- Humans, Aorta, Consanguinity, Arteries, Skin Diseases, Genetic genetics
- Abstract
Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disease caused by biallelic variants in the SLC2A10 gene (NG_016284.1) and characterised by tortuosity and elongation of the aorta and medium-sized arteries. It is considered an extremely rare disease; only 106 individuals with genetically confirmed ATS have been identified to date. Four cases of ATS from two families are described, contributing to the clinical delineation of this condition. A patient with microcephaly and a complex uropathy and two cases with diaphragmatic hernia are noticed. Regarding the vascular involvement, a predominant supra-aortic involvement stands out and only 1 patient with significant arterial stenoses was described. All presented severe tortuosity of the intracranial arteries. To reduce hemodynamic stress on the arterial wall, beta-adrenergic blocking treatment was prescribed. A not previously described variant (NM_030777.4:c.899T>G (p.Leu300Trp)) was detected in a proband; it has an allegedly deleterious effect in compound heterozygous state with the pathogenic variant c.417T>A (p.Tyr139Ter). The other 3 patients, siblings born to healthy consanguineous parents, had a variant in homozygous state: c.510G>A (p.Trp170Ter)., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
- Published
- 2023
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16. Non-hereditary arterial tortuosity syndrome in systemic sclerosis.
- Author
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Tessier S, Longo S, Numeir M, and Ido F
- Subjects
- Humans, Arteries diagnostic imaging, Skin Diseases, Genetic complications, Skin Diseases, Genetic genetics, Vascular Malformations complications, Vascular Malformations diagnostic imaging, Vascular Malformations genetics, Scleroderma, Systemic complications, Scleroderma, Systemic genetics
- Abstract
Competing Interests: Declaration of Competing Interest The author has no financial or other conflicts of interest to disclose.
- Published
- 2023
- Full Text
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17. Inherited Reticulate Pigmentary Disorders.
- Author
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Lin MH, Chou PC, Lee IC, Yang SF, Yu HS, and Yu S
- Subjects
- Humans, Hyperpigmentation genetics, Hyperpigmentation pathology, Skin Diseases, Genetic genetics
- Abstract
Reticulate pigmentary disorders (RPDs) are a group of inherited and acquired skin conditions characterized by hyperpigmented and/or hypopigmented macules. Inherited RPDs include dyschromatosis symmetrica hereditaria (DSH), dyschromatosis universalis hereditaria (DUH), reticulate acropigmentation of Kitamura (RAK), Dowling-Degos disease (DDD), dyskeratosis congenita (DKC), Naegeli-Franceschetti-Jadassohn syndrome (NFJS), dermatopathia pigmentosa reticularis (DPR), and X-linked reticulate pigmentary disorder. Although reticulate pattern of pigmentation is a common characteristic of this spectrum of disorders, the distribution of pigmentation varies among these disorders, and there may be clinical manifestations beyond pigmentation. DSH, DUH, and RAK are mostly reported in East Asian ethnicities. DDD is more common in Caucasians, although it is also reported in Asian countries. Other RPDs show no racial predilection. This article reviews the clinical, histological, and genetic variations of inherited RPDs.
- Published
- 2023
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18. The first case of VEXAS syndrome in Austria.
- Author
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Strasser B and Haushofer A
- Subjects
- Humans, Austria, Mutation, Myelodysplastic Syndromes genetics, Skin Diseases, Genetic genetics
- Published
- 2023
- Full Text
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19. Clinical and molecular diagnosis of genodermatoses: Review and perspectives.
- Author
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Salik D, Richert B, and Smits G
- Subjects
- Humans, Exome Sequencing, RNA, DNA, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic genetics, Skin Diseases, Genetic therapy
- Abstract
Genodermatoses are a complex and heterogeneous group of genetic skin disorders characterized by variable expression and clinical and genetic heterogeneity, rendering their diagnosis challenging. DNA-based techniques, like whole-exome sequencing, can establish a diagnosis in 50% of cases. RNA-sequencing is emerging as an attractive tool that can obtain information regarding gene expression while integrating functional genomic data with regard to the interpretation of variants. This increases the diagnostic rate by an additional 10-15%. In the present review, we detail the clinical steps involved in the diagnosis of genodermatoses, as well as the current DNA-based technologies available to clinicians. Herein, the intention is to facilitate a better understanding of the possibilities and limitations of these diagnostic technologies. In addition, this review could guide dermatologists through new emerging techniques, such as RNA-sequencing and its applications to familiarizing them with future techniques. Currently, this multi-omics approach is likely the best strategy designed to promote the diagnosis of patients with genodermatoses and discover new skin disease genes that could result in novel targeted therapies., (© 2022 European Academy of Dermatology and Venereology.)
- Published
- 2023
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20. Superimposed mosaicism in cutaneous sarcoidosis: A hypothesis.
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Happle R and Wetzke M
- Subjects
- Humans, Mosaicism, Skin pathology, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic genetics, Skin Diseases, Genetic pathology, Sarcoidosis diagnosis, Sarcoidosis genetics, Skin Diseases diagnosis, Skin Diseases genetics, Skin Diseases pathology
- Abstract
Sarcoidosis is a chronic granulomatous disorder affecting the lungs, skin, and many other organs. Twin studies suggest that genetic factors account, to a large degree, for the etiology of the disorder. Hence, theoretically, we could postulate that the phenomenon of superimposed mosaicism in the form of a pronounced segmental involvement, overlaying the disseminated non-segmental lesions, should also occur in sarcoidosis. Indeed, one case suggesting superimposed mosaicism in cutaneous sarcoidosis was found in the literature and is reassessed here., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
- Published
- 2023
- Full Text
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21. Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population.
- Author
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Beck DB, Bodian DL, Shah V, Mirshahi UL, Kim J, Ding Y, Magaziner SJ, Strande NT, Cantor A, Haley JS, Cook A, Hill W, Schwartz AL, Grayson PC, Ferrada MA, Kastner DL, Carey DJ, and Stewart DR
- Subjects
- Female, Humans, Male, Biopsy, Electronic Health Records, Prevalence, Mutation, Retrospective Studies, Exome, Middle Aged, United States epidemiology, Myelodysplastic Syndromes complications, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes epidemiology, Myelodysplastic Syndromes genetics, Ubiquitin-Activating Enzymes genetics, Skin Diseases, Genetic complications, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic epidemiology, Skin Diseases, Genetic genetics
- Abstract
Importance: VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes., Objective: To determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach., Design, Setting, and Participants: This retrospective observational study evaluated UBA1 variants in exome data from 163 096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record data from January 1, 1996, to January 1, 2022., Exposures: Exome sequencing was performed., Main Outcomes and Measures: Outcome measures included prevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other findings in individuals with somatic UBA1 variation on review of the electronic health record; review of laboratory data; bone marrow biopsy pathology analysis; and in vitro enzymatic assays., Results: In 163 096 participants (mean age, 52.8 years; 94% White; 61% women), 11 individuals harbored likely somatic variants at known pathogenic UBA1 positions, with 11 of 11 (100%) having clinical manifestations consistent with VEXAS syndrome (9 male, 2 female). A total of 5 of 11 individuals (45%) did not meet criteria for rheumatologic and/or hematologic diagnoses previously associated with VEXAS syndrome; however, all individuals had anemia (hemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic (10/11 [91%]) with concomitant thrombocytopenia (10/11 [91%]). Among the 11 patients identified, there was a pathogenic variant in 1 male participant prior to onset of VEXAS-related signs or symptoms and 2 female participants had disease with heterozygous variants. A previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) was found in a symptomatic patient, with in vitro data supporting a catalytic defect and pathogenicity. Together, disease-causing UBA1 variants were found in 1 in 13 591 unrelated individuals (95% CI, 1:7775-1:23 758), 1 in 4269 men older than 50 years (95% CI, 1:2319-1:7859), and 1 in 26 238 women older than 50 years (95% CI, 1:7196-1:147 669)., Conclusions and Relevance: This study provides an estimate of the prevalence and a description of the clinical manifestations of UBA1 variants associated with VEXAS syndrome within a single regional health system in the US. Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum.
- Published
- 2023
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22. A tangled picture: arterial tortuosity syndrome.
- Author
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Mazza GA, Ferroni F, and Agnoletti G
- Subjects
- Arteries abnormalities, Arteries diagnostic imaging, Humans, Joint Instability diagnostic imaging, Joint Instability surgery, Skin Diseases, Genetic diagnostic imaging, Skin Diseases, Genetic genetics, Vascular Malformations diagnostic imaging
- Published
- 2022
- Full Text
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23. Novel splice mutation in CDSN gene causing type b peeling skin syndrome.
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Navarro-Navarro I, Jiménez-Gallo D, de la Varga-Martínez R, Villegas-Romero I, Mora-López F, Linares-Barrios M, Youssefian L, Vahidnezhad H, and Uitto J
- Subjects
- Humans, Intercellular Signaling Peptides and Proteins, Mutation, Dermatitis, Exfoliative genetics, Skin Diseases, Genetic genetics
- Published
- 2022
- Full Text
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24. [VEXAS syndrome : when do we have to consider it ?]
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Coattrenec Y, De Lorenzi C, Samii K, Serratrice J, and Seebach JD
- Subjects
- Adult, Humans, Inflammation, Mutation, Pyoderma Gangrenosum, Ubiquitin-Activating Enzymes genetics, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic drug therapy, Skin Diseases, Genetic genetics, Vasculitis
- Abstract
VEXAS syndrome was recently discovered in patients who developed late in adulthood an inflammatory syndrome with fever, cytopenias, dysplastic bone marrow, cutaneous and pulmonary neutrophilic inflammation, arthritis, chondritis, or vasculitis. It is the result of an inactivating somatic mutation affecting methionine codon 41 of the UBA1 gene which encodes an ubiquitin activating enzyme (E1). Systemic corticosteroids generally reduce symptoms, while other immunosuppressive drugs only have limited long-term effects. Azacitidine is a promising treatment, but further studies are warranted. Here, we describe 2 new cases including one associated with pyoderma gangrenosum and cryoglobulinemia., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.
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- 2022
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25. A homozygous Y131X GPNMB mutation in a Chinese family with amyloidosis cutis dyschromica.
- Author
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Wang X and Sun J
- Subjects
- China, Homozygote, Humans, Membrane Glycoproteins, Mutation, Amyloidosis, Familial diagnosis, Amyloidosis, Familial genetics, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic genetics
- Published
- 2022
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26. Evaluating the variety of GNAS inactivation disorders and their clinical manifestations in 11 Chinese children.
- Author
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Chang G, Li Q, Li N, Li G, Li J, Ding Y, Huang X, Shen Y, Wang J, and Wang X
- Subjects
- Adolescent, Child, Child, Preschool, China, Female, Humans, Infant, Male, Pseudopseudohypoparathyroidism diagnosis, Pseudopseudohypoparathyroidism genetics, Pseudopseudohypoparathyroidism pathology, Bone Diseases, Metabolic diagnosis, Bone Diseases, Metabolic genetics, Bone Diseases, Metabolic pathology, Chromogranins genetics, GTP-Binding Protein alpha Subunits, Gs genetics, Ossification, Heterotopic diagnosis, Ossification, Heterotopic genetics, Ossification, Heterotopic pathology, Pseudohypoparathyroidism diagnosis, Pseudohypoparathyroidism genetics, Pseudohypoparathyroidism pathology, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic genetics, Skin Diseases, Genetic pathology
- Abstract
Background: The GNAS gene on chromosome 20q13.3, encodes the alpha-subunit of the stimulatory G protein, which is expressed in most tissues and regulated through reciprocal genomic imprinting. Disorders of GNAS inactivation produce several different clinical phenotypes including pseudohypoparathyroidism (PHP), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). The clinical and biochemical characteristics overlap of PHP subtypes and other related disorders presents challenges for differential diagnosis., Methods: We enrolled a total of 11 Chinese children with PHP in our study and analyzed their clinical characteristics, laboratory results, and genetic mutations., Results: Among these 11 patients, nine of them (9/11) presented with resistance to parathyroid hormone (PTH); and nine (9/11) presented with an Albright's hereditary osteodystrophy (AHO) phenotype. GNAS abnormalities were detected in all 11 patients, including nine cases with GNAS gene variations and two cases with GNAS methylation defects. These GNAS variations included an intronic mutation (c.212 + 3_212 + 6delAAGT), three missense mutations (c.314C > T, c.308 T > C, c.1123G > T), two deletion mutations (c.565_568delGACT*2, c.74delA), and two splicing mutations (c.721 + 1G > A, c.432 + 1G > A). Three of these mutations, namely, c.314C > T, c.1123G > T, and c.721 + 1G > A, were found to be novel. This data was then used to assign a GNAS subtype to each of these patients with six cases diagnosed as PHP1a, two cases as PHP1b, one as PPHP, and two as POH., Conclusions: Evaluating patients with PTH resistance and AHO phenotype improved the genetic diagnosis of GNAS mutations significantly. In addition, our results suggest that when GNAS gene sequencing is negative, GNAS methylation study should be performed. Early genetic detection is required for the differential diagnosis of GNAS disorders and is critical to the clinician's ability to distinguish between heterotopic ossification in the POH and AHO phenotype., (© 2022. The Author(s).)
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- 2022
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27. Severe dysplasminogenemia due to homozygous PLG Ala620Thr variant in a Korean woman without a history of venous thromboembolism: A case report and literature review.
- Author
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Lee B, Kim S, Lee JJ, Heo SH, Chung S, Jang SY, Kim SH, Kim DK, and Kim HJ
- Subjects
- Adult, Conjunctivitis diagnosis, Heart Neoplasms, Humans, Male, Myxoma, Plasminogen genetics, Skin Diseases, Genetic diagnosis, Thromboembolism, Conjunctivitis genetics, Plasminogen deficiency, Skin Diseases, Genetic genetics
- Abstract
Rationale: Plasminogen plays an important role in fibrinolysis and is encoded by the PLG gene. The missense variant PLG Ala620Thr is the major cause of dysplasminogenemia in East Asian countries, including Korea. Although dysplasminogenemia was first reported in a Japanese patient with recurrent venous thromboembolism (VTE), subsequent studies have not demonstrated any clear association between the PLG Ala620Thr variant and the risk of VTE. To the best of our knowledge, this is the first report of a homozygous PLG Ala620Thr variant case from Korea., Patient Concerns: Here, we report a Korean family with PLG Ala620Thr mutation. The proband was a 34-year-old man who presented with multiple thrombotic arterial embolism and cardiac myxoma., Interventions: Laboratory workup, including coagulation profile and PLG gene sequencing, was carried out for the affected family., Diagnosis and Outcome: The proband carried a heterozygous PLG Ala620Thr variant with decreased plasminogen activity of 65%. His 53-year-old mother, who had no reported history of VTE, was homozygous for the PLG Ala620Thr variant with decreased plasminogen activity of just 25%. Decreased plasminogen activity indicates dysplasminogenemia., Lessons: We believe that this clinically silent homozygous case supports the previous findings that isolated PLG Ala620Thr variant does not confer a significant risk of VTE., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2022
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28. VEXAS syndrome: relapsing polychondritis and myelodysplastic syndrome with associated immunoglobulin A vasculitis.
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Pàmies A, Ferràs P, Bellaubí-Pallarés N, Giménez T, Raventós A, and Colobran R
- Subjects
- Aged, Humans, IgA Vasculitis complications, Male, Mutation, Missense, Myelodysplastic Syndromes genetics, Polychondritis, Relapsing complications, Skin Diseases, Genetic genetics, Ubiquitin-Activating Enzymes genetics, IgA Vasculitis diagnosis, Myelodysplastic Syndromes diagnosis, Polychondritis, Relapsing diagnosis, Skin Diseases, Genetic diagnosis
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- 2022
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29. A novel pathogenic variant in the corneodesmosin gene causing generalized inflammatory peeling skin syndrome with marked eosinophilia and trichorrhexis invaginata.
- Author
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Gordon H, Yap P, Hsiao KC, Watson M, and Purvis D
- Subjects
- Humans, Infant, Intercellular Signaling Peptides and Proteins, Dermatitis, Exfoliative diagnosis, Dermatitis, Exfoliative genetics, Dermatitis, Exfoliative pathology, Eosinophilia, Hair Diseases, Netherton Syndrome diagnosis, Netherton Syndrome genetics, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic genetics
- Abstract
Generalized inflammatory peeling skin syndrome (PSS) is a rare autosomal recessive genodermatosis caused by loss-of-function disease-causing variants of the corneodesmosin gene (CDSN), resulting in excessive shedding of the superficial layers of the epidermis. We describe a case of generalized inflammatory PSS in an infant, presenting at day two of life with ichthyosiform erythroderma and superficial peeling of the skin. Hair microscopy showed trichorrhexis invaginata. Normal amounts of skin LEKT1, a product of SPINK5 on immunohistochemical staining excluded a diagnosis of Netherton syndrome. Genetic analysis revealed a homozygous novel complete CDSN deletion, estimated 4.6 kb in size, supporting the diagnosis of generalized inflammatory PSS., (© 2022 The Authors. Pediatric Dermatology published by Wiley Periodicals LLC.)
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- 2022
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30. Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of patients with VEXAS.
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van der Made CI, Potjewijd J, Hoogstins A, Willems HPJ, Kwakernaak AJ, de Sevaux RGL, van Daele PLA, Simons A, Heijstek M, Beck DB, Netea MG, van Paassen P, Elizabeth Hak A, van der Veken LT, van Gijn ME, Hoischen A, van de Veerdonk FL, Leavis HL, and Rutgers A
- Subjects
- Adult, Age of Onset, Aged, Hereditary Autoinflammatory Diseases diagnosis, Humans, Male, Middle Aged, Mutation, Myelodysplastic Syndromes diagnosis, Netherlands, Retrospective Studies, Skin Diseases, Genetic diagnosis, Hereditary Autoinflammatory Diseases genetics, Myelodysplastic Syndromes genetics, Skin Diseases, Genetic genetics, Ubiquitin-Activating Enzymes genetics
- Abstract
Background: A novel autoinflammatory syndrome was recently described in male patients who harbored somatic mutations in the X-chromosomal UBA1 gene. These patients were characterized by adult-onset, treatment-refractory inflammation with fever, cytopenia, dysplastic bone marrow, vacuoles in myeloid and erythroid progenitor cells, cutaneous and pulmonary inflammation, chondritis, and vasculitis, which is abbreviated as VEXAS., Objective: This study aimed to (retrospectively) diagnose VEXAS in patients who had previously been registered as having unclassified autoinflammation. We furthermore aimed to describe clinical experiences with this multifaceted, complex disease., Methods: A systematic reanalysis of whole-exome sequencing data from a cohort of undiagnosed patients with autoinflammation from academic hospitals in The Netherlands was performed. When no sequencing data were available, targeted Sanger sequencing was applied in cases with high clinical suspicion of VEXAS., Results: A total of 12 male patients who carried mutations in UBA1 were identified. These patients presented with adult-onset (mean age 67 years, range 47-79 years) autoinflammation with systemic symptoms, elevated inflammatory parameters, and multiorgan involvement, most typically involving the skin and bone marrow. Novel features of VEXAS included interstitial nephritis, cardiac involvement, stroke, and intestinal perforation related to treatment with tocilizumab. Although many types of treatment were initiated, most patients became treatment-refractory, with a high mortality rate of 50%., Conclusion: VEXAS should be considered in the differential diagnosis of males with adult-onset autoinflammation characterized by systemic symptoms and multiorgan involvement. Early diagnosis can prevent unnecessary diagnostic procedures and provide better prognostic information and more suitable treatment options, including stem cell transplantation., (Copyright © 2021. Published by Elsevier Inc.)
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- 2022
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31. Novel deletion of the POFUT1 gene associated with multiple seborrheic keratosis Dowling-Degos disease.
- Author
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Chen Y, Li Z, Song D, and Wang S
- Subjects
- Humans, Hyperpigmentation diagnosis, Hyperpigmentation genetics, Keratosis, Seborrheic diagnosis, Keratosis, Seborrheic genetics, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic genetics, Skin Diseases, Papulosquamous
- Published
- 2021
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32. Inherited skin disorders presenting with poikiloderma.
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Rayinda T, van Steensel M, and Danarti R
- Subjects
- Atrophy pathology, Humans, Skin pathology, Rothmund-Thomson Syndrome complications, Rothmund-Thomson Syndrome diagnosis, Rothmund-Thomson Syndrome genetics, Skin Abnormalities diagnosis, Skin Abnormalities genetics, Skin Abnormalities pathology, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic genetics, Skin Diseases, Genetic pathology
- Abstract
Poikiloderma is a skin condition that combines atrophy, telangiectasia, and macular pigment changes (hypo- as well as hyperpigmentation). It is often mistaken for mottled pigmentation by general practitioners or nondermatology specialists. Poikiloderma can be a key presenting symptom of Rothmund-Thomson syndrome (RTS), dyskeratosis congenita (DC), hereditary sclerosing poikiloderma (HSP), hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP), xeroderma pigmentosum (XP), Bloom syndrome (BS), Kindler syndrome (KS), and Clericuzio-type poikiloderma with neutropenia (PN). In these conditions, poikiloderma starts early in life, usually before the second or third year. They may also be associated with photosensitivity and other significant multi-organ manifestation developed later in life. Poikiloderma could indicate the presence of a genetic disorder with potentially serious consequences. Poikiloderma almost always precedes more severe manifestations of these genodermatoses. Prompt diagnosis at the time of presentation could help to prevent complications and mitigate the course of the disease. This review discusses these to help the practicing clinician manage patients presenting with the symptom. To further facilitate early recognition, this paper also proposes a simple diagnostic algorithm., (© 2021 the International Society of Dermatology.)
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- 2021
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33. Infantile-onset osteoma cutis with pseudopseudohypoparathyroidism.
- Author
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Stembridge N, Durack A, Gass JK, Firth HV, Park SM, McDonald S, Thankamony A, and Burrows NP
- Subjects
- Bone Diseases, Metabolic genetics, Chromogranins genetics, GTP-Binding Protein alpha Subunits, Gs genetics, Humans, Infant, Male, Mutation, Ossification, Heterotopic genetics, Pseudopseudohypoparathyroidism genetics, Skin Diseases, Genetic genetics, Bone Diseases, Metabolic pathology, Ossification, Heterotopic pathology, Pseudopseudohypoparathyroidism pathology, Skin pathology, Skin Diseases, Genetic pathology
- Published
- 2021
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34. Amyloidosis cutis dyschromica cases caused by GPNMB mutations with different inheritance patterns.
- Author
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Qin W, Wang H, Zhong W, Bai J, Qiao J, and Lin Z
- Subjects
- Adolescent, Age of Onset, Amyloidosis, Familial diagnosis, Amyloidosis, Familial pathology, Child, DNA Mutational Analysis, Female, HEK293 Cells, Humans, Hyperpigmentation diagnosis, Hyperpigmentation pathology, Hypopigmentation diagnosis, Hypopigmentation pathology, Inheritance Patterns, Male, Mutation, Pedigree, Skin pathology, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic pathology, Exome Sequencing, Amyloidosis, Familial genetics, Founder Effect, Hyperpigmentation genetics, Hypopigmentation genetics, Membrane Glycoproteins genetics, Skin Diseases, Genetic genetics
- Abstract
Background: Amyloidosis cutis dyschromica (ACD) is a rare form of primary cutaneous amyloidosis featured by reticulate dotted hypo- and hyperpigmentation. Recently, loss-of-function mutations in GPNMB, encoding glycoprotein (transmembrane) nonmetastatic melanoma protein B, were found in autosomal-recessive or semi-dominant ACD., Objective: This study aims to detect the genetic defect underlying ACD in nine separate cases and to investigate the functional consequences of the mutants., Methods: Nine ACD cases were collected including eight with autosomal-recessive pattern and one with autosomal-dominant pattern. Whole-exome sequencing or Sanger sequencing of the GPNMB gene was performed to detect the pathogenic mutations. Haplotype analysis was employed to determine the origin of mutation c.565C > T using adjacent highly polymorphic SNPs. Immunoblotting and subcellular localization assessments were performed to evaluate the expression of the mutants using HEK293 cells transfected with the GPNMB constructs., Results: We detected four recurrent mutations (c.393 T > G, p.Y131*; c.565C > T, p.R189*; c.1056delT, p.P353Lfs*20; c.1238 G > C, p.C413S) and two novel mutations (c.935delA, p.N312Tfs*4; c.969 T > A, p.C323*) in GPNMB. Mutation c.565C > T found in six separate ACD cases shared a common haplotype. The two novel mutations caused a decreased abundance of truncated proteins. The c.1238 G > C mutation, which was detected in the autosomal-dominant case, caused abnormal reticular subcellular localization of the protein. A major percentage of wildtype changed its expression pattern when co-expressed with this mutant., Conclusions: Our findings proved that the recurrent mutation c.565C > T originated from a founder effect. The autosomal-dominant ACD associated mutation p.C413S played its pathogenic role through a dominant-negative effect on wild-type GPNMB. This study expands the genotype and inherited modes of ACD and improves our understanding of the pathogenesis of this disorder., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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35. A large deletion in the Plasminogen gene is associated with ligneous membranitis in a Maltese dog.
- Author
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Turba ME, Ostan PC, Ghetti S, Dajbychova M, Dondi F, and Gentilini F
- Subjects
- Animals, Breeding, Conjunctivitis genetics, Male, Plasminogen genetics, Skin Diseases, Genetic genetics, Conjunctivitis veterinary, Dog Diseases genetics, Dogs genetics, Plasminogen deficiency, Skin Diseases, Genetic veterinary
- Abstract
Ligneous membranitis/conjunctivitis (LM, OMIM 217090) is a hereditary disorder caused by a congenital plasminogen (PLG) deficiency. In veterinary medicine, LM (OMIA 002020-9615) has rarely been reported in Golden Retrievers, Yorkshire Terriers, Doberman Pinschers and Scottish Terriers. In the latter breed, an A>T variation in an intron donor site of the PLG gene (PLG, c.1256+2T>A) has been found to be the sole causative molecular defect reported to date in dogs. Owing to the absence of plasmin enzymatic clearance which in turn depends on the lack of its proenzyme plasminogen, fibrin deposits tend to accumulate in viscous membranes on the eyes, triggering and sustaining an intense inflammatory response. A case of LM was diagnosed in a 7-month-old male Maltese dog. The dog was examined for severe recurrent conjunctivitis. A diagnosis of ligneous conjunctivitis was made by an ophthalmologist after a thorough eye examination and was confirmed by a complete lack of plasma activity of plasminogen. The main local signs were redness of the conjunctiva with persistent membranes having ligneous (wood-like) membranes on the eyes. The disease was associated with a complex rearrangement involving the plasminogen gene loci, causing the complete deletion of exon 1. This study provides a spontaneous animal model for LM associated with complete plasminogen deficiency and provides a method for detecting affected or carrier dogs., (© 2021 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.)
- Published
- 2021
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36. Highly branched poly(β-amino ester)s for gene delivery in hereditary skin diseases.
- Author
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Zeng M, Xu Q, Zhou D, A S, Alshehri F, Lara-Sáez I, Zheng Y, Li M, and Wang W
- Subjects
- Animals, Epidermolysis Bullosa Dystrophica genetics, Epidermolysis Bullosa Dystrophica pathology, Humans, Polymers chemistry, Skin Diseases, Genetic genetics, Skin Diseases, Genetic pathology, Skin Diseases, Genetic therapy, Translational Research, Biomedical methods, Epidermolysis Bullosa Dystrophica therapy, Gene Transfer Techniques, Genetic Therapy methods
- Abstract
Non-viral gene therapy for hereditary skin diseases is an attractive prospect. However, research efforts dedicated to this area are rare. Taking advantage of the branched structural possibilities of polymeric vectors, we have developed a gene delivery platform for the treatment of an incurable monogenic skin disease - recessive dystrophic epidermolysis bullosa (RDEB) - based on highly branched poly(β-amino ester)s (HPAEs). The screening of HPAEs and optimization of therapeutic gene constructs, together with evaluation of the combined system for gene transfection, were comprehensively reviewed. The successful restoration of type VII collagen (C7) expression both in vitro and in vivo highlights HPAEs as a promising generation of polymeric vectors for RDEB gene therapy into the clinic. Considering that the treatment of patients with genetic cutaneous disorders, such as other subtypes of epidermolysis bullosa, pachyonychia congenita, ichthyosis and Netherton syndrome, remains challenging, the success of HPAEs in RDEB treatment indicates that the development of viable polymeric gene delivery vectors could potentially expedite the translation of gene therapy for these diseases from bench to bedside., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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37. Spotted bones in an osteopoikilosis-related disease (Buschke Ollendorff Syndrome): Identifying this rare condition from the lab to the field.
- Author
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Zdral S and Trujillo-Tiebas MJ
- Subjects
- Humans, Rare Diseases, Retrospective Studies, Osteopoikilosis diagnostic imaging, Osteopoikilosis genetics, Skin Diseases, Genetic diagnostic imaging, Skin Diseases, Genetic genetics
- Abstract
Objective: To improve the differential diagnosis of osteopoikilosis in past populations using a clinical case as an example of this rare condition., Materials: A patient referred to our Genetic Service with suspected Buschke Ollendorff Syndrome after finding a connective nevus., Methods: Radiological images from different body regions were accompanied by a genetic study using next-generation sequencing., Results: Small circular-to-ellipsoid sclerotic lesions were found in the epiphysis and metaphysis of long bones, as well as in the pelvis. These lesions were bilaterally distributed and with well-defined margins, compatible with the characteristics of Buschke Ollendorff Syndrome, bone manifestation osteopoikilosis. A heterozygous mutation on LEMD3 (NM_001167614:c.1918 + 1G > C) was identified by next-generation sequencing. Based on this confirmed case, we have discussed the most probable causes of similar bone lesions found in the archaeological record., Conclusion: It has been demonstrated how a current case of a rare disease can provide useful tools to improve the differential diagnosis of this disease in ancient skeletons., Significance: This work underlines the great need for multidisciplinary platforms that integrates clinical research into paleopathology in order to successfully address the study of rare diseases from the past., Limitations: Since OPK is only detected by X-rays, suspected cases of this bone lesion will only be identified when radiographs are taken for other purposes., Suggestions for Further Research: Retrospective and large-scale studies of radiographs from other research in past populations., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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38. Two fetuses in one family of arterial tortuosity syndrome: prenatal ultrasound diagnosis.
- Author
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Liang M, Wen H, and Li S
- Subjects
- Arteries diagnostic imaging, Female, Fetal Diseases diagnostic imaging, Humans, Infant, Infant, Newborn, Joint Instability diagnostic imaging, Male, Mutation, Parents, Pregnancy, Prenatal Diagnosis, Siblings, Skin Diseases, Genetic diagnostic imaging, Tomography, X-Ray Computed, Ultrasonography, Prenatal, Vascular Malformations diagnostic imaging, Arteries abnormalities, Fetal Diseases diagnosis, Fetal Diseases genetics, Glucose Transport Proteins, Facilitative genetics, Joint Instability diagnosis, Joint Instability genetics, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic genetics, Vascular Malformations diagnosis, Vascular Malformations genetics, Exome Sequencing
- Abstract
Background: Arterial tortuosity syndrome (ATS) is a rare autosomal recessive connective tissue disorder chiefly characterized by elongated and tortuosity of the large and medium sized arteries and anomalies of the vascular elastic fibers. Here we reported cases of brother about ATS from the same family on the prenatal ultrasound diagnosis. Reports of this case are rare in antenatally and we draw the vessel simulated diagram to display visually., Case Presentation: Prenatal ultrasound scanning at 29 weeks of gestation of the first fetus showed obvious tortuous and elongated of the aortic arch, ductus arteriosus, left and right pulmonary arteries, carotid and subclavian arteries. Three months after delivery, Contrast-enhanced computed tomography images (CTA) were performed to clearly display vascular abnormalities consistent with prenatal diagnosis of ultrasound. Whole exome sequencing (WES) was performed eight months after birth, two heterozygous variants of SLC2A10 gene was detected in newborn and their father and mother, respectively. Prenatal ultrasound scan at 22 weeks of gestation of the second fetus showed similar cardiovascular imaging. After birth the siblings have facial characteristic features gradually as aging. No surgical intervention was performed in the siblings follow up 19 months., Conclusions: The key points of prenatal ultrasound diagnosis of ATS are the elongation and tortuosity of the large and medium sized arteries. Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions., (© 2021. The Author(s).)
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- 2021
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39. OSMRβ mutants enhance basal keratinocyte differentiation via inactivation of the STAT5/KLF7 axis in PLCA patients.
- Author
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Liu J, Chen J, Zhong Y, Yu X, Lu P, Feng J, Zhang X, Ma S, Yang C, Yang B, and Rong Z
- Subjects
- Amyloidosis, Familial metabolism, Amyloidosis, Familial pathology, Animals, Base Sequence, Cell Differentiation, Disease Models, Animal, Gene Expression Profiling, Gene Expression Regulation, Gene Ontology, Humans, Keratinocytes pathology, Kruppel-Like Transcription Factors metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Annotation, Mutation, Oncostatin M metabolism, Oncostatin M Receptor beta Subunit metabolism, STAT5 Transcription Factor metabolism, Signal Transduction, Skin metabolism, Skin pathology, Skin Diseases, Genetic metabolism, Skin Diseases, Genetic pathology, Amyloidosis, Familial genetics, Keratinocytes metabolism, Kruppel-Like Transcription Factors genetics, Oncostatin M genetics, Oncostatin M Receptor beta Subunit genetics, STAT5 Transcription Factor genetics, Skin Diseases, Genetic genetics
- Published
- 2021
- Full Text
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40. Genetic Susceptibility to Dry Skin in a General Middle-Aged to Elderly Population: A GWAS.
- Author
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Mekić S, Gunn DA, Jacobs LC, Hijnen D, Ikram MA, Mayes AE, Nijsten T, and Pardo LM
- Subjects
- Age Factors, Aged, Aged, 80 and over, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Skin Diseases, Genetic genetics
- Published
- 2021
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41. Co-occurrence of Dowling-Degos disease and pemphigus vulgaris.
- Author
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Balighi K, Dastgheib M, Ghannadan A, Qadikolaee PY, and Hamzelou S
- Subjects
- Humans, Hyperpigmentation diagnosis, Hyperpigmentation genetics, Pemphigus complications, Pemphigus diagnosis, Skin Diseases, Genetic complications, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic genetics, Skin Diseases, Papulosquamous diagnosis, Skin Diseases, Papulosquamous genetics
- Published
- 2021
- Full Text
- View/download PDF
42. Dowling-Degos disease: a review.
- Author
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Stephan C, Kurban M, and Abbas O
- Subjects
- Acantholysis diagnosis, Acantholysis genetics, Adult, Amyloid Precursor Protein Secretases, Fucosyltransferases, Glucosyltransferases, Humans, Keratin-5, Membrane Proteins, Hyperpigmentation diagnosis, Hyperpigmentation genetics, Skin Diseases, Genetic diagnosis, Skin Diseases, Genetic genetics, Skin Diseases, Papulosquamous diagnosis, Skin Diseases, Papulosquamous genetics
- Abstract
Dowling-Degos disease is a rare autosomal dominant genodermatosis. It is characterized by acquired reticulate hyperpigmentation over the flexures, comedone-like follicular papules, and pitted perioral scars that usually develop during adulthood. Mutations in genes affecting melanosome transfer, and melanocyte and keratinocyte differentiation have been implicated in the pathogenesis of this disease. These genes include KRT5, POFUT1, POGLUT1 and, most recently, PSENEN. Dowling-Degos disease can be found in isolation or with other associated findings, most notably hidradenitis suppurativa. This condition belongs to a spectrum of conditions that all result in reticulate hyperpigmentation that at times are hard to distinguish from each other. The most closely linked entity is Galli-Galli, which is clinically indistinguishable from Dowling-Degos disease and can only be distinguished by the presence of acantholysis on microscopy. Unfortunately, Dowling-Degos disease is generally progressive and recalcitrant to treatment., (© 2020 the International Society of Dermatology.)
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- 2021
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43. Identification of the novel SDR42E1 gene that affects steroid biosynthesis associated with the oculocutaneous genital syndrome.
- Author
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Bouhouche A, Albaroudi N, El Alaoui MA, Askander O, Habbadi Z, El Hassani A, Iraqi H, El Fahime E, and Belmekki M
- Subjects
- Child, Child, Preschool, DNA genetics, DNA Mutational Analysis, Eye Abnormalities metabolism, Eye Diseases, Hereditary metabolism, Humans, Joint Instability genetics, Joint Instability metabolism, Male, Pedigree, Short Chain Dehydrogenase-Reductases metabolism, Skin Abnormalities metabolism, Skin Diseases, Genetic metabolism, Abnormalities, Multiple, Eye Abnormalities genetics, Eye Diseases, Hereditary genetics, Joint Instability congenital, Mutation, Short Chain Dehydrogenase-Reductases genetics, Skin Abnormalities genetics, Skin Diseases, Genetic genetics, Steroids biosynthesis
- Abstract
Hereditary connective tissue diseases form a heterogeneous group of disorders that affect collagen and extracellular matrix components. The cornea and the skin are among the major forms of connective tissues, and syndromes affecting both organs are often due to mutations in single genes. Brittle cornea syndrome is one of the pathologies that illustrates this association well. Furthermore, sex hormones are known to play a role in the maintenance of the structure and the integrity of the connective tissue including the skin and cornea, and may be involved in pathogenesis of oculocutaneous diseases. Herein, a double consanguineous family of Moroccan origin with two affected siblings, with suspected brittle cornea syndrome, was recruited. Ophthalmic examinations and genetic testing were performed in all the nuclear family individuals. Clinical examinations showed that the two affected boys presented with thinning of the cornea, blue sclera, keratoconus, hyperelasticity of the skin, joint hypermobility, muscle weakness, hearing loss and dental abnormalities that are compatible with the diagnosis of BCS disease. They showed however additional clinical signs including micropenis, hypospadias and cryptorchidism, suggesting abnormalities in endocrine pathways. Using a duo exome sequencing analysis performed in the mother and the propositus, we identified the novel homozygous missense mutation c.461G > A (p.Arg154Gln) in the short-chain dehydrogenase/reductase family 42E member 1 (SDR42E1) gene. This novel mutation, which co-segregated with the disease in the family, was predicted to be pathogenic by bioinformatics tools. SDR42E1 stability analysis using DynaMut web-server showed that the p.Arg154Gln mutations has a destabilizing effect with a ΔΔG value of -1.039 kcal/mol. As this novel gene belongs to the large family of short-chain dehydrogenases/reductases (SDR) thought to be involved in steroid biosynthesis, endocrinological investigations subsequently revealed that the two patients also had low levels of cholesterol. Karyotyping revealed a normal 46,XY karyotype for the two boys, excluding other causes of disorders of sex development due to chromosomal rearrangements. In conclusion, our study reveals that mutation in the novel SDR42E1 gene alters the steroid hormone synthesis and associated with a new syndrome we named oculocutaneous genital syndrome. In addition, this study highlights the role of SDR42E1 in the regulation of cholesterol metabolism in the maintenance of connective tissue and sexual maturation in humans., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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44. Advances in gene therapy and their application to skin diseases: A review.
- Author
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Shinkuma S
- Subjects
- Clinical Trials as Topic, Dermatology trends, Genetic Therapy trends, Humans, Skin Diseases, Genetic genetics, Skin Neoplasms genetics, Treatment Outcome, Dermatology methods, Genetic Therapy methods, Skin Diseases, Genetic therapy, Skin Neoplasms therapy
- Abstract
With recent advances in genetic engineering technology, gene therapy is now being considered as a treatment not only for congenital diseases but also acquired diseases, such as cancer. Gene therapeutic agents for hereditary immune disorders, haemophilia, retinal diseases, neurodegenerative diseases, and lymphoma have been approved in the United States and Europe. In the field of dermatology, clinical trials of gene therapy have been conducted, because the skin is an easily accessible organ that represents an attractive tissue for gene therapy. In recent years, gene therapy has been attempted for a variety of skin diseases, such as genodermatoses (including epidermolysis bullosa and Netherton syndrome), cutaneous lymphoma, and malignant melanoma. As a result, it is difficult to grasp the current status of gene therapy in dermatology. This review focuses on each of the gene-transfer techniques currently in use and describes the current status of gene therapy for skin diseases using each technology., Competing Interests: Declaration of Competing Interest The author reports no declarations of interest., (Copyright © 2021 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)
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- 2021
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45. Development of hMC1R Selective Small Agonists for Sunless Tanning and Prevention of Genotoxicity of UV in Melanocytes.
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Koikov L, Starner RJ, Swope VB, Upadhyay P, Hashimoto Y, Freeman KT, Knittel JJ, Haskell-Luevano C, and Abdel-Malek ZA
- Subjects
- Cells, Cultured, DNA Damage radiation effects, Dermatologic Agents therapeutic use, Humans, Melanocytes drug effects, Melanocytes metabolism, Melanocytes radiation effects, Melanoma etiology, Melanoma prevention & control, Photosensitivity Disorders drug therapy, Photosensitivity Disorders genetics, Primary Cell Culture, Receptor, Melanocortin, Type 1 metabolism, Skin drug effects, Skin radiation effects, Skin Diseases, Genetic drug therapy, Skin Diseases, Genetic genetics, Skin Neoplasms etiology, Skin Neoplasms prevention & control, Skin Pigmentation radiation effects, Vitiligo drug therapy, Vitiligo genetics, alpha-MSH metabolism, DNA Damage drug effects, Dermatologic Agents pharmacology, Receptor, Melanocortin, Type 1 agonists, Skin Pigmentation drug effects, Ultraviolet Rays adverse effects
- Abstract
Activation of the human melanocortin 1 receptor (hMC1R) expressed on melanocytes by α-melanocortin plays a central role in regulating human pigmentation and reducing the genotoxicity of UV by activating DNA repair and antioxidant defenses. For the development of a hMC1R-targeted photoprotection strategy, we designed tetra- and tripeptide agonists with modifications that provide the necessary lipophilicity and hMC1R selectivity to be effective drugs. These peptides proved to be superior to most of the existing analogs of the physiological tridecapeptide α-melanocortin because of their small size and high hMC1R selectivity. Testing on primary cultures of human melanocytes showed that these peptides are highly potent with prolonged stimulation of melanogenesis, enhanced repair of UV-induced DNA photoproducts, and reduced apoptosis. One of the tripeptides, designated as LK-514 (5), with a molecular weight of 660 Da, has unprecedented (>100,000) hMC1R selectivity when compared with the other melanocortin receptors hMC3R, hMC4R, and hMC5R, and increases pigmentation (sunless tanning) in a cultured, three-dimensional skin model. These new analogs should be efficacious in preventing skin cancer, including melanoma, and treatment of skin disorders, such as vitiligo and polymorphic light eruptions., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2021
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46. Novel missense mutation of SASH1 in a Chinese family with dyschromatosis universalis hereditaria.
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Cao L, Zhang R, Yong L, Chen S, Zhang H, Chen W, Xu Q, Ge H, Mao Y, Zhen Q, Yu Y, Hu X, and Sun L
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- Humans, Male, Female, Tumor Suppressor Proteins genetics, Asian People genetics, Adult, Amino Acid Sequence, China, East Asian People, Mutation, Missense, Pedigree, Pigmentation Disorders genetics, Pigmentation Disorders congenital, Pigmentation Disorders pathology, Skin Diseases, Genetic genetics
- Abstract
Background: Dyschromatosis universalis hereditaria (DUH) is a pigmentary dermatosis characterized by generalized mottled macules with hypopigmention and hyperpigmention. ABCB6 and SASH1 are recently reported pathogenic genes related to DUH, and the aim of this study was to identify the causative mutations in a Chinese family with DUH., Methods: Sanger sequencing was performed to investigate the clinical manifestation and molecular genetic basis of these familial cases of DUH, bioinformatics tools and multiple sequence alignment were used to analyse the pathogenicity of mutations., Results: A novel missense mutation, c.1529G>A, in the SASH1 gene was identified, and this mutation was not found in the National Center for Biotechnology Information Database of Short Genetic Variation, Online Mendelian Inheritance in Man, ClinVar, or 1000 Genomes Project databases. All in silico predictors suggested that the observed substitution mutation was deleterious. Furthermore, multiple sequence alignment of SASH1 revealed that the p.S510N mutation was highly conserved during evolution. In addition, we reviewed the previously reported DUH-related gene mutations in SASH1 and ABCB6., Conclusion: Although the affected family members had identical mutations, differences in the clinical manifestations of these family members were observed, which reveals the complexity of the phenotype-influencing factors in DUH. Our findings reveal the mutation responsible for DUH in this family and broaden the mutational spectrum of the SASH1 gene.
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- 2021
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47. Development of a pathogenesis-based therapy for peeling skin syndrome type 1.
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Valentin F, Wiegmann H, Tarinski T, Nikolenko H, Traupe H, Liebau E, Dathe M, and Oji V
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- Glycoproteins, Humans, Intercellular Signaling Peptides and Proteins, Quality of Life, Dermatitis, Exfoliative, Skin Diseases, Genetic drug therapy, Skin Diseases, Genetic genetics
- Abstract
Background: Peeling skin syndrome type 1 (PSS1) is a rare and severe autosomal recessive form of congenital ichthyosis. Patients are affected by pronounced erythroderma accompanied by pruritus and superficial generalized peeling of the skin. The disease is caused by nonsense mutations or complete deletion of the CDSN gene encoding for corneodesmosin (CDSN). PSS1 severely impairs quality of life and therapeutic approaches are totally unsatisfactory., Objectives: The objective of this study was to develop the first steps towards a specific protein replacement therapy for CDSN deficiency. Using this approach, we aimed to restore the lack of CDSN and improve cell-cell cohesion in the transition area of the stratum granulosum (SG) to the stratum corneum., Methods: Human CDSN was recombinantly expressed in Escherichia coli. A liposome-based carrier system, prepared with a cationic lipopeptide to mediate the transport to the outer membrane of keratinocytes, was developed. This formulation was chosen for CDSN delivery into the skin. The liposomal carrier system was characterized with respect to size, stability and toxicity. Furthermore, the interaction with primary keratinocytes and human epidermal equivalents was investigated., Results: The liposomes showed an accumulation at the membranes of keratinocytes. CDSN-deficient epidermal equivalents that were treated with liposomal encapsulated CDSN demonstrated presence of CDSN in the SG. Finally, the penetration assay and histological examinations revealed an improved epidermal integrity for CDSN-deficient epidermal equivalents, if they were treated with liposomal encapsulated CDSN., Conclusions: This study presents the first preclinical in vitro experiments for a future specific protein replacement therapy for patients affected by PSS1., (© 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)
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- 2021
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48. A Novel mRNA Modification Mutation in a Patient With Ligneous Conjunctivitis Coexisting With Heterozygous Familial Mediterranean Fever Mutation.
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Koseoglu ND, Ceylaner S, and Yildirim N
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- DNA Mutational Analysis, Gene Frequency, Genetic Predisposition to Disease, Humans, Infant, Male, Plasminogen genetics, Conjunctivitis genetics, Familial Mediterranean Fever genetics, Mutation, Plasminogen deficiency, Pyrin genetics, RNA, Messenger genetics, Skin Diseases, Genetic genetics
- Abstract
Purpose: To describe a novel mRNA mutation associated with ligneous conjunctivitis (LC) in a patient with heterozygous familial Mediterranean fever (FMF) mutation., Methods: Case presentation of a patient with LC and heterozygous FMF mutation. The patient was evaluated for various genetically predisposed inflammatory diseases through whole exome sequencing., Results: LC is a rare inflammatory ocular pathology presenting with recurrent conjunctivitis episodes with eosinophilic fibrin-rich pseudomembranes. FMF is an autoinflammatory disease presenting with recurrent episodes of fever, arthritis, and other inflammatory conditions. Various plasminogen (PLG) gene mutations have been identified in LC, whereas a variety of mutations in the Mediterranean fever (MEFV) gene have been identified in FMF patients. Based on the inflammatory nature of both pathologies, we aimed to evaluate and identify any potential common genetic pathway. We were not able to identify any mutation in PLG gene through whole gene sequencing; however, the patient was positive for heterozygous M680I FMF mutation, and we observed 22% of NM_000301.3:c.2130T>G (p.T710=) variant in mRNA isolated from affected tissue, which was not present in DNA sequence., Conclusions: To the best of our knowledge, this is the first case of LC caused by an mRNA mutation coexisting with another genetically predisposed autoinflammatory disease mutation., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2021
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49. Two novel SASH1 mutations in Chinese families with dyschromatosis universalis hereditaria.
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Liu JW, Habulieti X, Wang RR, Ma DL, and Zhang X
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- Adult, China, Female, Humans, Infant, Male, Pedigree, Pigmentation Disorders genetics, Pigmentation Disorders pathology, Prognosis, Asian People genetics, Mutation, Pigmentation Disorders congenital, Skin Diseases, Genetic genetics, Skin Diseases, Genetic pathology, Tumor Suppressor Proteins genetics
- Abstract
Background: Dyschromatosis universalis hereditaria (DUH) is a rare genodermatosis characterized by hyper- and hypo-pigmented macules on the face, trunk, and extremities. The condition causes severe cosmetic problem which can lead to significant psychological distress to the patients and bear a negative impact on society. DUH is a condition with genetic heterogeneity. The SASH1 gene was recently identified as pathogenic genes in DUH patients., Methods: Two families clinically diagnosed with dyschromatosis universalis hereditaria were enrolled. Whole-exome sequencing combined with Sanger sequencing and bioinformatics analysis was performed in the probands. MutationTaster, CADD, SIFT, PolyPhen-2, and LRT software, and The American College of Medical Genetics and Genomics Standards and Guidelines were employed to assess the pathogenicity of detected missense mutations. One hundred healthy unrelated Chinese individuals were used as controls. All participants signed an informed consent form., Results: Genetic screening revealed a heterozygous SASH1 c.1547G>A (p.Ser516Asn) mutation for patients in family 1, and SASH1 c.1547G>T (p.Ser516Ile) for family 2. Both such de novo mutations are located in a highly conserved SLY domain in SASH1, have not been previously reported in any publication, and were not detected in any control databases., Conclusions: The novel heterozygous mutations, SASH1 c.1547G>A and c.1547G>T, are likely responsible for the DUH phenotype in these two families. Our study expands the mutation spectrum of DUH. Whole-exome sequencing showed its efficiency in the diagnostic of hereditary skin disorders., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)
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- 2021
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50. Two missense mutations in GPNMB cause autosomal recessive amyloidosis cutis dyschromica in the consanguineous pakistani families.
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Rahman OU, Kim J, Mahon C, Jelani M, and Kang C
- Subjects
- Adolescent, Adult, Amyloidosis, Familial pathology, Consanguinity, Female, Homozygote, Humans, Male, Mutation, Missense, Pedigree, Phenotype, Skin Diseases, Genetic pathology, Amyloidosis, Familial genetics, Membrane Glycoproteins genetics, Skin Diseases, Genetic genetics
- Abstract
Background: Amyloidosis cutis dyschromica (ACD) is a rare variant of cutaneous amyloidosis. This disorder often clusters in families, and it has been suggested that genetic factors might be involved in its development., Objective: To identify the genetic causes of ACD, we recruited a consanguineous Pakistani family with multiple cases of ACD that display a recessive mode of inheritance., Methods: We performed whole-exome sequencing of samples from 7 members of this family, followed by bioinformatic and in silico analyses to identify the causative variant. For the replication study, we recruited a British family with Pakistani ancestry, and sequenced all exons of glycoprotein non-metastatic melanoma protein b (GPNMB) to identify mutations. We also investigated effects of the mutations on the stability of the GPNMB protein using the I-TASSER three-dimensional modeling tool., Results: We found a novel homozygous mutation, p.Gly363Val (c.1088 G>T), in GPNMB in all affected cases. In a replication study, another homozygous missense mutation in GPNMB, pIle174Met (c.522 C>G), was carried by the affected son. The two mutations were not observed in our in-house data set comprising 217 healthy Pakistani individuals or in The Genome Aggregation Database. Our structural modeling of GPNMB suggested that p.Gly363Val enhanced its stability, whereas p.Ile174Met caused instability., Conclusions: This study reports two novel missense mutations in two Pakistani families that cause ACD. The mutations appear to influence GPNMB stability, as revealed by protein modeling.
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- 2021
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