The Power of Molecular Genetics in Understanding Heritable Skin Disorders: Introduction to the Special Theme on Genodermatosis

Among the over 7,000 heritable disorders,at least 1,000 of them have cutaneous manifestations.Some of these conditions are exclusively limited to the skin,thus being non-syndromic,while some of them are associated with a number of extracutaneous manifestations,that is,they are syndromic,with protean manifestations.These conditions,heritable skin diseases,display a tremendous collection of phenotypes as well as a broad spectrum of severity and the overall outcome.In most severe forms,some of these conditions are lethal at the early stages of life,while at the other end of the spectrum they may present with a relatively minor skin involvement primarily of cosmetic concern,with no effect on the longevity of the affected individuals.Considering the plethora of clinical manifestations,frequently with overlapping clinical features and complex classification schemes often riddled with eponyms,the heritable skin disorders frequently pose a diagnostic challenge for practicing dermatologists.

Atherogenic Diet Accelerates Ectopic Mineralization in a Mouse Model of Pseudoxanthoma Elasticum

Objective:Pseudoxanthoma elasticum(PXE)is a multisystem heritable disorder caused by mutations in the Abcc6 gene.The disease is characterized by ectopic mineralization of the skin,eyes,and arterial blood vessels.Previous studies have suggested that cardiovascular complications in patients with PXE are caused in part by premature atherosclerosis.The aim of this study is to determine the effect of an atherogenic diet on ectopic mineralization.Methods:We used Abcc6^(tm1JfK)mice(Abcc6^(-/-)mice)as an established preclinical model of PXE.The offspring at age of 4 weeks were divided into two groups and fed the standard control laboratory diet(control group)and the atherogenic diet.Serum lipid profiles and bile acids were measured,and steatosis and tissue mineralization were evaluated by histopathologic analysis and chemical calcium quantification assay,respectively.Results:After 50-58 weeks of feeding an atherogenic diet,the concentrations of total cholesterol,low-density lipoprotein/very-low-density lipoprotein cholesterol,and bile acids were significantly higher in the Abcc6^(-/-)mice on the atherogenic diet(180.9±14.8 g/L,145.9±12.9 g/L,and 9.7±1.4μmol/L,respectively)than in Abcc6^(-/-)mice on a control diet(85.2±4.8 g/L,25.1±5.5 g/L,and 3.3±0.5μmol/L,respectively)(P<0.001).Hypercholesterolemia was accompanied by extensive lipid accumulation in the liver and aorta,a characteristic feature of steatosis.The direct calcium assay demonstrated significantly increased mineralization of the muzzle skin containing the dermal sheath of vibrissae(57.2±4.4μmol Ca/gram tissue on the atherogenic diet and 43.9±2.2μmol Ca/gram tissue on control diet;P<0.01),a reproducible biomarker of the ectopic mineralization process in these mice.An increased frequency of mineralization was also observed in the kidneys and eyes of mice on the atherogenic diet(P<0.01).Conclusion:These observations suggest that the atherogenic diet caused hypercholesterolemia and accelerated ectopic mineralization in the Abcc6^(-/-)mice.Our findings have clinical implications for patients with PXE,a currently intractable disorder with considerable morbidity and occasional mortality.

Autozygosity Mapping by Genome-wide Single Nucleotide Polymorphism Array Identifies a Novel Homozygous HR Mutation in a Consanguineous Family with Universal Hereditary Hair Loss

Objective:Isolated hereditary hypotrichosis is caused by mutations in as many as 11 different genes.The conventional mutation detection strategy consists of sequencing of individual candidate genes separately,a time consuming and costly approach.In this study,we perform genome-wide single nucleotide polymorphism(SNP)array to identify candidate genes of hereditary hypotrichosis.Methods:A consanguineous family with two patients with hereditary hypotrichosis was enrolled,and autozygosity mapping by genome-wide SNP array was utilized to identify candidate genes.Results:Autozygosity mapping delineated runs of homozygosity,and alignment of the 11 genes identified the hairless(HR)gene as the candidate gene.Nucleotide sequencing revealed a novel homozygous mutation c.381delT,p.Ser127ArgfsTer40.Conclusion:This study illustrates how autozygosity mapping by a high-density SNP array streamlines mutation detection in heritable skin diseases.

Genetic Predisposition to Numerous Large Ulcerating Basal Cell Carcinomas and Response to Immune Therapy

Objective:Well-defined germ-line mutations in thePTCH1 gene are associated with syndromic multiple basal cell carcinomas(BCCs).Here,we used whole exome sequencing(WES)to identify the role of patched-1 in patients with multiple,unusually large BCCs.Methods:A 72-year old patient presenting with numerous BCCs progressing to large ulcerating lesions was enrolled.WES was used to identify the pathogenic gene locus.Results:Genetic work-up by WES identified a homozygousPTCH1 nonsense mutation in the tumor tissue but not present in her blood cells or in non-lesional skin.In addition,heterozygous missense mutations were identified in three cancer-associated genes(EPHB2,RET,andGALNT12)in blood cells as well as in lesional and non-lesional skin.We also tested systemic immune therapy as a potentially beneficial approach to treat patients with numerous large BCCs on scatted areas of involvement.A rapid and sustained response to nivolumab was noted,suggesting that it is an efficacious drug for long-term therapeutic outcome.Conclusion:PTCH1,EPHB2,RET,andGALNT12 may potentially contribute to the synergistic oncogene driven malignant transformation manifesting as multiple,unusually large BCCs.

Dynamics and Emerging Trends in Genodermatology: A Scientometric Analysis

With the improved power and precision with genome sequencing,the body of relevant literature on genodermatology has grown rapidly in recent years.In this study,we used CiteSpace,a scientometric software,to delineate the structure and dynamics of genodermatology and to further understand the emerging trends in this field.CiteSpace integrates individual citations and forms a cocitation network that demonstrates the evolution of a scientific field over time.Each reference cited by multiple articles is represented by a node in the network.The size of a node indicates how many times the reference has been cited.The nature of the connectivity between the nodes represents a dual relationship between the cited references and their citing articles.

Kidney Stones Are Prevalent in Individuals with Pseudoxanthoma Elasticum, a Genetic Ectopic Mineralization Disorder

Objective:Pseudoxanthoma elasticum(PXE)is a rare genetic disorder caused by loss-of-function mutations in the ABCC6 gene.While PXE is characterized by ectopic mineralization of connective tissues clinically affecting the skin,eyes,and cardiovascular system,kidney stones were reported in some individuals with PXE.The aim of this study is to determine whether kidney stones are an incidental finding or a frequent manifestation of PXE.Methods:We first investigated the genetic basis of two siblings diagnosed with PXE.The younger patient presented with recurrent kidney stones since 8 years old.Secondly,to address whether kidney stones are associated with PXE,the prevalence of kidney stones in a survey cohort of 563 respondents with PXE was compared to that of a general U.S.population survey,National Health and Nutrition Examination Survey,with 28,629 participants.Results:Genetic analysis in both patients identified compound heterozygous mutations in ABCC6,c.2787+1G>T,and c.3774_3775insC.The analysis of participants 20 years old and older revealed that 23.4%of PXE patients had previously had a kidney stone,a significant increase compared to 9.2%in the general population(P<0.01).In addition,17.8%of PXE patients reported their first kidney stone episode before age of 18 years old.Conclusions:PXE correlates with an increased risk of developing kidney stones with considerable morbidity and health-care cost.

Overview on Keloid Disorder:Phenotypic Spectrum,Connective Tissue Pathology,and Treatment Development

Histopathology Targetoid hemosiderotic nevus(THN)comprises two distinctive components:a central,mostly melanocytic component and a peripheral,mostly hemorrhagic component.1 The central melanocytic nevus can either be an intradermal nevus or a compound nevus.No junctional nevi have been reported yet.There are numerous dilated irregular vascular spaces present in the region below and surrounding the nevus,accompanied by scattered lymphocytes and histiocytes.The peripheral hemorrhagic halo comprises red blood cell extravasation and hemosiderin deposits in the papillary dermis(Fig.1).