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.

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.

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).

Lipoid Proteinosis Due to Homozygous Deletion Mutation(c.735delTG)in the ECM1 Gene Presents with Seizures and Hoarseness but No Skin Involvement

Histopathology The histopathological features of bowenoid papulosis(BP)are hyperkeratosis,focal keratosis,acanthosis,and cellular atypia of the epidermis characterized by hyperchromatic nuclei,prominent nucleoli,mitotic figures,epidermal multinucleated giant cells,and dyskeratotic cells.1 Slight or moderate perinuclear vacuole formation is occasionally observed.Histopathologically,BP shows similar but generally milder changes compared with Bowen's disease.Dilated capillaries and perivascular diffuse infiltration of lymphocytes can be observed in the upper dermis.The most characteristic finding of BP is an occasional transformation of bowenoid atypia to benign proliferation as time progresses,especially during the course of spontaneous regression.1 Parakeratosis,acanthosis,scattered cellular atypia of the epidermis,dyskeratotic cells,dilated capillaries,and perivascular diffuse infiltration of lymphocytes,all of which are typical histopathological features of BP,were observed in our patient(Fig.1).