BioNTech COVID-19 (BNT162b2) Vaccination and Varicella Zoster Reactivation: A Comprehensive Cross-sectional Study.

Herpes zoster (HZ) results from reactivation of latent varicella-zoster virus. Recent observations have suggested that HZ is associated with vaccination against COVID-19. To investigate the association between the vaccine and HZ severity, a single-centre, cross-sectional study of all patients diagnosed with HZ and 2 control diagnoses (cellulitis and bone fractures), between 2017 and 2021, was performed. Hospital visits and hospitalization rates were compared. All medical records of patients diagnosed with HZ in the first year after the COVID-19 vaccination campaign began were reviewed, in order to generate a retrospective cohort comparing vaccinated and unvaccinated patients with HZ. All participants had received the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine. During the study period, 2,413 patients were diagnosed with HZ, and when normalized to control diagnoses the number of cases remained stable. The retrospective cohort included 365 patients. A multivariate analysis controlling for sex, age, autoimmune diseases, malignancies, and immunosuppressive therapy showed higher admission rates in vaccinated compared with unvaccinated individuals (odds ratio (OR) 2.75, 95% CI 1.27-5.96, p = 0.01). However, matching techniques and stratification by age, used to better control for confounders, invalidated these findings. No differences were observed in other variables indicative of disease severity (hospital stay length and complications). In conclusion, COVID-19 vaccination was not found to be associated with an increased risk of HZ-related admission and complications.

Identification of Risk Factors for Gliptin-associated Bullous Pemphigoid among Diabetic Patients.

Drug-associated bullous pemphigoid has been shown to follow long-term gliptin (dipeptidyl-peptidase 4 inhibitors) intake. This study aimed at identifying risk factors for gliptin-associated bullous pemphigoid among patients with type 2 diabetes. A retrospective study was conducted in a tertiary centre among diabetic patients exposed to gliptins between the years 2008-2021. Data including demographics, comorbidities, medications, and laboratory results were collected using the MDClone platform. Seventy-six patients with type 2 diabetes treated with dipeptidyl-peptidase 4 inhibitors who subsequently developed bullous pemphigoid were compared with a cohort of 8,060 diabetic patients exposed to dipeptidyl-peptidase 4 inhibitors who did not develop bullous pemphigoid. Based on a multivariable analysis adjusted for age and other covariates, Alzheimer's disease and other dementias were significantly more prevalent in patients with bullous pemphigoid (p = 0.0013). Concomitant use of either thiazide or loop diuretics and gliptin therapy was associated with drug-associated bullous pemphigoid (p < 0.0001 for both). While compared with sitagliptin, exposure to linagliptin and vildagliptin were associated with bullous pemphigoid with an odds ratio of 5.68 and 6.61 (p < 0.0001 for both), respectively. These results suggest gliptins should be prescribed with caution to patients with type 2 diabetes with coexisting Alzheimer's and other dementias, or patients receiving long-term use of thiazides and loop diuretics. The use of sitagliptin over linagliptin and vildagliptin should be preferred in these patients.

Visual impairment and cognitive performance: A nationwide study of 1.4 million adolescents.

PURPOSE: Previous research highlights the adverse effects of visual impairment (VI) on academic achievement in children, yet its impact on cognitive performance among adolescents and young adults remains under-studied. Therefore, this investigation aimed to analyse this association in a nationwide sample of Israeli adolescents. METHODS: A retrospective population-based cross-sectional study was conducted among 1,410,616 Israeli-born adolescents aged 16-19 years, who were assessed before mandatory military service between 1993 and 2017. The definition of VI was based on best-corrected visual acuity (BCVA) measurements using a standard Snellen chart. Adolescents with BCVA worse than 6/9 in either or both eyes were classified as having unilateral or bilateral VI, respectively. Cognitive performance was measured using the General Intelligence Score (GIS), based on a validated four-domain test. Relationships were analysed using regression models yielding adjusted odds ratios (ORs) for low (<-1 standard deviation [SD]) and high (≥1 SD) cognitive Z-scores. RESULTS: Of 1,410,616 adolescents (56.1% men), 13,773 (1.0%) had unilateral and 3980 (0.3%) had bilateral VI. Unilateral VI was associated with adjusted ORs for low and high cognitive Z-scores of 1.24 (1.19-1.30) and 0.84 (0.80-0.89), respectively. ORs were accentuated for bilateral VI, reaching 1.62 (1.50-1.75) and 0.81 (0.74-0.90) for low and high cognitive Z-scores, respectively. Cognitive performance subscores mirrored these results, with the visual-spatial functioning subtest demonstrating the greatest effect size. These associations persisted in sub-analyses restricted to adolescents with amblyopia-related VI, mild VI and unimpaired health status. CONCLUSIONS: Visual impairment, including mild and unilateral cases, is associated with reduced cognitive performance scores assessed in late adolescence. Further research is required to gain a comprehensive understanding of the dynamics underlying this relationship.

Dominant frontonasal dysplasia with ectodermal defects results from increased activity of ALX4.

Frontonasal dysplasia (FND) refers to a group of rare developmental disorders characterized by abnormal morphology of the craniofacial region. We studied a family manifesting with clinical features typical for FND2 including neurobehavioral abnormalities, hypotrichosis, hypodontia, and facial dysmorphism. Whole-exome sequencing analysis identified a novel heterozygous frameshift insertion in ALX4 (c.985_986insGTGC, p.Pro329Argfs*115), encoding aristaless homeobox 4. This and a previously reported dominant FND2-causing variant are predicted to result in the formation of a similar abnormally elongated protein tail domain. Using a reporter assay, we showed that the elongated ALX4 displays increased activity. ALX4 negatively regulates the Wnt/ß-catenin pathway and accordingly, patient keratinocytes showed altered expression of genes associated with the WNT/ß-catenin pathway, which in turn may underlie ectodermal manifestations in FND2. In conclusion, dominant FND2 with ectodermal dysplasia results from frameshift variants in ALX4 exerting a gain-of-function effect.

Woolly hair in tricho-dento-osseous syndrome.

Tricho-dento-osseous syndrome (TDOS) is a rare ectodermal dysplasia caused by mutations in the DLX3 gene and it is not usually included as a cause of syndromic woolly hair. We present a new case of TDOS with a novel DLX3 variant and woolly hair.

Variant PADI3 in Central Centrifugal Cicatricial Alopecia.

BACKGROUND: Central centrifugal cicatricial alopecia (CCCA) is the most common form of scarring alopecia among women of African ancestry. The disease is occasionally observed to affect women in families in a manner that suggests an autosomal dominant trait and usually manifests clinically after intense hair grooming. We sought to determine whether there exists a genetic basis of CCCA and, if so, what it is. METHODS: We used exome sequencing in a group of women with alopecia (discovery set), compared the results with those in a public repository, and applied other filtering criteria to identify candidate genes. We then performed direct sequencing to identify disease-associated DNA variations and RNA sequencing, protein modeling, immunofluorescence staining, immunoblotting, and an enzymatic assay to evaluate the consequences of potential etiologic mutations. We used a replication set that consisted of women with CCCA to confirm the data obtained with the discovery set. RESULTS: In the discovery set, which included 16 patients, we identified one splice site and three heterozygous missense mutations in PADI3 in 5 patients (31%). (The approximate prevalence of the disease is up to 5.6%.) PADI3 encodes peptidyl arginine deiminase, type III (PADI3), an enzyme that post-translationally modifies other proteins that are essential to hair-shaft formation. All three CCCA-associated missense mutations in PADI3 affect highly conserved residues and are predicted to be pathogenic; protein modeling suggests that they result in protein misfolding. These mutations were found to result in reduced PADI3 expression, abnormal intracellular localization of the protein, and decreased enzymatic activity - findings that support their pathogenicity. Immunofluorescence staining showed decreased expression of PADI3 in biopsy samples of scalp skin obtained from patients with CCCA. We then directly sequenced PADI3 in an additional 42 patients (replication set) and observed genetic variants in 9 of them. A post hoc analysis of the combined data sets showed that the prevalence of PADI3 mutation was higher among patients with CCCA than in a control cohort of women of African ancestry (P = 0.002 by the chi-square test; P = 0.006 by Fisher's exact test; and after adjustment for relatedness of persons, P = 0.03 and P = 0.04, respectively). CONCLUSIONS: Mutations in PADI3, which encodes a protein that is essential to proper hair-shaft formation, were associated with CCCA. (Funded by the Ram Family Foundation and others.).

Loss-of-function variants in KLF4 underlie autosomal dominant palmoplantar keratoderma.

PURPOSE: Palmoplantar keratodermas (PPKs) form a group of disorders characterized by thickening of palm and sole skin. Over the past 2 decades, many types of inherited PPKs have been found to result from abnormal expression, processing, or function of adhesion proteins. METHODS: We used exome and direct sequencing to detect causative pathogenic variants. Functional analysis of these variants was conducted using reverse transcription quantitative polymerase chain reaction, immunofluorescence confocal microscopy, immunoblotting, a promoter reporter assay, and chromatin immunoprecipitation. RESULTS: We identified 2 heterozygous variants (c.1226A>G and c.633_634dupGT) in KLF4 in 3 individuals from 2 different unrelated families affected by a dominant form of PPK. Immunofluorescence staining for a number of functional markers revealed reduced epidermal DSG1 expression in patients harboring heterozygous KLF4 variants. Accordingly, human keratinocytes either transfected with constructs expressing these variants or downregulated for KLF4 displayed reduced DSG1 expression, which in turn has previously been found to be associated with PPK. A chromatin immunoprecipitation assay confirmed direct binding of KLF4 to the DSG1 promoter region. The ability of mutant KLF4 to transactivate the DSG1 promoter was significantly decreased when compared with wild-type KLF4. CONCLUSION: Loss-of-function variants in KLF4 cause a novel form of dominant PPK and show its importance in the regulation of epidermal differentiation.

Coexistence of pachyonychia congenita and hidradenitis suppurativa: more than a coincidence.

BACKGROUND: The coexistence of pachyonychia congenita (PC) and hidradenitis suppurativa (HS) has been described in case reports. However, the pathomechanism underlying this association and its true prevalence are unknown. OBJECTIVES: To determine the genetic defect underlying the coexistence of PC and HS in a large kindred, to delineate a pathophysiological signalling defect jointly leading to both phenotypes, and to estimate the prevalence of HS in PC. METHODS: We used direct sequencing and a NOTCH luciferase reporter assay to characterize the pathophysiological basis of the familial coexistence of HS and PC. A questionnaire was distributed to patients with PC registered with the International Pachyonychia Congenita Research Registry (IPCRR) to assess the prevalence of HS among patients with PC. RESULTS: Direct sequencing of DNA samples obtained from family members displaying both PC and HS demonstrated a missense variant (c.275A>G) in KRT17, encoding keratin 17. Abnormal NOTCH signalling has been suggested to contribute to HS pathogenesis. Accordingly, the KRT17 c.275A>G variant resulted in a significant decrease in NOTCH activity. To ascertain the clinical importance of the association of HS with PC, we distributed a questionnaire to all patients with PC registered with the IPCRR. Seventy-two of 278 responders reported HS-associated clinical features (25·9%). Disease-causing mutations in KRT17 were most prevalent among patients with a dual phenotype of PC and HS (43%). CONCLUSIONS: The coexistence of HS and KRT17-associated PC is more common than previously thought. Impaired NOTCH signalling as a result of KRT17 mutations may predispose patients with PC to HS. What is already known about this topic? The coexistence of pachyonychia congenita (PC) and hidradenitis suppurativa (HS) has been described in case reports. However, the pathomechanism underlying this association and its true prevalence are unknown. What does this study add? A dual phenotype consisting of PC and HS was found to be associated with a pathogenic variant in KRT17. This variant was found to affect NOTCH signalling, which has been previously implicated in HS pathogenesis. HS was found to be associated with PC in a large cohort of patients with PC, especially in patients carrying KRT17 variants, suggesting that KRT17 variants causing PC may also predispose to HS. What is the translational message? These findings suggest that patients with PC have a higher prevalence of HS than previously thought, and hence physicians should have a higher level of suspicion of HS diagnosis in patients with PC.

Myopia and Childhood Migration: A Study of 607 862 Adolescents.

PURPOSE: Immigration studies can shed light on myopia development and reveal high-risk populations. To this end, we investigated the association among immigration, age at immigration, and myopia occurrence during adolescence. DESIGN: Population-based, retrospective, cross-sectional study. PARTICIPANTS: Six hundred seven thousand eight hundred sixty-two adolescents, Israeli born and immigrants, with origins in the former Union of Soviet Socialist Republics (USSR), Ethiopia, or Israel, assessed for medical fitness for mandatory military service at 17 years of age between 1993 and 2016. METHODS: Myopia and high myopia were defined based on right eye refractive data. Age at immigration was categorized into 0 to 5 years of age, 6 to 11 years of age, and 12 to 19 years of age. Univariate and multivariate logistic regression models were created. Myopia odds ratios (ORs) were calculated according to immigration status, with Israeli-born natives as controls. Next, myopia ORs were calculated according to age at immigration, with Israeli-born of same origin as controls. MAIN OUTCOME MEASURES: Myopia prevalence and ORs. RESULTS: Myopia was less prevalent among immigrants than Israeli-born controls. When stratified according to age at immigration, a decrease in myopia prevalence and ORs with increasing age at migration were observed, most prominent in immigrants arriving after 11 years of age, who also showed lower high-myopia ORs. The immigrants from the USSR and Ethiopia arriving after 11 years of age showed a myopia OR of 0.65 (95% confidence interval [CI], 0.63-0.67; P < 10-205) and 0.52 (95% CI, 0.46-0.58; P < 10-27) compared with the Israeli-born controls. Notably, Ethiopians arriving earlier than 5 years of age showed a 2-fold higher myopia OR than those migrating after 11 years of age. CONCLUSIONS: Immigrants arriving after 11 years of age showed markedly lower ORs for myopia and high myopia relative to Israeli-born controls or those arriving during early childhood, likely because of environmental and lifestyle changes. Differences between immigrants arriving up to 5 years of age and those arriving between 6 and 11 years of age were relatively smaller, suggesting exposures at elementary school age play a greater role in this population.

Phenotypic suppression of acral peeling skin syndrome in a patient with autosomal recessive congenital ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) manifests with generalized scaling often associated with generalized erythema. Mutations in at least 13 different genes have been reported to cause ARCI. Acral peeling skin syndrome (APSS) is a rare autosomal recessive disorder manifesting with peeling over the distal limbs and dorsal surfaces of hands and feet. APSS is mostly due to mutations in TGM5, encoding transglutaminase 5. Both ARCI and APSS are fully penetrant genetic traits. Here, we describe a consanguineous family in which one patient with mild ARCI was found to carry a homozygous mutation in ALOXE3 (c.1238G > A; p.Gly413Asp). The patient was also found to carry a known pathogenic homozygous mutation in TGM5 (c.1335G > C; p.Lys445Asn) but did not display acral peeling skin. Her uncle carried the same homozygous mutation in TGM5 but carried the ALOXE3 mutation in a heterozygous state and showed clinical features typical of APSS. Taken collectively, these observations suggested that the ALOXE3 mutation suppresses the clinical expression of the TGM5 variant. We hypothesized that ALOXE3 deficiency may affect the expression of a protein capable of compensating for the lack of TGM5 expression. Downregulation of ALOXE3 in primary human keratinocytes resulted in increased levels of corneodesmosin, which plays a critical role in the maintenance of cell-cell adhesion in the upper epidermal layers. Accordingly, ectopic corneodesmosin expression rescued the cell-cell adhesion defect caused by TGM5 deficiency in keratinocytes as ascertained by the dispase dissociation assay. The present data thus provide evidence for phenotypic suppression in a human hereditary skin disorder.

Loss-of-function mutations in caspase recruitment domain-containing protein 14 (CARD14) are associated with a severe variant of atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a highly prevalent chronic inflammatory skin disease that is known to be, at least in part, genetically determined. Mutations in caspase recruitment domain-containing protein 14 (CARD14) have been shown to result in various forms of psoriasis and related disorders. OBJECTIVE: We aimed to identify rare DNA variants conferring a significant risk for AD through genetic and functional studies in a cohort of patients affected with severe AD. METHODS: Whole-exome and direct gene sequencing, immunohistochemistry, real-time PCR, ELISA, and functional assays in human keratinocytes were used. RESULTS: In a cohort of patients referred with severe AD, DNA sequencing revealed in 4 patients 2 rare heterozygous missense mutations in the gene encoding CARD14, a major regulator of nuclear factor κB (NF-κB). A dual luciferase reporter assay demonstrated that both mutations exert a dominant loss-of-function effect and result in decreased NF-κB signaling. Accordingly, immunohistochemistry staining showed decreased expression of CARD14 in patients' skin, as well as decreased levels of activated p65, a surrogate marker for NF-κB activity. CARD14-deficient or mutant-expressing keratinocytes displayed abnormal secretion of key mediators of innate immunity. CONCLUSIONS: Although dominant gain-of-function mutations in CARD14 are associated with psoriasis and related diseases, loss-of-function mutations in the same gene are associated with a severe variant of AD.

Identification of a Functional Risk Variant for Pemphigus Vulgaris in the ST18 Gene.

Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease caused by disruption of intercellular adhesion due to auto-antibodies directed against epithelial components. Treatment is limited to immunosuppressive agents, which are associated with serious adverse effects. The propensity to develop the disease is in part genetically determined. We therefore reasoned that the delineation of PV genetic basis may point to novel therapeutic strategies. Using a genome-wide association approach, we recently found that genetic variants in the vicinity of the ST18 gene confer a significant risk for the disease. Here, using targeted deep sequencing, we identified a PV-associated variant residing within the ST18 promoter region (p<0.0002; odds ratio = 2.03). This variant was found to drive increased gene transcription in a p53/p63-dependent manner, which may explain the fact that ST18 is up-regulated in the skin of PV patients. We then discovered that when overexpressed, ST18 stimulates PV serum-induced secretion of key inflammatory molecules and contributes to PV serum-induced disruption of keratinocyte cell-cell adhesion, two processes previously implicated in the pathogenesis of PV. Thus, the present findings indicate that ST18 may play a direct role in PV and consequently represents a potential target for the treatment of this disease.

Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis.

Despite recent advances in our understanding of the pathogenesis of ectodermal dysplasias (EDs), the molecular basis of many of these disorders remains unknown. In the present study, we aimed at elucidating the genetic basis of a new form of ED featuring facial dysmorphism, scalp hypotrichosis and hypodontia. Using whole exome sequencing, we identified 2 frameshift and 2 missense mutations in TSPEAR segregating with the disease phenotype in 3 families. TSPEAR encodes the thrombospondin-type laminin G domain and EAR repeats (TSPEAR) protein, whose function is poorly understood. TSPEAR knock-down resulted in altered expression of genes known to be regulated by NOTCH and to be involved in murine hair and tooth development. Pathway analysis confirmed that down-regulation of TSPEAR in keratinocytes is likely to affect Notch signaling. Accordingly, using a luciferase-based reporter assay, we showed that TSPEAR knock-down is associated with decreased Notch signaling. In addition, NOTCH1 protein expression was reduced in patient scalp skin. Moreover, TSPEAR silencing in mouse hair follicle organ cultures was found to induce apoptosis in follicular epithelial cells, resulting in decreased hair bulb diameter. Collectively, these observations indicate that TSPEAR plays a critical, previously unrecognized role in human tooth and hair follicle morphogenesis through regulation of the Notch signaling pathway.

Isolated Superior Rectus Muscle Hematoma Following Blunt Orbital Trauma.

Isolated ocular muscle hematoma due to blunt trauma is very rare. In this study, a 15-year-old patient presented with an isolated superior rectus hematoma due to an orbital hit from a cellular phone. He was treated with oral corticosteroids alone. Marked improvement in symptoms and eye movements was observed.

Unique Imaging Features Enabling the Prenatal Diagnosis of Developmental Venous Anomalies: A Persistent Echogenic Brain Lesion Drained by a Collecting Vein in Contrast with Normal Brain Parenchyma on MRI.

OBJECTIVE: To describe the prenatal imaging features enabling diagnosis of developmental venous anomalies (DVA). METHODS: Four fetuses with unexplained persistent echogenic parenchymal brain lesions were studied. The evaluation included dedicated neurosonography, fetal MRI, serology for intrauterine infection, screening for coagulation abnormalities, and chromosomal microarray. Postnatal neurodevelopmental follow-up or autopsy results were assessed. RESULTS: DVA presented as very slowly growing echogenic brain lesions without cystic components, calcifications, or structural changes on otherwise normal neurosonographic scans performed at 2- to 3-week intervals. A specific Doppler feature was a collecting vein draining the echogenic parenchyma. Fetal brain MRI depicted normal anatomy on half-Fourier acquisition single-shot turbo spin-echo and diffusion-weighted imaging. The rest of the evaluation was normal. CONCLUSIONS: In cases with a persistent, parenchymal echogenic lesion without clastic or structural changes, DVA should be considered. Demonstration of a collecting vein draining the lesion and normal brain anatomy on MRI confirm the diagnosis.

[IONIZING RADIATION AND THE RISK FOR CATARACT AND LENS OPACITIES].

INTRODUCTION: The lens of the eye is among the most sensitive organs to ionizing radiation in the human body. The cataract is the earliest documented side effect of ionizing radiation, first reported in lab animals in 1897, only a year after the discovery of X-rays, and in 1906 among human radiation technicians. However, the exact mechanisms underlining this pathology have yet to be uncovered. In particular, the question as to whether radiation-induced cataract is a deterministic event, meaning a threshold dose must be exceeded in order for it to develop, still remains. Recent epidemiological studies, performed on populations exposed to lower radiation doses than those previously perceived cataractogenic, have led the International Commission on Radiological Protection (ICRP) in April 2011 to reduce its eye dose threshold for cataract induction from 2 Gy to 0.5 Gy, and the occupational annual dose limit from 150 mSv to 20 mSv/year. However, the ICRP have yet to support a stochastic effect (linear non-threshold) for radiation- induced cataract, although suggested by several studies. In this article, we review the current knowledge on radiation-induced cataract, including the speculated mechanism for its development, evidence for genetically predisposed populations, and the main recent epidemiological studies.

Immigration to Israel during childhood is associated with diabetes at adolescence: a study of 2.7 million adolescents.

AIMS/HYPOTHESIS: Immigration studies can shed light on diabetes pathogenesis and risk factors. To this end, we investigated the association between age at immigration and diabetes occurrence at adolescence among immigrants to Israel. METHODS: We analysed cross-sectional data on 2,721,767 Jewish adolescents assessed for mandatory military service at approximately 17 years of age between 1967 and 2014. The study population comprised 430,176 immigrants with origins in Ethiopia, former USSR, Middle East and North Africa (ME/NA) and western countries. ORs for diabetes were calculated for men and women, grouped according to age at immigration, with Israel-born participants as controls. Unadjusted and fully adjusted models were made to account for possible confounders. Additionally, the study population was stratified by origin and each immigrant group was referenced to Israel-born participants of the same origin. RESULTS: There was a graded decrease in OR for diabetes across the study groups in the fully adjusted model. Immigrants arriving at age 0-5 years had comparable OR for diabetes to the Israeli-born reference group; those arriving at age 6-11 years had an OR of 0.82 (95% CI 0.70, 0.97; p = 0.017) and recent immigrants, arriving at age 12-19 years, had the lowest OR of 0.65 (95% CI 0.54, 0.77; p < 0.0001). When age at immigration was treated as a continuous variable, there was an adjusted risk for occurrence of diabetes of 0.97 (95% CI 0.96, 0.99; p = 0.001) for every year increment. The lower risk for diabetes among recent immigrants persisted in the unadjusted model and persisted when the study sample was stratified by sex and origin, except for immigrants arriving from ME/NA. Notably, Ethiopians born in Israel had a sixfold higher diabetes crude prevalence than Ethiopian immigrants arriving after the age of 5 years. CONCLUSIONS/INTERPRETATION: Immigrants of different ethnic groups arriving earlier in childhood lose their protection against diabetes at adolescence, relative to children born in Israel. This is perhaps due to environmental and lifestyle changes, especially those beginning at an early age.

Epidermolytic Ichthyosis Sine Epidermolysis.

Epidermolytic ichthyosis (EI) is a rare disorder of cornification caused by mutations in KRT1 and KRT10, encoding two suprabasal epidermal keratins. Because of the variable clinical features and severity of the disease, histopathology is often required to correctly direct the molecular analysis. EI is characterized by hyperkeratosis and vacuolar degeneration of the upper epidermis, also known as epidermolytic hyperkeratosis, hence the name of the disease. In the current report, the authors describe members of 2 families presenting with clinical features consistent with EI. The patients were shown to carry classical mutations in KRT1 or KRT10, but did not display epidermolytic changes on histology. These observations underscore the need to remain aware of the limitations of pathological features when considering a diagnosis of EI.

Somatic Mosaicism for a "Lethal" GJB2 Mutation Results in a Patterned Form of Spiny Hyperkeratosis without Eccrine Involvement.

BACKGROUND: Spiny hyperkeratosis refers to a rare clinical phenotype characterized by nonfollicular keratotic projections and sometimes associated with other acquired and inherited conditions. We describe a case of congenital patterned spiny hyperkeratosis. METHODS: To identify the cause of this disorder, we used a combination of whole exome sequencing, direct sequencing and TaqMan assay. RESULTS: We found that the peculiar clinical features displayed by the patient are due to somatic mosaicism for a heterozygous mutation in the GJB2 gene. CONCLUSION: Because histopathologic examination of two independent biopsies did not reveal porokeratotic eccrine ostial and dermal duct nevus (PEODDN), previously reported to result from somatic mutations in GJB2, it appears that mutations in this gene can cause nevoid spiny hyperkeratosis in the context of PEODDN or as an isolated finding.

Proteolytic and Antiproteolytic Activity in the Skin: Gluing the Pieces Together.

Epidermal differentiation is ultimately aimed at the formation of a functional barrier capable of protecting the organism from the environment while preventing loss of biologically vital elements. Epidermal differentiation entails a delicately regulated process of cell-cell junction formation and dissolution to enable upward cell migration and desquamation. Over the past two decades, the deciphering of the genetic basis of a number of inherited conditions has delineated the pivotal role played in this process by a series of proteases and protease inhibitors, including serpins, cathepsins, and cystatins, suggesting novel avenues for therapeutic intervention in both rare and common disorders of cornification.