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.

An Uncommon Presentation of Darier-White Disease with Hystrix-like Palmoplantar Keratoderma.

Darier-White disease is a relatively common autosomal dominant genodermatosis caused by mutation in the ATP2A2 gene. It is characterized by multiple warty papules coalescing into plaques in the seborrheic areas and by specific histological skin changes. Palm and sole involvement in Darier-White disease is usually mild, mainly featuring discrete and small keratotic papules. We present a unique case of Darier-White disease presenting with a diffuse, mutilating hystrix-like palmoplantar keratoderma.

FOXP3 Predicts Response to Treatment in Mycosis Fungoides.

BACKGROUND: The role of the T-regulatory cells (Tregs) marker forkhead box Protein 3 (FOXP3) in mycoses fungoides (MF) pathogenesis is unclear and the results of previous studies are inconclusive. OBJECTIVE: We aimed at ascertaining the possibility that FOXP3 expression may serve to predict MF stage and response to therapy. PATIENTS AND METHODS: Immunohistochemistry staining for FOXP3 was performed on 30 skin biopsies from patients with MF, and FOXP3 expression level was quantitatively graded. Disease stage, progression, and response to treatment were determined based on clinical and imaging evidence, and association with FOXP3 expression was assessed. RESULTS: FOXP3 expression in the dermis correlated with poor response to treatment (P=0.047). A negative non-significant relationship between epidermal FOXP3 expression and clinical stage severity was observed (P=0.17). CONCLUSIONS: Dermal FOXP3 expression in MF lesions could be used to predict response to treatment in patients with MF.

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.).

Comparative Study of Frozen and Paraffin-Embedded Sections: Evaluation of Inflammatory Dermatoses.

BACKGROUND: Frozen section (FS) is often performed when histopathological evaluations are urgently required for implementation of therapeutic measures. In dermatology, this method is most commonly used to evaluate excision margins of tumors. FS are also routinely employed to differentiate toxic epidermal necrolysis from staphylococcal scalded skin syndrome. However, little is currently known about the performance of FS in the diagnosis of inflammatory dermatoses. OBJECTIVES: To compare histopathological diagnoses in a series of patients with a clinical diagnosis of an inflammatory dermatosis for which FS and paraffin-section (PS) specimens were obtained on the same day. METHODS: We conducted a single-center retrospective analysis of 43 cases. All histological slides were reviewed by a single dermato-pathologist. Concordance was calculated between FS and PS. RESULTS: Patients were divided into three groups according to diagnosis: papulosquamous diseases (group I), drug eruptions (group II), and a heterogeneous group (group III) that included cases of bullous vasculitis and Sweet syndrome. Among the three groups, the results of FS and of PS were discordant only in five cases (5/43, 11.6%). Compared to PS, FS had a sensitivity of 92.9% [95% confidence interval (95%CI) 64.17-99.63%] and a specificity of 100% in group I, sensitivity of 90.9% (95%CI 57.12-99.52%) and specificity of 100% in group II, and sensitivity of 83.33% (95%CI 60.78-94.16%) and specificity of 100% in group III. The degree of agreement between the results of the FS and of the PS was almost perfect (kappa = 0.95, 0.93 and 0.85 respectively). CONCLUSIONS: This study suggests that FS is a valid approach for the rapid diagnosis of inflammatory dermatoses. This method is as specific as PS, although it is less sensitive.

Successful treatment of Schamberg's disease with fractional non-ablative 1540 nm erbium:glass laser.

Schamberg's disease is one of the pigmented purpuric dermatoses (PPD). PPD encompass a large and heterogeneous group of dermatologic disorders featuring purpuric lesions often located on the lower limbs. The various forms of PPD are notoriously known to be resistant to treatment. Fractional photothermolysis has been described as a successful and safe method to induce dermal remodeling. We report three patients with Schamberg's disease who were successfully treated with 4 monthly sessions of fractional non-ablative 1540 nm erbium:glass laser, with resolution of their purpuric pigmented rash lasting up to 9 months after the last treatment session.

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.

Mycosis Fungoides Associated with Kaposi's Sarcoma, T-cell Rich B-cell Lymphoma, and T-cell Lymphoma with Angioimmunoblastic Features.

A patient with mycosis fungoides (MF), Kaposi's sarcoma, T-cell rich B-cell lymphoma, and T-cell lymphoma with angioimmunoblastic features is described. The appearance of multiple malignancies in this patient may have been caused by previous exposure to radiation in the Chernobyl accident and/or systemic chemotherapy for the initial T-cell rich B-cell lymphoma which he underwent.

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.

Childhood Pemphigus Foliaceus with Exclusive Immunoglobulin G Autoantibodies to Desmocollins.

Pemphigus refers to a group of potentially fatal blistering skin diseases that are often due to the deleterious effects of autoantibodies directed against desmosomal antigens. Although desmogleins have been mainly implicated as autoantigens in pemphigus, a steadily growing body of evidence suggests that other desmosomal proteins may be causally involved as well. Antibodies directed against desmocollin-3 have been shown to play a direct role in the pathogenesis of several types of pemphigus. Here we describe the case of a child with localized pemphigus foliaceus and immunoglobulin G (IgG) reactivity exclusively directed to desmocollins. The present report suggests that autoantibodies against nondesmoglein antigens may play a role in the pathogenesis of superficial pemphigus, in addition to pemphigus vulgaris, paraneoplastic pemphigus, and IgA pemphigus.

Concomitant occurrence of pyoderma gangrenosum and erythema nodosum in inflammatory bowel disease.

Erythema nodosum and pyoderma gangrenosum are common skin manifestations in inflammatory bowel diseases. Curiously, these two cutaneous features have seldom been reported to occur simultaneously. We present three patients affected with inflammatory bowel disease with concomitant erythema nodosum and pyoderma gangrenosum.

Increased expression of CD24 in nonmelanoma skin cancer.

BACKGROUND: Skin cancer detection is based on the macroscopic and microscopic appearance of the lesions and the experience of the surgeon. The final diagnosis is done by pathological analysis, based on established criteria. Currently, there is no serum marker that can be used for the diagnosis of skin cancer. CD24, a mucin-like glycoprotein, is overexpressed in a variety of cancers including skin malignancies. OBJECTIVE: Evaluate the potential utility of CD24 expression in peripheral blood leukocytes (PBLs) for the detection of nonmelanoma skin cancers (NMSC). METHODS: Twenty-nine consented individuals attending Tel Aviv Sourasky Medical Center for excision of suspected skin lesions, and 21 age- and gender-matched subjects were prospectively recruited. The resected lesions were examined by an expert dermatopathologist. PBLs were isolated from blood samples and protein extracts were subjected to sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting. The study was double blinded. RESULTS: CD24 expression in PBLs distinguishes between NMSC and healthy subjects, with high sensitivity (81%) and specificity (67%) for basal cell carcinoma, and 100% and 71%, respectively, for squamous cell carcinoma. CONCLUSION: The CD24 test can successfully distinguish NMSC from healthy subjects. CD24 may serve as a new potential and promising diagnostic biomarker for the detection and surveillance of NMSC.

New syndrome of congenital circumferential skin folds associated with multiple congenital anomalies.

Congenital circumferential skin folds can be found in individuals with no additional defects, as well as in patients with multiple congenital anomalies and developmental abnormalities. Current data point to etiological heterogeneity of syndromic cases. We describe a 7-month-old girl with a novel combination of symmetrical congenital circumferential skin folds, dysmorphic features, and multiple congenital abnormalities. Examination of the patient revealed symmetrical congenital circumferential skin folds and dysmorphic features, as well as multiple congenital anomalies including nasal pyriform aperture stenosis, ventricular septal defect, absent spleen, camptodactyly, and severe psychomotor retardation. Skin biopsy demonstrated subcutaneous fat extending into the superficial and deep reticular dermis. Sequencing of the CDON, SHH, ZIC2, SIX3, and TGIF genes (associated with holoprosencephaly) did not disclose pathogenic alterations. Extensive review of previously described cases of syndromic congenital circumferential skin folds did not reveal a similar combination of clinical and histopathological findings.

RIN2 deficiency results in macrocephaly, alopecia, cutis laxa, and scoliosis: MACS syndrome.

Inherited disorders of elastic tissue represent a complex and heterogeneous group of diseases, characterized often by sagging skin and occasionally by life-threatening visceral complications. In the present study, we report on an autosomal-recessive disorder that we have termed MACS syndrome (macrocephaly, alopecia, cutis laxa, and scoliosis). The disorder was mapped to chromosome 20p11.21-p11.23, and a homozygous frameshift mutation in RIN2 was found to segregate with the disease phenotype in a large consanguineous kindred. The mutation identified results in decreased expression of RIN2, a ubiquitously expressed protein that interacts with Rab5 and is involved in the regulation of endocytic trafficking. RIN2 deficiency was found to be associated with paucity of dermal microfibrils and deficiency of fibulin-5, which may underlie the abnormal skin phenotype displayed by the patients.

Unilateral spiny hyperkeratosis: case report and review of the literature.

We describe the first case of unilateral spiny hyperkeratosis (SH) of the left hand, review the literature and discuss possible patho- mechanisms. SH can be sporadic or familial, often appearing in healthy individuals. However, there is an association with various malignancies in a significant number of the sporadic cases. Although there is no satisfactory explanation of this association, we agree with previous authors that a patient with SH appearing in adult life should be evaluated and followed for the presence of malignancy. Other patients with SH may suffer from a variety of nonmalignant diseases, which may be coincidental or causally related. SH is not a premalignant lesion of the skin and should not be confused with porokeratosis which has a malignant potential. Except for excision of individual lesions, there is no permanent cure.

Expression of vinculin in autoimmune cutaneous diseases.

BACKGROUND: Reports have appeared that sera of patients with systemic autoimmune disorders have demonstrated autoantibodies to vinculin. OBJECTIVE: To determine the presence and distribution of vinculin in the skin of patients with cutaneous autoimmune disorders. METHODS: Semiquantitative immunohistochemistry investigations for presence of vinculin were conducted on skin biopsy specimens from patients with pemphigus vulgaris (PV), bullous pemphigoid (BP), and various collagen vascular diseases, and from healthy controls. RESULTS: Results of staining for vinculin were positive in 2 of 7 PV patients, 6 of 9 BP patients, and all 6 cutaneous autoimmune patients. Staining results were negative in all controls. Strong immunostaining to vinculin was found in 3 of 6 vinculin-positive BP patients and 5 of 6 vinculin-positive cutaneous autoimmune patients. CONCLUSIONS: The expression and distribution of vinculin are accentuated in patients with various skin autoimmune diseases and appear to be stronger in diseases involving the basement membrane, where it is thought to be relatively more important than in other skin disorders.

Focal asymmetric breast density: mammographic, sonographic and pathological correlation in 97 lesions--a call to restrain biopsies.

BACKGROUND: The imaging parameters that mandate further diagnostic workup in focal asymmetric breast densities are not clearly defined. OBJECTIVES: To identify indications for further workup in FABD by comparing mammographic and ultrasonographic findings with the pathology results of women with FABD. METHODS: Ninety-four women (97 FABD) were referred for core needle biopsy after incidental discovery of FABD on routine mammograms (n=83) or on diagnostic mammograms performed for palpable masses (n=11). Clinical data included the patient's age, use of hormone replacement therapy, family history of breast cancer, and the presence of a palpable mass. Mammograms and sonograms were evaluated for lesion size and location, associated calcifications, architectural distortion, and change from previous examinations when available. Two patient groups emerged according to the pathological findings and the data were compared. RESULTS: The average age, size and location of the lesions in the malignant (n=5) and benign (n=92) groups were similar. There was a significant difference (P<0.05) for the presence of a clinically palpable mass (60% vs. 9%, respectively), a cluster of calcifications (60% vs. 12%), associated architectural distortion (exclusively in the malignant group) and a solid mass on sonography (50% vs. 9%). The malignant group had a higher rate of family history of breast cancer and HRT use. CONCLUSIONS: FABD usually present a benign etiology and can safely be managed by follow-up. The presence of an architectural distortion, a cluster of malignant-appearing or indeterminate calcifications, a sonographic mass with features of possible malignancy, or a clinically palpable mass mandates tissue diagnosis.

Immunohistochemical expression of platelet growth factor and vascular endothelial growth factor in patients with melanoma with and without redness (Brenner sign).

OBJECTIVE: To assess whether an erythematous eruption in the vicinity of or distant from a melanoma lesion might be related to the vascular endothelial growth factor, the platelet-derived endothelial cell growth factor, or both. METHODS: Biopsy specimens from 13 patients with primary melanoma, 6 of whom had erythematous eruptions and 7 who did not, were studied by immunohistochemistry for the expression of vascular endothelial growth factor and platelet-derived endothelial cell growth factor. RESULTS: Vascular endothelial growth factor was positive in 3 of 6 patients (50%) with melanoma and redness (Brenner sign) and in 4 of 7 patients (57%) with melanoma without redness. Platelet-derived endothelial cell growth factor was positive in all 6 patients (100%) with melanoma and redness and in 4 of 7 patients (57%) with melanoma without redness. CONCLUSION: Platelet-derived endothelial cell growth factor may have a part in the pathogenesis of the redness observed in patients with melanoma, called Brenner sign, by affecting vasculature function.