Reuven Bergman

Rambam Medical Center, H̱efa, Haifa, Israel

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Publications (218)795.34 Total impact

  • No preview · Article · Feb 2016 · American Journal of Dermatopathology
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    ABSTRACT: Aberrant sonic hedgehog signaling, mostly due to PTCH1 mutations, has been shown to play a central role in the pathogenesis of basal cell carcinoma (BCC), as well as in Basal Cell Nevus Syndrome (BCNS). Mutations in Smoothened (SMO) encoding a receptor for sonic hedgehog, have been reported in sporadic BCCs but not in BCNS. We report a case with multiple BCCs, pits and comedones in a segmental distribution over the upper part of the body, along with other findings compatible with BCNS. Histopathologically, there were different types of BCC. A heterozygous mutation (c.1234C>T, p.L412F) in SMO was detected in 3 BCCs but not in peripheral blood lymphocytes or the uninvolved skin. These were compatible with type 1 mosaic form of BCNS. The p.L412F mutation was found experimentally to result in an increased SMO transactivating activity, and the patient responded to vismodegib therapy. Activating mutations in SMO may also cause BCNS. The identification of a gain-of-function mutation in SMO causing a type 1 mosaic form of BCNS further expands our understanding of the pathogenesis of BCC, with implications for the treatment of these tumors, whether sporadic or inherited. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · British Journal of Dermatology
  • Emily Avitan-Hersh · Reuven Bergman
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    ABSTRACT: Background: The classical histopathological findings in the epidermis of pityriasis rubra pilaris (PRP) do not include acantholysis; however, acantholysis was described in several case reports and a few series of PRP with variable frequencies. We sought to establish the incidence of acantholysis in biopsies from consecutively referred PRP cases using multiple-step sections and clinicopathologic correlations. Methods: Twenty-three biopsies from 12 consecutively referred patients with classical (type 1) PRP were studied histopathologically. Each specimen was completely step sectioned. The clinical files of the patients were also reviewed. Results: Small foci of acantholysis were observed in some of the step sections of 5 of 23 (22%) biopsies obtained from 4 patients. Three biopsies showed suprabasal acantholysis, 1 of which also demonstrated mild dyskeratosis and 2 showed midepidermal acantholytic foci as well. The remaining 2 biopsies demonstrated midepidermal and subcorneal acantholysis, respectively. Small erosions were described in the physical examination of 2 of the 4 (50%) patients with acantholysis and in 1 of the 8 (12.5%) patients without acantholysis. Limitations: The number of cases. Conclusions: Small foci of acantholysis may be found in the minority of PRP biopsies, and it may be related to small erosions clinically in some patients.
    No preview · Article · Sep 2015 · The American Journal of dermatopathology
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    Elad Bergman · Yifat Sarda · Noa Ritz · Edmond Sabo · Gil Navon · Reuven Bergman · Uri Nevo
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    ABSTRACT: Human skin undergoes morphological and biochemical changes as a result of chronological aging and exposure to solar ultraviolet irradiation (photoaging). Noninvasive detection of these changes may aid in the prevention and treatment of both types of aging. This article presents a noninvasive method for the evaluation of aging skin with a unilateral stray field NMR scanner. These portable and inexpensive scanners may be suitable for in-depth skin characterization. In vivo profiles of sun-protected and sun-exposed skin from the forearms of female subjects of different ages (n = 9) were measured. Skin biopsies for histopathological examination were used as reference. T2 analysis with a bi-exponential decay model was applied and the extracted parameters were examined as markers for dermal aging. In the upper reticular dermis, a significant increase in the fraction of the slow T2 component and in the T2 value itself was found to correlate with chronological aging. For most subjects, there was an additional increase in the values of the slow T2 component and the T2 values from the sun-exposed forearm, superimposed on that measured for the sun-protected forearm. These results are in agreement with the decline in collagen content and the increase in free water content with aging. The results suggest that such a technique can be used as a tool for the assessment of aging, and that bi-exponential fitting can produce sensitive fingerprint parameters for the dermal alterations that occur during aging. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Full-text · Article · Apr 2015 · NMR in Biomedicine

  • No preview · Article · Mar 2015

  • No preview · Article · Feb 2015 · American Journal of Dermatopathology
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    ABSTRACT: : Alemtuzumab is a humanized mouse antibody targeting the CD52 cell surface, which has been effective in patients with advanced stage mycosis fungoides (MF) including erythrodermic MF and Sézary syndrome. There are a few descriptions of large cell transformation after its administration. A young patient with an acute onset of Sézary syndrome treated initially unsuccessfully with fludarabine and cyclophosphamide and later on successfully with alemtuzumab has been described. Three weeks after the beginning of therapy, however, she developed transformed T-cell lymphoma indistinguishable from CD30 anaplastic large-cell lymphoma. After bone marrow transplantation, the transformed CD30 cutaneous T-cell lymphoma recurred as a transformed CD30 plaque MF. All 3 types of lesions showed the same T-cell receptor clonal gene rearrangement, which supports the notion that Sézary syndrome, CD30 anaplastic large-cell lymphoma, and MF are interrelated.
    No preview · Article · Jan 2015 · American Journal of Dermatopathology
  • Noa Ritz · Dvora Sahar · Reuven Bergman
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    ABSTRACT: : T-cell receptor gene rearrangement studies are considered to be an adjunct to the histopathological diagnosis of mycosis fungoides (MF). Fluorophore-coupled primers in polymerase chain reactions followed by fragment analysis with a capillary electrophoresis device (GeneScan analysis) have been recently advocated and widely used. This study was performed to assess T-cell receptor γ-gene rearrangement GeneScan as an adjunct to the histopathological diagnosis of MF. We studied 163 cases. The rates of clonality using this technique were found to be 22/37 (59.5%) in early patch MF, 30/46 (65.2%) in more advanced stages, 13/34 (38.2%) in inconclusive cases, and 10/46 (21.7%) in benign inflammatory dermatoses. Our results support the histopathological criteria for the diagnosis of early patch MF, because of the close rates of clonality obtained in early patch MF with subtle histopathological findings, and in the more advanced subtypes of MF with more overt and specific histopathological criteria.
    No preview · Article · Sep 2014 · American Journal of Dermatopathology
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    ABSTRACT: : Bone involvement has been described in tumors with melanocytic differentiation such as melanotic neuroectodermal tumor of infancy, and very rarely in cellular blue nevi and neurocristic cutaneous hamartoma. We present an unusual case of facial congenital melanocytic tumor that involved the underlying bones and maxillary sinus and led to unilateral blindness. A newborn with a large red bluish patch with peripheral brown and black macules overlying marked swelling on the left side of his face was presented. The tumor was shown by magnetic resonance imaging, scintigraphy, and histopathology to invade the underlying bones and maxillary sinus and to compress the left eyeball resulting in blindness. Histopathology, immunohistochemistry, morphometric computerized microscopy, molecular genetic mutation analysis, and fluorescent in situ hybridization studies were more congruent with a melanocytic nevus. An 8.5-year follow-up was uneventful, with spontaneous partial shrinkage of the tumor.
    No preview · Article · Sep 2014 · American Journal of Dermatopathology

  • No preview · Article · Jul 2014 · American Journal of Dermatopathology
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    ABSTRACT: Importance Many drugs have been reported to induce skin and/or mucous membrane discoloration. Ezogabine (retigabine) was recently approved as an add-on drug for the treatment of partial seizures in adults with epilepsy. Mucocutaneous discoloration induced by antiepileptic drugs in general and ezogabine in particular has not been previously reported.Observations Two patients who had received multiple antiepileptic drugs for several years presented with a blue-gray skin dyspigmentation that was most pronounced on the face and lips and was associated with nail pigmentation, blue pigmentation on the hard palate, and black pigment deposits on the conjuctivae. The sole drug common to the therapeutic regimens of both patients was ezogabine. Histopathologically, the main finding was perivascular and periadnexal dermal cells heavily laden with coarse melanin granules, which appeared ultrastructurally as intracellular electron-dense granules. Four months after discontinuing ezogabine, our first patient showed a significant improvement in the mucocutaneous and nail dyspigmentation.Conclusions and Relevance The temporal relationship, clinical features, histologic and ultrastructure findings, and improvement following withdrawal of ezogabine indicate that the dyspigmentation was drug induced. Ezogabine should be added to the list of drugs that can induce mucocutaneous discoloration. The incidence of this significant adverse effect requires further investigation.
    No preview · Article · Jul 2014 · JAMA Dermatology
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    ABSTRACT: Importance Marfan syndrome (MFS) is a dominantly inherited disorder of connective tissue caused by mutations in the fibrillin 1 gene (FBN1). The most common skin finding in MFS is striae distensae. Particular individuals referred for suspected MFS who do not completely fulfill the MFS diagnostic criteria are classified as having a MASS phenotype. The acronym represents the following manifestations: a prolapsed mitral valve, myopia, aortic root enlargement, and skeletal and skin manifestations. Mutations in FBN1 have been shown to be associated in some cases with the MASS phenotype. Skin manifestations may be an important clue to the diagnosis of these disorders.Observations We studied a patient referred for unusual atrophic skin patches on the buttocks. Results of histopathological examination and electron microscopy demonstrated markedly abnormal elastic fibers. Subsequent medical genetics evaluation led ultimately to the diagnosis of the MASS phenotype and the discovery of an underlying FBN1 mutation.Conclusions and Relevance Although the clinical suspicion and diagnosis of MFS and related disorders are usually established by its main associated clinical features, including ophthalmologic, skeletal, and vascular involvement, clinicians should be aware of the associated skin manifestations, including unusual atrophic patches with abnormal elastic fibers that can sometimes be the first noted sign of the genetic disorder.
    No preview · Article · Apr 2014
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    ABSTRACT: Background: Human amnion membrane (HAM) was suggested to be a superior antigenic substrate for immunoblotting in detecting autoantibodies of autoimmune bullous skin diseases. Objectives: To determine the properties of HAM as an antigenic substrate for the detection of autoantibodies in pemphigus vulgaris and bullous pemphigoid. Methods: Immunomapping and tandem liquid chromatography mass spectrometry were used to delineate the antigenic structure of HAM. Immunoblotting and indirect immunofluorescence were used to study the diagnostic utility of HAM in 25 pemphigus patients, 41 pemphigoid patients, and 36 controls, and the results were compared to those of indirect immunofluorescence on monkey esophagus, immunoblotting using normal human skin, and enzyme-linked immunosorbent assay. Results: Immunomapping demonstrated the presence of all the antigens known to be targeted in autoimmune bullous skin diseases, in both normal human skin and HAM, except for the absence of BP230, and low threshold levels of Dsg1, Dsg3 and Dsc3 in HAM. HAM indirect immunofluorescence demonstrated anti-basement membrane zone antibodies in 48.7% of the pemphigoid patients, and anti-intercellular space antibodies in 72.0% of the pemphigus patients. HAM immunoblotting did not demonstrate anti-BP230 antibodies, but detected anti-BP180 antibodies in 53.7% of the pemphigoid patients. It did not demonstrate anti-Dsg1 and/ or anti-Dsg3 antibodies in any of the pemphigus patients. These results were inferior to those of ELISA and monkey esophagus indirect immunofluorescence. Conclusions: Compared to other studied methods, HAM does not offer advantages in detecting autoantibodies in bullous pemphigoid and pemphigus vulgaris.
    No preview · Article · Apr 2014 · The Israel Medical Association journal: IMAJ
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    ABSTRACT: Background: Comèl-Netherton syndrome is a rare congenital autosomal recessive disorder characterized by congenital ichthyosis, hair shaft abnormalities and atopic diathesis. It is caused by mutations in SPINK5, which encodes the serine protease inhibitor LEKTI. Objectives: To delineate the spectrum of mutations carried by a series of Israeli patients in an attempt to establish an effective diagnostic strategy for this disease in Israel. Methods: Mutations were identified by direct sequencing of the entire coding sequence of SPINK5 and confirmed using polymerase chain reaction-restriction fragment length polymorphism. Results: Three mutations were identified in seven families, of which two were novel. All mutations were predicted to result in premature termination of protein translation. Conclusions: This report presents the first case series of patients affected with Comèl-Netherton syndrome in Israel and suggests that some mutations reoccur in a substantial portion of cases in our country, a fact that should be taken into consideration when designing molecular analysis in new cases. © 2014 S. Karger AG, Basel.
    No preview · Article · Feb 2014 · Dermatology
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    ABSTRACT: Abbreviations: OS, Olmsted syndrome; PPK, palmoplantar keratoderma; RFLP, restriction fragment length polymorphism; TRPV, vanilloid family of transient receptor potential
    No preview · Article · Jan 2014 · Journal of Investigative Dermatology
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    ABSTRACT: Pityriasis rubra pilaris (PRP; MIM 173200) encompasses a spectrum of rare chronic papulosquamous inflammatory disorders, which have been classified into 6 subtypes(1) . Clinical features include palmoplantar keratoderma and follicular hyperkeratotic papules which coalesce into large, scaly, erythematous plaques, with frequent progression to exfoliative erythroderma. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2013 · British Journal of Dermatology
  • Ziad Khamaysi · Reuven Bergman · Gregory Telman · Dorith Goldsher
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    ABSTRACT: Most patients with neurosyphilis are considered asymptomatic. The diagnosis is challenging and the role of neuroimaging is not yet well established. The present study was conducted to focus on the clinical findings and further characterize the imaging features of the disease, along with a review of the pertinent literature. Six male patients with neurosyphilis based on abnormal cerebrospinal fluid findings, five of whom were asymptomatic at presentation, underwent cranial computerized tomography (CT) and magnetic resonance imaging (MRI). They also underwent a complete physical, neurological, and ophthalmological examination, with special attention paid to atherosclerotic vascular risk factors. In addition, all were examined for cardiac involvement using electrocardiography and cardiac ultrasound. The meticulous neurological and ophthalmological examination revealed abnormalities in five patients, most commonly cranial nerve involvement (three patients) and hemiparesis (two patients). The CT and MRI studies revealed abnormalities in five of the six patients, and in all six patients, respectively. The most common findings were brain infarcts, which were demonstrated in four of the six patients. MRI was found to be more sensitive than CT in detecting these brain infarcts, as expected. Vascular insult was the most common neuroimaging finding in our patients with neurosyphilis, probably due to meningovascular endarteritis. Neurosyphilis should always be considered in young patients with unexplained brain infarcts.
    No preview · Article · Nov 2013 · International journal of dermatology
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    ABSTRACT: Introduction: Epidermal nevus syndrome is a rare group of disorders characterized by the combination of congenital epidermal nevi and extracutaneous features, including skeletal, neurological, ocular, and other systemic findings. We report a case of keratinocytic epidermal nevus syndrome that includes a thymoma, bone dysplasia, and hypophosphatemia with elevated fibroblast growth factor 23 (FGF23) levels associated with postzygotic HRAS mutation. Case report: A 14-year-old boy was admitted due to recent limping. The physical examination revealed multiple right-sided linear epidermal nevi along Blaschko's lines. Magnetic resonance imaging showed cystic lesions in cervical bones and thymoma, and x-ray examination showed cystic lesions in the hands. Biochemical studies demonstrated severe hypophosphatemia, normocalcemia, high normal PTH, low 25-hydroxyvitamin D and low 1,25-dihydroxyvitamin D levels. The serum FGF23 C-terminal level was normal, but the intact FGF23 level was found to be elevated. Genetic evaluation revealed a heterozygote mutation in the HRAS gene in both the keratinocytic epidermal nevus and thymoma but not in DNA extracted from blood lymphocytes, thus establishing the mutation as postzygotic. Discussion: Postzygotic mutations in HRAS lead to elevation of FGF23 levels, as found in mutated PHEX, FGF23, DMP1, and ENPP1 genes, which lead to hypophosphatemia. Conclusion: An identical postzygotic HRAS mutation was shown to be present in both keratinocytic epidermal nevus and thymoma and to be associated with bone lesions and hypophosphatemia due to elevated FGF23 levels. These may all be related to the HRAS mutation.
    No preview · Article · Nov 2013 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: The relative contribution of immunological dysregulation and impaired epithelial barrier function to allergic diseases is still a matter of debate. Here we describe a new syndrome featuring severe dermatitis, multiple allergies and metabolic wasting (SAM syndrome) caused by homozygous mutations in DSG1. DSG1 encodes desmoglein 1, a major constituent of desmosomes, which connect the cell surface to the keratin cytoskeleton and have a crucial role in maintaining epidermal integrity and barrier function. Mutations causing SAM syndrome resulted in lack of membrane expression of DSG1, leading to loss of cell-cell adhesion. In addition, DSG1 deficiency was associated with increased expression of a number of genes encoding allergy-related cytokines. Our deciphering of the pathogenesis of SAM syndrome substantiates the notion that allergy may result from a primary structural epidermal defect.
    Full-text · Article · Aug 2013 · Nature Genetics
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    ABSTRACT: Importance: Bullous pemphigoid (BP) has been previously described to develop after vaccination in 26 patients. Immunoblotting or enzyme-linked immunosorbent assays (ELISAs), which were performed for 7 of these patients, have always shown circulating autoantibodies against BP180 and/or BP230 antigens. A case of anti-laminin-332 mucous membrane pemphigoid (MMP) that developed shortly after a diphtheria tetanus vaccination is described, with a review of the literature on postvaccination BP. Observations: A 29-year-old man developed an acute eruption of oral and cutaneous blisters and erosions 2 days after receiving a diphtheria tetanus vaccination. The histopathological, immunohistochemical, immunofluorescent, ELISA, and immunoblotting assay results were compatible with anti-laminin-332 MMP. The serum autoantibodies reacted with the α3 and β3 subunits of laminin-332. The disease was controlled by administering a combination of glucocorticosteroids and dapsone. Conclusions and relevance: The development of acute MMP shortly after a diphtheria tetanus vaccination may have been serendipitous, a result of a nonspecific bystander activation of the immune system, or due to structural mimicry between domains of the toxoid molecule and a subunit of laminin-332.
    No preview · Article · May 2013

Publication Stats

5k Citations
795.34 Total Impact Points


  • 1988-2015
    • Rambam Medical Center
      • • Department of Dermatology
      • • Department of Pathology
      • • Department of Oncology
      H̱efa, Haifa, Israel
  • 1985-2015
    • Technion - Israel Institute of Technology
      • • Rambam Medical Center
      • • Ruth and Bruce Rappaport Faculty of Medicine
      H̱efa, Haifa, Israel
  • 2005
    • Tel Aviv University
      • Department of Dermatology
      Tell Afif, Tel Aviv, Israel
  • 2002
    • Hungarian Academy of Sciences
      • Institute of Enzymology
      Budapeŝto, Budapest, Hungary
    • Bnai Zion Medical Center, Haifa
      H̱efa, Haifa District, Israel
  • 2000
    • CLALIT
      Tell Afif, Tel Aviv, Israel