Emily Avitan-Hersh

A case of H syndrome showing immunophenotye similarities to Rosai-Dorfman disease.

H syndrome (OMIM 612391) is a recently described autosomal recessive genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin and systemic manifestations including hepatosplenomegaly, cardiac anomalies, hearing loss, hypogonadism, low height, hypertriglyceridemia, hallux valgus, and flexion contractures. H syndrome results from mutations in the SLC29A3 gene, which encodes the human equilibrative nucleoside transporter hENT3. The cutaneous histopathology is characterized by a striking mononuclear cell infiltrate in the dermis consisting of CD68+ monocyte-derived cells and CD34+ and factor XIIIa+ dendrocytes. We describe a case of H syndrome in which the infiltrating mononuclear cells were CD68+, CD163+, S-100+, and CD1a-, thus simulating the immunophenotype observed in Rosai-Dorfman disease (RDD). The immunostaining for CD21, fascin, and CD34 were negative, and there were also many factor XIIIa+ dendrocytes interspersed within the dense mononuclear cell infiltrate. Recent findings of biallelic mutations in SLC29A3 in 2 families reported to have familial RDD and in a kindred with Faisalabad histiocytosis (OMIM 602782), which is an autosomal inherited form of histiocytosis with similarities to RDD, may explain the RDD-like immunophenotype in our H syndrome case.

Postzygotic HRAS Mutation Causing Both Keratinocytic Epidermal Nevus and Thymoma and Associated With Bone Dysplasia and Hypophosphatemia Due to Elevated FGF23

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 Blaschkos 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.

Anti-Laminin-332 Mucous Membrane Pemphigoid Developing After a Diphtheria Tetanus Vaccination

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.

A novel nonsense CDH3 mutation in hypotrichosis with juvenile macular dystrophy

Hypotrichosis with juvenile macular dystrophy (HJMD, MIM 601553) is a rare autosomal recessive disorder characterized by diffuse scalp hair loss and progressive retinal degeneration. While hypotrichosis is usually evident at birth, the deterioration of visual acuity develops during the first or second decade of life, resulting in early blindness. HJMD was found to result from mutations in CDH3, encoding P-cadherin, a classical cadherin molecule. P-cadherin is responsible for adherence junction and is expressed in both follicular epithelium and retinal pigment epithelium, as well as in other epithelial tissues. It is assumed that the loss of P-cadherin in the follicular and retinal epithelium cannot be compensated for by other cadherin molecules, and therefore these tissues are primarily affected when P-cadherin is altered. In a previous study, we have shown that the alopecia in HJMD is characterized by an increased number of catogen–telogen hair follicles, thus alluding to a cell cycle defect. We describe herein a case of HJMD in whom the molecular genetic study revealed an underlying novel nonsense mutation in CDH3.

Acrokeratosis verruciformis of Hopf showing P602L mutation in ATP2A2 and overlapping histopathological features with Darier disease.

Abstract: The relationship between acrokeratosis verruciformis (AKV) of Hopf and Darier disease (DD) has been debated for several decades. Both diseases are now thought to result from mutations in the same gene, that is, the ATP2A2 gene encoding the sarco (endo) plasmic reticulum Ca2+ ATPase2 pump (SERCA2), although their histopathological features are different. We sought to detect possible overlapping histopathological features between AKV and DD. Fourteen members of a family affected by AKV were analyzed for the underlying molecular genetic derangement, and 3 cases were studied histopathologically using multiple step sections. A heterozygous P602L mutation in ATP2A2 was identified as the underlying cause in this family. This mutation and a heterozygous A698V were previously described in AKV. Both mutations were not among the 162 mutations in ATP2A2, which were reported to date in DD. The histopathological study demonstrated in several consecutive step sections of 2 of the 3 studied cases, foci of small suprabasal clefts with acantholytic keratinocytes, some of which were mildly dyskeratotic. These focal features were reminiscent of the basic histopathological characteristics of DD. These shared histopathological features of AKV with DD suggest that AKV and DD are allelic disorders with variable expression of the same disease, although identical mutations in ATP2A2 in AKV and DD were not reported to date.

The Incidence of Acantholysis in Pityriasis Rubra Pilaris-Histopathological Study Using Multiple-Step Sections and Clinicopathologic Correlations.

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.

Epidermolytic Acanthoma of the Genitalia Does Not Show Mutations in KRT1 or KRT10.

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Mycophenolate mofetil therapy in adult patients with recalcitrant atopic dermatitis

Abstract Background: Patients with severe atopic dermatitis (AD) may require potent immunosuppressive therapy to control their disease. Mycophenolate mofetil (MMF) has been suggested as a safe and effective drug in these cases. Objectives: To investigate effectiveness and tolerability of oral MMF in adult patients with severe recalcitrant AD. Methods: During the years 2010–2017 oral MMF 2–3 g/day was administered to adult patients with severe recalcitrant AD who failed other major systemic drugs, or where other drugs, including cyclosporine (CSA), methotrexate, and azathioprine, were contraindicated. Results: Of 9 consecutive adult patients, 4 (44%) responded completely, 2 (22%) had partial response, and 3 (33%) did not respond at all. The MMF therapy was continued for 5–36 months (average 21 months) without major side effects. Conclusions: Oral MMF may be an effective drug in AD. Due to its good safety profile, it may be recommended as a first-line systemic therapy, or successive to CSA in the long term.

Targeting the Ubiquitin-Dependent Transcriptional and Epigenetic Landscape in Cancer

AbstractUbiquitin and ubiquitin-like (Ub/UbL) pathways play essential roles in regulating protein function and homeostasis. Dysregulation of these pathways is intimately associated with tumorigenesis. Furthermore, sensitivity to proteotoxic stress is emerging as an “Achilles heel” of cancer cells and tumors. Purpose of Review The purpose of this review was to discuss the recent discoveries in ubiquitin-regulated transcriptional and epigenetic mechanisms and potential inhibitors, targeting these mechanisms for cancer therapeutics. Recent Findings The remarkable discovery that proteasome inhibitors, such as bortezomib, are powerful therapeutics in multiple myeloma has led to the development of inhibitors that target activation enzymes (E1s) of distinct Ub/UbL pathways. Moreover, ubiquitin-dependent transcriptional and epigenetic networks have surfaced as essential for gene regulation. Components of these networks include E2s, E3s, deubiquitinating enzymes, and ancillary factors that enhance stability and activity of oncogenes, or inactivate tumor suppressors. Other regulators impinge upon the chromatin landscape of cancer, which was previously considered “undruggable.” Interestingly, approaches for targeting “degradation-resistant tumors,” where key oncogenic regulators evade their physiological degradation, are on the horizon. Additionally, inhibitors of Ub-related enzymes capable of stalling the activity of oncogenic epigenetic complexes, which all contain intrinsic ubiquitin-related activity, are emerging as potent inhibitors for their oncogenic transcription. Summary Fundamental mechanisms regarding the role of Ub/UbL pathways in cancer are now translated into inhibitors targeting Ub/UbL-dependent oncogenic gene expression. These small-molecule inhibitors and experimental drugs are making their way to the clinic, providing hope for cancer patients.