Granulomatous Skin Lesions Research Articles

Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide

Artemis deficiency is known to result in classical T-B- severe combined immunodeficiency (SCID) in case of Artemis null mutations, or Omenn's syndrome in case of hypomorphic mutations in the Artemis gene. We describe two unrelated patients with a relatively mild clinical T-B- SCID phenotype, caused by different homozygous Artemis splice-site mutations. The splice-site mutations concern either dysfunction of a 5' splice-site or an intronic point mutation creating a novel 3' splice-site, resulting in mutated Artemis protein with residual activity or low levels of wild type (WT) Artemis transcripts. During the first 10 years of life, the patients suffered from recurrent infections necessitating antibiotic prophylaxis and intravenous immunoglobulins. Both mutations resulted in increased ionizing radiation sensitivity and insufficient variable, diversity and joining (V(D)J) recombination, causing B-lymphopenia and exhaustion of the naive T-cell compartment. The patient with the novel 3' splice-site had progressive granulomatous skin lesions, which disappeared after stem cell transplantation (SCT). We showed that an alternative approach to SCT can, in principle, be used in this case; an antisense oligonucleotide (AON) covering the intronic mutation restored WT Artemis transcript levels and non-homologous end-joining pathway activity in the patient fibroblasts.

Behavioral and Recreational Risk Factors for Free‐Living Amebic Infections

Free‐living amebae of the genera Acanthamoeba , Balamuthia , Naegleria , and Sappinia are rare causes of infectious diseases in humans with the exception of Acanthamoeba keratitis (AK), which is reported in over 10,000 soft contact lens wearers annually worldwide. Unlike several Acanthamoeba species, which can cause both AK and granulomatous amebic encephalitis (GAE), only one species of Naegleria , Naegleria fowleri , is known to infect humans by causing an acute, fulminant, usually lethal, central nervous system (CNS) infection, known as primary amebic meningoencephalitis (PAM). 1–6 Both Acanthamoeba species and N fowleri are distributed worldwide; found commonly in freshwater; and have even been isolated from tap water, air conditioning systems, and improperly maintained swimming pools. 1–5 Balamuthia mandrillaris , formerly known as leptomyxid ameba, is another opportunistic, free‐living ameba. Like Acanthamoeba spp, B mandrillaris is capable of causing skin lesions and GAE in individuals with compromised or competent immune systems, who inhale infective spores or develop indolent, granulomatous skin lesions in soil‐contaminated wounds. Lastly, Sappinia pedata , a recently identified free‐living ameba that lives in soil and domestic animal feces, has caused a single case of non‐GAE in an immunocompetent Texas farmer. CNS infections caused by these ubiquitous organisms remain rare despite expanding world populations; but are, nevertheless, increasing today due to a combination of factors including increased freshwater recreational activities during heat waves for PAM, more immunocompromised individuals susceptible to GAE, and more soft contact lens wearers at risk of AK. 6,7 The purpose of this review will be to describe the epidemiology, pathophysiology, clinical manifestations, diagnosis, and management of free‐living amebic infections. In addition, United States Centers for Disease Control and Prevention (CDC) laboratory‐confirmed cases of PAM, B mandrillaris GAE, and AK will be analyzed statistically to determine significant risk factors for exposure and infection; and to … Corresponding Author: James H. Diaz, MD, MPH&TM, Dr PH, School of Public Health, Louisiana State University Health Sciences Center (LSUHSC) in New Orleans, 1615 Poydras Street, Suite 1400, New Orleans, LA 70112, USA. E‐mail: jdiaz{at}lsuhsc.edu

Granulomatous skin lesions complicating Varicella infection in a patient with Rothmund-Thomson syndrome and immune deficiency: case report

Rothmund-Thomson syndrome (RTS)(OMIM 268400) is a rare autosomal recessive genodermatosis characterized by poikiloderma, small stature, skeletal and dental abnormalities, cataract and an increased risk of cancer. It is caused by mutations in RECQL4 at 8q24. Immune deficiency is not described as a classical feature of the disease. Here we report the appearance of granulomatous skin lesions complicating primary Varicella Zoster Virus infection in a toddler with Rothmund Thomson syndrome and immune deficiency. Although granulomatous disorders are sometimes seen after Herpes zoster, they are even more rare after Varicella primary infection. Granulomas have hitherto not been described in Rothmund-Thomson syndrome. With this report we aim to stress the importance of screening for immune deficiency in patients with Rothmund-Thomson syndrome.

CD8‐positive granulomatous mycosis fungoides: a case report with review of the literature

Granulomatous mycosis fungoides (GMF) represents an uncommon variant of mycosis fungoides (MF) characterized by the presence of an associated granulomatous reaction. Most cases of GMF are CD4 positive, and CD8 positive cases are extremely rare. Herein, we report a case of CD8-positive GMF. A 75-year-old Japanese woman presented with brownish maculae on the trunk and upper and lower extremities. She had been diagnosed with MF, and most of the eruption improved by psoralen ultraviolet A therapy. However, the eruption relapsed and gradually expanded 5 months prior to her visit to our hospital. Histopathology showed an atypical lymphocytic infiltrate in the dermis accompanied by granulomatous reaction with multinucleated giant cells. Epidermotropism was evident and elastophagocytosis was also found. Immunohistochemically, the atypical lymphocytes expressed betaF1, CD3 and CD8, and some of the atypical lymphocytes were also T cell intracellular antigen-1 positive. These findings were consistent with CD8-positive GMF. The dermatopathological diagnosis of GMF is challenging in some cases because of the prominent secondary granulomatous reaction. Therefore, when dermatopathologists diagnose granulomatous skin lesions, GMF should also be considered. In addition, the prognosis of GMF, especially CD8-positive GMF, is still controversial. Additional studies are required to clarify the clinicopathological features of CD8-positive GMF.

Mycobacterium ulcerans and Other Mycolactone-Producing Mycobacteria Should Be Considered a Single Species

Mycobacterium ulcerans and Other Mycolactone-Producing Mycobacteria Should Be Considered a Single Species

T Regulatory Cells and Plasmocytoid Dentritic Cells in Hansen Disease: A New Insight Into Pathogenesis?

Leprosy is characterized by spectrum of histologically different granulomatous skin lesions that reflects the patient's immune response to Mycobacterium leprae. Presence, frequency, and distribution of both CD4+ CD25+ FoxP3+ T regulatory cells (T-regs) and CD123+ plasmacytoid dendritic cells in leprosy have never been investigated. We performed a retrospective immunohistochemical study on 20 cases of leprosy [tuberculoid tuberculoid (TT): 1 patient; borderline tuberculoid (BT): 3 patients; borderline lepromatous (BL): 5 patients; lepromatous lepromatous (LL): 5 patients; borderline borderline in reversal reaction (BB-RR): 1 patient; BT-RR: 2 patients; and erythema nodosum leprosum (ENL): 3 patients]. FoxP3-positive cells were present in 95% of the cases with an average density of 2.9% of the infiltrate. Their distribution was not related to granulomatous structures or special locations. There was no statistical difference of FoxP3 expression between TT, BT, BL, and LL, whereas a statistical significant increment (P = 0.042) was observed in patients affected by reversal leprosy reactions (BT-RR and BB-RR) compared with patients affected by ENL and patients with nonreactional disease forms (BL, LL, BT, TT). CD123 expression was not observed in any of the biopsy specimens evaluated; with the exception of 2 cases of ENL, in which a focal positivity for CD123 was observed. Our results show that plasmacytoid dendritic cells are not involved in the immune response against M. leprae while T-regs are present in leprosy skin lesions. These data raise the question if T-regs have a pathogenetic role in HD as previously demonstrated in Leishmania major and Mycobacterium tuberculosis.

Increasing Intracerebral Infections Caused by Free-Living Amebae in the United States and Worldwide

Free-living amebae of the genera Acanthamoeba, Balamuthia, Naegleria, and Sappinia are rare causes of infectious diseases in humans with the exception of Acanthamoeba keratitis (AK) which is reported in millions of soft contact lens wearers worldwide each year. Unlike several Acanthamoeba species, only one species of Naegleria, N. fowleri, is known to infect humans by causing an acute, fulminant, usually lethal, central nervous system (CNS) infection, known as primary amebic meningoencephalitis (PAM). Balamuthia mandrillaris, another opportunistic, free-living ameba, is, like Acanthamoeba spp., capable of causing skin lesions and granulomatous amebic encephalitis (GAE) in individuals with compromised or competent immune systems, who inhale infective cysts or develop indolent, granulomatous skin lesions in soil-contaminated wounds. Lastly, Sappinia pedata, a recently identified free-living ameba that lives in soil and animal and reptile feces, has caused a single case of nongranulomatous amebic encephalitis in an immunocompetent Texas farmer. CNS infections caused by these ubiquitous organisms remain rare, but are, nevertheless, increasing today in the US and worldwide due to a combination of environmental and host susceptibility factors. The purpose of this review will be to describe the current epidemiology, pathophysiology, clinical manifestations, diagnosis, management, and prevention of free-living amebic infections of the CNS.

Modified fine‐needle aspiration technique for diagnosis of granulomatous skin lesions with special reference to leprosy and cutaneous tuberculosis

Skin infections are commonly assessed by slit skin or scrape methods. Fine-needle aspiration biopsy (FNAB) is highly effective especially with blanching of skin to ensure good yield and reduced bleeding. The aim of this study was to assess usefulness of cytology, especially modified FNAB technique, in diagnosis of leprosy and cutaneous tuberculosis and to identify specific cytological characteristics for diagnosis and classification. The study was conducted on 40 patients-25 cases of leprosy and 15 cases of cutaneous tuberculosis. Smears were prepared using modified FNAB technique, slit skin, and scrape methods (depending on type of lesion). Cytological diagnosis was confirmed by histopathology where the Ridley-Jopling system was used to classify cases of leprosy. A similar attempt was made for diagnosis and classification of leprosy on cytology. Diagnoses rendered by both modalities were compared to assess the efficacy of cytological examination. Cytological diagnosis was made in 23 cases of leprosy and 12 cases of cutaneous tuberculosis. The smears showed good cellularity. A broad division into tuberculoid and lepromatous leprosy could be made fairly accurately on cytology. Maximum agreement among clinical, cytological, and histopathological diagnosis was observed in cases of tuberculoid leprosy. Smears of cutaneous tuberculosis were characterized by epithelioid cell granulomas with caseation. Overall accuracy of diagnosis was 92% in leprosy and 80% in tuberculosis. FNAB is an inexpensive and accurate procedure for diagnosis of leprosy and cutaneous tuberculosis. The modified technique yields good results. However, clinical correlation, acid-fast staining, and culture are essential as they provide valuable supportive information.

Mycobacterium gordonae infection in a colony of African clawed frogs (Xenopus tropicalis)

Mycobacterium gordonae is an occasional human pathogen associated with cutaneous infections and nodular granulomatous skin lesions. A case of cutaneous nodular infection caused by M. gordonae in a colony of African clawed frogs (Xenopus tropicalis) is described and confirms this organism to be an opportunistic frog pathogen.

Lesões de pele causadas pelos espinhos de Mimosa pudica (Leg. Mimosoideae) nos membros de bovinos e ovinos no estado do Pará

Foi estudada uma doença em bovinos e ovinos caracterizada por lesões ulcerativas e granulomatosas da pele dos membros. Os estudos epidemiológicos e patológicos permitiram concluir que essas lesões são causadas pelos espinhos de Mimosa pudica (Leg. Mimosoideae). A doença foi observada somente em pastagens acentuadamente infestadas e os animais se recuperaram rapidamente após retirados destes pastos. Nos ovinos as lesões atingiam partes mais altas dos membros do que nos bovinos, devido ao seu menor porte.

Lymphoma-associated cutaneous granulomas

Granuloma formation has been observed as an incidental histopathological phenomenon in several lymphoproliferative disorders.The patterns of cutaneous granulomas associated with lymphomas are classified into two types.The first type is characterized by granulomatous infiltrates admixed with neoplastic cells within specific skin lesions of lymphomas,such as granulomatous mycosis fungoides and granulomatous slack skin.The second type refers to unspecific granulomatous skin lesions commonly seen in systemic iymphomas.Histopathologically,these granulomas can be sarcoid-like,granuloma annulare-like,tuberculoid,and so on.The pathogenesis and prognostic significance of cutaneous granuloma need to be clarified.Granulomas can result in specific manifestations,and obscure the nature of lymphomas,hence,cautions should be given to clinical and histological diagnosis of cutaneous granulomas. Key words: Skin; Granuloma; Lymphoma

Metastatic Crohn’s disease: a histopathologic study of 12 cases

Perhaps, the most intriguing cutaneous sequela of Crohn's disease (CD) is 'metastatic' CD, defined as sterile granulomatous skin lesions arising at sites discontinuous from the gastrointestinal tract. Though various histopathologic patterns have been described, a lack of a large series has precluded a comprehensive characterization and distinction from the pathologic differential diagnoses. The histopathology features of 12 new cases of metastatic CD were reviewed. Non-suppurative granulomata with a slight cuff of lymphocytes in a nodular or diffuse pattern with an associated superficial and deep perivascular mixed inflammatory infiltrate was the most common pattern. Other common features included an accompanying infiltrate which was often rich in eosinophils, and ulceration of the overlying epidermis. These features are emphasized as potentially useful in distinguishing this entity from its greatest mimicker, cutaneous sarcoidosis.

Interstitial Granulomatous Lesions as Part of the Spectrum of Presenting Cutaneous Signs in Pediatric Sarcoidosis

Skin findings in childhood sarcoidosis vary greatly, but only a few occurrences have been published in which the histopathology has been characterized well. We describe a child with sarcoidosis in whom the cutaneous findings were atypical, resembling granuloma annulare. Histologic examination of these cutaneous lesions, however, revealed areas of sarcoid-like epithelioid cell granulomas, a palisading granulomatous process with features of granuloma annulare, as well as palisading neutrophilic and granulomatous dermatitis and interstitial granulomatous dermatitis. This underscores the variability of skin findings in childhood sarcoidosis--even within the same patient--and suggests that sarcoidosis should be considered in the differential diagnosis of children initially diagnosed with granulomatous skin lesions, such as granuloma annulare, palisading neutrophilic, and granulomatous dermatitis or interstitial granulomatous dermatitis, who demonstrate associated signs of systemic disease.

Trichophytic Majocchi granuloma mimicking Kaposi sarcoma

A 68-year-old man presented with a one month history of painful blue-red papules and nodules on an erythematous base on the top of his feet, as well as dystrophic toenails. He had undergone renal transplantation six months previously for membranous glomerulonephritis, and was immunosuppressed with tacrolimus 3 g, mycophenolate mofetil 1500 mg and prednisolone 5 mg daily. His tacrolimus level was 29.8 ng/ml (expected level 6-8 ng/ml). Even though the cutaneous lesions strongly suggested Kaposi sarcoma, the histological examination revealed a dermal abscess in which hyphae and spores were seen with PAS staining. ELISA-PCR of the biopsy identified Trichophyton rubrum, which was also grown on culture of the biopsy tissue. The diagnosis of Majocchi granuloma secondary to excessive immunosuppression was made. Systemic treatment with terbinafine 250 mg per day and topical ciclopirox olamine completely cured the granulomatous skin lesions, and later the nails.

Diffuse and Aggressive Cutaneous Granulomatosis Revealing a Cytotoxic Cell Systemic Lymphoma

Sir, Systemic lymphomas may give rise to a variety of nonspecific skin manifestations, such as pigmentation, urticaria, erythroderma, ichthyosis, erythema multiforme, erythema nodosa (1) and, rarely, cutaneous granulomas. The development of non-infectious granulomas in involved and non-involved organs, such as spleen, liver, bone marrow or lymph nodes, is a classical occurrence in systemic lymphomas, even though skin involvement is less frequently reported (2–4). We report here a patient with diffuse sarcoidosis-like granulomatous skin lesions associated with and revealing a Hodgkin’s-like T-cell systemic lymphoma.

MMP‐21 is expressed by macrophages and fibroblasts in vivo and in culture

Matrix metalloproteinase (MMP)-21 and MMP-26 (matrilysin-2) are two recently cloned epithelial metalloproteases. Here we examined their expression in various benign skin disorders, in which macrophages and fibroblasts have been implicated as well as in cultures of these cells. Expression of MMP-21 was detected by immunohistochemistry in a subset of macrophages of granulomatous skin lesions and in fibroblasts in dermatofibromas. MMP-21 mRNA was found in THP-1, U937, HEL 299 and Hs68 cells. Furthermore, MMP-21 protein was detected by immunohistochemistry in cultures of the same cell lines. In culture MMP-21 was upregulated by phorbol myristate acetate in THP-1 cells and by retinoic acid (RA) in U937 cells, and downregulated by transforming growth factor beta 1 (TGF-beta1) in HEL 299 as assessed by Taqman quantitative polymerase chain reaction (PCR). Expression of MMP-26 was detected by immunohistochemistry in granulomatous skin diseases and actinic elastosis. MMP-26 at both mRNA and protein levels was only found in HEL 299 cells. In culture it was downregulated by TGF-beta1, RA and IL-1beta as assessed by Taqman quantitative PCR. Our results suggest these two novel MMPs are not only associated with cancer but may be important in connective tissue remodelling and pathobiology of various benign skin disorders.

A novel mutation for TAP deficiency and its possible association with Toxoplasmosis

We describe two siblings (a male patient and his older sister) with a novel mutation in the peptide transporter associated to antigen processing (TAP). The index case presented with not only granulomatous skin lesions and recurrent sino-pulmonary infections, often associated with this deficiency, but also a severe pulmonary toxoplasmosis. His toxoplasmosis and skin lesions were successfully treated.

Disseminated Hyperkeratotic and Granulomatous Nodules in a Child with Fatal Epstein–Barr‐Virus–Associated Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis is a rare and potentially fatal syndrome associated with a variety of genetic, malignant, autoimmune, or infectious conditions. The importance of cutaneous presentations of this syndrome has only recently been brought forward. We report the first case of Epstein-Barr-virus-associated hemophagocytic lymphohistiocytosis presenting with papulonodular and granulomatous skin lesions. A girl of African origin developed several umbilicated papules on her extremities and face at the age of 18 months. She was born in Germany, had never visited Africa, and was otherwise healthy. Over the next 5 months the lesions progressed in size and number and became hyperkeratotic. Histopathologic analysis of early lesions revealed a superficial lympho- and plasmacellular dermatitis with some features of panniculitis. Later biopsy specimens from nodular lesions showed the formation of tuberculoid granulomas in the deep dermis. At the age of 23 months she became severely ill, rapidly developing high fever, hepatosplenomegaly, icterus, pancytopenia, and ascites. On the basis of bone marrow and lymph node biopsies, the diagnosis of hemophagocytic lymphohistiocytosis was established. However, this phenomenon could not be detected in any of the skin specimens. An active Epstein-Barr virus infection was diagnosed by polymerase chain reaction in blood, lymphoid tissue, and skin. Despite chemotherapy with etoposide and cortisone, the girl expired 14 days after clinical onset of her systemic disease.

Protease activities of Acanthamoeba polyphaga and Acanthamoeba castellanii

Acanthamoeba spp. are free-living amoebae that cause amoebic granulomatous encephalitis, skin lesions, and ocular amoebic keratitis in humans. Several authors have suggested that proteases could play a role in the pathogenesis of these diseases. In the present work, we performed a partial biochemical characterization of proteases in crude extracts of Acanthamoeba spp. and in conditioned medium using 7.5% SDS-PAGE copolymerized with 0.1% m/v gelatin as substrate. We distinguished a total of 17 bands with proteolytic activity distributed in two species of Acanthamoeba. The bands ranged from 30 to 188 kDa in A. castellanii and from 34 to 144 kDa in A. polyphaga. Additionally, we showed that the pattern of protease activity differed in the two species of Acanthamoeba when pH was altered. By using protease inhibitors, we found that the proteolytic activities belonged mostly to the serine protease family and secondly to cysteine proteases and that the proteolytic activities from A. castellanii were higher than those in A. polyphaga. Furthermore, aprotinin was found to inhibit crude extract protease activity on Madin-Darby canine kidney (MDCK) monolayers. These data suggest that protease patterns could be more complex than previously reported.

Compound Heterozygeous RAG-1 Mutations in 2 Patients Presenting with Chronic Disfiguring Granulomatous Skin Lesions.

IntroductionMutations of the recombinase activating genes (RAG) cause a severe combined immunodeficiency (SCID) characterized by absent or low T and B cells due to defective T/B cell receptor rearrangement and failure of lymphocyte maturation. Presenting clinical features commonly are failure to thrive and opportunistic infections in early infancy. We observed 2 patients with RAG mutations where partial T- and B-cell immunity is preserved. These patients did not suffer from severe infections but presented with unusual symptoms and signs, e.g. unexplained lymphogranulomatous skin lesions mimicking malignant lymphoma and lupus vulgaris.Case presentationBoth patients, who are offsprings of unrelated German parents, underwent genetic screening because of unclear primary immunodeficiencies and were found to have compound heterozygeous RAG-1 mutations (Patient 1: R507W, R737H; R314W and patient 2: R778Q; R975W). Both have no evidence of thymic tissue on ultrasound and have persistant lymphopenia with low T-cell numbers, but are capable of mounting positive antibody responses to tetanus toxoid. In both patients unusual skin lesions were leading clinical abnormalities.Patient 1, a 6 year-old girl, has been suffering from progressive papulonodular skin lesions of extremities and face since the age of 1 year. Biopsy showed highly monomorphous T-cell infiltrates leading initially to a diagnosis of cutaneous T-cell lymphoma treated with chemotherapy. As progression occurred chemotherapy was stopped and the lesions were reinterpreted as poorly organised sarcoid-like granulomas of unknown etiology. At 5 years of age the girl developed an EBV lymphoma of her right tonsil treated with rituximab. The patient is undergoing at present hematopoetic stem cell transplantation (HSCT).Patient 2 is an 8 year-old girl, who at the age of 2 years developed persistant ulcerative skin lesions on her face and extremities. Granulomatous epitheloid tissue was found in skin biopsies, and later also in lung and tongue biopsies. No pathogens including mycobacteria were isolated. No improvement was seen on immunosuppression. Skin grafting was necessary in her lower extremity twice after partial destruction of the Achilles tendon by progressive ulceration. HSCT is planned in the near future.ConclusionRAG mutations may be associated with a combined immunodeficiency where uncontrolled granuloma formations of the skin, but not opportunistic infections, are leading clinical findings. It is unclear whether these disfiguring lesions are caused by pathogens such as mycobacteria which are difficult to culture or whether they represent reactive sarcoid-like granulomas as seen in other primary IDs, e.g. common variable immunodeficiency.