Rare Variant Of Disease Research Articles

Biallelic tumour suppressor loss and DNA repair defects in de novo small-cell prostate carcinoma.

Small-cell prostate carcinoma (SCPC) is an aggressive malignancy that is managed similarly to small-cell lung cancer. SCPC can evolve from prostate adenocarcinoma in response to androgen deprivation therapy, but, in rare cases, is present at initial cancer diagnosis. The molecular aetiology of de novo SCPC is incompletely understood, owing to the scarcity of tumour tissue and the short life-expectancy of patients. Through a retrospective search of our regional oncology pharmacy database, we identified 18 patients diagnosed with de novo SCPC between 2004 and 2017. Ten patients had pure SCPC pathology, and the remainder had some admixed adenocarcinoma foci, but all were treated with first-line platinum-based chemotherapy. The median overall survival was 28 months. We performed targeted DNA sequencing, whole exome sequencing and mRNA profiling on formalin-fixed paraffin-embedded archival tumour tissue. We observed frequent biallelic deletion and/or mutation of the tumour suppressor genes TP53, RB1, and PTEN, similarly to what was found in treatment-related SCPC. Indeed, at the RNA level, pure de novo SCPC closely resembled treatment-related SCPC. However, five patients had biallelic loss of DNA repair genes, including BRCA1, BRCA2, ATM, and MSH2/6, potentially underlying the high genomic instability of this rare disease variant. Two patients with pure de novo SCPC harboured ETS gene rearrangements involving androgen-driven promoters, consistent with the evolution of de novo SCPC from an androgen-driven ancestor. Overall, our results reveal a highly aggressive molecular landscape that underlies this unusual pathological variant, and suggest opportunities for targeted therapy strategies in a disease with few treatment options. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Two cases of Galli-Galli disease – An acantholytic variant of Dowling-Degos disease

Galli-Galli disease (GGD) is thought to be a rare acantholytic variant of the genodermatosis Dowling-Degos disease (DDD) with less than 30 cases reported in the literature. Here we present two cases with clinicopathologic features suggestive of Gali-Gali disease.

Risk of solid cancer in patients with mast cell activation syndrome: Results from Germany and USA

Background: It has been shown repeatedly that mast cells can promote or prevent cancer development and growth. If development and/or progression of a solid cancer is substantially influenced by mast cell activity, the frequencies of occurrence of solid cancers in patients with primary mast cells disorders would be expected to differ from the corresponding prevalence data in the general population. In fact, a recent study demonstrated that patients with systemic mastocytosis (i.e., a rare neoplastic variant of the primary mast cell activation disease) have increased risk for solid cancers, in particular melanoma and non-melanoma skin cancers. The aim of the present study is to examine whether the risk of solid cancer is increased in systemic mast cell activation syndrome (MCAS), the common systemic variant of mast cell activation disease. Methods: In the present descriptive study, we have analysed a large (n=828) patient group with MCAS, consisting of cohorts from Germany and the USA, for occurrence of solid forms of cancer and compared the frequencies of the different cancers with corresponding prevalence data for German and U.S. general populations. Results: Sixty-eight of the 828 MCAS patients (46 female, 22 male) had developed a solid tumor before the diagnosis of MCAS was made. Comparison of the frequencies of the malignancies in the MCAS patients with their prevalence in the general population revealed a significantly increased prevalence for melanoma and cancers of the breast, cervix uteri, ovary, lung, and thyroid in MCAS patients. Conclusions: Our data support the view that mast cells may promote development of certain malignant tumors. These findings indicate a need for increased surveillance of certain types of cancer in MCAS patients irrespective of its individual clinical presentation.

Risk of solid cancer in patients with mast cell activation syndrome: Results from Germany and USA.

Background: It has been shown repeatedly that mast cells can promote or prevent cancer development and growth. If development and/or progression of a solid cancer is substantially influenced by mast cell activity, the frequencies of occurrence of solid cancers in patients with primary mast cells disorders would be expected to differ from the corresponding prevalence data in the general population. In fact, a recent study demonstrated that patients with systemic mastocytosis (i.e., a rare neoplastic variant of the primary mast cell activation disease) have increased risk for solid cancers, in particular melanoma and non-melanoma skin cancers. The aim of the present study is to examine whether the risk of solid cancer is increased in systemic mast cell activation syndrome (MCAS), the common systemic variant of mast cell activation disease. Methods: In the present descriptive study, we have analysed a large (n=828) patient group with MCAS, consisting of cohorts from Germany and the USA, for occurrence of solid forms of cancer and compared the frequencies of the different cancers with corresponding prevalence data for German and U.S. general populations. Results: Sixty-eight of the 828 MCAS patients (46 female, 22 male) had developed a solid tumor before the diagnosis of MCAS was made. Comparison of the frequencies of the malignancies in the MCAS patients with their prevalence in the general population revealed a significantly increased prevalence for melanoma and cancers of the breast, cervix uteri, ovary, lung, and thyroid in MCAS patients. Conclusions: Our data support the view that mast cells may promote development of certain malignant tumors. These findings indicate a need for increased surveillance of certain types of cancer in MCAS patients irrespective of its individual clinical presentation.

Incidence, predictors, clinical profile, management and outcome of patients with isolated left main coronary artery ostial disease

ObjectivesIsolated left main coronary artery (LMCA) ostial disease is a rare variant of LMCA disease. Earlier studies on this disease are limited by small number of patients enrolled. The aim of the present study was to analyze the incidence, risk factors, clinical profile and long term outcome of patients with isolated LMCA ostial disease. Methods15,553 patients who underwent coronary angiogram in a single tertiary care cardiac hospital were analyzed for LMCA disease. 351(2.2%) patients were found to have significant LMCA disease out of which 28(0.18%) had isolated LMCA ostial disease. These 28 patients were compared with 323 non-ostial and non-isolated LMCA disease patients. ResultsThe mean age of isolated LMCA ostial disease group was significantly less than the other group (p=0.009). Females were more affected than males (p=0.008). They also had low incidence of coronary risk factors (especially dyslipidemia, p=0.04). They tend to present more with stable angina and less with myocardial infarction. They had higher ejection fraction and normal regional wall motion (p=0.04). There was no mortality difference between two groups at the end of 1 year (p=0.234). ConclusionIn one of the largest studies done in these patients, we found that isolated LMCA ostial disease is more common in middle aged females with few coronary risk factors. These patients also had a better ejection fraction and normal regional wall motion compared to patients with non-ostial and non-isolated LMCA disease. The clinical and angiographic profile of these patients suggests that they may represent a distinct clinical entity.

TAFRO syndrome: A case report and review of the literature

TAFRO syndrome is a rare clinicopathologic variant of idiopathic multicentric Castleman disease characterized by Thrombocytopenia, Ascites (anasarca), myeloFibrosis, Renal dysfunction, and Organomegaly. Here, we report a case of TAFRO syndrome in an HIV-negative young Caucasian male who presented with fever, normocytic anemia, thrombocytopenia, and acute renal insufficiency. The serum interleukin-6 (IL-6) level was elevated. Chest and abdominal CT revealed bilateral pleural effusion, ascites, splenomegaly, and multiple mildly enlarged lymph nodes. An excisional biopsy of inguinal lymph node showed a few atrophic follicles and expansion of interfollicular areas by marked vascular proliferation and polytypic plasmacytosis. HHV-8 was negative. Subsequent bone marrow biopsy was normocellular with moderately increased megakaryocytes and occasional megakaryocytic emperipolesis. His signs and symptoms improved after treatment with methylprednisolone and tocilizumab (anti-IL-6 receptor antibody). Our study confirms the distinctive nature of this syndrome, which should allow for better recognition and appropriate therapy.

Sublamina densa-type linear IgA bullous dermatosis with IgA autoantibodies specific for type VII collagen: a case report and clinicopathological review of 32 cases

Linear IgA bullous dermatosis (LABD) is a rare autoimmune bullous disorder characterized by linear deposits of IgA at the basement membrane zone(BMZ) and/or by circulating IgA anti-BMZ antibodies. Comparing with other immuno-bullous diseases, LABD represents a heterogeneous disease entitywith diversity of pathogenic IgA autoantibodies to different hemidesmosomal antigens and an association with malignancies and occasional drug use. We herein present an 82-year-old Japanese man with LABD, whose indirect immunofluorescence using 1M NaCl-split skin showed positive staining for IgA at the dermal side alone. Fluorescence overlay antigen mapping using laser scanning confocal microscopy (FOAM-LSCM) was employed to examine the in vivo bound patient's IgA, which was specific for type VII collagen (COL7), a prominent antigen of the sublamina densa. One year later, he developed malignant lymphoma, suggesting the diagnosis of paraneoplastic LABD. We reviewed 32 cases of sublamina-densa type LABD with anti-COL7 IgA antibodies thus far reported in the literature to compare the clinicopathological characteristics of this rare disease variant and emphasize that COL7 is the main autoantigen in sublamina densa disease.

Primary Cutaneous Hodgkin Lymphoma: A Rare Disease Variant and Review of the Literature

Primary Cutaneous Hodgkin Lymphoma: A Rare Disease Variant and Review of the Literature

INCIDENCE, PREDICTORS, CLINICAL PROFILE, MANAGEMENT AND OUTCOME OF PATIENTS WITH ISOLATED LEFT MAIN CORONARY ARTERY OSTIAL DISEASE

Isolated left main coronary artery (LMCA) ostial disease is a rare variant of LMCA disease. Earlier studies on this disease are limited by small number of patients enrolled. The aim of the present study was to analyze the incidence, risk factors, demographics, clinical profile and long term outcome

The clinicopathologic characteristics and outcome of atypical anti-glomerular basement membrane nephritis

Classic anti-glomerular basement membrane (GBM) disease presents with rapidly progressive glomerulonephritis (GN) with or without pulmonary hemorrhage. On biopsy typical disease displays bright polytypic linear GBM staining for IgG by immunofluorescence and diffuse crescentic/necrotizing GN on light microscopy. Here, we studied 20 patients with atypical anti-GBM nephritis typified by bright linear GBM staining for immunoglobulins but without a diffuse crescentic phenotype. Patients had hematuria, proteinuria, and mild renal insufficiency, without pulmonary hemorrhage. Light microscopy showed endocapillary proliferative GN in 9 patients, mesangial proliferative GN in 6, membranoproliferative GN in 3, and focalsegmental glomerulosclerosis with mesangial hypercellularity in 2. Eight of the 20 showed features of microangiopathy. Crescents/necrosis were absent in 12 and were focal in 8 patients. Bright linear GBM staining for IgG was seen in 17 patients, IgM in 2, and IgA in 1 patient, which was polytypic in 10 patients and monotypic in 10 patients. No circulating α3NC1 antibodies were detected by commercial ELISA. The 1-year patient and renal survival rates were 93% and 85%, respectively. Thus, atypical anti-GBM nephritis is a rare variant of anti-GBM disease characterized clinically by an indolent course, no pulmonary involvement, and undetectable circulating α3NC1 antibodies. Further studies are needed to characterize the molecular architecture of GBM autoantigens in these patients and establish optimal therapy.

Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease

IntroductionThe genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain. MethodsWe genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study. ResultsWe confirm that variation in/near APOE/TOMM40 (P = 6 × 10−14) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10−4), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10−10 OR = 1.9 [1.5–2.3]); rs72907046 near FAM46A (P = 1 × 10−9 OR = 3.2 [2.1–4.9]); and rs2525776 near SEMA3C (P = 1 × 10−8, OR = 3.3 [2.1–5.1]). DiscussionWe provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.

Monomelic amyotrophy: a rare variant of lower motor neuron disorder (2 clinical cases)

Monomelic amyotrophy (MMA) is a rare variant of lower motor neuron disease with benign progression. The disease is characterized by muscular weakness and atrophy in the hand and forearm on one side or asymmetrical lesion of both upper limbs with the presence of cold paresis, fasciculations, and fine tremor of the fingers. Sensory disorders, pyramidal symptoms, and involvement of the leg muscles are not typical of it. The final diagnosis of MMA can be made only on the basis of clinical neurological and electrophysiological tests as well as long-term follow-up of the patient. Timely recommendations for correction of the movement pattern and prevention of flexion compression may slow down the disease progression in some cases and, thereby, improve the quality of life of patients. The article describes two clinical cases with a probable diagnosis of MMA.

Plasmacytoid dendritic cells in hypertrophic discoid lupus erythematosus: an objective evaluation of their diagnostic value.

Hypertrophic discoid lupus erythematosus (HDLE), a rare variant of lupus skin disease, is difficult to distinguish from squamous neoplasms and certain dermatoses microscopically. Recently, recognition of the pathogenetic significance of plasmacytoid dendritic cells (PDCS) in cutaneous lupus erythematosus (LE) and of their patterns of distribution in different manifestations of the disease prompted us to study their diagnostic value in the context of HDLE. Using immunohistochemistry (CD123) to label the cells, we examined their quantities and patterns of distribution in 27 tissue samples of HDLE from nine patients compared with 39 inflammatory and neoplastic control samples from 36 patients. Using three parameters pertaining to PDCs: (i) their representation of 10% or more of the inflammatory infiltrate, (ii) their arrangement in clusters of 10 cells or more and (iii) their presence at the dermoepidermal junction, we found them to have significant diagnostic value, with accuracies of 77%, 74% and 71%, respectively. This study supports the careful descriptive observations of previous authors in the field. It also lends validity to the diagnostic step of mapping, immunohistochemically, the density and distribution of PDCs in suspected cases of HDLE.

Ulcerative keratitis in psoriasis: a rare variant of psoriatic ocular inflammatory disease

Ulcerative keratitis in psoriasis: a rare variant of psoriatic ocular inflammatory disease

Distinguishing neutral from deleterious mutations in growing populations

Distinguishing neutral from deleterious mutations in growing populations

A Case of Diffuse Cutaneous Mastocytosis in a Newborn

Diffuse cutaneous mastocytosis (DCM) is a rare variant of mast cell disease with widespread erythema and is clinically apparent in early infancy. We report the case of a 1-day-old female neonate who presented with diffuse flush, pruritus, and extensive blistering. DCM was diagnosed by immunohistochemical staining with anti-CD117, which revealed mast cell infiltration. DCM is a severe and heterogeneous cutaneous disease, and is associated with mast cell mediator-related symptoms and risk of anaphylactic shock. We describe this case and provide the first literature review of neonatal onset DCM in Korea.

Unilateral Pigmented Extramammary Paget's Disease of the Axilla Associated with a Benign Mole: A Case Study and a Review of Literature.

Pigmented extramammary Paget's disease (PEMPD) is an uncommon intraepithelial adenocarcinoma and a rare variant of Paget's disease affecting skin that is rich in apocrine sweat glands such as the axilla, perianal region and vulva. It most commonly occurs in postmenopausal women and presents as a superficial pigmented scaly macule, mimicking a melanocytic lesion. The histological presentation is adenocarcinoma in situ with an increased number of melanocytes scattered between the Paget's cells. Therefore, PEMPD may be misdiagnosed as a melanocytic tumour both clinically and histologically. The tumour cells are usually positive for cytokeratin 7, epithelial membrane antigen, Cam 5.2, HER2, and mucicarmine stain while S100 and human melanoma black-45 highlight the processes of reactive dendritic cells. The association between Paget's cells and intratumoural reactive melanocytes is still unclear. We report our first case of PEMPD associated with an intradermal naevus involving the axilla in a 63-year-old woman.

Case for diagnosis

Linear Darier is a rare variant of Darier's Disease. The keratotic papules follow Blaschko's lines, characterizing the cutaneous mosaicism. We report the case of a 42-year-old woman who presented with small, linearly distributed, reddish-brown papules on the left mammary region, from the left flank to the hypogastrium and on the pretibial area of the left leg. Histologically, suprabasal acantholysis and dyskeratotic cells were seen, confirming the diagnosis.

Late-onset pretibial recessive dystrophic epidermolysis bullosa

Pretibial epidermolysis bullosa (EB) is a rare form of localized dystrophic EB, characterized by recurrent blistering and scarring plaques occurring predominantly in the pretibial area. In most cases, nail dystrophy, especially of the toenails, is also present. Often there are no clinical abnormalities at birth, and the disorder may only appear after several years. We report a patient who developed symptoms in his fifth decade. Genetic testing identified compound heterozygosity for two pathogenic mutations in the COL7A1 gene. This case highlights a rare variant of mechanobullous disease, and stresses the importance of molecular screening in establishing a correct diagnosis. Precisely why the disorder specifically localizes to the shins or why it may only become apparent in later life is not known.

Pulmonary Thromboembolism in a Child with Sickle Cell Hemoglobin D Disease in the Setting of Acute Chest Syndrome

Introduction. Sickle cell hemoglobin D disease (HbSD) is a rare variant of sickle cell disease (SCD). Incidence of pulmonary thromboembolism (PE) and deep venous thrombosis (DVT) in children with HbSD is unknown. PE and DVT are known complications of SCD in adults but have not been reported in the literature in children with HbSD. Case Report. We are reporting a case of a 12-year-old boy with HbSD with acute chest syndrome (ACS) complicated by complete thrombosis of the branch of the right pulmonary artery and multiple small pulmonary artery emboli seen on computed tomography (CT) pulmonary angiogram and thrombosis of the right brachial vein seen on Doppler ultrasound. Our patient responded to treatment with anticoagulant therapy. Conclusion. There are no cases reported in children with HbSD disease presenting as ACS with pulmonary thromboembolism. We suggest that PE should be suspected in patients presenting with ACS who do not show improvement with standard management. CT pulmonary angiogram should be utilized for early diagnosis and appropriate management as there is no current protocol for management of PE/DVT in pediatric patients with SCD.