Cutaneous Collagenous Vasculopathy: A Short Case Series and Literature Review.

ABSTRACT: Cutaneous collagenous vasculopathy (CCV) is a rare and idiopathic microangiopathy of superficial dermal blood vessels. There have been 75 cases described in the literature to date, not including the current report; however, given its clinical similarity to other primary telangiectasias, it is likely to be underreported and underdiagnosed. Here, we describe the clinical and histological features of 2 patients we newly diagnosed with CCV. Both generally fit the profile of prior cases and confirm previously described associations-they both are older White women, have rashes on their lower extremities, and have conditions and medications that are common among other reported cases. However, both are also somewhat atypical, as Patient 1 had symptomatic CCV and Patient 2 had a papular rash. As such, both cases broaden the spectrum of our current understanding of CCV. We also provide a comprehensive review of all published reports of CCV to date and uncover 2 previously unreported associations: one with visceral malignancy, and the other with hypothyroidism. Whether these association are coincidental is worth investigating in future studies.

TEMPI syndrome: A clinical, light-microscopic and phenotypic evaluation with review of the literature.

BACKGROUND AND OBJECTIVES: TEMPI (telangiectasias, elevated erythropoietin and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonaryshunting) syndrome is a rare multisystemic disease classified as a monoclonal gammopathy of cutaneous significance. The pathogenesis and etiology of TEMPIare not well known because of the rarity of this disorder. Although telangiectasias are the hallmark of this syndrome, skin biopsies are rarely performed. We aim to further characterize TEMPI syndrome through the evaluationof a skin biopsy. METHODS: We reviewed the histopathology and immunophenotypic profile of a skin biopsy from a 53-year-oldwoman diagnosed with TEMPI syndrome. Other components of her syndromic complex included an IgA myeloma, elevated vascular endothelial growth factor (VEGF), and erythrocytosis. RESULTS: A biopsy showed prominent vascular ectasia with some degree of microvascular basement membranezone thickening. Our patient had a reduction in neoplastic plasma cell burdenand clearing of her telangiectasias following myeloma directed treatment. CONCLUSIONS: TEMPI can beviewed as a reactive vascular paraneoplastic syndrome in the setting of a plasma cell dyscrasia. Elaboration of VEGF from neoplastic plasma cells is likely pathogenetically implicated and appears to be a common link that explains other vascular lesions associated with monoclonal gammopathy syndromes.

Unusual presentation of telangiectasia macularis eruptiva perstans at the site of healed herpes zoster; Wolf's isotopic response.

There are several reported cases of Wolf's isotopic response, including infections, cancers, inflammatory and immune-related disorders. It is interesting that the majority of these occurred after herpes zoster (HZ) had healed. In this article, we describe an unusual case of adult mastocytosis/telangiectasia macularis eruptiva perstans (TMEP) at the location of recovered HZ. Given that adult mastocytosis is thought to be caused by dysregulation of the mast cell growth factor receptor, the c-Kit proto-oncogene (CD117), and the fact that the varicella zoster virus-infected cutaneous lesions contain CD117-positive mast cells (CD117+MCs), we hypothesize that CD117+ MCs may be in charge of the local immunological response and cytokine release those results in TMEP after HZ.

Comprehensive Next-Generation Sequencing Testing in a Patient with TEMPI Syndrome.

TEMPI syndrome is a new and poorly understood disease that is currently considered a type of plasma cell neoplasm with paraneoplastic manifestations. The TEMPI acronym defines the hallmarks of the syndrome: T for telangiectasia; E for erythrocytosis with elevated erythropoietin; M, monoclonal gammopathy; P, perinephric collections; and I, intrapulmonary shunting. Due to the marked erythrocytosis as the most common presenting feature, TEMPI is often misdiagnosed as polycythemia vera. However, unlike polycythemia vera, TEMPI is not associated with a JAK2 mutation. The pathogenesis of TEMPI syndrome is unknown, although a few hypothetical disease mechanisms have been previously discussed. Here we present a new case of TEMPI syndrome, discuss results of a next-generation sequencing (NGS) panel covering 1,425 known cancer-related genes, and review the current literature with focus on an update of the genetics of TEMPI syndrome. This is the first report of TEMPI that includes results of comprehensive NGS testing.

Statistical evaluation and positive predictive value of key features of periorbital basal cell carcinoma.

OBJECTIVE: To determine the accuracy of using the suspicious features of periorbital lesions-telangiectasias, madarosis, and ulceration-to identify basal cell carcinoma (BCC). This may impact whether a histopathologic confirmation is always necessary. METHODS: This retrospective review of patients who underwent biopsy of eyelid lesions was conducted over a five-year period, between 2015 and 2020 at a single clinical site. Specifically, the histopathologic diagnosis and the presence or absence of clinical signs of madarosis, ulceration and telangiectasia were recorded. The positive predictive value (PPV) for eyelid BCC and odds ratio of each of these clinical signs was calculated. RESULTS: 179 patients underwent incisional biopsies of eye lid lesions. Of the 79 patients with eyelid BCC, 96% had ulceration, 95% had madarosis, and 75% had telangiectasias over the lid lesion; this contrasted with the 3%, 4% and 6% respectively in the 100 patients with benign lid lesions. The PPV for eyelid BCC of ulceration was 95.0%, madarosis was 96.2% and telangiectasias was 90.8%. The presence of two or all three signs in a patient was strongly predictive of BCC (PPV=100%). CONCLUSION: The presence of two or more suspicious features almost ensures the accuracy of the suspected diagnosis of a BCC. This suggests that biopsy of eyelid lesions before complete surgical excision that demonstrate several defining features may not be necessary in all cases. However, lesions that do not demonstrate multiple explicit features that indicate a malignancy will still require histopathologic confirmation.

Photodistributed eruptive telangiectasias: an uncommon adverse drug reaction. A retrospective case series.

Drug-induced photodistributed telangiectasia (PT) is a cutaneous adverse effect (AE) resulting from the interaction of ultraviolet radiation with pharmacotherapy. Reports of PT in the literature are scarce. We report 25 cases of drug-induced PT highlighting the potential relationship between the onset of skin lesions, drug intake and photo exposure. We alert practitioners that PT is a possible dermatological phototoxic AE of many drugs.

TEMPI Syndrome: Update on Clinical Features, Management, and Pathogenesis.

TEMPI (telangiectasias, elevated erythropoietin level and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting) syndrome is a rare and newly defined multisystemic disease, which belongs to "monoclonal gammopathy of clinical significances". Due to its rarity, the etiology, pathogenesis, and clinical features of this disease remain largely unknown. Owing to its hidden and diverse clinical manifestations, missed diagnosis and misdiagnosis are common. In recent years, as more patients (including three fatal cases) were identified, some special clinical manifestations other than the typical pentad of TEMPI syndrome have been reported. Meanwhile, several studies attempting to identify the pathogenesis of TEMPI syndrome were conducted. In this review, we summarize the reported clinical characteristics of TEMPI syndrome and discuss the current and potential treatment options for patients with TEMPI syndrome, including those with relapsed/refractory disease. Furthermore, we provide an overview of current knowledge on the pathophysiology of TEMPI syndrome.

Long-Term Complete Clinical and Hematological Response With Bortezomib: The Report of a Case With TEM(P)I Syndrome and a Review of the Literature.

TEMPI syndrome was first defined in 2011 and classified as a plasma cell neoplasm with associated paraneoplastic syndrome in 2016. The pathogenesis of the syndrome is not well understood. Recognition of a combination of telangiectasia, erythrocytosis with a high erythropoietin level, monoclonal gammopathy, perinephric fluid collection, and intrapulmonary shunt is the first step in managing the disease. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other dermatological, renal, and pulmonary disorders. Without early diagnosis significant disability results from the pulmonary damage. The article we present here describes a clinical case of TEMPI-syndrome in a 58-year-old woman, which illustrates the difficulties associated with the timely recognition of this unusual disease. Here, we also review the clinical features of TEMPI syndrome, differential diagnosis and available treatment options, based on current literature. Although limited in number, with the addition of new patients to the literature, TEMPI syndrome is evolving into a well characterized multisystem syndrome. This rare disorder should not be missed, especially if the patient has a putative diagnosis of essential telangiectasia with a monoclonal gammopathy and polistemia. Increasing the awareness of clinicians about the disease and adding new patient data to the literature may contribute to a better understanding of the pathophysiology of the disease and standardization of treatment.

A deep learning approach to detect blood vessels in basal cell carcinoma.

PURPOSE: Blood vessels called telangiectasia are visible in skin lesions with the aid of dermoscopy. Telangiectasia are a pivotal identifying feature of basal cell carcinoma. These vessels appear thready, serpiginous, and may also appear arborizing, that is, wide vessels branch into successively thinner vessels. Due to these intricacies, their detection is not an easy task, neither with manual annotation nor with computerized techniques. In this study, we automate the segmentation of telangiectasia in dermoscopic images with a deep learning U-Net approach. METHODS: We apply a combination of image processing techniques and a deep learning-based U-Net approach to detect telangiectasia in digital basal cell carcinoma skin cancer images. We compare loss functions and optimize the performance by using a combination loss function to manage class imbalance of skin versus vessel pixels. RESULTS: We establish a baseline method for pixel-based telangiectasia detection in skin cancer lesion images. An analysis and comparison for human observer variability in annotation is also presented. CONCLUSION: Our approach yields Jaccard score within the variation of human observers as it addresses a new aspect of the rapidly evolving field of deep learning: automatic identification of cancer-specific structures. Further application of DL techniques to detect dermoscopic structures and handle noisy labels is warranted.

A case of cutaneous collagenous vasculopathy associated with multiple myeloma and with a pathogenic variant of the glucocerebrosidase gene.

Cutaneous collagenous vasculopathy (CCV) is an extremely rare acquired microangiopathy of unknown etiology. The authors describe a case of a 68-year-old man, a carrier of a heterozygous pathogenic variant of the glucocerebrosidase (GBA) gene, who was diagnosed with CCV, revealing uncommon fibrinogen positivity in direct immunofluorescence. The patient was subsequently diagnosed with multiple myeloma. Treatment of the myeloma with combined chemotherapy including bortezomib, followed by autologous stem cell transplantation, led to significant reduction of cutaneous lesions. To the best of the authors' knowledge, this is the first published case of CCV in a carrier of a pathogenic variant of the GBA gene, associated with multiple myeloma and with significant regression of CCV after myeloma treatment. Direct immunofluorescence examination revealed an unusual fibrinogen deposition. Hypothetical causative role of bortezomib treatment was proposed regarding significant regression of CCV.

Cutaneous collagenous vasculopathy: A report of three cases.

Cutaneous collagenous vasculopathy is a rare pauci-inflammatory, superficial, cutaneous vasculopathy characterized by progressive fine-branching telangiectasias clinically, while light microscopically one observes dilated venules and capillaries within the superficial dermis exhibiting excessive Type IV collagen within the vessel wall. We present three cases of collagenous vasculopathy. Two cases were associated with certain autoimmune stigmata, including a positive serologic anti-endothelial cell antibody assay and positive lupus anticoagulant in one, while the third case had positive anti-ribonucleoprotein (RNP) antibodies. The latter case was associated with chronic hydroxyurea therapy for an underlying myeloproliferative disorder. We explore the role of immune- and non-immune-based endothelial cell injury in the pathogenesis of collagenous vasculopathy.

Evaluation of the efficacy of pro-yellow laser in the management of vascular skin disorders.

BACKGROUND: Lasers have great importance in the management of vascular skin lesions. AIM: To determine the efficacy of 577-nm pro-yellow laser in cure of certain vascular skin diseases. MATERIAL AND METHODS: Seventy-four patients who are diagnosed as vascular skin diseases were involved in this study. All participants were treated with 577-nm pro-yellow laser with 4-week intervals. The photographs that were taken before and at every following visit were used to evaluate improvement. RESULTS: A significant improvement occurred in port-wine stain, rosacea, facial telangiectasia, venous lake, scrotal angiokeratoma, and cherry angioma cases. CONCLUSION: Vascular skin lesions can be treated with 577-nm pro-yellow laser with a minimal adverse effect and great success rate.

Mixed vascular naevus syndrome: report of three children with somatic GNA11 mutation and new systemic associations.

Mixed vascular naevus (MVN) is characterized by the co-occurrence of telangiectatic capillary malformation and naevus anaemicus, which can appear as a pure cutaneous phenotype or be combined with systemic manifestations such as brain malformations, neurological abnormalities and musculoskeletal disorders. Recently, GNA11 and GNAQ somatic mutations have been reported in some patients with isolated and syndromic MVN. We report three children with MVN syndrome with generalized cutaneous manifestations and a number of systemic associations not reported to date, including ophthalmological anomalies, musculoskeletal abnormalities such as Sprengel deformity and posterior vertebral fusion anomalies, and septal heart defects. We also confirm a somatic mutation of GNA11 in both telangiectatic naevus and naevus anaemicus in two of our patients and discuss a possible common pathogenic mechanism underlying the different manifestations of the syndrome. Currently, there are no guidelines for the evaluation of patients with MVN syndrome, but according to the different known aspects of the disease, a complete clinical examination should be made, and complementary laboratory and imaging tests should be considered.

Macular Dystrophy with Bilateral Macular Telangiectasia Related to the CYP2U1 Pathogenic Variant Assessed with Multimodal Imaging Including OCT-Angiography.

PURPOSE: We report the case of a neurologically asymptomatic young boy presenting with an unusual phenotype of CYP2U1 related macular dystrophy associating bilateral macular telangiectasia (MacTel) and fibrotic choroidal neovascularization (CNV), assessed with complete multimodal imaging including optical coherence tomography angiography (OCT-A). CASE PRESENTATION: A twelve-year-old boy from a non-consanguineous family complained of bilateral progressive visual loss and photophobia. The best-corrected visual acuity was 2/10 on the right eye and 3/10 on the left eye. Fundus examination showed central pigmented fibrotic macular scar and yellowish punctuate deposits in both eyes. En face OCT-A detected typical macular telangiectasia (MacTel) in both eyes with dilated telangiectatic capillaries in the deep capillary plexus associated with vascular anomalies in the superficial and deep capillary plexus. Typical hypo-reflective cavities were observed within the inner foveal layers on structural OCT. En face OCT-A also confirmed the presence of bilateral inactive CNV within the fibrotic scars, showing high-flow vascular network at the level of the subretinal hyperreflective lesions. Whole exome sequencing identified a known homozygous pathogenic variant in CYP2U1 gene (c.1168C > T, p.Arg390*), which is a disease-causing mutation in autosomal recessive spastic paraplegia type 56 (SPG56). The neurological examination was normal, and electromyography and brain magnetic resonance imaging were unremarkable as well. CONCLUSION: Macular dystrophy can be the first manifestation in SPG56. A particular phenotype with MacTel was observed, and neovascular complications are possible. CYP2U1 should be included in the panels of genes tested for macular dystrophies, especially in the presence of MacTel and/or neurological manifestations.

A dominant-negative SOX18 mutant disrupts multiple regulatory layers essential to transcription factor activity.

Few genetically dominant mutations involved in human disease have been fully explained at the molecular level. In cases where the mutant gene encodes a transcription factor, the dominant-negative mode of action of the mutant protein is particularly poorly understood. Here, we studied the genome-wide mechanism underlying a dominant-negative form of the SOX18 transcription factor (SOX18RaOp) responsible for both the classical mouse mutant Ragged Opossum and the human genetic disorder Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome. Combining three single-molecule imaging assays in living cells together with genomics and proteomics analysis, we found that SOX18RaOp disrupts the system through an accumulation of molecular interferences which impair several functional properties of the wild-type SOX18 protein, including its target gene selection process. The dominant-negative effect is further amplified by poisoning the interactome of its wild-type counterpart, which perturbs regulatory nodes such as SOX7 and MEF2C. Our findings explain in unprecedented detail the multi-layered process that underpins the molecular aetiology of dominant-negative transcription factor function.

Dermoscopy of topical steroid-dependent or damaged face: A cross-sectional study.

BACKGROUND: Topical corticosteroid (TCS) abuse is rampant and results in steroid addiction labeled as topical steroid-dependent or damaged face (TSDF). Indian market is replete with triple combination creams containing TCS sold as over-the-counter products at low cost, luring people to use them without prescription. The resultant damage if detected late is irreversible and difficult to treat. Dermoscopy can help in the early identification of features of TSDF at a preclinical stage resulting in better prognosis. However, the literature on the same is limited. AIMS: This study is undertaken to characterize dermoscopic features of TSDF and to correlate them with potency and duration of application of the TCS. METHODS: One hundred and thirty-two patients aged 18 years or above, with clinical symptoms and signs suggestive of TSDF and with history of application of TCS on the face for a period of more than one month, were enrolled in the study. Their demographic details, clinical features, and dermoscopy findings were recorded using a predesigned structured format. Comparison of dermoscopic findings with clinical examination, gender, potency of TCS, and duration of TCS use was done using Chi-square test, Fisher's exact test, and one-tailed Z-test. RESULTS: Mean age of the patients was 31.7 ± 8.1 years. Male to female ratio was 2:9. Sixty-nine (52.3%) patients abused TCS for more than one year. Clinical findings noted in the patients were erythema (81.1%), hyperpigmentation (80.3%), and hypertrichosis (68.2%). The most common dermoscopy findings seen were brown globules (96.2%), red diffuse areas (92.4%), vessels (87.1%), white structureless areas (86.4%), and hypertrichosis (80.3%). Red diffuse areas, vessels, brown globules, white structureless areas, and white hair were observed in a statistically higher proportion of cases dermoscopically. Y-shaped vessels and brown globules were seen in significantly higher number of patients, using TCS for more than three months and in those continuing it beyond six months, polygonal vessels were predominant. LIMITATIONS: Lack of histopathological correlation is the limitation of our study. Furthermore, brown globules seen in 96.2% patients of TSDF on dermoscopy may have been over-estimated and not always signify TSDF; instead, it could represent melasma for which patient applied TCS. CONCLUSION: Dermoscopy in TSDF can help dermatologists in a multitude of ways from confirming the diagnosis to differentiating from other causes of red face and predicting the approximate duration of TCS abuse.