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ABSTRACT A male infant presented with progressive jaundice immediately after birth. Fecal acholia and choluria associated with extensive bullous skin lesions in his trunk, abdomen, and upper and lower limbs developed during phototherapy. Several diagnostic hypotheses were presented, including neonatal porphyria, hemochromatosis, Alagille syndrome, and neonatal lupus. A 24-hour urine sample for the dosage of urinary porphyrins was collected, showing high results (1823.6µg in 100mL). At 50 days of life, fluorescence spectroscopy using a Wood’s lamp revealed simultaneous bright red fluorescence of urine-stained diapers and sample blood. A definitive diagnosis of congenital erythropoietic porphyria was made following identification of a mutation of the uroporphyrinogen synthetases III gene on genetic testing. The patient was subsequently maintained in a low light environment since then, resulting in improvement of the lesions. Congenital erythropoietic porphyria is a disease of the group of porphyrias that presents shortly after birth with blistering occurring in regions exposed to the sun or other ultraviolet light. Atrophic scars, mutilated fingers, and bright red fluorescence of the urine and teeth may also be observed. There is no specific treatment, and prophylaxis comprising a total avoidance of sunlight is generally recommended. A high degree of suspicion is required for diagnosis. An early diagnosis can lead to less damage. Here, we present the case of a newborn with congenital erythropoietic porphyria diagnosed after presenting with bullous lesions secondary to phototherapy.

A male infant presented with progressive jaundice immediately after birth. Fecal acholia and choluria associated with extensive bullous skin lesions in his trunk, abdomen, and upper and lower limbs developed during phototherapy. Several diagnostic hypotheses were presented, including neonatal porphyria, hemochromatosis, Alagille syndrome, and neonatal lupus. A 24-hour urine sample for the dosage of urinary porphyrins was collected, showing high results (1823.6µg in 100mL). At 50 days of life, fluorescence spectroscopy using a Wood's lamp revealed simultaneous bright red fluorescence of urine-stained diapers and sample blood. A definitive diagnosis of congenital erythropoietic porphyria was made following identification of a mutation of the uroporphyrinogen synthetases III gene on genetic testing. The patient was subsequently maintained in a low light environment since then, resulting in improvement of the lesions. Congenital erythropoietic porphyria is a disease of the group of porphyrias that presents shortly after birth with blistering occurring in regions exposed to the sun or other ultraviolet light. Atrophic scars, mutilated fingers, and bright red fluorescence of the urine and teeth may also be observed. There is no specific treatment, and prophylaxis comprising a total avoidance of sunlight is generally recommended. A high degree of suspicion is required for diagnosis. An early diagnosis can lead to less damage. Here, we present the case of a newborn with congenital erythropoietic porphyria diagnosed after presenting with bullous lesions secondary to phototherapy. [ABSTRACT FROM AUTHOR]

Abstract Lipoid proteinosis is a rare autosomal recessive disease, characterized by hyaline deposits of PAS-positive material in tissues due to mutations in the ECM1 gene. This study evaluated the ultrastructure of the skin of a 6-year-old child affected by this condition. The light microscopy identified PAS-positive hyaline deposits, which were more intense in the papillary dermis. Scanning electron microscopy of the dermis showed a compact papillary dermis and fibrillar deposits in the middle dermis. Transmission electron microscopy clearly showed the deposition of fibrillar material in the dermis, forming clusters adherent to elastic fibers, between the collagen bundles and the collagen fibers, and also filling up the cytoplasm of dermal fibroblasts.

Competing Interests: The authors declare no conflicts of interest.

The polymorphic presentation of annular dermatoses in the pediatric population renders them a diagnostic challenge to the clinician. They include various distinct disease entities that can be vaguely categorized according to the age of onset. Herein, we report on a young girl with clinical characteristics of Wells' syndrome, while histological findings favored the diagnosis of annular erythema of infancy (AEI). Although morphological and histological similarities do exist, AEI and eosinophilic annular erythema (EAE) of childhood are considered as distinct entities in the literature. Wells' syndrome (WS) is an eosinophilic dermatosis and histologically characterized by eosinophilic dermal infiltration with the hallmark feature of "flame figures." Based on this case, we discuss and review the differential diagnoses of annular dermatoses in children., (© 2023. The Author(s).)

Prolidase deficiency is an extremely rare, autosomal recessive disorder resulting in defective collagen formation. We report a case of prolidase deficiency in a male child, highlighting the dermatologic features. Early diagnosis is important as these patients encounter significant multisystem comorbidities requiring multispecialty care. [ABSTRACT FROM AUTHOR]

Cervicocerebral artery dissection stands out as a significant contributor to ischemic stroke in young adults. Several studies have shown that arterial tortuosity is associated with dissection. We searched Pubmed and Embase to identify studies on the association between arterial tortuosity and cervicocerebral artery dissection, and to perform a review on the epidemiology of cervicocerebral artery tortuosity and dissection, pathophysiology, measurement of vessels tortuosity, strength of association between tortuosity and dissection, clinical manifestation and management strategies. The prevalence of tortuosity in dissected cervical arteries was reported to be around 22%-65% while it is only around 8%-22% in non-dissected arteries. In tortuous cervical arteries elastin and tunica media degradation, increased wall stiffness, changes in hemodynamics as well as arterial wall inflammation might be associated with dissection. Arterial tortuosity index and vertebrobasilar artery deviation is used to measure the level of vessel tortuosity. Studies have shown an independent association between these two measurements and cervicocerebral artery dissection. Different anatomical variants of tortuosity such as loops, coils and kinks may have a different level of association with cervicocerebral artery dissection. Symptomatic patients with extracranial cervical artery dissection are often treated with anticoagulant or antiplatelet agents, while patients with intracranial arterial dissection were often treated with antiplatelets only due to concerns of developing subarachnoid hemorrhage. Patients with recurrent ischemia, compromised cerebral blood flow or contraindications for antithrombotic agents are usually treated with open surgery or endovascular technique. Those with subarachnoid hemorrhage and intracranial artery dissection are often managed with surgical intervention due to high risk of re-hemorrhage., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Abstract: Intravenous plasminogen replacement therapy for patients with plasminogen deficiency type 1 (hypoplasminogenemia) was recently approved for marketing in the US. In this case report, the authors describe a 33-year-old man with hypoplasminogenemia who developed nonhealing postsurgical wounds following trauma to his right hand despite receiving standard treatment for 4 months. The patient was enrolled in a compassionate-use protocol with intravenous plasminogen replacement therapy and experienced prompt resolution of surgical wounds. He was the first human patient to receive replacement therapy with plasminogen, human-tvmh in the US and first to demonstrate cutaneous wound healing in addition to resolution of ligneous lesions attributable to plasminogen deficiency type 1., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

The effect of arterial tortuosity on intracranial atherosclerosis (ICAS) is not well understood. This study aimed to evaluate the effect of global intracranial arterial tortuosity on intracranial atherosclerotic burden in patients with ischemic stroke. We included patients with acute ischemic stroke who underwent magnetic resonance angiography (MRA) and classified them into three groups according to the ICAS burden. Global tortuosity index (GTI) was defined as the standardized mean curvature of the entire intracranial arteries, measured by in-house vessel analysis software. Of the 516 patients included, 274 patients had no ICAS, 140 patients had a low ICAS burden, and 102 patients had a high ICAS burden. GTI increased with higher ICAS burden. After adjustment for age, sex, vascular risk factors, and standardized mean arterial area, GTI was independently associated with ICAS burden (adjusted odds ratio [adjusted OR] 1.33; 95% confidence interval [CI] 1.09-1.62). The degree of association increased when the arterial tortuosity was analyzed limited to the basal arteries (adjusted OR 1.48; 95% CI 1.22-1.81). We demonstrated that GTI is associated with ICAS burden in patients with ischemic stroke, suggesting a role for global arterial tortuosity in ICAS., (© 2024. The Author(s).)

An adult-onset autoinflammatory syndrome caused by somatic mutations in the UBA1 gene on the X chromosome was first reported in 2020. This VEXAS syndrome (acronym for vacuoles, E1 enzyme, X‑linked, autoinflammatory, somatic) is characterized by an overlap of rheumatic inflammatory diseases with separate hematologic abnormalities. A substantial number of affected patients suffer from treatment refractory relapsing polychondritis and nearly always show signs of macrocytic anemia. This case report illustrates the diagnostic key points to recognizing patients with VEXAS syndrome., (© 2023. The Author(s).)

We report the case of a man in his late 30s who presented with a history of breathlessness and cough with haemoptysis. Complete blood counts revealed pancytopenia. High-resolution CT showed diffuse bilateral ground glass opacities. Sequential bronchoalveolar lavage confirmed alveolar haemorrhage. Bone marrow aspiration showed vacuoles in erythroid and myeloid precursor cells. The genome was sequenced, and the UBA1 gene revealed a c.121 A>G mutation (p.Met41Val), confirming vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome. The patient was managed with high-dose prednisolone pulse therapy. He improved with the complete resolution of the alveolar haemorrhage and an improvement in lung function and cytopenias., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic mutation) syndrome is a novel autoinflammatory, late-onset, disorder first identified in 2020. It is caused by mutations in the UBA1 gene. The most prominent clinical features reported by VEXAS patients are cutaneous and haematological, having characteristic skin features reported as the initial presenting findings of the disease. VEXAS is a severe and treatment-resistant condition with high morbidity and mortality rates. Here, we examine all case reports and case series of VEXAS syndrome through March 2023 focusing on those presenting cutaneous manifestations. We discuss these manifestations and their reported treatment strategies. In many cases, it might be first suspected and diagnosed by dermatologists, highlighting their vital role in initiating timely multidisciplinary care., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Competing Interests: The authors have no conflicts of interest regarding this article, and have received no funding for this work.

The VEXAS syndrome, a genetically defined autoimmune disease, associated with various hematological neoplasms has been attracting growing attention since its initial description in 2020. While various therapeutic strategies have been explored in case studies, the optimal treatment strategy is still under investigation and allogeneic cell transplantation is considered the only curative treatment. Here, we describe 2 patients who achieved complete molecular remission of the underlying UBA1 mutant clone outside the context of allogeneic HCT. Both patients received treatment with the hypomethylating agent azacitidine, and deep molecular remission triggered treatment de-escalation and even cessation with sustained molecular remission in one of them. Prospective studies are necessary to clarify which VEXAS patients will benefit most from hypomethylating therapy and to understand the variability in the response to different treatment strategies., (© 2024. The Author(s).)

An 8 year-old boy, previously healthy, presented on the emergency department, during the summer, with air-filled blisters on the volar aspect of the extremities of fingers on the hands (Fig. 1). On follow-up as an outpatient, he showed resolution of the first lesions but with various relapses associated with contact with water for a long period of time, showing posterior peeling of the skin and posterior resolution. What is your diagnosis?

Abstract: Vohwinkel syndrome belongs to the group of hereditary palmoplantar keratoderma, having an autosomal dominant inheritance. In this report, the authors present a case of a four-year-old boy with diffuse scaling over his entire body and transgredient palmoplantar hyperkeratosis with some fissured areas. Family evaluation revealed that his mother and other family members were affected. Based on his clinical findings and on family history, the diagnosis of the ichthyotic Vohwinkel syndrome subtype, characterized by generalized ichthyosis and palmoplantar hyperkeratosis, was established.

Introduction: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an acquired autoinflammatory monogenic disease with a poor prognosis whose determinants are not well understood. We aimed to describe serious infectious complications and their potential risk factors., Methods: Retrospective multicentre study including patients with VEXAS syndrome from the French VEXAS Registry. Episodes of serious infections were described, and their risk factors were analysed using multivariable Cox proportional hazards models., Results: Seventy-four patients with 133 serious infections were included. The most common sites of infection were lung (59%), skin (10%) and urinary tract (9%). Microbiological confirmation was obtained in 76%: 52% bacterial, 30% viral, 15% fungal and 3% mycobacterial. Among the pulmonary infections, the main pathogens were SARS-CoV- 2 (28%), Legionella pneumophila (21%) and Pneumocystis jirovecii (19%). Sixteen per cent of severe infections occurred without any immunosuppressive treatment and with a daily glucocorticoid dose ≤10 mg. In multivariate analysis, age >75 years (HR (95% CI) 1.81 (1.02 to 3.24)), p.Met41Val mutation (2.29 (1.10 to 5.10)) and arthralgia (2.14 (1.18 to 3.52)) were associated with the risk of serious infections. JAK inhibitors were most associated with serious infections (3.84 (1.89 to 7.81)) compared with biologics and azacitidine. After a median follow-up of 4.4 (2.5-7.7) years, 27 (36%) patients died, including 15 (56%) due to serious infections., Conclusion: VEXAS syndrome is associated with a high incidence of serious infections, especially in older patients carrying the p.Met41Val mutation and treated with JAK inhibitors. The high frequency of atypical infections, especially in patients without treatment, may indicate an intrinsic immunodeficiency., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Relapsing polychondritis is a chronic autoimmune inflammatory condition characterized by recurrent episodes of inflammation at the level of cartilaginous structures and tissues rich in proteoglycans. The pathogenesis of the disease is complex and still incompletely elucidated. The data support the important role of a particular genetic predisposition, with HLA-DR4 being considered an allele that confers a major risk of disease occurrence. Environmental factors, mechanical, chemical or infectious, act as triggers in the development of clinical manifestations, causing the degradation of proteins and the release of cryptic cartilage antigens. Both humoral and cellular immunity play essential roles in the occurrence and perpetuation of autoimmunity and inflammation. Autoantibodies anti-type II, IX and XI collagens, anti-matrilin-1 and anti-COMPs (cartilage oligomeric matrix proteins) have been highlighted in increased titers, being correlated with disease activity and considered prognostic factors. Innate immunity cells, neutrophils, monocytes, macrophages, natural killer lymphocytes and eosinophils have been found in the perichondrium and cartilage, together with activated antigen-presenting cells, C3 deposits and immunoglobulins. Also, T cells play a decisive role in the pathogenesis of the disease, with relapsing polychondritis being considered a TH1-mediated condition. Thus, increased secretions of interferon γ, interleukin (IL)-12 and IL-2 have been highlighted. The "inflammatory storm" formed by a complex network of pro-inflammatory cytokines and chemokines actively modulates the recruitment and infiltration of various cells, with cartilage being a source of antigens. Along with RP, VEXAS syndrome, another systemic autoimmune disease with genetic determinism, has an etiopathogenesis that is still incompletely known, and it involves the activation of the innate immune system through different pathways and the appearance of the cytokine storm. The clinical manifestations of VEXAS syndrome include an inflammatory phenotype often similar to that of RP, which raises diagnostic problems. The management of RP and VEXAS syndrome includes common immunosuppressive therapies whose main goal is to control systemic inflammatory manifestations. The objective of this paper is to detail the main etiopathogenetic mechanisms of a rare disease, summarizing the latest data and presenting the distinct features of these mechanisms.

Purpose: Actinic conjunctivitis (AC), along with cheilitis (AChe), is part of the clinical spectrum of actinic prurigo (AP), a rare photo dermatosis that affects high-risk populations. We analyzed the clinical manifestations and onset of actinic conjunctivitis (AC), and its relationship with prurigo (AP) in a susceptible population., Methods: This prospective observational cohort study was performed on Indigenous populations from the highlands of Chiapas, Mexico. Thorough dermatological and ophthalmological examinations were performed in patients attending a primary health care center. The clinical features, labor and environmental factors, onset timing, and clinical staging of AC and AP were analyzed., Results: Of the 2913 patients studied, 54 patients (108 eyes) (1.8%) had AC, and 14 patients (25.9%) had AP. The mean age at diagnosis was 36.18 ± 18.52 years (6-70 years). The mean residential altitude was 1884 ± 434.2 m above sea level. Mean self-reported sun exposure was 5.14 ± 3.1 h a day (0.5-12 h). A total of 90.7% reported exposure to biomass fuels during cooking, and 50% to farm animals. AC was the sole manifestation in 70% of the cases. All patients had nasal and temporal photo-exposed conjunctiva. Among the eyes, 12.9% were classified as stage-1, 64.8% as stage-2, and 22.2% stage-3. A total of 83.3% of the patients had hyperpigmented lesions, and 35.1% had evaporative dry eye disease., Conclusions: AC may be the initial or sole manifestation of AP. Most AC cases (87%) were initially observed at the advanced stages of the disease. Although solar exposure was not associated with late AC stages, a positive association was found with farm animal exposure. Evaporative dry eye associated with meibomian gland dysfunction has not been previously reported in patients with AC., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The presence of vacuoles in myeloid and erythroid progenitor cells in bone marrow aspirates is a key feature of vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. The mere observation of vacuolated progenitor cells is not specific to VEXAS syndrome; in this Viewpoint, we point out the causes to be considered in this situation. Vacuoles, in particular, can be observed in individuals with wild-type UBA1 and with persistent inflammatory features or myelodysplastic syndromes. However, several clues support the diagnosis of VEXAS syndrome in the presence of vacuolated bone marrow progenitors: a high number of vacuolated progenitors and of vacuoles per cell, the predominance of vacuoles in early rather than late progenitors, and the vacuolisation of both myeloid and erythroid progenitors with predominance of myeloid ones. Some criteria derived from these observations have been proposed with great diagnostic performances. However, the absence or a low proportion of vacuolated cells should not prevent UBA1 gene sequencing., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Autoinflammatory diseases (AIDs) characterized by recurrent episodes of localized or systemic inflammation are disorders of the innate immune system. Skin lesions are commonly found in AIDs and cutaneous vasculitis can coexist with AIDs and even present as the most striking feature. This review aims to focus on the frequent cutaneous vasculitis association in three monogenic AIDs including familial Mediterranean fever (FMF), deficiency of adenosine deaminase type 2 (DADA2), and the recently identified adult-onset VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Cutaneous vasculitis in FMF is characterized by: (1) small-vessel vasculitis similar to IgA vasculitis with palpable purpura but increased intussusception complication and less vascular IgA deposit, and (2) cutaneous arteritis-like vasculitis presenting as subcutaneous nodules most often with higher glomerular involvement. DADA2 has a wide spectrum of clinical presentations ranging from fatal systemic vasculitis with multiple strokes, especially in pediatric patients, to limited cutaneous disease in middle-aged patients. DADA2 shares similar clinical and histopathological features with polyarteritis nodosa (PAN). As a result, DADA2 is commonly initially misdiagnosed as childhood PAN. Livedo racemosa reveals the most common cutaneous manifestation of cutaneous vasculitis in patients with DADA2. VEXAS syndrome is a life-threatening disease. A diagnosis of VEXAS syndrome should be strongly considered or could be made in patients with skin lesions characterized by Sweet syndrome-like eruption, livedo racemosa, concomitant relapsing polychondritis, deep venous thrombosis, pulmonary involvement, and progressive hematologic abnormalities such as myelodysplastic syndrome with a unique finding of cytoplasmic vacuoles in myeloid and erythroid precursor cells from bone marrow aspirate smear. As skin involvement is common in AIDs and may present as the most frequent manifestation, especially in DADA2 (70% to 90%) and VEXAS syndrome (83% to 91%), dermatologists play a crucial role in contributing to the early diagnosis of these AIDs with early initiation of the appropriate therapy to avoid progressing fatal outcomes., (© 2023 Japanese Dermatological Association.)

VEXAS is a prototypic hemato-inflammatory disease combining rheumatologic and hematologic disorders in a molecularly defined nosological entity. In this nationwide study, we aimed at screenshotting the current diagnostic capabilities and clinical-genomic features of VEXAS, and tracked UBA1 longitudinal clonal dynamics upon different therapeutics, including allogeneic hematopoietic cell transplant. We leveraged a collaboration between the Italian Society of Experimental Hematology and of Rheumatology and disseminated a national survey to collect clinical and molecular patient information. Overall, 13/29 centers performed UBA1 genomic testing locally, including Sanger sequencing (46%), next-generation sequencing (23%), droplet digital polymerase chain reaction (8%), or combination (23%). A total of 41 male patients were identified, majority (51%) with threonine substitutions at Met41 hotspot, followed by valine and leucine (27% and 8%). Median age at VEXAS diagnosis was 67 years. All patients displayed anemia (median hemoglobin 9.1 g/dL), with macrocytosis. Bone marrow vacuoles were observed in most cases (89%). The most common rheumatologic association was polychondritis (49%). A concomitant myelodysplastic neoplasm/syndrome (MDS) was diagnosed in 71% of patients (n = 28), chiefly exhibiting lower Revised International Prognostic Scoring System risk profiles. Karyotype was normal in all patients, except three MDS cases showing -Y, t(12;16)(q13;q24), and +8. The most frequently mutated gene was DNMT3A (n = 10), followed by TET2 (n = 3). At last follow-up, five patients died and two patients progressed to acute leukemia. Longitudinal UBA1 clonal dynamics demonstrated mutational clearance following transplant. We collected a nationwide interdisciplinary VEXAS patient cohort, characterized by heterogeneous rheumatologic manifestations and treatments used. MDS was diagnosed in 71% of cases. Patients exhibited various longitudinal UBA1 clonal dynamics., (© 2023 Wiley Periodicals LLC.)