Cutaneous Manifestations not Considered Diagnostic Criteria for Neurofibromatosis Type 1. A Case-Control Study.

BACKGROUND: The diagnosis of Neurofibromatosis type 1 (NF1) is usually delayed in children without a family history. We aimed to define the prevalence and characteristics of prevalent skin manifestations in NF1 compared to the general population, which continue to be excluded from the diagnostic criteria for NF1. PATIENTS AND METHODS: Case-control study, matched by age groups, in which 108 patients with a diagnosis of NF1 and 137 healthy controls were included. RESULTS: The prevalence of nevus anemicus (NA) (p<0.001) and juvenile xanthogranulomas (JXG) (p<0.001) was significantly higher in the population affected by NF1 than in the control population. A specificity of 99.27% [confidence interval (CI): 95.4-99.96%] and a positive predictive value (PPV) of 98.80% [92.54-99.94%] were estimated for NA and a specificity of 99.27% [95.4-99.96%] and a PPV of 92.86% [64.17-99.63%] for JXG in the diagnosis of NF1 in children who present 6 or more Café-au-lait macules. Statistically significant differences were also evidenced in the distribution by phototypes (p 0.025) and in relation to generalized itching with no other cause (p<0.001). CONCLUSIONS: NA and JXG are relevant clinical findings for the diagnosis of NF1, especially during the first years of life. We consider that its inclusion among the diagnostic criteria of the disease should be evaluated.

Cutaneous Manifestations not Considered Diagnostic Criteria for Neurofibromatosis Type 1. A Case-Control Study. / Hallazgos cutáneos no considerados criterios diagnósticos de la NF1. Estudio de casos y controles.

BACKGROUND: The diagnosis of Neurofibromatosis type 1 (NF1) is usually delayed in children without a family history. We aimed to define the prevalence and characteristics of prevalent skin manifestations in NF1 compared to the general population, which continue to be excluded from the diagnostic criteria for NF1. PATIENTS AND METHODS: Case-control study, matched by age groups, in which 108 patients with a diagnosis of NF1 and 137 healthy controls were included. RESULTS: The prevalence of nevus anemicus (NA) (P<.001) and juvenile xanthogranulomas (JXG) (P<.001) was significantly higher in the population affected by NF1 than in the control population. A specificity of 99.27% (confidence interval): 95.4-99.96%] and a positive predictive value (PPV) of 98.80% [92.54-99.94%] were estimated for NA and a specificity of 99.27% [95.4-99.96%] and a PPV of 92.86% [64.17-99.63%] for JXG in the diagnosis of NF1 in children who present 6 or more Café-au-lait macules. Statistically significant differences were also evidenced in the distribution by phototypes (P=.025) and in relation to generalized itching with no other cause (P<.001). CONCLUSIONS: NA and JXG are relevant clinical findings for the diagnosis of NF1, especially during the first years of life. We consider that its inclusion among the diagnostic criteria of the disease should be evaluated.

Childhood rosacea and related disorders.

Rosacea is a chronic inflammatory condition that affects the skin and the eyes. The pathogenesis of rosacea is complex and includes the interaction between genetic and environmental factors, dysregulation of the innate immune system, neurovascular modifications and the interaction with skin commensals. Clinical manifestations in children include the telangiectatic form, papulopustular rosacea, ocular rosacea, periorificial dermatitis, granulomatous rosacea and idiopathic facial aseptic granuloma. Management is aimed at identifying and avoiding triggers. Topical therapy is used for mild cases with topical antibiotics and anti-inflammatory agents. Oral agents are indicated, in combination with topical therapy, for moderate to severe cases. Prolonged therapy may be required.

SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases.

BACKGROUND: Chilblains ('COVID toes') are being seen with increasing frequency in children and young adults during the COVID-19 pandemic. Detailed histopathological descriptions of COVID-19 chilblains have not been reported, and causality of SARS-CoV-2 has not yet been established. OBJECTIVES: To describe the histopathological features of COVID-19 chilblains and to explore the presence of SARS-CoV-2 in the tissue. METHODS: We examined skin biopsies from seven paediatric patients presenting with chilblains during the COVID-19 pandemic. Immunohistochemistry for SARS-CoV-2 was performed in all cases and electron microscopy in one. RESULTS: Histopathology showed variable degrees of lymphocytic vasculitis ranging from endothelial swelling and endotheliitis to fibrinoid necrosis and thrombosis. Purpura, superficial and deep perivascular lymphocytic inflammation with perieccrine accentuation, oedema, and mild vacuolar interface damage were also seen. SARS-CoV-2 immunohistochemistry was positive in endothelial cells and epithelial cells of eccrine glands. Coronavirus particles were found in the cytoplasm of endothelial cells on electron microscopy. CONCLUSIONS: Although the clinical and histopathological features were similar to other forms of chilblains, the presence of viral particles in the endothelium and the histological evidence of vascular damage support a causal relation of the lesions with SARS-CoV-2. Endothelial damage induced by the virus could be the key mechanism in the pathogenesis of COVID-19 chilblains and perhaps also in a group of patients severely affected by COVID-19 presenting with features of microangiopathic damage. What is already known about this topic? Despite the high number of cases of chilblains seen during the COVID-19 pandemic, a definite causative role for SARS-CoV-2 has not yet been proven. Different pathogenetic hypotheses have been proposed, including coagulation anomalies, interferon release and external factors. What does this study add? The demonstration of SARS-CoV-2 in endothelial cells of skin biopsies by immunohistochemistry and electron microscopy confirms that these lesions are part of the spectrum of COVID-19. Virus-induced vascular damage and secondary ischaemia could explain the pathophysiology of COVID-19 chilblains. Our findings support the hypothesis that widespread endothelial infection by SARS-CoV-2 could have a pathogenetic role in the severe forms of COVID-19. Linked Comment: Wetter. Br J Dermatol 2020; 183:611.

Immune cell metabolism in autoimmunity.

Immune metabolism is a rapidly moving field. While most of the research has been conducted to define the metabolism of healthy immune cells in the mouse, it is recognized that the overactive immune system that drives autoimmune diseases presents metabolic abnormalities that provide therapeutic opportunities, as well as a means to understand the fundamental mechanisms of autoimmune activation more clearly. Here, we review recent publications that have reported how the major metabolic pathways are affected in autoimmune diseases, with a focus on rheumatic diseases.

Evidence of the high prevalence of neurological disorders in nonsyndromic X-linked recessive ichthyosis: a retrospective case series.

BACKGROUND: X-linked recessive ichthyosis (XLI) is a relatively common type of ichthyosis caused by a deficiency in the steroid sulfatase (STS) enzyme. It is the only type of ichthyosis that can be both syndromic and nonsyndromic. Typical clinical features include dark-brown scale of variable size favouring the extensor surfaces of the extremities. OBJECTIVES: To characterize clinically nonsyndromic XLI, with a particular focus on extracutaneous manifestations. METHODS: This was a multicentre retrospective review of clinical findings from a case series of patients with a clinical and genetic diagnosis of XLI. RESULTS: We identified 30 patients with XLI belonging to 25 different families carrying a deletion in the STS locus. All patients had dark scales of variable size on the extensor surfaces of the extremities. Lack of flexural involvement and pruritus were common but inconsistent findings, whereas palmoplantar hyperlinearity was absent in all but one patient. A history of orchiopexy was present in 10% and thus was more common than expected vs. the general population (3%). Neurological disorders including epilepsy (13%) and attention deficit hyperactivity disorder (ADHD; 30%) were over-represented in patients with XLI. CONCLUSIONS: This was a retrospective study with a limited number of patients. In the absence of confirmatory genetic testing and family history of the disease, dark-brown scale of the extensor surfaces and the absence of palmoplantar hyperlinearity appear to be the most reliable clinical findings supporting a diagnosis of XLI. Dermatologists should be aware of the high prevalence of ADHD and epilepsy in patients with nonsyndromic XLI.

A Skint6 allele potentially contributes to mouse lupus.

Our previous study uncovered that the overlapping region of murine lupus susceptibility Sle2c1rec1a and Sle2c1rec1d subloci is strongly associated with lymphadenopathy and systemic autoimmunity. In order to identify the specific candidate gene, we generated a novel shorter recombinant, named as Sle2c1re1d1 (rec1d1), from Sle2c1rec1d sublocus (rec1d). The rec1d1 interval corresponds precisely to the overlapping region of Sle2c1rec1a and Sle2c1rec1d subloci. Functionally, this rec1d1 sublocus showed a strong epistatic interaction with lpr, similar to that seen with Sle2c1rec1a or.Sle2c1rec1d. The Skint6 gene in the red1d1 interval was identified to have a point mutation, which inserts a premature stop codon and converts the membrane Skint6 protein into a truncated secretory peptide. However, other protein-coding genes in the rec1d1 interval have no mutation in exon sequence. The heterozygous rec1d1 interval in B6.lpr demonstrates exacerbated autoimmunity. For example, non-hematopoietic stem cell-derived cells of the B6.Sle2c1rec1d1.lpr mice promote T-cell proliferation in vivo. These findings led us to conclude that the Skint6 variant in the rec1d1 interval is the most likely causative gene of mouse lupus.

Cyclosporine A for severe atopic dermatitis in children. efficacy and safety in a retrospective study of 63 patients.

BACKGROUND: Cyclosporine A (CSA) is an immunosuppressant agent widely used in severe atopic dermatitis (AD). However, experience in children is limited. OBJECTIVES: To assess the efficacy and adverse events of CSA therapy in children. METHODS: Retrospective study of children with severe AD treated with CSA between January 2009 and December 2015. RESULTS: Data from 63 patients were collected. Mean age at the beginning of treatment was 8.4 years (±3.6). The median starting dose was 4.27 (±0.61) mg/kg/day. After 4 weeks of treatment, the outcome was excellent in 35% of cases, good in 29% and poor in 36% of the patients. The response was better in patients without eosinophilia (P < 0.05). The median duration of treatment was 4.6 months (range 1.5-21.6). Side-effects were frequent but mild, being more common in patients after longer treatment periods (P < 0.05). Mean time of follow-up was 19.4 months (±12.7). Prolonged remission (>6 months) was observed in 13 patients (20%). LIMITS: This is a retrospective review. The follow-up period is limited. CONCLUSIONS: Our data confirm that CSA is efficacious and acts rapidly in the majority of children with severe AD. CSA therapy can provide sustained remission in some patients. CSA seems to be well tolerated in children, but strict monitoring is mandatory.

Recurrent lipoatrophic panniculitis of children.

BACKGROUND: Recurrent panniculitis in children with lipoatrophy has been loosely described and reported under different names, but has never been systematically evaluated by immunohistochemical stains. OBJECTIVE: To depict the profile of children with recurrent idiopathic panniculitis. METHODS: Study of clinical, histopathological and immunohistochemical features in five cases with recurrent idiopathic panniculitis. RESULTS: Five children with repeated attacks of painful subcutaneous nodules in association with fever, malaise and abdominal pain or arthralgia, with subsequent lipoatrophy were reviewed. In two patients, extensive involvement led to loss of the cutaneous fatty tissue. Laboratory abnormalities included increased acute phase reactants, leukocytosis with mild neutrophilia, microcytic anaemia and elevated liver enzymes. Histopathology showed lobar panniculitis without vasculitis and with a mixed infiltrate, composed of neutrophils, mononuclear cells, lymphocytes, macrophages and myeloid cells. Neutrophils and myeloid cells were more prominent in early lesions, whereas macrophages predominated in late stages, leading to lipophagia and lipoatrophy. Immunohistochemistry showed positive staining for myeloperoxidase around the necrotic adipocytes in early stages and CD68/PGM1 macrophages in late stages. Intense STAT1 staining was observed in the inflammatory infiltrate. All patients improved with methotrexate and corticosteroids. CONCLUSION: We present five cases of lobar panniculitis and lipoatrophy in childhood. The clinico-pathologic presentation shares features with other autoinflammatory diseases.

Autoinflammatory Diseases in Pediatric Dermatology-Part 2: Histiocytic, Macrophage Activation, and Vasculitis Syndromes. / Enfermedades autoinflamatorias en dermatología pediátrica. Parte 2: síndromes histiocítico-macrofágicos y síndromes vasculopáticos.

The discovery of new autoinflammatory syndromes and novel mutations has advanced at breakneck speed in recent years. Part 2 of this review focuses on vasculitis syndromes and the group of histiocytic and macrophage activation syndromes. We also include a table showing the mutations associated with these autoinflammatory syndromes and treatment alternatives.

Autoinflammatory Diseases in Pediatric Dermatology-Part 1: Urticaria-like Syndromes, Pustular Syndromes, and Mucocutaneous Ulceration Syndromes. / Enfermedades autoinflamatorias en dermatología pediátrica. Parte 1: síndromes urticariformes, síndromes pustulosos y síndromes con ulceraciones cutáneo-mucosas.

Monogenic autoinflammatory diseases are a heterogeneous emergent group of conditions that are currently under intensive study. We review the etiopathogenesis of these syndromes and their principal manifestations. Our aim is to propose a classification system based on the clinicopathologic features of typical skin lesions for routine clinical use in dermatology. Our focus is on diagnosis in pediatric practice given that this is the period when the signs and symptoms of these syndromes first appear. In Part 1 we discuss the course of urticaria-like syndromes, which include cryopyrin-associated periodic conditions and hereditary periodic fever syndromes. Pustular syndromes are also covered in this part. Finally, we review the range of therapies available as well as the genetic mutations associated with these autoinflammatory diseases.

The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.

Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.

Two cases of overlap severe cutaneous adverse reactions to benznidazole treatment for asymptomatic Chagas disease in a nonendemic country.

Chagas disease is a parasitosis endemic to South America. It is normally treated with benznidazole as first choice, which has been associated with numerous cutaneous reactions. However, very few benznidazole-associated severe cutaneous adverse reactions have been reported to date. The rise of Chagas disease in nonendemic countries represents a growing public health challenge. We report two patients who met the criteria for drug reaction with eosinophilia and systemic symptoms syndrome and Stevens-Johnson syndrome/toxic epidermal necrolysis according to the RegiSCAR scoring systems. They were thus deemed overlapping cases, with a lymphocyte transformation test positive for benznidazole. Both required intensive care unit admission and both survived. Considering the rising application of this drug for trypanosomiasis in immigrant populations, clinicians should be aware of this newly reported, potentially life-threatening risk.

LEOPARD syndrome without hearing loss or pulmonary stenosis: a report of 2 cases.

LEOPARD syndrome is an autosomal dominant disease caused by germline mutations in the RAS-MAPK (mitogen-activated protein kinase) pathway. LEOPARD is an acronym for the main manifestations of the syndrome, namely, multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retardation of growth, and sensorineural Deafness. None of these characteristic features, however, are pathognomonic of LEOPARD syndrome, and since they are highly variable, they are often not present at the time of diagnosis. We describe 2 cases of LEOPARD syndrome without hearing loss or pulmonary stenosis in which diagnosis was confirmed by identification of a mutation in the PTPN11 gene. Regular monitoring is important for the early detection of complications, as these can occur at any time during the course of disease.

Early-onset acral basal cell carcinomas in Gorlin syndrome.

Two patients are reported in whom early-onset, distal papules with a histopathological diagnosis of basal cell carcinoma were the first manifestation of Gorlin syndrome (GS). These lesions showed no progression and remained stable through follow-up. Two different PTCH1 gene mutations were detected in the two patients, and thus a phenotype-genotype correlation of this manifestation of GS was not possible.

A Mathematical Analysis of Clustering-Free Local SAR Compression Algorithms for MRI Safety in Parallel Transmission.

Parallel transmission (pTX) is a versatile solution to enable UHF MRI of the human body, where radiofrequency (RF) field inhomogeneity appears very challenging. Today, state of the art monitoring of the local SAR in pTX consists in evaluating the RF power deposition on specific SAR matrices called Virtual Observation Points (VOPs). It essentially relies on accurate electromagnetic simulations able to return the local SAR distribution inside the body in response to any applied pTX RF waveform. In order to reduce the number of SAR matrices to a value compatible with real time SAR monitoring ( << 103) , a VOP set is obtained by partitioning the SAR model into clusters, and associating a so- called dominant SAR matrix to every cluster. More recently, a clustering-free compression method was proposed, allowing for a significant reduction in the number of SAR matrices. The concept and derivation however assumed static RF shims and their extension to dynamic pTX is not straightforward, thereby casting doubt on the strict validity of the compression approach for these more complicated RF waveforms. In this work, we provide the mathematical framework to tackle this problem and find a rigorous justification of this criterion in the light of convex optimization theory. Our analysis led us to a variant of the clustering-free compression approach exploiting convex optimization. This new compression algorithm offers computational gains for large SAR models and for high-channel count pTX RF coils.

The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T-cell-mediated pathology in B6.Fas(lpr) mice.

The NZM2410 Sle2c1 lupus susceptibility locus is responsible for the expansion of the B1a cell compartment, and for the induction of T-cell induced renal and skin pathology on a CD95-deficient (Fas(lpr)) background. We have previously shown that deficiency in the cyclin-dependent kinase inhibitor p18(INK4c) (p18) was responsible for the B1a cell expansion but was not sufficient to account for the pathology in B6.lpr mice. This study was designed to map the additional Sle2c1 loci responsible for autoimmune pathology when co-expressed with CD95 deficiency. The production, fine-mapping and phenotypic characterization of five recombinant intervals indicated that three interacting subloci were responsive for inducting autoimmune pathogenesis in B6.lpr mice. One of these subloci corresponds most likely to p18 deficiency. Another major locus mapping to a 2-Mb region at the telomeric end of Sle2c1 is necessary to both renal and skin pathology. Finally, a third locus centromeric to p18 enhances the severity of lupus nephritis. These results provide new insights into the genetic interactions leading to systemic lupus erythematosus disease presentation, and represent a major step towards the identification of novel susceptibility genes involved in T-cell-mediated organ damage.