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.

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.

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.

Spitz Nevus and Other Spitzoid Tumors in Children -Part 1: Clinical, Histopathologic, and Immunohistochemical Features. / Nevo de Spitz y otros tumores spitzoides en la infancia. Parte 1: aspectos clínicos, histológicos e inmunohistoquímicos.

A Spitz nevus is a melanocytic neoplasm of epithelioid and/or spindle cells that usually appears in childhood. These lesions are by nature benign, but their features can sometimes make them difficult to distinguish from melanomas. Spitzoid melanocytic lesions have been grouped into 3 types in recent decades: Spitz nevi, atypical Spitz tumors, and spitzoid melanomas. Atypical Spitz tumors are spitzoid melanocytic proliferations that have atypical histopathologic features that are insufficient to support a diagnosis of melanoma. The malignant potential of these lesions is at present uncertain. This review examines the clinical, dermoscopic, and histopathologic features of this group of lesions.

Spitz Nevus and Other Spitzoid Tumors in Children. Part 2: Cytogenetic and Molecular Features. Prognosis and Treatment. / Nevo de Spitz y otros tumores spitzoides en la infancia. Parte 2: características citogenéticas y moleculares. Pronóstico y tratamiento.

Melanocytic neoplasms with spitzoid morphology (Spitz nevi, atypical Spitz tumors, and spitzoid melanomas) may be benign or malignant. Because the malignant potential of atypical Spitz tumors is uncertain, the proper therapeutic approach has been much debated over the years. Promising new techniques for molecular analysis have enabled better predictions of the biological behavior of these tumors. We review their cytogenetic features and prognosis and also provide an update of the most recent recommendations for management.

A Retrospective Study of Systemic Treatment of Severe Atopic Dermatitis With Azathioprine: Effectiveness and Tolerance in 11 Pediatric Patients. / Estudio retrospectivo del tratamiento sistémico de la dermatitis atópica grave con azatioprina. Eficacia y tolerancia en 11 pacientes pediátricos.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease that typically affects children. Severe forms may have a profound effect on patients' quality of life. Some forms are resistant to conventional treatment and require the use of systemic immunosuppressants such as azathioprine (AZA) to adequately manage the disease. OBJECTIVE: To evaluate the effectiveness and tolerance of AZA in children with severe AD. PATIENTS AND METHODS: We performed a retrospective study of children with severe AD treated with AZA between January 2007 and May 2017. RESULTS: We reviewed the cases of 11 patients (6 boys and 5 girls) with a mean age of 13 years (range, 8-18 years). The mean (SD) age at start of treatment was 10.9 (2.2) years (95% CI 8.6-13.1). The mean initial dosage of AZA was 1.8 (0.2) mg/kg/d. We evaluated treatment response after 4 weeks, 12 to 16 weeks, and 6 months. Mean treatment duration was 10.8 (5.7) months. Treatment had to be suspended in 2 patients because of adverse effects. Seven of the 9 remaining patients presented complete or almost complete clearance of the AD after 6 months of treatment. CONCLUSION: In our experience, AZA is well tolerated and may be considered as a treatment option in children with severe AD resistant to conventional treatment.

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.

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.

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.

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.

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.

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.