DAB2IP associates with hereditary angioedema: Insights into the role of VEGF signaling in HAE pathophysiology.

BACKGROUND: In the recent years, there was an important improvement in the understanding of the pathogenesis of hereditary angioedema (HAE). Notwithstanding, in a large portion of patients with unknown mutation (HAE-UNK) the genetic cause remains to be identified. OBJECTIVES: To identify new genetic targets associated with HAE, a large Argentine family with HAE-UNK spanning 3 generations was studied. METHODS: Whole exome sequencing was performed on affected family members to identify potential genetic variants associated with HAE-UNK. In silico analyses and experimental studies were applied to assess the role of the identified gene variant. RESULTS: A missense variant (p.D239N) in DAB2IP was identified. The variant occurred in the C2-domain, the region interacting with vascular endothelial growth factor receptor 2 (VEGFR2). It was found to be rare, and predicted to have a detrimental effect on the functionality of DAB2IP. Protein structure modeling predicted changes in the mutant p.D239N protein structure, impacting protein stability. The p.D239N variant affected the subcellular localization of VEGFR2. Cells transfected with the DAB2IP-239N transcript exhibited an intracellular distribution, and VEGFR2 remained associated with the cell membrane. The altered localization pattern indicated reduced colocalization of the mutant protein with VEGFR2, suggesting a diminished ability of VEGFR2 binding. CONCLUSIONS: The study identified a novel missense variant (p.D239N) in DAB2IP in a family with HAE-UNK and highlighted the role of dysregulated VEGF-mediated signaling in altered endothelial permeability. DAB2IP loss-of-function pathogenic variants lead to the impairment of the endothelial VEGF/VEGFR2 ligand system and represent a new pathophysiologic cause of HAE-UNK.

Differences between preschoolers with asthma and allergies in urban and rural environments.

OBJECTIVE: Previous studies have provided conflicting results about how living in a rural or urban environment influences schoolchildren with asthma and allergic diseases in different ways. The aim of the present study was to evaluate if recurrent wheezing preschoolers from rural or urban areas differ in asthma, allergic diseases, and atopy. METHODS: A cross-sectional-study in Rafaela, Argentina, on 143 preschoolers with recurrent wheezing from rural and urban settings was performed (2010-2012). Diagnosis of asthma (by positive asthma predictive index [API]), allergic diseases (rhinitis, dermatitis), and atopy (by skin prick test [SPT], peripheral blood eosinophils, and serum total IgE) were assessed. RESULTS: Preschoolers from rural settings had significantly higher prevalence of vaginal delivery, longer breastfeeding, earlier onset of wheezing, more parental smoking, siblings, shared a bedroom, and more exposure to chemicals used in plant fumigation or farm animals, and unpasteurized milk consumption, in comparison to preschoolers living in urban setting. In contrast, preschoolers from urban areas had significantly higher prevalence of parental history of allergy, positive skin prick test, and positive API. After multivariate analysis adjusting for covariates, maternal smoking [odds ratio (OR) = 3.44] and positive SPT (OR = 5.57) significantly increase the risk of asthma diagnosis (positive API); in contrast, living in rural setting (OR = 0.04), and having more siblings (OR = 0.51) decrease their risk. CONCLUSIONS: Recurrent wheezing preschoolers from rural areas had a significant inverse odds of being diagnosed with asthma (type-2 inflammation) when compared to those from urban areas. Exposure to farm animals and consumption of unpasteurized milk might have a role.

[Health related to quality life of patients with hereditary angioedema in Argentina. A multicenter study]. / Calidad de vida relacionada con la salud en pacientes con angioedema hereditario de Argentina. Estudio multicéntrico.

OBJECTIVE: To describe health relaed quality of life in a cohort of stable adult outpatients with hereditary an-gioedema (HAE) with validated tools. METHODS: An observational, cross-sectional, and descriptive study was performed, carried out in patients with hereditary angioedema, coming from the City of Buenos Aires and its provinces: Corrientes, Chubut, Entre Ríos and Santa Fe. The HAE-QoL and SF-12v2 health questionnaires were applied to assess the related quality of life. with health. RESULTS: 100 patients were included; median age: 41.5 years (range: 18-77); 65% were female, and 79% had type 1 HAE. Asymptomatic, mild, moderate and severe cases accounted for 6, 29, 38, and 27% of participants, respectively. Seventeen percent of patients were receiving long-term prophylaxis. Icatibant was the most fre-quent treatment for acute episodes. All health domains SF-12v2 scores were lower than expected in general population, excepting "vitality" and "physical functioning". Total and all specific domains HAE-QoL scores were reduced. Differences between women and men and in every age-defined group were demonstrated for sev-eral specific domains. CONCLUSIONS: Health relaed to quality life was notably reduced in Argentinean patients with HAE, when imple-menting the HAE.QoL, and SF-12v2 questionnaries. The need for multidisciplinary strategies approaching this complex disease is highlighted.

OBJECTIVO: Describir la calidad de vida relacionada con la saluden pacientes adultos, ambulatorios y estables con angioedema hereditario, mediante cuestionarios validados. MÉTODOS: Estudio descriptivo, transversal y observacional, llevado a cabo en pacientes con angioedema here-ditario, procedentes de la Ciudad de Buenos Aires y sus provincias: Corrientes, Chubut, Entre Ríos y Santa Fe. Se aplicaron los cuestionarios HAE-QoL y SF-12v2 para evaluar la calidad de vida relacionada con la salud. RESULTADOS: Se incluyeron 100 pacientes, con mediana de edad de 41.5 años (rango: 18-77), principalmente de género femenino (65%). La forma más frecuente de angioedema hereditario fue el tipo 1 (79%). Los casos asintomáticos, leves, moderados y severos representaron el 6, 29, 38 y 27%, respectivamente. El 17% recibía profilaxis a largo plazo. Icatibant fue el tratamiento más prescrito para los episodios agudos de angioedema. Todos los puntajes de los dominios de salud del SF-12v2 fueron menores de lo esperado, excepto "vitalidad" y "funcionamiento físico". Se observó disminución en los puntajes totales y en todos los dominios del HAE-QoL. Se reconocieron diferencias entre las mujeres y los hombres, y para grupo etario en los puntajes de los dominios específicos. CONCLUSIONES: La calidad de vida relacionada con la salud disminuyó considerablemente en pacientes argentinos con angioedema hereditario al aplicar los cuestionarios HAE-QoL y SF-12v2. Es importante desarrollar estra-tegias multidisciplinarias para abordar esta enfermedad compleja.

[Argentine Consensus of the Diagnosis and Treatment of Hereditary Angioedema]. / Consenso argentino de diagnóstico y tratamiento del angioedema hereditario.

OBJECTIVES: Hereditary angioedema (HAE) is a rare disease. During the last years, many studies and advances have been developed with the aim of better understanding the pathophysiology, as well as optimizing patient management. Several international working groups have attempted to clarify and standardize the care of HAE communicated as guidelines and consensus recommendations. We considered necessary to provide recommendations for the diagnosis and treatment of patients with HAE in Argentina. METHODS: A group of specialists of allergy and immunology from Argentina by using the online surveys methodology as well as face to face meetings developed the intended consensus. RESULTS: Recommendations were established based on published evidence and the expert opinion. The consensus focused on diagnosis, acute management of attacks, short and long-term prophylaxis, special situations (pediatrics and pregnancy) and disease management considering the health care system in Argentina. CONCLUSION: The recommendations established in this consensus guidelines will optimize the management of patients with HAE in Argentina.

Objetivos: El angioedema hereditario es una enfermedad poco frecuente. Durante los últimos años se han desarrollado muchas investigaciones y registrado avances con el objetivo de entender mejor la fisiopatología y optimizar la atención a los pacientes. Diversos grupos de trabajo internacionales han intentado clarificar y normalizar el cuidado de pacientes con angioedema hereditario, lo que se ha reflejado en guías y consensos. Consideramos necesario desarrollar un documento de consenso con recomendaciones para el diagnóstico y tratamiento del angioedema hereditario en Argentina. Metodología: Un grupo de expertos de Argentina, conformado por especialistas en Alergia e Inmunología mediante metodología de ronda de encuestas a distancia y reuniones presenciales llevó adelante la elaboración del consenso pretendido. Resultados: Se establecieron recomendaciones basadas en la evidencia publicada y en el criterio de los expertos participantes. Las recomendaciones se enfocaron en el diagnóstico, tratamiento y profilaxis de las crisis a corto y largo plazo, control de situaciones especiales y consideraciones del sistema de salud en Argentina. Conclusión: Las recomendaciones establecidas en este consenso permitirán optimizar la atención médica de los pacientes con angioedema hereditario en Argentina.

Prurigo actínico: A propósito de un caso / Actinic prurigo: consideration about one case

El prurigo actínico es una fotodermatosis idiopática poco frecuente,que afecta habitualmente a mestizos de diversos países americanos. Es más común en mujeres y suele iniciarse durante la primera década de vida. Compromete preferentemente la piel de áreas fotoexpuestas, así como la semimucosa labial y la conjuntiva. Con menor frecuencia se observan lesiones en pielcubierta. Clínicamente se presenta con pápulas eritematosas prurigoides, liquenificación, hiperpigmentación posinflamatoria e inclusive cicatrices, asociadas a prurito intenso. La histopatología de las lesiones cutáneas es inespecífica. El diagnósticose realiza estableciendo una correcta correlación clínico-patológica. El tratamiento de esta entidad constituye unverdadero desafío. Presentamos un caso de prurigo actínico en una paciente de 8 años de edad, que fue tratada satisfactoriamente con talidomida