Late-Onset Cryopyrin-Associated Periodic Syndromes Caused by Somatic NLRP3 Mosaicism-UK Single Center Experience.

Cryopyrin-associated periodic syndrome (CAPS) is caused by gain-of-function NLRP3 mutations. Recently, somatic NLRP3 mosaicism has been reported in some CAPS patients who were previously classified as "mutation-negative." We describe here the clinical and laboratory findings in eight British adult patients who presented with symptoms typical of CAPS other than an onset in mid-late adulthood. All patients underwent comprehensive clinical and laboratory investigations, including analysis of the NLRP3 gene using Sanger and amplicon-based deep sequencing (ADS) along with measurements of extracellular apoptosis-associated speck-like protein with CARD domain (ASC) aggregates. The clinical phenotype in all subjects was consistent with mid-spectrum CAPS, except a median age at disease onset of 50 years. Sanger sequencing of NLRP3 was non-diagnostic but ADS detected a somatic NLRP3 mutation in each case. In one patient, DNA isolated from blood demonstrated an increase in the mutant allele from 5 to 45% over 12 years. ASC aggregates in patients' serum measured during active disease were significantly higher than healthy controls. This series represents 8% of CAPS patients diagnosed in a single center, suggesting that acquired NLRP3 mutations may not be an uncommon cause of the syndrome and should be sought in all patients with late-onset symptoms otherwise compatible with CAPS. Steadily worsening CAPS symptoms in one patient were associated with clonal expansion of the mutant allele predominantly affecting myeloid cells. Two patients developed AA amyloidosis, which previously has only been reported in CAPS in association with life-long germline NLRP3 mutations.

Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1.

The importance of actin dynamics in the activation of the inflammasome is becoming increasingly apparent. IL-1ß, which is activated by the inflammasome, is known to be central to the pathogenesis of many monogenic autoinflammatory diseases. However, evidence from an autoinflammatory murine model indicates that IL-18, the other cytokine triggered by inflammasome activity, is important in its own right. In this model, autoinflammation was caused by mutation in the actin regulatory gene WDR1 We report a homozygous missense mutation in WDR1 in two siblings causing periodic fevers with immunodeficiency and thrombocytopenia. We found impaired actin dynamics in patient immune cells. Patients had high serum levels of IL-18, without a corresponding increase in IL-18-binding protein or IL-1ß, and their cells also secreted more IL-18 but not IL-1ß in culture. We found increased caspase-1 cleavage within patient monocytes indicative of increased inflammasome activity. We transfected HEK293T cells with pyrin and wild-type and mutated WDR1 Mutant protein formed aggregates that appeared to accumulate pyrin; this could potentially precipitate inflammasome assembly. We have extended the findings from the mouse model to highlight the importance of WDR1 and actin regulation in the activation of the inflammasome, and in human autoinflammation.

[Autoinflammatory syndromes]. / Síndromes auto-inflamatórias.

Autoinflammatory syndromes (AIS) are a heterogeneous group of congenital diseases characterized by the presence of recurrent episodes of fever and local or generalized inflammation, in the absence of infectious agents, detectable auto-antibodies or antigen-specific autoreactive T-cells. These diseases have been much better understood during the past 15 years, mainly due to the marked advances of the Human Genoma Project and its implications in the identification and characterization of genetic mutations. In this paper we make a revision of the classification of AIS and focus our attention specially on the cryopyrin-associated periodic syndromes (CAPS), in particular the CINCA syndrome that shares many clinical characteristics with juvenile idiopathic arthritis.

Intraventricular hemorrhage risk factors in very low birth weight newborns: a case-control study / Fatores de risco para hemorragia intraventricular em recém-nascidos de muito baixo peso: estudo caso-controle

Objective: Identification of variables that affect the risk of severe intraventricular hemorrhage (IVH) in very low birth weight (VLBW) newborns. Methods: Analytic case-control study, in a population consisting of all VLBW newborns admitted to the Neonatal Intensive Care Unit of a maternity hospital, between January 2002 and December 2007. The authors considered as cases all VLBW newborns with severe IVH (grade ? 3), and control all VLBW newborns without IVH. Independent variables included obstetric, perinatal and neonatal diagnosis and therapy. Bivariate analysis and multivariate logistic regression analysis were performed. Results: During this period, of the 864 VLBW newborns admitted to the Neonatal Intensive Care Unit, 9.7% had severe IVH. With bivariate analysis an association between severe IVH, gestational age and birth weight was found. Prenatal care and pre-eclampsia were associated with a decrease in the incidence of severe IVH. Amnionitis, being outborn, vaginal delivery, male gender, intubation in the delivery room, surfactant, hyaline membrane disease, pneumothorax, necrotizing enterocolitis (NEC) perforation and oscillatory high frequency ventilation were associated with an increased incidence of severe IVH. By multivariate logistic regression, the variables associated with increased risk of severe IVH were: pneumothorax (OR = 3.8; 95%CI = 1.7-8.3), NEC with perforation (OR = 8.8; 95%CI = 1.7-45.0), vaginal delivery (OR = 2.0; 95%CI = 1.0-4.1) and high frequency ventilation (OR = 4.8; 95%CI = 1.3-17.3). The following were protective of severe IVH: gestational age (OR = 0.61; 95%CI = 0.52-0.72), patent ductus arteriosus treatment with indomethacin (OR = 0.26; 95%CI = 0.11-0.6) and fertility treatment (OR = 0.24; 95%CI = 0.06-0.94). Conclusion: These data outline the importance of improvement of pre and neonatal care to reduce severe IVH

Objetivo: Identificação de variáveis que influenciem o risco de hemorragia intraventricular (HIV) grave em recém-nascidos de muito baixo peso (RNMBP). Métodos: Efetuou-se um estudo analítico, caso-controle, em uma população constituída por todos os RNMBP admitidos em uma Unidade de Cuidados Intensivos Neonatal (UCIN), no período compreendido entre Janeiro de 2002 e Dezembro de 2007. Consideraram-se casos todos os RNMBP com HIV grave (grau ? 3) e controle todos os RNMBP sem HIV. As variáveis independentes foram dados obstétricos, perinatais, diagnóstico e terapêutica neonatal. Realizou-se análise bivariada e análise de regressão logística multivariada. Resultados: Foram admitidos na Unidade de Cuidados Intensivos Neonatal, neste período, 864 RNMBP, dos quais 9,7% apresentaram HIV grave. Na análise bivariada, verificou-se uma associação entre HIV grave, idade gestacional e peso ao nascer. A atenção pré-natal e pré-eclampsia foram associadas a uma menor incidência de HIV grave. Amnionite, nascimento no exterior, parto vaginal, sexo masculino, intubação na sala de parto, surfactante, doença da membrana hialina, pneumotórax, enterocolite necrotizante (EN) com perfuração e a ventilação de alta frequência oscilatória foram associados a uma maior incidência de HIV grave. No modelo de regressão logística multivariada, as variáveis associadas a um maior risco de HIV grave foram pneumotórax (OR = 3,8; IC95% = 1,7-8,3), EN com perfuração (OR = 8,8; IC95% = 1,7-45,0), parto vaginal (OR = 2,0; IC95% = 1,0-4,1) e ventilação de alta frequência oscilatória (OR = 4,8; IC95% = 1,3-17,3). Foram fatores protetores para HIV grave: idade gestacional (OR = 0,61; IC95% = 0,52-0,72), tratamento da persistência do ducto arterioso com indometacina (OR = 0,26; IC95% = 0,11-0,60) e tratamento de fertilidade (OR = 0,24; IC95% = 0,06-0,94). Conclusão: Os resultados obtidos neste estudo realçam a importância da melhoria da prestação de cuidados pré e neonatais na redução da HIV grave

Breastfeeding-associated hypernatraemic dehydration / Desidratação hipernatrêmica associada ao aleitamento materno

Objective: In the last few years there has been an increase in case reports of hypernatraemic dehydration in breastfed newborns. Insufficient intake has an important role in the pathophysiology of this condition. The aim of this study was to evaluate exclusively breastfed neonates admitted for hypernatraemic dehydration. Methods: Retrospective study of breastfed neonates diagnosed with hypernatraemic dehydration, between March 2002 and March 2008, in a level 1 maternity. Results: Nineteen cases were identified (0.44% of neonatal intermediate care hospitalizations), 53% of them were male. The annual distribution revealed a higher number of cases in 2008: 26.3% in only three months. Median birth weight was 3,000 g and the median gestational age was 38 weeks. Vaginal delivery was the most frequent form of birth (42%), and 79% of mothers were primiparas. Admissions were made through the emergency department in 68.4%. The main reasons for seeking medical attention were: poor oral intake (32%), weight loss (26%), and jaundice (26%). The median age at admission was four days. Percentage of weight loss: 6.7 to 40%, median was 11%. Dehydration signs were absent in 42% of the patients. Median Na+ values were 152 mEq/l. Jaundice was the most frequent comorbidity found (74%). Intravenous fluids were administered in 89% and acute neurological complications were found in 21%, there were no deaths. Conclusions: Breastfeeding-associated hypernatraemic dehydration seems to be a consequence of breastfeeding difficulties in inexperienced mothers. Since many cases are paucisymptomatic, there should be a high level of suspicion, especially in those patients with jaundice.

Objetivo: Nos últimos anos verificou-se um aumento do número de casos descritos de desidratação hipernatrêmica em recém-nascidos em aleitamento materno exclusivo, sendo o déficit de aporte o desencadeante habitual. O objetivo deste estudo foi caracterizar a população de recém-nascidos com desidratação hipernatrêmica, associada ao aleitamento materno exclusivo numa maternidade de nível 1. Métodos: Estudo retrospectivo, entre Março de 2002 e Março de 2008, dos recém-nascidos internados por desidratação hipernatrêmica em aleitamento materno exclusivo. Resultados: Foram 19 casos (0,44% das internações), sendo que 53% eram do sexo masculino. A distribuição anual revelou um maior número de casos em 2008 (26,3%, em apenas três meses). O parto eutócico foi o mais frequente (42%). A mediana de peso ao nascer foi de 3.000 g e a da idade gestacional, 38 semanas; 79% das mães eram primíparas, e 68,4% dos recém-nascidos foram admitidos pelo serviço de urgência, sendo os principais motivos de consulta: recusa alimentar (32%), perda ponderal (26%) e icterícia (26%). A mediana de idade à internação foi de quatro dias. A percentagem de peso perdido foi de 6,7 a 40% (mediana de 11 %) e 42% não apresentavam sinais de desidratação. A mediana dos valores de Na+ à admissão foi de 152 mEq/l. A comorbidade mais frequente (74%) foi icterícia. O tratamento foi prioritariamente intravenoso (89%). Complicações neurológicas agudas foram observadas em 21% e não houve óbitos. Conclusões: A desidratação hipernatrêmica associada ao aleitamento materno exclusivo surge como consequência de dificuldades na amamentação em mães inexperientes. Dado que muitos casos são oligossintomáticos, é necessário ter um elevado índice de suspeita desta alteração, especialmente nos que se apresentam com icterícia.