Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

CROUP: Estridor laríngeo.

Croup é a designação de laringotraqueíte aguda e consiste na obstrução da via aérea superior, secundária a infecção viral e caracterizada pela presença de estridor inspiratório, tosse rouca e dificuldade respiratória. É uma das principais causas de obstrução das vias aéreas superiores na idade pediátrica, mais frequente entre os 6 meses e os 3 anos de idade, consequência da inflamação e edema da laringe e traqueia. O início abrupto dos sintomas, com agravamento nocturno e a exacerbação por agitação e choro, fazem com que o croup seja motivo frequente de apresentação no Serviço de Urgência Pediátrica. Apesar da adrenalina nebulizada ser eficaz no alívio sintomático imediato, os corticóides são o tratamento base para todos os graus de gravidade da doença. O croup apresenta evolução e prognóstico favoráveis.info:eu-repo/semantics/publishedVersio

Ectima Gangrenoso: Um Alerta Para Imunodeficiência

As infeções graves, atípicas, recorrentes ou por agentes oportunistas devem ser sempre um sinal de alerta para imunodeficiência primária. Apresenta-se o caso clínico de uma lactente de 8 meses, previamente saudável, internada por sépsis e lesão na região lombosagrada com necrose central e bordos inflamatórios, sugestiva de ectima gangrenoso. Analiticamente apresentava anemia, neutropenia e proteína C reativa elevada e iniciou antibioticoterapia de largo espetro. Isolou-se Pseudomonas aeruginosa na hemocultura. Nos cinco meses seguintes apresentou várias intercorrências infecciosas, incluindo pneumonia complicada de abcesso, e manteve a neutropenia. Foi identificada a mutação c.3G>A (p.Met1lle) no gene da elastase dos neutrófilos, confirmando o diagnóstico de neutropenia congénita. A terapêutica com fator estimulador das colónias de granulócitos reduziu as complicações infecciosas. O reconhecimento precoce do ectima gangrenoso, a antibioterapia dirigida e a administração de fator estimulador das colónias de granulócitos permitiram uma evolução sem complicações. As crianças com ectima gangrenoso devem ser investigadas para exclusão de imunodeficiência subjacente

Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype

Familial hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism caused by pathogenic/likely pathogenic variants in LDLR, APOB, and PCSK9 genes. Variants in FH-phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, and ABCG8), polygenic hypercholesterolemia, and hyperlipoprotein (a) [Lp(a)] can also mimic a clinical FH phenotype. We aim to present a new diagnostic tool to unravel the genetic background of clinical FH phenotype. Biochemical and genetic study was performed in 1,005 individuals with clinical diagnosis of FH, referred to the Portuguese FH Study. A next-generation sequencing panel, covering eight genes and eight SNPs to determine LDL-C polygenic risk score and LPA genetic score, was validated, and used in this study. FH was genetically confirmed in 417 index cases: 408 heterozygotes and 9 homozygotes. Cascade screening increased the identification to 1,000 FH individuals, including 11 homozygotes. FH-negative individuals (phenotype positive and genotype negative) have Lp(a) >50 mg/dl (30%), high polygenic risk score (16%), other monogenic lipid metabolism disorders (1%), and heterozygous pathogenic variants in FH-phenocopy genes (2%). Heterozygous variants of uncertain significance were identified in primary genes (12%) and phenocopy genes (7%). Overall, 42% of our cohort was genetically confirmed with FH. In the remaining individuals, other causes for high LDL-C were identified in 68%. Hyper-Lp(a) or polygenic hypercholesterolemia may be the cause of the clinical FH phenotype in almost half of FH-negative individuals. A small part has pathogenic variants in ABCG5/ABCG8 in heterozygosity that can cause hypercholesterolemia and should be further investigated. This extended next-generation sequencing panel identifies individuals with FH and FH-phenocopies, allowing to personalize each person’s treatment according to the affected pathway

Resumos em andamento - Direito

Resumos em andamento - Direit

Resumos em andamento - Direito

Resumos em andamento - Direit