RESUMO
ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder.
Assuntos
Anormalidades Craniofaciais/etiologia , Heterozigoto , Deficiência Intelectual/etiologia , Transtornos do Desenvolvimento da Linguagem/etiologia , Mutação com Perda de Função , Proteínas de Ligação a RNA/genética , Adolescente , Adulto , Criança , Pré-Escolar , Anormalidades Craniofaciais/patologia , Feminino , Haploinsuficiência , Humanos , Lactente , Deficiência Intelectual/patologia , Transtornos do Desenvolvimento da Linguagem/patologia , Masculino , Linhagem , Fenótipo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Síndrome , Adulto JovemRESUMO
OBJECTIVE: To determine the predictive value of the fetal omphalocele circumference/abdominal circumference (OC/AC) ratio for type of surgical closure and survival and to describe the trajectory of OC/AC ratio throughout gestation. METHODS: This cohort study included all live-born infants prenatally diagnosed with an omphalocele in our tertiary centre (2000-2017) with an intention to treat. The OC/AC ratio and liver position were determined using 2D ultrasound at three periods during gestation (11-16, 17-26, and/or 30-38 weeks). Primary outcome was type of closure; secondary outcome was survival. In the secondary analyses, the predictive value of the OC/AC-ratio trend for type of closure and survival was assessed. RESULTS: Primary closure was performed in 37/63 (59%) infants, and 54/63 (86%) survived. The OC/AC ratio was predictive for type of closure and survival in all periods. Optimal cut-off values for predicting closure decreased throughout gestation from 0.69 (11-16 weeks) to 0.63 (30-38 weeks). Repeated OC/AC-ratio measurements were available in 33 (73%) fetuses. The trend of the OC/AC ratio throughout gestation was not significantly associated with type of closure. All infants without liver herniation underwent primary closure. CONCLUSION: Type of omphalocele surgical closure and survival can be predicted prenatally on the basis of the OC/AC ratio and liver herniation independent of associated anomalies. LEARNING OBJECTIVE: The reader will be able to use the OC/AC ratio throughout gestation in all omphalocele cases for prediction of type of closure and survival and thus patient counselling.
Assuntos
Cavidade Abdominal/patologia , Técnicas de Fechamento de Ferimentos Abdominais , Hérnia Umbilical/diagnóstico , Hérnia Umbilical/cirurgia , Vísceras/patologia , Cavidade Abdominal/diagnóstico por imagem , Técnicas de Fechamento de Ferimentos Abdominais/efeitos adversos , Técnicas de Fechamento de Ferimentos Abdominais/classificação , Técnicas de Fechamento de Ferimentos Abdominais/normas , Estudos de Coortes , Feminino , Desenvolvimento Fetal/fisiologia , Idade Gestacional , Hérnia Umbilical/mortalidade , Hérnia Umbilical/patologia , Humanos , Recém-Nascido , Masculino , Tamanho do Órgão , Valor Preditivo dos Testes , Gravidez , Terceiro Trimestre da Gravidez/fisiologia , Prognóstico , Reprodutibilidade dos Testes , Análise de Sobrevida , Ultrassonografia Pré-Natal/métodos , Ultrassonografia Pré-Natal/normas , Vísceras/diagnóstico por imagem , Circunferência da Cintura/fisiologiaRESUMO
The European Medicines Agency's conditional marketing authorization (CMA) aims to expedite patient access to medicines for unmet medical needs by shifting a part of the drug development process post-authorization. We highlight ethical issues surrounding CMA, comprising (i) the complexity of defining unmet medical need; (ii) poor understanding of CMA and its impact on informed consent; (iii) hope versus unrealistic optimism; (iv) implications of prolonged post-authorization studies and potential patient harm; (v) rights and duties of patients surrounding participation in post-authorization studies; (vi) access to previously authorized CMA medicines; and (vii) the "benefit slippage" phenomenon, defined as the gradual shift of strict criteria to less strict criteria. We propose a comprehensive research agenda to address these ethical issues, and stress the need for multi-stakeholder engagement to ensure patient-centered use of CMA.
RESUMO
BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder with a high risk for arterial, bowel, and uterine rupture, caused by heterozygous pathogenic variants in COL3A1. The aim of this cohort study is to provide further insights into the natural history of vEDS and describe genotype-phenotype correlations in a Dutch multicenter cohort to optimize patient care and increase awareness of the disease. METHODS: Individuals with vEDS throughout the Netherlands were included. The phenotype was charted by retrospective analysis of molecular and clinical data, combined with a one-time physical examination. RESULTS: A total of 142 individuals (50% female) participated the study, including 46 index patients (32%). The overall median age at genetic diagnosis was 41.0 years. More than half of the index patients (54.3%) and relatives (53.1%) had a physical appearance highly suggestive of vEDS. In these individuals, major events were not more frequent (P=0.90), but occurred at a younger age (P=0.01). A major event occurred more often and at a younger age in men compared with women (P<0.001 and P=0.004, respectively). Aortic aneurysms (P=0.003) and pneumothoraces (P=0.029) were more frequent in men. Aortic dissection was more frequent in individuals with a COL3A1 variant in the first quarter of the collagen helical domain (P=0.03). CONCLUSIONS: Male sex, type and location of the COL3A1 variant, and physical appearance highly suggestive of vEDS are risk factors for the occurrence and early age of onset of major events. This national multicenter cohort study of Dutch individuals with vEDS provides a valuable basis for improving guidelines for the diagnosing, follow-up, and treatment of individuals with vEDS.
Assuntos
Colágeno Tipo III , Síndrome de Ehlers-Danlos , Humanos , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/epidemiologia , Feminino , Masculino , Países Baixos/epidemiologia , Adulto , Colágeno Tipo III/genética , Pessoa de Meia-Idade , Estudos Retrospectivos , Estudos de Coortes , Fenótipo , Adolescente , Estudos de Associação Genética , Adulto Jovem , Idoso , Síndrome de Ehlers-Danlos Tipo IVRESUMO
OBJECTIVES: To compare the prenatal frame of reference of omphalocele (ie, survival of fetuses) with that after birth (ie, survival of liveborn neonates), and to assess physical growth and neurodevelopment in children with minor or giant omphalocele up to 2 years of age. DESIGN: We included fetuses and neonates diagnosed in 2000-2012. Physical growth (SD scores, SDS) and mental and motor development at 12 and 24 months were analysed using general linear models, and outcomes were compared with reference norms. Giant omphalocele was defined as defect ≥5 cm, with liver protruding. RESULTS: We included 145 fetuses and neonates. Of 126 (87%) who were diagnosed prenatally, 50 (40%) were liveborn and 35 (28%) survived at least 2 years. Nineteen (13%) neonates were diagnosed after birth. Of the 69 liveborn neonates, 52 (75%) survived and 42 children (81% of survivors) were followed longitudinally. At 24 months, mean (95% CI) height and weight SDS were significantly below 0 in both minor (height: -0.57 (-1.05 to -0.09); weight: -0.86 (-1.35 to -0.37)) and giant omphalocele (height: -1.32 (-2.10 to -0.54); weight: -1.58 (-2.37 to -0.79)). Mental development was comparable with reference norms in both groups. Motor function delay was found significantly more often in children with giant omphalocele (82%) than in those with minor omphalocele (21%, P=0.002). CONCLUSIONS: The prenatal and postnatal frames of reference of omphalocele differ considerably; a multidisciplinary approach in parental counselling is recommended. As many children with giant omphalocele had delayed motor development, we recommend close monitoring of these children and early referral to physical therapy.