Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients.

BACKGROUND: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype-phenotype correlation has been reported. METHODS: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature. RESULTS: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions. CONCLUSION: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.

Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): A multicenter, retrospective study.

Background: Most children and adolescents infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain asymptomatic or develop a mild coronavirus disease 2019 (COVID-19) that usually does not require medical intervention. However, a small proportion of pediatric patients develop a severe clinical condition, multisystem inflammatory syndrome in children (MIS-C). The involvement of epigenetics in the control of the immune response and viral activity prompted us to carry out an epigenomic study to uncover target loci regulated by DNA methylation that could be altered upon the appearance of MIS-C. Methods: Peripheral blood samples were recruited from 43 confirmed MIS-C patients. 69 non-COVID-19 pediatric samples and 15 COVID-19 pediatric samples without MIS-C were used as controls. The cases in the two groups were mixed and divided into discovery (MIS-C = 29 and non-MIS-C = 56) and validation (MIS-C = 14 and non-MIS-C = 28) cohorts, and balanced for age, gender and ethnic background. We interrogated 850,000 CpG sites of the human genome for DNA methylation variants. Findings: The DNA methylation content of 33 CpG loci was linked with the presence of MIS-C. Of these sites, 18 (54.5%) were located in described genes. The top candidate gene was the immune T-cell mediator ZEB2; and others highly ranked candidates included the regulator of natural killer cell functional competence SH2D1B; VWA8, which contains a domain of the Von Willebrand factor A involved in the pediatric hemostasis disease; and human leukocyte antigen complex member HLA-DRB1; in addition to pro-inflammatory genes such as CUL2 and AIM2. The identified loci were used to construct a DNA methylation profile (EPIMISC) that was associated with MIS-C in both cohorts. The EPIMISC signature was also overrepresented in Kawasaki disease patients, a childhood pathology with a possible viral trigger, that shares many of the clinical features of MIS-C. Interpretation: We have characterized DNA methylation loci that are associated with MIS-C diagnosis. The identified genes are likely contributors to the characteristic exaggerated host inflammatory response observed in these patients. The described epigenetic signature could also provide new targets for more specific therapies for the disorder. Funding: Unstoppable campaign of Josep Carreras Leukaemia Foundation, Fundació La Marató de TV3, Cellex Foundation and CERCA Programme/Generalitat de Catalunya.

Epigenome-wide association study of COVID-19 severity with respiratory failure.

BACKGROUND: Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities. METHODS: Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (n = 207) and validation (n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients. FINDINGS: The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease. INTERPRETATION: We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2. FUNDING: The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.

Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene.

The neurological phenotype of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) and short-chain enoyl-CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11; HIBCH, n = 6) and paroxysmal dystonia (SCEH, n = 2). Basal ganglia lesions (18 patients) were associated with small cysts in the putamen/pallidum in half of the cases, a characteristic hallmark for diagnosis. Eighteen pathogenic variants were identified, 11 were novel. Among all 89 cases, we observed a longer survival in HIBCH compared to SCEH patients, and in HIBCH patients carrying homozygous mutations on the protein surface compared to those with variants inside/near the catalytic region. The SCEH p.(Ala173Val) change was associated with a milder form of paroxysmal dystonia triggered by increased energy demands. In a child harbouring SCEH p.(Ala173Val) and the novel p.(Leu123Phe) change, an 83.6% reduction of the protein was observed in fibroblasts. The SCEH and HIBCH defects in the catabolic valine pathway were a frequent cause of Leigh syndrome in our cohort. We identified phenotype and genotype associations that may help predict outcome and improve clinical management.

Longitudinal Voice Outcomes After Voice Therapy in Unilateral Vocal Fold Paralysis.

OBJECTIVES: To investigate the long-term effectiveness of voice therapy in vocal outcomes of patients with unilateral vocal fold paralysis (UVFP) and vocal productions of patients with long-standing treatment-naïve UVFP treated with voice therapy. STUDY DESIGN: Prospective observational study. METHODS: A voice therapy protocol was applied individually in three stages. Fifteen sessions were scheduled twice a week in 70 patients with UVFP. Forty-seven patients were treated within a year of the diagnosis (group 1). The remaining patients had delayed therapy (at least 1 year after diagnosis) (group 2). Multidisciplinary assessment included nasofibroscopy, videostroboscopy, acoustic and aerodynamic parameters, and perception of voice impairment measures. A subgroup of the 70 patients (n = 32) was reassessed after 1 year of follow-up. RESULTS: Our voice therapy protocol significantly improved voice productions and perception of voice impairment in group 1 (P < 0.0001). Patients in group 2 experienced less hoarseness and had improved perception of voice impairment (P = 0.007). The improvement was long lasting and persisted at 1 year of follow-up in both groups. CONCLUSIONS: Voice therapy is effective in patients with UVFP and its benefits are sustained over time. Early referral for voice therapy seems to be associated with greater benefit, but quality of life also improves for patients despite delayed treatment.

[Recurring post-traumatic growing skull fracture]. / Fractura craneal evolutiva postraumática recidivada.

INTRODUCTION: Growing skull fracture, also known as post-traumatic bone absorption or leptomeningeal cyst, is a rare complication of traumatic brain injuries and occurs almost exclusively in children under 3 years of age. CASE REPORT: We report the case of a 6-month-old child who presented, two months after an apparently unimportant traumatic skull injury, persistence of left temporoparietooccipital cephalohaematoma with no other signs. A transfontanellar ultrasonography scan revealed a bone defect with brain herniation, and computerised tomography and magnetic resonance imaging also confirmed the existence of a growing fracture. Excision of the leptomeningeal cyst, dural closure and repair of the bone defect with plates and lactate material were performed. Three months after the operation, the patient still presented collection of fluid and recurrence of the growing fracture was confirmed. Following the second operation, a baby helmet was fitted in order to prevent renewed recurrences. One year after the traumatic injury occurred, the patient remains asymptomatic. CONCLUSIONS: Any child under 3 years of age with a post-traumatic cephalohaematoma should be checked periodically until the full resolution of the collection of fluid, especially if they present a fractured skull. The presence of a cephalohaematoma that remains more than two weeks after traumatic brain injury must make us suspect a growing fracture and reparation of the dura mater and a cranioplasty will be needed to treat it. The use of resorbable material allows it to be remodelled as the patient's skull grows, but its fragility increases the risk of recurrence. The use of a baby helmet after the operation could prevent complications.

TITLE: Fractura craneal evolutiva postraumatica recidivada.Introduccion. La fractura craneal evolutiva, tambien llamada absorcion osea postraumatica o quiste leptomeningeo, es una rara complicacion de los traumatismos craneoencefalicos y ocurre de forma casi exclusiva en ninos menores de 3 anos. Caso clinico. Nino de 6 meses que presentaba, dos meses despues de un traumatismo craneal aparentemente banal, persistencia de cefalohematoma temporooccipital izquierdo sin otros signos. El estudio de ecografia transfontanelar revelo un defecto oseo con herniacion cerebral, y la tomografia computarizada y la resonancia magnetica confirmaron, ademas, una fractura evolutiva. Se realizo reseccion del quiste encefalomeningeo, cierre dural y reparacion del defecto oseo con placas y material de lactato. Tres meses despues de la intervencion, presentaba persistencia de coleccion liquida y se confirmo recidiva de la fractura evolutiva. Tras la reintervencion, se coloco casco ortesico para evitar nuevas recidivas. Un ano despues del traumatismo, el paciente continua asintomatico. Conclusiones. Todo nino menor de 3 anos con cefalohematoma postraumatico deberia ser revisado de forma periodica hasta comprobar la resolucion de la coleccion, en particular si presenta fractura craneal. La presencia de un cefalohematoma persistente mas de dos semanas despues de un traumatismo craneoencefalico debe hacernos sospechar un proceso de fractura creciente, y son necesarias la reparacion de la duramadre y una craneoplastia para su tratamiento. La colocacion de material reabsorbible permite su remodelacion con el crecimiento craneal del paciente, pero su fragilidad conlleva riesgo de recidiva. La colocacion de un casco ortesico tras la intervencion podria prevenir complicaciones.