Homozygous mutations in WWOX were reported in eight individuals of two families with autosomal recessive spinocerebellar ataxia type 12 and in two siblings with infantile epileptic encephalopathy ...(IEE), including one who deceased prior to DNA sampling.
By combining array comparative genomic hybridisation, targeted Sanger sequencing and next generation sequencing, we identified five further patients from four families with IEE due to biallelic alterations of WWOX.
We identified eight deleterious WWOX alleles consisting in four deletions, a four base-pair frameshifting deletion, one missense and two nonsense mutations. Genotype-phenotype correlation emerges from the seven reported families. The phenotype in four patients carrying two predicted null alleles was characterised by (1) little if any psychomotor acquisitions, poor spontaneous motility and absent eye contact from birth, (2) pharmacoresistant epilepsy starting in the 1st weeks of life, (3) possible retinal degeneration, acquired microcephaly and premature death. This contrasted with the less severe autosomal recessive spinocerebellar ataxia type 12 phenotype due to hypomorphic alleles. In line with this correlation, the phenotype in two siblings carrying a null allele and a missense mutation was intermediate.
Our results obtained by a combination of different molecular techniques undoubtedly incriminate WWOX as a gene for recessive IEE and illustrate the usefulness of high throughput data mining for the identification of genes for rare autosomal recessive disorders. The structure of the WWOX locus encompassing the FRA16D fragile site might explain why constitutive deletions are recurrently reported in genetic databases, suggesting that WWOX-related encephalopathies, although likely rare, may not be exceptional.
Understanding the clinical presentation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and prognosis in children is a major issue. Children often present mild symptoms, and ...some severe forms require paediatric intensive care, with in some cases a fatal prognosis. Our aim was to identify the epidemiological characteristics, clinical presentation, and prognosis of children with coronavirus disease 2019 (Covid-19) hospitalized in Paris suburb hospitals. In this prospective, observational, multicentre study, we included children hospitalized in paediatric departments of Paris suburb hospitals from 23 March 2020 to 10 May 2020, during the national lockdown in France with confirmed SARS-CoV-2 infection (positive RNA test on a nasopharyngeal swab) or highly suspected infection (clinical, biological, and/or radiological data features suggestive for SARS-CoV-2 infection). A total of 192 children were included for confirmed (n = 157) or highly suspected (n = 35) SARS-CoV-2 infection. The median age was one year old (interquartile range 0.125–11) with a sex ratio 1.3:1. Fever was recorded in 147 (76.6%) children and considered poorly tolerated in 29 (15.1%). The symptoms ranged from rhinorrhoea (34.4%) and gastrointestinal (35.5%) to respiratory distress (25%). Only 10 (5.2%) children had anosmia and five (2.6%) had chest pain. An underlying condition was identified in almost 30% of the children in our study. Overall, 24 (12.5%) children were admitted to paediatric intensive care units, 12 required mechanical ventilation, and three died. For children in Paris suburbs, most cases of Covid-19 showed mild or moderate clinical expression. However, one-eighth of children were admitted to paediatric intensive care units and three died.
IMPORTANCE: Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially ...life-threatening, but the optimal therapeutic strategy remains unknown. OBJECTIVE: To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study drawn from a national surveillance system with propensity score–matched analysis. All cases with suspected MIS-C were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling the World Health Organization definition were included. The study started on April 1, 2020, and follow-up ended on January 6, 2021. EXPOSURES: IVIG and methylprednisolone vs IVIG alone. MAIN OUTCOMES AND MEASURES: The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure. Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit. The primary analysis involved propensity score matching with a minimum caliper of 0.1. RESULTS: Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females 52%; median age, 8.6 years interquartile range, 4.7 to 12.1). Five children did not receive either treatment. Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment. Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, −0.28 95% CI, −0.48 to −0.08; odds ratio OR, 0.25 95% CI, 0.09 to 0.70; P = .008). IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, −0.22 95% CI, −0.40 to −0.04; OR, 0.19 95% CI, 0.06 to 0.61; P = .004), hemodynamic support (absolute risk difference, −0.17 95% CI, −0.34 to −0.004; OR, 0.21 95% CI, 0.06 to 0.76), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, −0.18 95% CI, −0.35 to −0.01; OR, 0.20 95% CI, 0.06 to 0.66), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, −2.4 95% CI, −4.0 to −0.7). CONCLUSIONS AND RELEVANCE: Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course. Study interpretation is limited by the observational design.
The objective was to determine whether high-flow nasal cannula (HFNC), a promising respiratory support in infant bronchiolitis, could reduce the proportion of treatment failure requiring escalation ...of care.
In this randomised controlled trial, we assigned infants aged <6 months who had moderate bronchiolitis to receive either HFNC at 3 L·kg
·min
or standard oxygen therapy. Crossover was not allowed. The primary outcome was the proportion of patients in treatment failure requiring escalation of care (mostly noninvasive ventilation) within 7 days following randomisation. Secondary outcomes included rates of transfer to the paediatric intensive care unit (PICU), oxygen, number of artificial nutritional support-free days and adverse events.
The analyses included 268 patients among the 2621 infants assessed for inclusion during two consecutive seasons in 17 French paediatric emergency departments. The percentage of infants in treatment failure was 14% (19 out of 133) in the study group, compared to 20% (27 out of 135) in the control group (OR 0.66, 95% CI 0.35-1.26; p=0.21). HFNC did not reduce the risk of admission to PICU (21 (15%) out of 133 in the study group
26 (19%) out of 135 in the control group) (OR 0.78, 95% CI 0.41-1.41; p=0.45). The main reason for treatment failure was the worsening of modified Wood clinical asthma score (m-WCAS). Short-term assessment of respiratory status showed a significant difference for m-WCAS and respiratory rate in favour of HFNC. Three pneumothoraces were reported in the study group.
In patients with moderate bronchiolitis, there was no evidence of lower rate of escalating respiratory support among those receiving HFNC therapy.
Initial reports on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in children suggested that very young age and comorbidities may increase risk of severe evolution, but these ...findings remained to be confirmed. We aimed to analyze the clinical spectrum of hospitalized pediatric SARS-CoV-2 infection and predictors of severe disease evolution.
We conducted a French national prospective surveillance of children hospitalized with SARS-CoV-2 infection. We included all children with confirmed SARS-CoV-2 infection in 60 hospitals during February 15 to June 1, 2020. The main outcome was the proportion of children with severe disease, defined by hemodynamic or ventilatory (invasive or not) support requirement.
We included 397 hospitalized children with SARS-CoV-2 infection. We identified several clinical patterns, ranging from paucisymptomatic children, admitted for surveillance, to lower respiratory tract infection or multisystem inflammatory syndrome in children. Children <90 days old accounted for 37% of cases (145 of 397), but only 4 (3%) had severe disease. Excluding children with multisystem inflammatory syndrome in children (
= 29) and hospitalized for a diagnosis not related to SARS-CoV-2 (
= 62), 23 of 306 (11%) children had severe disease, including 6 deaths. Factors independently associated with severity were age ≥10 years (odds ratio OR = 3.4, 95% confidence interval: 1.1-10.3), hypoxemia (OR = 8.9 2.6-29.7), C-reactive protein level ≥80 mg/L (OR = 6.6 1.4-27.5).
In contrast with preliminary reports, young age was not an independent factor associated with severe SARS-CoV-2 infection, and children <90 days old were at the lowest risk of severe disease evolution. This may help physicians to better identify risk of severe disease progression in children.
Bardet--Biedl Syndrome (BBS) is an emblematic recessive genetically highly heterogeneous ciliopathy characterised mainly by polydactyly, retinitis pigmentosa, obesity, cognitive impairment, and ...kidney dysfunction. The 16 BBS genes known to date are implied in the primary cilia related cellular pathways.
Single nucleotide polymorphism (SNP) array analysis followed by exome sequencing was performed in a consanguineous family diagnosed with BBS with unusual developmental features, namely situs inversus and insertional polydactyly. A homozygous 5 bp deletion (NM_020347.2:c.402-406del, p.Pro136ThrfsX5) in LZTFL1 was identified. No LZTFL1 transcript was found in the patient's fibroblasts and no protein could be detected. The sonic hedgehog (Shh) pathway analysis conducted on the patient's fibroblast showed a significant increase in Smo. Patched1 as well as the downstream target GLI2 were also found to be upregulated, indicating an overall massive activation of the Shh signalling in the absence of LZTFL1.
LZTFL1, encoding the human leucine zipper transcription factor like 1, has been recently shown to be an important negative regulator of BBSome ciliary trafficking and Shh signalling. This study shows that absence of LZTFL1 leads to a BBS phenotype with enhanced developmental abnormalities associated with cellular Shh dysfunction. LZTFL1 is a novel BBS gene (BBS17).
ALG3‐CDG is one of the very rare types of congenital disorder of glycosylation (CDG) caused by variants in the ER‐mannosyltransferase ALG3. Here, we summarize the clinical, biochemical, and genetic ...data of four new ALG3‐CDG patients, who were identified by a type I pattern of serum transferrin and the accumulation of Man5GlcNAc2‐PP‐dolichol in LLO analysis. Additional clinical symptoms observed in our patients comprise sensorineural hearing loss, right‐descending aorta, obstructive cardiomyopathy, macroglossia, and muscular hypertonia. We add four new biochemically confirmed variants to the list of ALG3‐CDG inducing variants: c.350G>C (p.R117P), c.1263G>A (p.W421*), c.1037A>G (p.N346S), and the intron variant c.296+4A>G. Furthermore, in Patient 1 an additional open‐reading frame of 141 bp (AAGRP) in the coding region of ALG3 was identified. Additionally, we show that control cells synthesize, to a minor degree, a hybrid protein composed of the polypeptide AAGRP and ALG3 (AAGRP‐ALG3), while in Patient 1 expression of this hybrid protein is significantly increased due to the homozygous variant c.160_196del (g.165C>T). By reviewing the literature and combining our findings with previously published data, we further expand the knowledge of this rare glycosylation defect.
Multisystem inflammatory syndrome in children (MIS-C) is the most severe clinical entity associated with pediatric SARS-CoV-2 infection with a putative role of the spike protein into the immune ...system activation. Whether COVID-19 mRNA vaccine can induce this complication in children is unknown. We aimed to assess the risk of hyper-inflammatory syndrome following COVID-19 mRNA vaccine in children.
We conducted a post-authorization national population-based surveillance using the French enhanced pharmacovigilance surveillance system for COVID-19 vaccines. All cases of suspected hyper-inflammatory syndrome following COVID-19 mRNA vaccine in 12–17-year-old children between June 15th, 2021 and January 1st, 2022, were reported. Cases were reviewed according to WHO criteria for MIS-C. The reporting rate of this syndrome was compared to the MIS-C rate per 1,000,000 12–17-year-old children infected by SARS-CoV-2.
Up to January 2022, 8,113,058 COVID-19 mRNA vaccine doses were administered to 4,079,234 12–17-year-old children. Among them, 12 presented a hyper-inflammatory syndrome with multisystemic involvement. Main clinical features included male predominance (10/12, 83%), cardiac involvement (10/12, 83%), digestive symptoms (10/12, 83%), coagulopathy (7/12, 58%), cytolytic hepatitis (6/12, 50%), and shock (5/12, 42%). 4/12 (33%) required intensive care unit transfer, and 3/12 (25%) hemodynamic support. All cases recovered. In eight cases, no evidence of previous SARS-CoV-2 infection was found. The reporting rate was 1.5 (95%CI 0.8; 2.6) per 1,000,000 doses injected, i.e. 2.9 (95%CI 1.5; 5.1) per 1,000,000 12–17-year-old vaccinated children. As a comparison, 113 MIS-C (95%CI 95; 135) occurred per 1,000,000 12–17-year-old children infected by SARS-CoV-2.
Very few cases of hyper-inflammatory syndrome with multi-organ involvement occurred following COVID-19 mRNA vaccine in 12–17-year-old children. The low reporting rate of this syndrome, compared to the rate of post-SARS-CoV-2 MIS-C in the same age-group, largely supports the vaccination in a context of an important circulation of SARS-CoV-2.
ESPID Fellowship Award; Grandir–Fonds de Solidarité Pour L'enfance.
Newborn screening (NBS) for β-thalassemia is based on measuring the expression of the hemoglobin A (HbA) fraction. An absence or very low level of HbA at birth may indicate β-thalassemia. The ...difficulty is that the HbA fraction at birth is correlated with gestational age (GA) and highly variable between individuals. We used HbA expressed in multiples of the normal (MoM) to evaluate relevant thresholds for NBS of β-thalassemia.
The chosen threshold (HbA≤0.25 MoM) was prospectively applied for 32 months in our regional NBS program for sickle cell disease, for all tests performed, to identify patients at risk of β-thalassemia. Reliability of this threshold was evaluated at the end of the study.
In all, 343,036 newborns were tested, and 84 suspected cases of β-thalassemia were detected by applying the threshold of HbA≤0.25 MoM. Among the n=64 cases with confirmatory tests, 14 were confirmed using molecular analysis as β-thalassemia diseases, 37 were confirmed as β-thalassemia trait and 13 were false-positive. Determination of the optimum threshold for β-thalassemia screening showed that HbA≤0.16 MoM had a sensitivity of 100% and a specificity of 95.3%, whatever the GA.
NBS for β-thalassemia diseases is effective, regardless of the birth term, using the single robust threshold of HbA≤0.16 MoM. A higher threshold would also allow screening for carriers, which could be interesting when β-thalassemia constitutes a public health problem.
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