ABSTRACT
Introduction: Multisystemic inflammatory syndrome in children (MIS-C) is a therapeutic emergency and can lead to myocardial dysfunction (17%-75%) and heart failure (52%-53%). Intravenous immunoglobulins (IVIG) and corticosteroids (CST) have been validated for the management of this condition. Recent reports suggest that an interleukin-1 (IL-1) receptor antagonist, namely anakinra, may be a valuable add-on to the 2019 novel coronavirus disease (COVID-19) treatment for refractory patients. The purpose of this study was to describe the clinico-biological characteristics of patients treated with anakinra as well as the efficacy and safety of subcutaneous anakinra therapy in this condition. Methods: The prospective multicentre study of children hospitalized for MIS-C between March 2020 and September 2022, including 23 international paediatric centres, followed for a mean duration of 3.072 ± 3.508 months. The patient data were extracted from the Juvenile Inflammatory Rheumatism (JIR) cohort. The clinico-pathological characteristics, cardiac ultrasound data, and adverse events were reported in patients receiving anakinra. Results: Of the 470 children admitted with MIS-C, 18 French patients (50% girls) with a mean age of 10.06 ± 3.9 years were treated with subcutaneous anakinra. Anakinra was used in two situations, macrophage activation syndrome (MAS) (4 patients) and heart failure (14 patients) with a median left ventricular ejection fraction (LVEF) of 39.5% (30%-45%). The average dose of anakinra received was 2.53 ± 1.3â mg/kg/day for a median duration of 3 days. Prior to introduction, 78% (n = 14/18) of the patients had received CST and 56% (n = 10/18) had received IVIG. Only two patients received IVIG alone and six received CST alone plus anakinra. In 10% of cases, IVIG was poorly tolerated from a cardiovascular point of view and was discontinued. Transient elevations in serum transaminases were noted in four patients on anakinra without the need for treatment or dose modification. In all patients, rapid (48â h) improvement in myocardial function was observed (LVEF > 55%) with a concomitant significant decrease in myocardial enzymes (p < 0.05). All patients survived with complete recovery of cardiac function without sequelae. Conclusions: Subcutaneous anakinra appears to be a safe and effective treatment for the management of heart failure or MAS in MIS-C patients. The value of IVIG in these two situations remains to be reviewed.
ABSTRACT
Achaete-Scute Family basic-helix-loop-helix (bHLH) Transcription Factor 1 (ASCL1) is a proneural transcription factor involved in neuron development in the central and peripheral nervous system. While initially suspected to contribute to congenital central hypoventilation syndrome-1 (CCHS) with or without Hirschsprung disease (HSCR) in three individuals, its implication was ruled out by the presence, in one of the individuals, of a Paired-like homeobox 2B (PHOX2B) heterozygous polyalanine expansion variant, known to cause CCHS. We report two additional unrelated individuals sharing the same sporadic ASCL1 p.(Glu127Lys) missense variant in the bHLH domain and a common phenotype with short-segment HSCR, signs of dysautonomia, and developmental delay. One has also mild CCHS without polyalanine expansion in PHOX2B, compatible with the diagnosis of Haddad syndrome. Furthermore, missense variants with homologous position in the same bHLH domain in other genes are known to cause human diseases. The description of additional individuals carrying the same variant and similar phenotype, as well as targeted functional studies, would be interesting to further evaluate the role of ASCL1 in neurocristopathies.
Subject(s)
Homeodomain Proteins , Transcription Factors , Humans , Basic Helix-Loop-Helix Transcription Factors/genetics , Homeodomain Proteins/genetics , Mutation , Mutation, Missense/genetics , Phenotype , Transcription Factors/geneticsABSTRACT
Our study aimed to compare children under 5 years hospitalized with respiratory syncytial virus in prepandemic and late-pandemic periods. We included 209 children at the Dijon University Hospital (France). We observed a nearly 3-fold increase in the number of cases in the late period, with older children, but less frequently requiring intensive care. These observations could help prepare a new pandemic.
Subject(s)
COVID-19 , Respiratory Syncytial Virus Infections , Respiratory Syncytial Virus, Human , Respiratory Tract Infections , Child , Humans , Infant , Child, Preschool , Adolescent , Respiratory Syncytial Virus Infections/epidemiology , Pandemics , COVID-19/epidemiology , Critical CareABSTRACT
BACKGROUND: Classical infantile-onset Pompe disease (IOPD) is the most severe form of Pompe disease. Enzyme replacement therapy (ERT) has significantly increased survival but only a few studies have reported long-term outcomes. METHODS: We retrospectively analyzed the outcomes of classical IOPD patients diagnosed in France between 2004 and 2020. RESULTS: Sixty-four patients were identified. At diagnosis (median age 4 months) all patients had cardiomyopathy and most had severe hypotonia (57 of 62 patients, 92%). ERT was initiated in 50 (78%) patients and stopped later due to being ineffective in 10 (21%). Thirty-seven (58%) patients died during follow-up, including all untreated and discontinued ERT patients, and 13 additional patients. Mortality was higher during the first 3 years of life and after the age of 12 years. Persistence of cardiomyopathy during follow-up and/or the presence of heart failure were highly associated with an increased risk of death. In contrast, cross-reactive immunologic material (CRIM)-negative status (n = 16, 26%) was unrelated to increased mortality, presumably because immunomodulation protocols prevent the emergence of high antibody titers to ERT. Besides survival, decreased ERT efficacy appeared after the age of 6 years, with a progressive decline in motor and pulmonary functions for most survivors. CONCLUSIONS: This study reports the long-term follow-up of one of the largest cohorts of classical IOPD patients and demonstrates high long-term mortality and morbidity rates with a secondary decline in muscular and respiratory functions. This decreased efficacy seems to be multifactorial, highlighting the importance of developing new therapeutic approaches targeting various aspects of pathogenesis.
Subject(s)
Cardiomyopathies , Glycogen Storage Disease Type II , Humans , Child , Infant , Glycogen Storage Disease Type II/drug therapy , Follow-Up Studies , Retrospective Studies , Enzyme Replacement Therapy/adverse effects , Enzyme Replacement Therapy/methodsABSTRACT
BACKGROUND AND OBJECTIVE: In the European Union, the record of cocaine-related seizures indicates an expanding supply. The purity has also been increasing. The health impact of these trends remains poorly documented, in particular, the changes and clinical manifestations of intoxication in young children. We attempted to evaluate the trend in French pediatric admissions for cocaine intoxication/exposure over an 11-year period (2010-2020). METHODS: A retrospective, national, multicenter, study of a pediatric cohort. All children less than 15 years of age admitted to a tertiary-level pediatric emergency unit for proven cocaine intoxication (compatible symptoms and positive toxicological screening) during the reference period were included. RESULTS: Seventy-four children were included. Forty-six percent were less than 6 years old. Annual admissions increased by a factor of 8 over 11 years (+700%) and 57% of all cases were admitted in the last two years. The main clinical signs were neurologic (59%) followed by cardiovascular symptoms (34%). Twelve patients were transferred to the pediatric intensive care unit. Factors significantly associated with the risk of being transferred to the pediatric intensive care unit were initial admission to the pediatric resuscitation area (P < 0.001), respiratory impairment (P < 0.01), mydriasis (P < 0.01), cardiovascular symptoms (P = 0.014), age of less than 2 years (P = 0.014). Blood and/or urine toxicological screening isolated eighteen other substances besides cocaine in 46 children (66%). CONCLUSION: Children are collateral victims of the changing trends in cocaine availability, use and purity. Admissions of intoxicated children to pediatric emergency departments are more frequent and there is an increase in severe presentations. Therefore, this is a growing public health concern.
Subject(s)
Cocaine , Child , Humans , Child, Preschool , Retrospective Studies , Seizures , Hospitalization , Emergency Service, HospitalABSTRACT
Objectives: To examine the changes in diagnostic practices and clinical management of patients with 5α-reductase type 2 (SRD5A2) or 17ß-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency since molecular diagnoses became available. Methods: Clinical, laboratory, and therapeutic data were retrieved from the medical records of 52 patients with a molecular diagnosis of SRD5A2 (n = 31) or HSD17B3 (n = 21) deficiency. Temporal trends regarding age at assessment and initial sex assignment over 1994-2020 were qualitatively analyzed. Age at molecular diagnosis was compared between two subgroups of patients according to their year of birth. Results: Fifty-eight percent (n = 30) patients were diagnosed during the perinatal period, 33% (n = 17) during infancy, and 9% (n = 5) during adolescence or adulthood. Over the studied period, the patients' age at initial assessment and diagnosis frankly decreased. The median (range) age at diagnostic confirmation was 10.5 (0-53.2) years for patients born before 2007 and 0.4 (0-9.3) years for those born in 2007 or later (P = 0.029). Genetic testing identified 27 different variants for the SRD5A2 gene (30% novel, n = 8) and 18 for the HSD17B3 gene (44% novel, n = 8). Before 2002, most patients were initially assigned as females (95%, n = 19), but this proportion dropped for those born later (44%, n = 14; P < 0.001). The influence of initial genital appearance on these decisions seemingly decreased in the most recent years. Therapeutic interventions differed according to the sex of rearing. Ten percent (n = 2) patients requested female-to-male reassignment during adulthood. Conclusion: This study showed, over the past two decades, a clear trend toward earlier diagnosis and assignment of affected newborns as males.
ABSTRACT
Hepatitis-associated aplastic anemia (HAAA) accounts for 4% of autoimmune hepatitis in children. An episode of seronegative autoimmune hepatitis is followed a few days or months later by aplastic anemia or full aplasia. This autoimmune disease could be due to a regulation defect in the immune response to a viral trigger, in a genetically predisposed individual. Other causes of hepatitis or aplastic anemia have to be ruled out. Steroids and azathioprine usually control the liver damage but do not prevent the development of aplastic anemia. Aplastic anemia is treated with either hematopoietic stem cell transplantation in patients with a sibling donor or anti-thymocyte globulins and cyclosporine. We propose guidelines to explore and treat this rare disease. We emphasize on the necessary close collaboration between hepatologists and hematologists.
Subject(s)
Anemia, Aplastic , Hematopoietic Stem Cell Transplantation , Hepatitis, Autoimmune , Child , Humans , Anemia, Aplastic/complications , Anemia, Aplastic/therapy , Hepatitis, Autoimmune/complications , Hepatitis, Autoimmune/therapy , Cyclosporine/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , SiblingsABSTRACT
Considering that some Inherited Metabolic Disorders (IMDs) can be diagnosed in patients with no distinctive clinical features of IMDs, we aimed to evaluate the power of exome sequencing (ES) to diagnose IMDs within a cohort of 547 patients with unspecific developmental disorders (DD). IMDs were diagnosed in 12% of individuals with causative diagnosis (177/547). There are clear benefits of using ES in DD to diagnose IMD, particularly in cases where biochemical studies are unavailable. SYNOPSIS: Exome sequencing and diagnostic rate of Inherited Metabolic Disorders in individuals with developmental disorders.
ABSTRACT
BACKGROUND: Resistant Kawasaki disease (KD) represents 10%-15% of KD patients and increases risk of coronary artery abnormalities (CAAs). Different scores exist to predict resistant KD but only in Japanese population, although a French team has recently proposed a new scoring system. The principal objective of this study is to establish criteria to predict resistant KD in our representative French population. The second objective is an attempt to develop a predictive score of resistant KD. METHODS: We conducted a retrospective multicenter study including 2 universities and five secondary hospitals in Eastern France. Patients were included over a period from January 1, 2010 through December 31, 2019. Diagnosis of KD was recorded to the European Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) initiative criteria. RESULTS: Two hundred two eligible patients had KD and 194 patients were analyzed: 160 sensitive KD and 34 (17.5%) resistant KD. In univariate model, serum sodium <133 mmol/L (odds ratio [OR] 2.97 [1.40-6.45]), hemoglobin level <110 g/L (OR 3.17 [1.46-7.34]), neutrophils >80% (OR 2.36 [1.03-5.25]), C reactive protein level >150 mg/L (OR 4.47 [2.07-10.19]), CAA (OR 3.85 [1.67-8.79]) or myocarditis (OR 6.98 [1.47-36.95]) at the diagnosis were statistically significant, but only serum sodium was an independent factor of resistant KD. CONCLUSION: This study shows an association between resistant KD and biologic and echocardiography criteria, but only serum sodium is an independent predictive factor. A score to predict resistant KD could not yet be established.
Subject(s)
Drug Resistance , Mucocutaneous Lymph Node Syndrome/classification , Mucocutaneous Lymph Node Syndrome/diagnosis , Adolescent , Biomarkers/blood , Child , Child, Preschool , Coronary Aneurysm/complications , Coronary Artery Disease/complications , Echocardiography , France/epidemiology , Humans , Infant , Models, Statistical , Myocarditis/complications , Retrospective Studies , Risk FactorsABSTRACT
Neonatal screening for cystic fibrosis has optimised the prognosis for patients allowing very early multidisciplinary care. Over the past 20 years, screening programmes have undergone major international expansion. The performances of the French neonatal cystic fibrosis screening programme, established in 2002, has met European guideline standards, with positive predictive value of 0.31 (against a minimum of 0.30) and sensitivity value of 0.95 (against a minimum of 0.95). It is also important to highlight the very high percentage of sweat tests performed (95.5%), of mutations identified (96.6%), the 9:1 ratio of cystic fibrosis cases to cases of inconclusive diagnosis achieved and the effectiveness of the strategy implemented for the detection of false negative cases. A new organisation for cystic fibrosis neonatal screening has now been established in France. It is vital that effectiveness is maintained throughout the process, from newborn maternity care to diagnosis in cystic fibrosis care centres, and that further knowledge is gained through exhaustive data collection and validation.
TITLE: Dépistage néonatal de la mucoviscidose. ABSTRACT: Le dépistage néonatal (DNN) de la mucoviscidose a permis une prise en charge multidisciplinaire très précoce des nourrissons et a amélioré le pronostic de cette maladie. Il a connu, en une vingtaine d'années, un développement international spectaculaire. Les performances du DNN national français, réalisé depuis 2002, répondent aux exigences des standards européens en termes de valeur prédictive positive et de sensibilité. Nous pouvons noter, en particulier, un nombre très faible de cas en attente de conclusion, un pourcentage très élevé de tests de la sueur réalisés et d'identification des mutations du gène cystic fibrosis transmembrane conductance regulator (CFTR), un ratio important de cas de mucoviscidose par rapport aux cas de diagnostics non conclus, ainsi qu'une stratégie efficace pour repérer les faux-négatifs. Une nouvelle organisation du DNN français a été mise en place. Il est donc capital de maintenir l'efficacité du processus ainsi mis en place, du nouveau-né en maternité jusqu'au diagnostic dans des centres de ressources et de compétences de la mucoviscidose, avec le recueil exhaustif des données et leur validation.
Subject(s)
Cystic Fibrosis , Maternal Health Services , Cystic Fibrosis/diagnosis , Cystic Fibrosis/epidemiology , Cystic Fibrosis/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Female , France/epidemiology , Humans , Infant, Newborn , Mutation , Neonatal Screening , PregnancyABSTRACT
Lung damage in cystic fibrosis (CF) is strongly associated with lower airway infections. Early treatment of Pseudomonas aeruginosa is recommended. Pathogen detection requires sampling of lower airway secretions, which remains a challenge in nonexpectorating patients. Our hypothesis was that chest physiotherapy would improve the quality of airway secretion samples and increase the rates of pathogens detected in nonexpectorating patients. This prospective multicentre study compared three successive methods for sampling airway secretions applied through the same session: 1) an oropharyngeal swab (OP), 2) a chest physiotherapy session followed by a provoked cough to obtain sputum (CP-SP) and 3) a second oropharyngeal swab collected after chest physiotherapy (CP-OP). Haemophilus influenzae, Staphylococcus aureus and P. aeruginosa growth cultures were assessed. Accuracy tests and an equivalence test were performed to compare the three successive methods of collection. 300 nonexpectorating children with CF were included. P. aeruginosa was detected cumulatively in 56 (18.9%) children, and according to the different collection methods in 28 (9.8%), 37 (12.4%) and 44 (14.7%) children by using OP, CP-OP and CP-SP, respectively. Compared with OP, the increased detection rate was +22% for CP-OP (p=0.029) and +57% for CP-SP (p=0.003). CP-SP had the best positive predictive value (86.3%) and negative predictive value (96.0%) for P. aeruginosa compared with the overall detection. The results of this adequately powered study show differences in the rates of pathogens detected according to the sampling method used. Chest physiotherapy enhanced detection of P. aeruginosa in nonexpectorating children with CF.
ABSTRACT
Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with a characteristic behavioural phenotype. A multidisciplinary approach to care is required to prevent multiple medical complications in individuals affected by PWS. The aim of this study was to describe the rehabilitation, medical care, educational and social support provided to school-aged French PWS patients with varying neuropsychological profiles. Data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Nineteen PWS subjects with a mean age of 9.2 years were included. The mean full-scale intellectual quotient (IQ) was 58 (Wechsler scale). There were frequent dissociations between verbal and performance IQ that were not associated with a specific profile. We also observed lower autonomy and communication scores (5.3 years and 5.9 years equivalent, respectively, Vineland scale), the absence of hyperactivity (Conners scale), and the presence of behavioural abnormalities (CBCL scale). Multidisciplinary medical supervision was generally coordinated by the paediatric endocrinologist and did not always include follow-up with all of the recommended specialists, in particular with a paediatric psychiatrist. Analysis of multidisciplinary rehabilitation conducted in public and private-sector establishment revealed failings in psychological support, occupational therapy and dietary follow-up. Regarding education, most children younger than 10 years were in normal schools, while older individuals were often cared for in medico-social institutions. In conclusion, children and adolescents with PWS generally received appropriate care. Though there have been considerable improvements in the management of children with PWS, reference centres should continue reinforcing the coordination of multidisciplinary supervision.
Subject(s)
Cognition , Neurological Rehabilitation/statistics & numerical data , Prader-Willi Syndrome/rehabilitation , Social Support , Adolescent , Child , Child, Preschool , Education, Special/statistics & numerical data , Female , France , Hormone Replacement Therapy/statistics & numerical data , Humans , Male , Prader-Willi Syndrome/drug therapy , Prader-Willi Syndrome/physiopathology , Young AdultABSTRACT
From March 2, 2020, to April 26, 2020, 52,588 reverse transcription polymerase chain reaction (RT-PCR) tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were performed in France, 6490 in children and 46,098 in adults. The rate of RT-PCR-positive SARS-CoV-2 tests for children (5.9%) was always less than that for adults (20.3%) but vary according to the epidemic stage. The risk ratio of RT-PCR-positive SARS-CoV-2 tests for adults compared with children was 3.5 (95% confidence interval: 3.2-3.9) for the whole study period.
Subject(s)
Betacoronavirus/genetics , Clinical Laboratory Techniques/methods , Coronavirus Infections/virology , Pneumonia, Viral/virology , Adult , Age Factors , Betacoronavirus/isolation & purification , COVID-19 , COVID-19 Testing , Child , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , France/epidemiology , Humans , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Reverse Transcriptase Polymerase Chain Reaction/methods , SARS-CoV-2ABSTRACT
The MTOR gene encodes the mechanistic target of rapamycin (mTOR), which is a core component of the PI3K-AKT-mTOR signaling pathway. Postzygotic MTOR variants result in various mosaic phenotypes, referred to in OMIM as Smith-Kinsgmore syndrome or focal cortical dysplasia. We report here the case of a patient, with an MTOR mosaic gain-of-function variant (p.Glu2419Lys) in the DNA of 41% skin cells, who received compassionate off-label treatment with everolimus for refractory epilepsy. This 12-year-old-girl presented with psychomotor regression, intractable seizures, hypopigmentation along Blaschko's lines (hypomelanosis of Ito), asymmetric regional body overgrowth, and ocular anomalies, as well as left cerebral hemispheric hypertrophy with some focal underlying migration disorders. In response to the patient's increasingly frequent epileptic seizures, everolimus was initiated (after approval from the hospital ethics committee) at 5 mg/day and progressively increased to 12.5 mg/day. After 5 months of close monitoring (including neuropsychological and electroencephalographic assessment), no decrease in seizure frequency was observed. Though the physiopathological rationale was good, no significant clinical response was noticed under everolimus treatment. A clinical trial would be needed to draw conclusions, but, because the phenotype is extremely rare, it would certainly need to be conducted on an international scale.
Subject(s)
Compassionate Use Trials , Craniofacial Abnormalities/drug therapy , Epilepsies, Partial/drug therapy , Everolimus/therapeutic use , Gain of Function Mutation , Malformations of Cortical Development/drug therapy , Protein Kinase Inhibitors/therapeutic use , TOR Serine-Threonine Kinases/genetics , Child , Craniofacial Abnormalities/genetics , Epilepsies, Partial/genetics , Everolimus/administration & dosage , Female , Humans , Malformations of Cortical Development/genetics , Mosaicism , Phenotype , Protein Kinase Inhibitors/administration & dosageABSTRACT
PURPOSE: Marfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan-Fryns syndrome explain no more than 20% of subjects. METHODS: To further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic. RESULTS: We identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2). Using simulation models, we showed that five genes (DLG4, NFIX, EHMT1, ZEB2 and ATP1A1) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including NSD1 and NFIX, which are known to be mutated in overgrowth syndromes. CONCLUSION: We demonstrated that DNVs were enriched in chromatin remodelling (p=2×10-4) and genes regulated by the fragile X mental retardation protein (p=3×10-8), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.
Subject(s)
Craniofacial Abnormalities/genetics , Histone-Lysine N-Methyltransferase/genetics , Intellectual Disability/genetics , Marfan Syndrome/genetics , Mental Retardation, X-Linked/genetics , NFI Transcription Factors/genetics , Adolescent , Adult , Child , Chromatin Assembly and Disassembly , Craniofacial Abnormalities/pathology , Exome/genetics , Female , Genetic Predisposition to Disease , Humans , Intellectual Disability/pathology , Male , Marfan Syndrome/pathology , Mental Retardation, X-Linked/pathology , Middle Aged , Mutation/genetics , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/pathology , Exome Sequencing , Young AdultABSTRACT
Autopsy investigation of a fatal case of rotavirus severe acute gastroenteritis and multiple organ failure in a 16-month boy with previous intrauterine growth retardation showed colocalization of nonstructural and structural rotavirus proteins within viroplasms in nephrons. This case brings new insights into extraintestinal rotavirus infection and new clues to its abilities to bind to human histo-blood group antigens.
Subject(s)
Gastroenteritis/complications , Gastroenteritis/virology , Multiple Organ Failure/virology , Rotavirus Infections/complications , Rotavirus Infections/pathology , Acute Kidney Injury/virology , Autopsy , Fatal Outcome , Fetal Growth Retardation , Gastroenteritis/pathology , Humans , Infant , Male , Nephrons/virology , Rotavirus , Rotavirus Infections/diagnosis , Shock, Septic/virologyABSTRACT
Alpha-mannosidosis (AM) is a very rare (prevalence: 1/500000 births) autosomal recessive lysosomal storage disorder. It is characterized by multi-systemic involvement associated with progressive intellectual disability, hearing loss, skeletal anomalies, and coarse facial features. The spectrum is wide, from very severe and lethal to a milder phenotype that usually progresses slowly. AM is caused by a deficiency of lysosomal alpha-mannosidase. A diagnosis can be established by measuring the activity of lysosomal alpha-mannosidase in leucocytes and screening for abnormal urinary excretion of mannose-rich oligosaccharides. Genetic confirmation is obtained with the identification of MAN2B1 mutations. Enzyme replacement therapy (LAMZEDER ) was approved for use in Europe in August 2018. Here, we describe seven individuals from four families, diagnosed at 3-23 years of age, and who were referred to a clinical geneticist for etiologic exploration of syndromic hearing loss, associated with moderate learning disabilities. Exome sequencing had been used to establish the molecular diagnosis in five cases, including a two-sibling pair. In the remaining two patients, the diagnosis was obtained with screening of urinary oligosaccharides excretion and the association of deafness and hypotonia. These observations emphasize that the clinical diagnosis of AM can be challenging, and that it is likely an underdiagnosed rare cause of syndromic hearing loss. Exome sequencing can contribute significantly to the early diagnosis of these nonspecific mild phenotypes, with advantages for treatment and management.
Subject(s)
Hearing Loss/genetics , Intellectual Disability/genetics , alpha-Mannosidase/genetics , alpha-Mannosidosis/genetics , Adolescent , Adult , Child , Child, Preschool , Female , Hearing Loss/blood , Hearing Loss/complications , Hearing Loss/pathology , Humans , Intellectual Disability/blood , Intellectual Disability/complications , Intellectual Disability/pathology , Lysosomes/enzymology , Male , Phenotype , Siblings , Exome Sequencing , Young Adult , alpha-Mannosidase/blood , alpha-Mannosidosis/blood , alpha-Mannosidosis/complications , alpha-Mannosidosis/pathologyABSTRACT
Cystic fibrosis (CF) patients are commonly colonized by bacterial pathogens, which can induce persistent lung inflammation and may contribute to clinical deterioration. Colonization of CF patients and cross-transmission by Corynebacterium diphtheriae have not been reported so far. The aim of this article was to investigate the possibility of a cross-transmission of C. diphtheriae biovar Belfanti between four patients of a CF center. C. diphtheriae biovar Belfanti (now formally called C. belfantii) isolates were collected from four patients in a single CF care center over a period of 6 years and analyzed by microbiological methods and whole-genome sequencing. Epidemiological links among patients were investigated. Ten isolates were collected from 4 patients. Whole-genome sequencing of one isolate from each patient showed that a single strain was shared among them. In addition, one patient was found to have the same strain in two consecutive samplings performed 9 months apart. The strain was nontoxigenic and was susceptible to most antimicrobial agents. Ciprofloxacin resistance was observed in one patient. The idea of transmission of the strain among patients was supported by the occurrence of same-day visits to the CF center. This study demonstrated colonization of CF patients by C. diphtheriae biovar Belfanti (C. belfantii), and the data suggest persistence and transmission of a unique strain during at least 6 years in a single CF patient care center.
Subject(s)
Asymptomatic Infections , Corynebacterium diphtheriae/isolation & purification , Cystic Fibrosis/microbiology , Diphtheria/transmission , Adult , Anti-Bacterial Agents/pharmacology , Corynebacterium diphtheriae/drug effects , Corynebacterium diphtheriae/genetics , Cystic Fibrosis/complications , Cystic Fibrosis/epidemiology , Diphtheria/epidemiology , Diphtheria/microbiology , Female , France , Humans , Male , Whole Genome SequencingABSTRACT
Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.
Subject(s)
Bone and Bones/pathology , Cholestasis/genetics , Diarrhea/genetics , Hearing Loss/genetics , Intracellular Signaling Peptides and Proteins/genetics , Loss of Function Mutation/genetics , Adolescent , Animals , Child, Preschool , Diarrhea/physiopathology , Family , Female , Fibroblasts/pathology , Gastrointestinal Motility , Humans , Infant, Newborn , Lymphocytes/pathology , Male , Pedigree , Phenotype , Syndrome , Young Adult , ZebrafishABSTRACT
Fungal respiratory colonization of cystic fibrosis (CF) patients emerges as a new concern; however, the heterogeneity of mycological protocols limits investigations. We first aimed at setting up an efficient standardized protocol for mycological analysis of CF sputa that was assessed during a prospective, multicenter study: "MucoFong" program (PHRC-06/1902). Sputa from 243 CF patients from seven centers in France were collected over a 15-month period and submitted to a standardized protocol based on 6 semi-selective media. After mucolytic pretreatment, sputa were plated in parallel on cycloheximide-enriched (ACT37), erythritol-enriched (ERY37), benomyl dichloran-rose bengal (BENO37) and chromogenic (CAN37) media incubated at 37 °C and on Sabouraud-chloramphenicol (SAB27) and erythritol-enriched (ERY27) media incubated at 20-27 °C. Each plate was checked twice a week during 3 weeks. Fungi were conventionally identified; time for detection of fungal growth was noted for each species. Fungal prevalences and media performances were assessed; an optimal combination of media was determined using the Chi-squared automatic interaction detector method. At least one fungal species was isolated from 81% of sputa. Candida albicans was the most prevalent species (58.8%), followed by Aspergillus fumigatus (35.4%). Cultivation on CAN37, SAB27, ACT37 and ERY27 during 16 days provided an optimal combination, detecting C. albicans, A. fumigatus, Scedosporium apiospermum complex and Exophiala spp. with sensitivities of 96.5, 98.8, 100 and 100%. Combination of these four culture media is recommended to ensure the growth of key fungal pathogens in CF respiratory specimens. The use of such consensual protocol is of major interest for merging results from future epidemiological studies.