S. Pierrot

In vitro prediction of stop-codon suppression by intravenous gentamicin in patients with cystic fibrosis: a pilot study.

BackgroundCystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which acts as a chloride channel activated by cyclic AMP (cAMP). The most frequent mutation found in 70% of CF patients is F508del, while premature stop mutations are found in about 10% of patients. In vitro aminoglycoside antibiotics (e.g. gentamicin) suppress nonsense mutations located in CFTR permitting translation to continue to the natural termination codon. Pharmacologic suppression of stop mutations within the CFTR may be of benefit to a significant number of patients. Our pilot study was conducted to determine whether intravenous gentamicin suppresses stop codons in CF patients and whether it has clinical benefits.MethodsA dual gene reporter system was used to determine the gentamicin-induced readthrough level of the most frequent stop mutations within the CFTR in the French population. We investigated readthrough efficiency in response to 10 mg/kg once-daily intravenous gentamicin perfusions in patients with and without stop mutations. Respiratory function, sweat chloride concentration, nasal potential difference (NPD) and CFTR expression in nasal epithelial cells were measured at baseline and after 15 days of treatment.ResultsAfter in vitro gentamicin incubation, the readthrough efficiency for the Y122X mutation was at least five times higher than that for G542X, R1162X, and W1282X. In six of the nine patients with the Y122X mutation, CFTR immunodetection showed protein at the membrane of the nasal epithelial cells and the CFTR-dependent Cl- secretion in NPD measurements increased significantly. Respiratory status also improved in these patients, irrespective of the gentamicin sensitivity of the bacteria present in the sputum. Mean sweat chloride concentration decreased significantly and normalised in two patients. Clinical status, NPD and sweat Cl- values did not change in the Y122X patients with no protein expression, in patients with the other stop mutations investigated in vitro and those without stop mutations.ConclusionSuppression of stop mutations in the CFTR gene with parenteral gentamicin can be predicted in vitro and is associated with clinical benefit and significant modification of the CFTR-mediated Cl- transport in nasal and sweat gland epithelium.

Acute mastoiditis in children: a retrospective study of 188 patients.

OBJECTIVEnThe aim of this study is to define the clinical and bacteriological characteristics of acute mastoiditis (AM) in children in order to optimize diagnostic work-up and treatment.nnnMETHODSnIn this retrospective study, 188 children between 3 months and 15 years of age (15±24 months; median±SD) were referred to our pediatric ENT emergency center for AM during a 7-year period (December 2001-January 2008).nnnRESULTSnFifty seven percent were male and 43% were female. Clinical follow-up duration was 3.9±0.7 months (mean±SEM). The incidence of AM remained stable during the whole study period. Microbiological samples (n=236) were negative in 33% of cases. The most frequently isolated germs were Streptococcus pneumoniae (51%), Streptococcus pyogenes (11.5%), Anaerobes (6.5%), and coagulase-negative Staphylococcus (6.5%). Paracentesis, puncture of retro auricular abscess under local anesthesia, and peroperative samples all contributed to isolate the involved germ(s). All the patients were hospitalized and received intravenous antibiotics, and 36.2% (n=68) underwent surgery. Several surgical procedures were necessary in 4 cases (2.1%). AM recurrences requiring a second hospitalization were observed in 8 patients (4.3%). The only observed complication was lateral sinus thrombosis (n=6; 3.2%). Surgical failures, requiring more than one surgical procedure, were more frequent in case of: (i) presence of Anaerobes (p≤0.001) or Gram-negative bacteria (p≤0.05) in microbiological samples; (ii) surgical drainage without mastoidectomy (p≤0.001). Recurrences were more frequent in AM due to Streptococcus pneumoniae.nnnCONCLUSIONSnBased on our findings and on literature data, a protocol was established in order to standardize the management of pediatric AM in our center. The mains points are: no systematic surgery; if surgery is indicated, it must encompass a mastoidectomy; broad-spectrum intravenous antibiotic treatment covering the most commonly involved germs (3rd generation cephalosporin) and secondarily adapted to the results of microbiological samples. If the infection is not controlled after 48 h of intravenous antibiotherapy, a mastoidectomy had to be performed.

Retropharyngeal infections in children. Treatment strategies and outcomes

OBJECTIVEnTo optimize the treatment of retropharyngeal infections in children.nnnMETHODSnRetrospective chart review of 101 consecutive pediatric cases of retropharyngeal infections referred to our center from January 2006 to July 2009.nnnRESULTSnTwo-thirds of patients were males. Their mean age was 52 months (range: 6-163). Upper airway obstruction was observed in three patients. In another child, the infection evolved towards a diffuse cervical cellulitis. Medical treatment was initially planned in 44% of patients. Failures requiring surgical drainage occurred in 18% of them. In 56% of cases, surgical treatment was immediately instigated. It failed in 16% of patients, requiring a second surgical drainage. There was no difference in the duration of fever and of hospital stay between patients initially treated medically or surgically. Both medical and surgical treatment failures were associated with longer durations of fever (p=0.002, and p<0.0001, respectively) and of hospital stay (p=0.0006, and p=0.0005, respectively). Some characteristics of CT-scan anomalies were correlated with treatment failure. A hypodense core surrounded by rim enhancement, with a largest long axis ≥ 20 mm, was more frequent in case of medical failure (p=0.02). Surgical failure was associated with the same feature, but with a largest long axis ≥ 30 mm (p=0.05).nnnCONCLUSIONSnThe present study suggests that severe complications are rare in pediatric retropharyngeal adenitis, and that CT-scan is a useful tool to choose between medical and surgical treatment.

Endoscopic balloon dilatation of esophageal strictures in children

AIM OF THE STUDYnTo assess the efficacy and safety of endoscopic balloon dilatation of esophageal strictures in children.nnnMATERIAL AND METHODSnnnnDESIGNnretrospective case series; population: 49 patients under 18 years of age referred to our center for esophageal strictures; treatment: endoscopic balloon dilatation; outcome parameters: residual dysphagia, weight gain, iatrogenic esophageal perforation, assessment of the esophageal lumen by endoscopy or esophagogram.nnnRESULTSnThe three main etiologies were esophageal atresia (49%; n=24), corrosive injury (25%; n=12), and epidermolysis bullosa (14%; n=7), followed by a heterogeneous group of rarer causes (12%; n=6). The number of dilatations ranged from 1 to 8 sessions per patient (median ± SEM: 2 ± 0.3). The length of the follow-up period ranged from 20 to 109 months (median ± SEM: 40 ± 4 months). Treatment was successful in 86% of cases (n=42). Twelve percent of patients (n=6) had a residual stenosis requiring surgery, and a further one still experienced swallowing difficulties requiring enteral nutrition via gastrostomy in spite of the absence of significant residual stricture. Results were less satisfactory in cases of corrosive injury than with other etiologies. Three esophageal perforations were observed (6% of patients; 2% of procedures). All were medically treated.nnnCONCLUSIONSnEndoscopic balloon dilatation is a simple, safe and efficacious treatment of esophageal strictures in children.

Heterogeneity of mutational mechanisms and modes of inheritance in auriculocondylar syndrome

Background Auriculocondylar syndrome (ACS) is a rare craniofacial disorder consisting of micrognathia, mandibular condyle hypoplasia and a specific malformation of the ear at the junction between the lobe and helix. Missense heterozygous mutations in the phospholipase C, β 4 (PLCB4) and guanine nucleotide binding protein (G protein), α inhibiting activity polypeptide 3 (GNAI3) genes have recently been identified in ACS patients by exome sequencing. These genes are predicted to function within the G protein-coupled endothelin receptor pathway during craniofacial development. Results We report eight additional cases ascribed to PLCB4 or GNAI3 gene lesions, comprising six heterozygous PLCB4 missense mutations, one heterozygous GNAI3 missense mutation and one homozygous PLCB4 intragenic deletion. Certain residues represent mutational hotspots; of the total of 11 ACS PLCB4 missense mutations now described, five disrupt Arg621 and two disrupt Asp360. The narrow distribution of mutations within protein space suggests that the mutations may result in dominantly interfering proteins, rather than haploinsufficiency. The consanguineous parents of the patient with a homozygous PLCB4 deletion each harboured the heterozygous deletion, but did not present the ACS phenotype, further suggesting that ACS is not caused by PLCB4 haploinsufficiency. In addition to ACS, the patient harbouring a homozygous deletion presented with central apnoea, a phenotype that has not been previously reported in ACS patients. Conclusions These findings indicate that ACS is not only genetically heterogeneous but also an autosomal dominant or recessive condition according to the nature of the PLCB4 gene lesion.

Dissection of the Internal Carotid Artery following Trauma of the Soft Palate in Children

Objectives: We undertook this report to underline the risks of lesions of the internal carotid artery after lateral oropharyngeal trauma in children and to discuss the diagnosis and treatment of this complication. Methods: We present 2 pediatric cases of carotid dissection following lateral soft palate trauma. Results: In 1 case, transient symptomatic cerebral ischemia occurred 24 hours after the initial traumatic injury. In both patients, the carotid dissection was assessed by magnetic resonance imaging with vascular and diffusion sequences. Treatment with low–molecular weight heparin calcium was maintained for several months. At the end of follow-up, both children were asymptomatic. Conclusions: We suggest noninvasive imaging of the carotid artery by enhanced computed tomographic scanning after trauma to the lateral part of the soft palate in children. Magnetic resonance imaging with vascular and diffusion sequences is useful in assessing the extension of the dissection toward the cerebral circulation and in early detection of cerebral ischemia. Anticoagulation with heparin probably reduces the risks of cerebral infarction. Patients must regularly undergo physical examination and noninvasive imaging of the carotid artery for at least 1 year after the traumatic injury.

Mutations in the Endothelin Receptor Type A Cause Mandibulofacial Dysostosis with Alopecia

The endothelin receptor type A (EDNRA) signaling pathway is essential for the establishment of mandibular identity during development of the first pharyngeal arch. We report four unrelated individuals with the syndrome mandibulofacial dysostosis with alopecia (MFDA) who have de novo missense variants in EDNRA. Three of the four individuals have the same substitution, p.Tyr129Phe. Tyr129 is known to determine the selective affinity of EDNRA for endothelin 1 (EDN1), its major physiological ligand, and the p.Tyr129Phe variant increases the affinity of the receptor for EDN3, its non-preferred ligand, by two orders of magnitude. The fourth individual has a somatic mosaic substitution, p.Glu303Lys, and was previously described as having Johnson-McMillin syndrome. The zygomatic arch of individuals with MFDA resembles that of mice in which EDNRA is ectopically activated in the maxillary prominence, resulting in a maxillary to mandibular transformation, suggesting that the p.Tyr129Phe variant causes an EDNRA gain of function in the developing upper jaw. Our inxa0vitro and inxa0vivo assays suggested complex, context-dependent effects of the EDNRA variants on downstream signaling. Our findings highlight the importance of finely tuned regulation of EDNRA signaling during human craniofacial development and suggest that modification of endothelin receptor-ligand specificity was a key step in the evolution of vertebrate jaws.

Diagnostic performance of multidetector computed tomography for foreign body aspiration in children

OBJECTIVEnTo evaluate the sensitivity of multidetector computed tomography for confirming suspected foreign body aspiration into the airways in children.nnnMETHODnWe conducted a multicentre prospective study of 303 children evaluated using multidetector computed tomography with axial analysis complemented by multiplanar reconstruction when required. The images were read by a radiologist before endoscopy then reviewed later by a senior radiologist blinded to the endoscopy findings. Endoscopy was performed routinely.nnnRESULTSnForeign bodies were found by endoscopy in 70 of the 303 children. The initial multidetector computed tomography reading was 94% sensitive and 95% specific. For the review, the images for 91 patients were excluded because of motion blurring or absence of larynx visualisation; in the remaining 212 patients, sensitivity was 98% and specificity 97%.nnnCONCLUSIONnMultidetector computed tomography as performed in our patients cannot replace endoscopy, which remains the reference standard. Nevertheless, multidetector computed tomography is sufficiently sensitive to be of value when foreign body aspiration is not considered initially or when endoscopy is likely to prove challenging.

Developmental outcome in Pierre Robin sequence: a longitudinal and prospective study of a consecutive series of severe phenotypes.

Pierre Robin sequence (PRS) is a congenital condition with a heterogeneous and imprecise developmental prognosis. We conducted a longitudinal prospective study analyzing the long‐term developmental outcome of a consecutive series of 39 children with PRS who had an a priori good prognosis (isolated PRS or PRS associated with a Stickler syndrome) but severe neonatal disorders (respiratory and feeding difficulties). Psychomotor and cognitive levels, speech, and eating behavior were assessed at 15 months of age and 3 and 6 years of age; 24 of the oldest children were interviewed at age 11 or 12 years. Results were analyzed by diagnosis, extent of respiratory and feeding disorders, and treatment modalities. Cognitive scores were within normal ranges and increased over time, from 90.5 at 15 months of age to 109.1 at 6 years. The 24 oldest children were enrolled in the appropriate junior high school grade at the normal age. For children 15 months of age, language scores were below the average, as were scores for vocabulary at 3 years for half of the patients. At 6 years, childrens speech showed persistent rhinolalia, which was mild (47%), moderate (11%), or major (11%). At 15 months of age, 74% of the children had satisfactory eating behavior, and 15% had serious difficulties. At 3 and 6 years, 18% and 6% of the children, respectively, had eating problems. Treatment modalities had no significant effect on long‐term outcome. Global developmental quotient scores were lower but not significantly for children with an associated Stickler syndrome than those with isolated PRS. Children with isolated PRS showed good prognosis.

Progressive hearing loss associated with a unique cervical node due to a homozygous SLC29A3 mutation: a very mild phenotype.

In 2008, SLC29A3 has been implicated in a syndromic form of genodermatosis: H syndrome. The major features encountered in H syndrome are Hearing loss, Hyperglycaemia, Heart anomalies, Hypertrichosis, Hyperpigmentation, Hepatomegaly and Hypogonadism. More recently, SLC29A3 mutations have been described in families presenting syndromes associating generalized histiocytosis to systemic progressive features: severe camptodactyly, hearing loss, hypogonadism, hepatomegaly, heart defects and skin hyperpigmentation. We have identified a homozygous missense SLC29A3 mutation in a patient presenting with only a progressive sensorineural hearing impairment and a single cervical node (Rosai Dorfman). SLC29A3 mutations appear to be involved in a large phenotypic continuum which should prompt physicians to study this gene even in mild clinical presentations.