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 in vitro and in vivo 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.

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, ß 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.

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, children's 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.

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

BACKGROUND: Cystic 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. METHODS: A 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. RESULTS: After 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. CONCLUSION: Suppression 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.

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.

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

OBJECTIVE: To evaluate the sensitivity of multidetector computed tomography for confirming suspected foreign body aspiration into the airways in children. METHOD: We 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. RESULTS: Foreign 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%. CONCLUSION: Multidetector 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.

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.

Pathogens implicated in acute otitis media failures after 7-valent pneumococcal conjugate vaccine implementation in France: distribution, serotypes, and resistance levels.

BACKGROUND: Before 7-valent pneumococcal conjugate vaccine (PCV7) implementation in France, several studies had described the microbiology of acute otitis media (AOM) treatment failures. The causative pathogens were Streptococcus pneumoniae (Sp) followed by nontypable Haemophilus influenzae (NTHi). The aim of this study was to describe the epidemiology of pathogens involved in AOM treatment failures or recurrences. METHODS: This French multicentric prospective study enrolled 143 children with AOM treatment failure between 2007 and 2009 observed by 8 ear, nose, and throat specialists. Failure was defined as the persistence of AOM symptoms after at least 48 hours of antibiotic therapy or their recurrence within 4 days after the end of treatment. Standardized history and physical examination findings were recorded, and culture of middle ear fluid (MEF) was obtained. RESULTS: Mean age was 16.9 ± 9.9 months (median, 13.7). Eighty-eight percent of children had received more than 1 dose of PCV7, and 70.6% attended day care. The most common antibiotic used at the time of treatment failure or recurrence was a combination of amoxicillin and clavulanate (51.1%). Bacteriologic sampling demonstrated that in 35% of cases (n=50), no otopathogen was cultured at the time of treatment failure or recurrence. Similar proportions of Sp and NTHi were observed in the 86 patients (60.1%) from whom only a single species was recovered from MEF (46.5% for Sp, n=40 and 45.3% for NTHi, n=39). Among Sp strains, 4.4% were penicillin susceptible, 77.8% were penicillin intermediate, and 17.8% were fully penicillin resistant, and serotype 19A represented 84.5% of all serotypes detected. Among NTHi isolates, 15.5% (n=7) were ß-lactamase-producing strains (including 2 strains with only this mechanism of resistance), and strains with reduced susceptibility by changes in protein binding to penicillin (ß-lactamase-negative ampicillin resistant strains) represented 35.5% of cases. Among the 50 sterile MEF samples, polymerase chain reaction was performed in 32, of which 4 were positive for HI, 3 for Sp, and 3 for both. CONCLUSIONS: Among children with AOM treatment failures in France, Sp and NTHi were equally distributed; 19A was the main Sp serotype, and the main resistance mechanism for NTHi was ß-lactamase-negative ampicillin resistance.