Neck Point-of-Care Ultrasound for the Identification of Tongue-Base Cysts in Infants With Stridor: A Case Series.

ABSTRACT: Tongue-base cysts, which are occasionally categorized as vallecular cysts, are a rare yet potentially life-threatening cause of stridor in pediatric patients. Studies reporting the use of point-of-care ultrasound (POCUS) to identify tongue-base cysts are lacking. We present the case series of four infants in whom tongue-base cysts were detected using neck POCUS.

Can the effectiveness of tonsillectomy for PFAPA syndrome be predicted based on clinical factors.

OBJECTIVES: To evaluate the clinical factors associated with the outcome of tonsillectomy in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, thereby clarifying who would most likely benefit from that surgery. METHODS: This was a case-control study of 53 PFAPA patients who underwent tonsillectomy and were divided into a complete-resolution group and a postoperative-fever group. Logistic regression analyses were performed using 17 clinical factors as variables to identify factors associated with the surgical outcome. Hierarchical cluster analysis was also performed to evaluate for relationships between phenotypes and surgical outcomes. RESULTS: Thirty-nine (73.6%) patients had complete resolution after tonsillectomy. In simple logistic regression analysis, the surgical outcome showed significant positive trends with late-onset (odds ratio [OR] 7.1, P = 0.02) and presence of headache (OR 6.5, P = 0.01). In stepwise multiple logistic regression analysis adjusted for age at onset, presence of headache was significantly associated with complete resolution (OR 6.5, P = 0.01). The complete resolution rates for each combination of headache status and age at onset were as follows: presence of headache/age at onset ≥36 months, 100% (14/14); presence of headache/age at onset <36 months, 76.9% (10/13); absence of headache/age at onset ≥36 months, 75.0% (6/8); and absence of headache/age at onset <36 months, 43.8% (7/16). In hierarchical cluster analysis, complete resolution, age at onset, and headache were in the same cluster. CONCLUSIONS: PFAPA patients with headache and late onset responded well to tonsillectomy. The mechanisms underlying this association may warrant further investigation.

Phenotype-genotype correlation in patients with typical and atypical branchio-oto-renal syndrome.

Some patients have an atypical form of branchio-oto-renal (BOR) syndrome, which does not satisfy the diagnostic criteria, despite carrying a pathogenic variant (P variant) or a likely pathogenic variant (LP variant) of a causative gene. P/LP variants phenotypic indices have yet to be determined in patients with typical and atypical BOR syndrome. We hypothesized that determining phenotypic and genetic differences between patients with typical and atypical BOR syndrome could inform such indices. Subjects were selected from among patients who underwent genetic testing to identify the cause of hearing loss. Patients were considered atypical when they had two major BOR diagnostic criteria, or two major criteria and one minor criterion; 22 typical and 16 atypical patients from 35 families were included. Genetic analysis of EYA1, SIX1, and SIX5 was conducted by direct sequencing and multiplex ligation-dependent probe amplification. EYA1 P/LP variants were detected in 25% and 86% of atypical and typical patients, respectively. Four EYA1 P/LP variants were novel. Branchial anomaly, inner ear anomaly, and mixed hearing loss were correlated with P/LP variants. Development of refined diagnostic criteria and phenotypic indices for atypical BOR syndrome will assist in effective detection of patients with P/LP variants among those with suspected BOR syndrome.

The Incidence of Sleep Disordered Breathing One Week After Primary Palatoplasty: Evaluation With Overnight Pulse Oximetry.

BACKGROUND: Sleep disordered breathing (SDB) is defined as a series of disorders including snoring, obstructive sleep apnea, and hypopnea. Few studies investigated the incidence of SDB following primary palatoplasty with objective testing. The aims of this study were to elucidate the prevalence and degree of SDB approximately 1 week following primary palatoplasty with objective testing and to clarify the risk factors. METHOD: A retrospective review was performed on children who underwent primary palatoplasty between April 2013 and July 2017 at National Center for Child Health and Development, Tokyo, Japan. As a national center, the authors accept many syndromic patients. The authors keep all patients after palatoplasty intubated and observe them overnight in intensive care unit to reduce the risks of respiratory events. Patients were evaluated with overnight pulse oximetry on 5 to 7 days postoperatively. RESULTS: Forty-four patients were included, and 30% of the patients were associated with congenital anomaly. Thirteen patients (30%) were diagnosed with SDB. None of the patients required additional treatment after the evaluation. Laryngomalacia and postoperative oxygen requirement significantly correlated with postoperative SDB. CONCLUSION: Approximately one-third of the patients may be at the risk of SDB 1 week after primary palatoplasty. Patients with history of laryngomalacia or those who required oxygen support for prolonged time after primary palatoplasty should be cared for significantly high risk of postoperative SDB.

[Tonsillectomy in Cases with Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome].

The periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an autoinflammatory disease, characterized, as its name suggests, by periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis. This syndrome is the most common cause of recurrent fever in children, however the rate of recognition of this syndrome is still low. Tonsillectomy has been suggested as an effective treatment, even though the precise, pathophysiology underlying this syndrome remains unknown. In this study, we investigated the outcomes in patients who underwent tonsillectomy. In particular, we examined the surgical outcomes and clinical features of the patients who underwent tonsillectomy. A total of 19 patients with PFAPA syndrome underwent tonsillectomy at our hospital from July 2013 to May 2016. Before the surgery, while all the patients had received medications, none showed complete resolution of the syndromes. However, of the 19 patients, 15 showed complete resolution of the syndrome immediately after the surgery. Four patients had fever even after the surgery. Three patients showed partial remission, with the frequency and duration of the episodes decreasing after the surgery. However, in one patient, the fever persisted as before the surgery. There were no significant differences in the clinical characteristics, such as the age at onset, fever episodes, associated symptoms, or age at surgery among the three groups. However, we observed a trend towards a higher frequency of a family history in patients with persistent symptoms after surgery. Tonsillectomy was highly effective against PFAPA syndrome, however, some patients failed to respond to the procedure. Therefore, it is important to carefully evaluate the risks and benefits in each case. The indications for tonsillectomy have not yet been clearly established. It is essential to continue further investigations to establish effective therapeutic strategies for this syndrome.

Anti-stress effects of ONO-2952, a novel translocator protein 18 kDa antagonist, in rats.

Accumulating evidence has shown the pathophysiological significance of the translocator protein 18 kDa (TSPO) in the central nervous system. In this study, we evaluated the beneficial effects of ONO-2952, a novel TSPO antagonist in rat stress models. ONO-2952 potently bound both rat and human TSPO (Ki=0.330-9.30 nmol/L) with high selectivity over other receptors, transporters, ion channels and enzymes. ONO-2952 inhibited both neurosteroid accumulation and noradrenaline release in the brain of rats exposed to acute stress. The inhibitory effect of ONO-2952 on stress-induced noradrenaline release was attenuated by co-treatment with the TSPO agonist CB34 in a dose-dependent manner. ONO-2952, at 0.3 mg/kg or higher, dose-dependently suppressed restraint stress-induced defecation in rats with brain TSPO occupancy of more than 50%. In addition, ONO-2952, at 1 mg/kg or higher, suppressed conditioned fear stress-induced freezing behavior in rats with an efficacy equivalent to that of diazepam, given orally at 3 mg/kg. Results of the passive avoidance learning test revealed that ONO-2952, unlike diazepam, did not affect learning and memory even at doses 10 times higher than its effective doses in the stress models. The present findings indicate that ONO-2952 is a promising candidate for the treatment of stress-related disorders.

Cricopharyngeal achalasia treated with myectomy and post-operative high-resolution manometry.

Cricopharyngeal achalasia is an uncommon cause of dysphagia in neonates or children. A nine-year-old female patient was referred to us with a long history of dysphagia, recurrent pulmonary infection and growth stunting. A gastrostomy was introduced to improve her nutritional condition and to minimize potential inflammation in the pharynx. Subsequently, cervical cricopharyngeal myectomy was conducted. The surgical intervention allowed prompt resolution of symptoms without complications. High-resolution manometry post myectomy demonstrated a significant reduction in upper esophageal pressure together with proper relaxation at deglutition. The patient was able to consume solid food and liquid normally, and remained asymptomatic without medications six months after the surgery.

CT and endoscopic evaluation of larynx and trachea in mucopolysaccharidoses.

BACKGROUND: Mucopolysaccharidoses (MPSs) are lysosomal storage disorders caused by lysosomal enzyme deficiencies that result in systemic accumulation of glycosaminoglycans (GAGs). Accumulation of GAGs in the upper airway can lead to respiratory failure. The aim of this study was to investigate changes of the airway by flexible endoscopy and CT. METHODS: Thirty-five patients aging from 2 to 16 years (mean: 9.2±4.4 years) participated in this study. The majority had MPS I (n=5) or MPS II (n=25). The shape of the trachea and the cross-sectional trachea surface area (TSA) was determined at the Th1 and Th2 levels. Airway obstruction was evaluated from endoscopic findings and classified into 3 grades (Grades 0, 1, and 2). Forty-five patients in the control group who underwent tracheal CT for other conditions were retrospectively selected from the database. RESULTS: Tracheal morphology was abnormal in 50-60%, which showed a transversely collapsing narrow trachea. Tracheal deformity was severe in MPS II and MPS IV. The mean TSA of the MPS patients was 55.5±29.0 mm(2) at Th1 and 61.4±29.0 mm(2) at Th2, while that of the control group was 90.1±41.9 mm(2) and 87.9±39.3 mm(2), respectively. Respiratory distress was noted in 15 of the 35 patients, among whom 7 patients showed tracheal deformity and 7 patients had laryngeal redundancy. Three patients had no abnormalities of the larynx or trachea, so other factors such as pharyngeal stenosis or lower airway stenosis might have contributed to their respiratory distress. CONCLUSION: CT and flexible endoscopy allow quantitative and morphological evaluation of airway narrowing, which is beneficial for airway management in MPS children.

Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients: a cross-sectional, multi-center next-generation sequencing study.

BACKGROUND: Genetic tests for hereditary hearing loss inform clinical management of patients and can provide the first step in the development of therapeutics. However, comprehensive genetic tests for deafness genes by Sanger sequencing is extremely expensive and time-consuming. Next-generation sequencing (NGS) technology is advantageous for genetic diagnosis of heterogeneous diseases that involve numerous causative genes. METHODS: Genomic DNA samples from 58 subjects with hearing loss from 15 unrelated Japanese families were subjected to NGS to identify the genetic causes of hearing loss. Subjects did not have pathogenic GJB2 mutations (the gene most often associated with inherited hearing loss), mitochondrial m.1555A>G or 3243A>G mutations, enlarged vestibular aqueduct, or auditory neuropathy. Clinical features of subjects were obtained from medical records. Genomic DNA was subjected to a custom-designed SureSelect Target Enrichment System to capture coding exons and proximal flanking intronic sequences of 84 genes responsible for nonsyndromic or syndromic hearing loss, and DNA was sequenced by Illumina GAIIx (paired-end read). The sequences were mapped and quality-checked using the programs BWA, Novoalign, Picard, and GATK, and analyzed by Avadis NGS. RESULTS: Candidate genes were identified in 7 of the 15 families. These genes were ACTG1, DFNA5, POU4F3, SLC26A5, SIX1, MYO7A, CDH23, PCDH15, and USH2A, suggesting that a variety of genes underlie early-childhood hearing loss in Japanese patients. Mutations in Usher syndrome-related genes were detected in three families, including one double heterozygous mutation of CDH23 and PCDH15. CONCLUSION: Targeted NGS analysis revealed a diverse spectrum of rare deafness genes in Japanese subjects and underscores implications for efficient genetic testing.

GJB2-associated hearing loss undetected by hearing screening of newborns.

The hearing loss caused by GJB2 mutations is usually congenital in onset, moderate to profound in degree, and non-progressive. The objective of this study was to study genotype/phenotype correlations and to document 14 children with biallelic GJB2 mutations who passed newborn hearing screening (NHS). Genetic testing for GJB2 mutations by direct sequencing was performed on 924 individuals (810 families) with hearing loss, and 204 patients (175 families) were found to carry biallelic GJB2 mutations. NHS results were obtained through medical records. A total of 18 pathological mutations were identified, which were subclassified as eight inactivating and 10 non-inactivating mutations. p.I128M and p.H73Y were identified as novel missense GJB2 mutations. Of the 14 children with biallelic GJB2 mutations who passed NHS, eight were compound heterozygotes and 3 were homozygous for the c.235delC mutation in GJB2, and the other three combinations of non-c.235delC mutations identified were p.Y136X-p.G45E/p.V37I heterozygous, c.512ins4/p.R143W heterozygous, and p.V37I/p.R143W heterozygous. These 14 cases demonstrate that the current NHS does not identify all infants with biallelic GJB2 mutations. They suggest that the frequency of non-penetrance at birth is approximately 6.9% or higher in DFNB1 patients and provide further evidence that GJB2 hearing loss may not always be congenital in onset.

Gorham-Stout syndrome affecting the temporal bone with cerebrospinal fluid leakage.

Gorham-Stout syndrome is a rare disorder characterized by progressive osteolysis that leads to the disappearance of bone. Lymphvascular proliferation causes the local destruction of bony tissue. Owing to the low incidence of this syndrome, little is known about its etiology or treatment. We present an 11-year-old girl with Gorham-Stout syndrome that involved right petrous apex in temporal bone and upper clivus, which cause intracranial pressure increase and cerebrospinal fluid (CSF) leakage. The patient required surgical repair of CSF leakage by extradural middle fossa approach with temporal fascia flap. Combined treatment with interferon and propranolol prevented the progression of osteolysis.

Langerhans cell histiocytosis with disequilibrium.

Langerhans cell histiocytosis (LCH) is a very rare disease in which granulation tissue forms in various organs and the central nervous system (CNS) due to monoclonal proliferation of Langerhans cells. Some patients develop ataxia, tremor, or neurodegenerative abnormalities (such as personality changes and mental deterioration) several years after the onset as the late effects of LCH. We report a case of a 4-year-old boy with LCH, showing speech disorder, truncal ataxia and a wide-based gait with abnormal findings of central nervous system in CT and MRI image. The results of auditory brain stem response revealed a conduction block in the auditory conduction pathway, suggesting an axonopathy of the brain stem. Disequilibrium may be due to brainstem dysfunction associated with paraneoplastic syndrome because an anti-GluRε2 antibody was seen. Paraneoplastic syndrome is a neuropathy induced through an autoimmune mechanism caused by an antibody directed against the nervous system. Neuro-otological examination is helpful for the assessment of CNS neurodegeneration associated with LCH.

Myocardial apoptosis associated with the expression of proinflammatory cytokines during the course of myocardial infarction.

To clarify the role of myocardial apoptosis associated with the expression of proinflammatory cytokines in human myocardial infarction (MI), we have analyzed the expression of apoptosis positive for single-stranded DNA (ss-DNA) antibody, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-8 in 147 samples of infarcted myocardial tissue from 65 patients. ss-DNA-positive apoptotic nuclei were found mainly in cardiomyocytes in the border zones and granulation tissue cells in the infarct foci. The ss-DNA index (SI) of cardiomyocytes (average 0.13%) peaked at stage II (established myocardial necrosis), the value being significantly higher than at stages III (macrophage infiltration), IV (granulation formation), and V (scar formation) (P<0.05), whereas the SI of granulation tissue (average 0.08%) at stages III, IV, and V showed no significant differences between the three stages. These results suggest that cardiomyocyte apoptosis in the border zone is responsible for cellular loss in the acute stage of MI, whereas granulation tissue apoptosis may not be involved in the process of ventricular remodeling. TNF-alpha was expressed in cardiomyocytes in the border zones of infarct foci, but no significant positive correlation was found between SI and TNF-alpha index in cardiomyocytes (r=0.08, P = 0.37), suggesting that TNF-alpha does not serve as a direct trigger of cardiomyocyte apoptosis in vivo. The number of IL-8-positive cells peaked at stage II, and IL-8-myeloperoxidase-double-positive neutrophils were frequently detected, indicating that infiltrating neutrophils are the predominant source of IL-8 in the infarcted myocardium. These results suggest that, in human MI, TNF-alpha produced by cardiomyocytes does not play a critical role in their apoptosis, and that IL-8 produced by neutrophils is responsible for the subsequent accumulation and activation of neutrophils, thus increasing the degree of myocardial damage.

[Congenital laryngeal stridor].

We reviewed the diagnosis, complications and treatment of congenital laryngeal stridor (CLS), in 97 patients who consulted our clinic between 1991 and 2001. The 97 patients were diagnosed with laryngeal malacia (32%), vocal cord paralysis and laryngeal stenosis (22%), a neoplastic disease like hemagioma and papilloma (11%), or cystic disease (7%). The cases with vocal cord paralysis, laryngeal stenosis or laryngeal cysts were usually diagnosed within 2 months of birth based on severe dyspnea. Two of the 31 cases of laryngeal malacia and 2 of the 22 cases of vocal cord paralysis were associated with neuromuscular disorders. Three patients suffered from vocal cord paralysis complicated by laryngeal stenosis. Thirty-three of the 97 cases required a tracheostomy; these 33 cases included the one case of laryngeal papilloma (100%), 9 of the 10 cases of hemangioma (90%), and 18 of the 24 cases of laryngeal stenosis (75%). Since any disorders of the upper airway can potentially induce stridor, establishing an accurate diagnosis is sometimes difficult when stridor is the only presenting symptom. Hence, information on associated symptoms and the past history of the subject is particularly important for an accurate diagnosis. In addition, decisions regarding the course of treatment course require adequate consideration of possible complications.

Mondini dysplasia and recurrent bacterial meningitis in a girl with relapsing Langerhans cell histiocytosis.

We report a case of a girl with Langerhans cell histiocytosis (LCH) of multifocal bone disease, who developed recurrent bacterial meningitis and unilateral sensorineural hearing loss during the relapsing course of the disease. Mondini dysplasia, a congenital inner ear anomaly, was suspected by high resolution computed tomographic scan and the dysplasia with cerebrospinal fluid leakage was confirmed by surgery in the ipsilateral ear showing hearing loss. Although rare, congenital inner ear anomalies such as Mondini dysplasia should be kept in mind in pediatric patients with hearing impairment and/or recurrent bacterial meningitis during chemotherapy for various types of neoplasms including LCH.