Practical guide for the diagnosis and management of primary ciliary dyskinesia.

OBJECTIVE: Primary ciliary dyskinesia (PCD) is a relatively rare genetic disorder that affects approximately 1 in 20,000 people. Approximately 50 genes are currently known to cause PCD. In light of differences in causative genes and the medical system in Japan compared with other countries, a practical guide was needed for the diagnosis and management of Japanese PCD patients. METHODS: An ad hoc academic committee was organized under the Japanese Rhinologic Society to produce a practical guide, with participation by committee members from several academic societies in Japan. The practical guide including diagnostic criteria for PCD was approved by the Japanese Rhinologic Society, Japanese Society of Otolaryngology-Head and Neck Surgery, Japanese Respiratory Society, and Japanese Society of Pediatric Pulmonology. RESULTS: The diagnostic criteria for PCD consist of six clinical features, six laboratory findings, differential diagnosis, and genetic testing. The diagnosis of PCD is categorized as definite, probable, or possible PCD based on a combination of the four items above. Diagnosis of definite PCD requires exclusion of cystic fibrosis and primary immunodeficiency, at least one of the six clinical features, and a positive result for at least one of the following: (1) Class 1 defect on electron microscopy of cilia, (2) pathogenic or likely pathogenic variants in a PCD-related gene, or (3) impairment of ciliary motility that can be repaired by correcting the causative gene variants in iPS cells established from the patient's peripheral blood cells. CONCLUSION: This practical guide provides clinicians with useful information for the diagnosis and management of PCD in Japan.

Pediatric allergies in Japan: Coronavirus disease pandemic-related risk factors.

Background: The coronavirus disease 2019 (COVID-19) pandemic impacted various parts of society, including Japanese children with allergies. Objective: This study investigated risk factors for pediatric allergic diseases associated with the state of emergency owing to the COVID-19 pandemic in Japan, including during school closures. Methods: Parents of pediatric patients (0-15 years) with allergies were enrolled and queried regarding the impact of school closure on pediatric allergies compared to that before the COVID-19 pandemic. Results: A valid response was obtained from 2302 parents; 1740 of them had children with food allergies. Approximately 4% (62/1740) of the parents reported accidental food allergen ingestion was increased compared to that before the COVID-19 pandemic. Accidental ingestion during school closures was associated with increased contact with meals containing allergens meant for siblings or other members of the family at home. The exacerbation rate during the pandemic was highest for atopic dermatitis at 13% (127/976), followed by allergic rhinitis at 8% (58/697), and bronchial asthma at 4% (27/757). The main risk factors for worsening atopic dermatitis, allergic rhinitis, and bronchial asthma were contact dermatitis of the mask area (34/120 total comments); home allergens, such as mites, dogs, and cats (15/51 total comments); and seasonal changes (6/25 total comments), respectively. Conclusion: The main factors affecting allergic diseases were likely related to increased time at home, preventive measures against COVID-19, and refraining from doctor visits. Children with allergies were affected by changes in social conditions; however, some factors, such as preventing accidental ingestion and the management of allergens at home, were similar to those before the COVID-19 pandemic. Patients who had received instructions on allergen avoidance at home before the pandemic were able to manage their disease better even when their social conditions changed.

Development of an Oral Immunotherapy-Related Parental Burden Scale.

INTRODUCTION: Oral immunotherapy (OIT) imposes a burden on parents and their children with food allergies (FAs). We already developed a questionnaire for OIT-related Parental Burden (OIT-PB) scale. However, the previous questionnaire had some problems. This study modified OIT-PB and verified its reliability and validity. METHODS: A 20-item draft covering the physical and mental burdens caused by OIT was prepared jointly with multiple allergists. The Food Allergy Quality of Life Questionnaire-Parental Burden (FAQLQ-PB) and Stress Response Scale-18 (SRS-18) were used to verify concurrent validity. A questionnaire survey was administered during treatment to parents of FA children who had started OIT for the first time. An additional OIT-PB survey was performed at one specific institution 1 week after the posttreatment survey. RESULTS: The responses of 64 of the 76 recruited parents were analyzed. Of the 20 questions, 1 item was excluded owing to the floor effect, 1 was excluded because its commonality was less than 0.2, and 2 were excluded because their factor loading values were less than 0.4. Factor analysis was used to classify the OIT-PB into the following 4 subscales: "burden caused by adherence to treatment plan," "anxiety about symptom-induced risk," "burden due to patient's eating behavior," and "anxiety about treatment effect." The Cronbach's α for all 16 items of the OIT-PB was 0.893; Cronbach's α for each subscale was 0.876, 0.898, 0.874, and 0.717. The re-test reliability coefficient was 0.864 (95% confidence interval [CI]: 0.720-0.937, p < 0.001). A significant positive correlation was found between the OIT-PB and FAQLQ-PB (R = 0.610 [95% CI: 0.422-0.747], p < 0.001) and the SRS-18 (R = 0.522 [95% CI: 0.306-0.687], p < 0.001). A significant negative correlation was found between the rate of increase in OIT food intake and the "anxiety about treatment effect" score (R = -0.355 [95% CI: -0.558-0.112], p < 0.001). Parents of children on the hen's egg OIT treatment scored higher on the "burden due to patient's eating behavior" subscale than did parents of children on the milk and wheat OIT treatment. CONCLUSION: The burden of OIT experienced by parents can be broadly classified into four categories. The modified OIT-PB was able to evaluate them individually and was shown to have reliability and validity. This scale is expected to be useful in the development of OIT that considers not only therapeutic effect but also the burden experienced by FA children and their parents.

Parents' Fears about Hospital Visits and Trait Anxiety in the COVID-19 Pandemic.

Anxiety in parents of children with allergic diseases during the COVID-19 pandemic may impact hospital visits. This study explored the effect of the pandemic on parents' fears about hospital visits and their relationship with their personality traits. A cross-sectional, questionnaire-based study was conducted between September 2020 and March 2021, with parents of children aged 0-15 years, who regularly visited 24 outpatient facilities for allergic disease. The survey included patient information, fears about hospital visits, desired information, and the State-Trait Anxiety Inventory. Responses were compared between parents with high and low trait anxiety. The response rate was 97.6% (2439/2500). The most common fear was "Fear of getting medical care as usual (85.2%)" and "Fear of COVID-19 infection during hospital visits (87.1%)". High trait anxiety showed a significant association with "Fear of worsening of children's allergies" (adjusted OR: 1.31, 95%CI: 1.04 to 1.65, p = 0.022), and "Fear of worsening of COVID-19 due to allergy" (adjusted OR: 1.52, 95%CI: 1.27 to 1.80, p < 0.01). Healthcare professionals should share updates on COVID-19 and healthcare system to reduce parents' fear. Subsequently, they should communicate the importance of continuing treatment to prevent worsening of COVID-19 and avoid emergency visits, considering parental trait anxiety.

Clinical practice guidelines for the diagnosis and management of otitis media with effusion (OME) in children in Japan - 2022 update.

This is an update of the 2015 Guidelines developed by the Japan Otological Society and Oto-Rhino-Laryngeal Society of Japan defining otitis media with effusion (OME) in children (younger than 12 years old) and describing the disease rate, diagnosis, and method of examination. Recommended therapies that received consensus from the guideline committee were updated in consideration of current therapies used in Japan and based on available evidence. METHOD: Regarding the treatment of OME in children, we developed Clinical Questions (CQs) and retrieved documents on each theme, including the definition, disease state, method of diagnosis, and medical treatment. In the previous guidelines, no retrieval expression was used to designate a period of time for literature retrieval. Conversely, a literature search of publications from March 2014 to May 2019 has been added to the JOS 2015 Guidelines. For publication of the CQs, we developed and assigned strengths to recommendations based on the collected evidence. RESULTS: OME in children was classified into one group lacking the risk of developing chronic or intractable disease and another group at higher risk (e.g., children with Down syndrome, cleft palate), and recommendations for clinical management, including follow-up, is provided. Information regarding management of children with unilateral OME and intractable cases complicated by adhesive otitis media is also provided. CONCLUSION: In clinical management of OME in children, the Japanese Clinical Practice Guidelines recommends management not only of complications of OME itself, such as effusion in the middle ear and pathologic changes in the tympanic membrane, but also pathologic changes in surrounding organs associated with infectious or inflammatory diseases.

Pharmacotherapy focusing on for the management of otitis media with effusion in children: Systematic review and meta-analysis.

OBJECTIVE: To examine the evidence for treating children with otitis media with effusion with pharmacotherapy. DATA SOURCES: For the systematic review, data were retrieved from PubMed, Cochrane database, and the Japan Medical Abstracts Society Database (1st January 1995 through 31th May 2019). STUDY SELECTION: Articles addressing pharmacotherapy for the management of otitis media with effusion in children were selected in English. DATA EXTRACTION: The database was searched using the keywords "Otitis Media with effusion or secretory otitis media" and the following medical agents: carbocysteine, antihistamines, leukotriene receptor antagonist, and steroid nasal spray. DATA SYNTHESIS: After a critical review of 18 studies, studies addressing steroid nasal spray were eligible for quantitative synthesis. Intranasal steroids for OME showed no benefit with OR 1.155 (95% CI 0.834-1.598) within one month. Conversely, intranasal steroids have effects for OME with OR 1.858 (95% CI 1.240-2.786) for more than one month. CONCLUSIONS: We found evidence of benefit from treatment of OME in children with intranasal steroids and S-carboxymethylcysteine at longer-term follow-up.

Whole exome analysis of patients in Japan with hearing loss reveals high heterogeneity among responsible and novel candidate genes.

BACKGROUND: Heterogeneous genetic loci contribute to hereditary hearing loss; more than 100 deafness genes have been identified, and the number is increasing. To detect pathogenic variants in multiple deafness genes, in addition to novel candidate genes associated with hearing loss, whole exome sequencing (WES), followed by analysis prioritizing genes categorized in four tiers, were applied. RESULTS: Trios from families with non-syndromic or syndromic hearing loss (n = 72) were subjected to WES. After segregation analysis and interpretation according to American College of Medical Genetics and Genomics guidelines, candidate pathogenic variants in 11 previously reported deafness genes (STRC, MYO15A, CDH23, PDZD7, PTPN11, SOX10, EYA1, MYO6, OTOF, OTOG, and ZNF335) were identified in 21 families. Discrepancy between pedigree inheritance and genetic inheritance was present in one family. In addition, eight genes (SLC12A2, BAIAP2L2, HKDC1, SVEP1, CACNG1, GTPBP4, PCNX2, and TBC1D8) were screened as single candidate genes in 10 families. CONCLUSIONS: Our findings demonstrate that four-tier assessment of WES data is efficient and can detect novel candidate genes associated with hearing loss, in addition to pathogenic variants of known deafness genes.

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.

Clinical and genetic analysis of children with hearing loss and bilateral enlarged vestibular aqueducts.

OBJECTIVES: To evaluate the clinical and genetic features of children with hearing loss associated with one of the most common malformations of the inner ear: bilateral enlargement of vestibular aqueducts (EVA). METHODS: Clinical and genetic features were investigated in 28 children with hearing loss diagnosed with bilateral EVA by computed tomography from January 2008 to September 2019. RESULTS: Fourteen subjects had undergone newborn hearing screening (NHS). Nine subjects (64.3%) were referred in both ears, 4 subjects (28.6%) were referred in one ear, and one subject (7.1%) passed in both ears. Nineteen of 26 subjects (73.1%) who were followed for more than 3 years had hearing fluctuations, while 17 (65.4%) had hearing loss progression. Eleven of 28 subjects (39.2%) had vertigo attacks. Pathogenic variants were identified in two alleles of the SLC26A4 gene in 24 of 27 subjects (88.9%) by sequencing of all exons and flanking introns, leading to genetic diagnosis of Pendred syndrome/DFNB4. Our results indicate that genetic screening for specific SLC26A4 variants using a commercial clinical laboratory test in Japan would have achieved genetic diagnoses in 13 of the 27 subjects (54.2%). Although there was no statistically significance in the frequency of hearing fluctuation or progression depending on the presence or absence of the gene variant, mean hearing level was severe in subjects with two pathogenic variants in SLC26A4 gene. The most common variant detected in our subjects was p.His723Arg (13 alleles, 27.1%), followed by c. 919-2A > G (four alleles, 8.3%). Two novel variants were detected in this study: c.1544+1G > T and c.1614+5G > A. CONCLUSIONS: Our data suggest that some subjects may present with bilateral EVA that cannot be detected by NHS. We estimated that genetic diagnosis for SLC264 gene would not have been made in almost half subjects with the commercial genetic screening approach used in the present study in Japan. Although there were some limitations in this study, the subjects with pathogenic variants in two alleles of the SLC26A4 gene could have more severe hearing loss.

A High Risk of Missing Congenital Cytomegalovirus-Associated Hearing Loss through Newborn Hearing Screening in Japan.

It remains unclear to what extent newborn hearing screening (NHS) detects congenital cytomegalovirus (cCMV)-associated sensorineural hearing loss (SNHL) in Japan. This study aimed to clarify the NHS results and audiological characteristics of patients with cCMV-associated SNHL. A total of 541 individuals with unilateral or bilateral hearing loss of unknown etiology were examined for cCMV infection. cCMV infection was defined by the presence of CMV DNA in the dried umbilical cord detected using real-time quantitative PCR. NHS results and audiological data were retrospectively obtained from medical records. Forty-four cases (8.1%) were positive for cCMV infection. Of them, 33 cases underwent NHS and 13 cases (39.4%) passed NHS bilaterally. The pure-tone audiograms of 21 patients were obtained. There were seven cases of unilateral SNHL, five cases of asymmetric bilateral SNHL, and nine cases of symmetric bilateral SNHL. cCMV-related hearing loss is highly heterogeneous, and there is a high risk of missing this condition through NHS.

Progress of Home-Based Food Allergy Treatment during the Coronavirus Disease Pandemic in Japan: A Cross-Sectional Multicenter Survey.

The coronavirus disease 2019 (COVID-19) pandemic's impact on food allergy treatment such as home-based oral immunotherapy (OIT) is not known. This cross-sectional, questionnaire-based anonymized survey screened 2500 parents of children with allergic diseases and was conducted in the pediatric outpatient clinics of 24 hospitals. Basic clinical data of the children were collected along with the degree of allergy control, parental anxiety about emergency visits, and the risk of COVID-19 in the first state of emergency. A total of 2439 (97.6%) questionnaires were collected, and 1315 parents who were instructed to initiate home-based OIT for their children were enrolled (OIT group). Subjective OIT progress compared to before the COVID-19 pandemic was ascertained as "Full", "Middle", "Low", "Little", and "Stop" in 264 (20.1%), 408 (31.0%), 384 (29.2%), 203 (15.4%), and 56 (4.3%) participants, respectively. Anxiety about emergency visits and the risk of COVID-19 were negatively associated with the subjective OIT progress. In Japan, approximately half of the children continued smoothly the home-based OIT during the COVID-19 pandemic. Parents with high levels of anxiety about the disruption of the medical care system due to COVID-19 and the risk of COVID-19 did not experience a smooth continuation of home-based OIT.

The influence of tonsillectomy on allergic diseases in pediatric patients.

BACKGROUND: The influence of tonsillectomy on allergic airway diseases is not well known. OBJECTIVES: In the present study, the influence of tonsillectomy on perennial allergic rhinitis (PAR) and bronchial asthma (BA) among pediatric subjects was prospectively investigated. METHODS: The tonsillectomy (surgery group) and the age-matched non-surgical subjects (control group) were examined and followed prospectively. In addition, immunological analysis was conducted. RESULTS: After in vitro allergen stimulation, the production of a small number of allergen-specific Th2 cells was induced in the tonsillar cells, even in sensitized subjects. Flow cytometry analysis detected more effector regulatory T cells (Tregs) in the tonsils than in peripheral blood. Clinically, after surgery, the PAR and BA symptoms improved in the surgery group but not in the control group. The total IgE in the surgery group was significantly lower than in the control group; after surgery, IgE levels slightly increased but remained lower. The postoperative Dermatophagoides farina (Der f)-specific IgE level increased in the sensitized subjects but not in the non-sensitized subjects. CONCLUSION: Tonsillectomy did not improve the underlying mechanisms of the allergy, however the decreased risk of infection and upper airway obstruction could lead to improved symptoms of allergic airway diseases.

Differences in hearing levels between siblings with hearing loss caused by GJB2 mutations.

OBJECTIVE: Hearing loss caused by GJB2 mutations is inherited in an autosomal recessive manner (DFNB1); thus siblings of an affected child have a 25% chance of also being affected. Hearing loss among subsequent siblings carrying the same GJB2 mutation is a concern for parents and a frequent topic of enquiry during genetic counseling. Evidence exists for genotype-phenotype correlations of GJB2 mutations; however, no analysis of differences in hearing among siblings, in whom the common genetic background may decrease variation, has been reported. The purpose of the present study was to investigate hearing differences between siblings with identical GJB2 mutations. METHODS: We examined the hearing levels of 12 pairs of siblings; each pair had the same pathogenic GJB2 mutations. Differences in hearing acuity between sibling pairs detected by auditory evaluation. RESULTS: No significant correlation was detected between the average hearing levels of first and second affected siblings. Average differences in acoustic threshold >30 dB were observed between four pairs of siblings, whereas the remaining eight pairs had average threshold values within 20 dB of one another. CONCLUSION: Our results indicate that auditory acuity would be expected to approximate that found in the first child in approximately 70% of subsequent children with GJB2-mediated hearing loss, whereas 30% of subsequent siblings would have average differences of >30 dB.

Deterioration in Distortion Product Otoacoustic Emissions in Auditory Neuropathy Patients With Distinct Clinical and Genetic Backgrounds.

OBJECTIVES: Auditory neuropathy (AN) is a clinical disorder characterized by the absence of auditory brainstem response and presence of otoacoustic emissions. A gradual loss of otoacoustic emissions has been reported for some cases of AN. Such cases could be diagnosed as cochlear hearing loss and lead to misunderstanding of the pathology when patients first visit clinics after the loss of otoacoustic emissions. The purpose of this study was to investigate the time course of changes in distortion product otoacoustic emissions (DPOAEs) in association with patients' genetic and clinical backgrounds, including the use of hearing aids. DESIGN: DPOAE measurements from 31 patients with AN were assessed. Genetic analyses for GJB2, OTOF, and mitochondrial m.1555A> G and m.3243A> G mutations were conducted for all cases, and the analyses for CDH23 and OPA1 were conducted for the selected cases. Patients who were younger than 10 years of age at the time of AN diagnosis were designated as the pediatric AN group (22 cases), and those who were 18 years of age or older were designated as the adult AN group (9 cases). DPOAE was measured at least twice in all patients. The response rate for DPOAEs was defined and analyzed. RESULTS: The pediatric AN group comprised 10 patients with OTOF mutations, 1 with GJB2 mutations, 1 with OPA1 mutation, and 10 with indefinite causes. Twelve ears (27%) showed no change in DPOAE, 20 ears (46%) showed a decrease in DPOAE, and 12 ears (27%) lost DPOAE. Loss of DPOAE occurred in one ear (2%) at 0 years of age and four ears (9%) at 1 year of age. The time courses of DPOAEs in patients with OTOF mutations were divided into those with early loss and those with no change, indicating that the mechanism for deterioration of DPOAEs includes not only the OTOF mutations but also other common modifier factors. Most, but not all, AN patients who used hearing aids showed deterioration of DPOAEs after the start of using hearing aids. A few AN patients also showed deterioration of DPOAEs before using hearing aids. The adult AN group comprised 2 patients with OPA1 mutations, 2 with OTOF mutations, and 5 with indefinite causes. Four ears (22%) showed no change in DPOAE, 13 ears (72%) showed a decrease, and one ear (6%) showed a loss of DPOAE. Although the ratio of DPOAE decrease was higher in the adult AN group than in the pediatric AN group, the ratio of DPOAE loss was lower in the adult AN group. DPOAE was not lost in all four ears with OPA1 mutations and in all four ears with OTOF mutations in the adult group. CONCLUSIONS: DPOAE was decreased or lost in approximately 70% of pediatric and about 80% of adult AN patients. Eleven percent of pediatric AN patients lost DPOAEs by 1 year of age. Genetic factors were thought to have influenced the time course of DPOAEs in the pediatric AN group. In most adult AN patients, DPOAE was rarely lost regardless of the genetic cause.

High-level heteroplasmy for the m.7445A>G mitochondrial DNA mutation can cause progressive sensorineural hearing loss in infancy.

OBJECTIVE: Hearing loss caused by mutation of mitochondrial DNA typically develops in late childhood or early adulthood, but rarely in infancy. We report the investigation of a patient to determine the cause of his early onset hearing loss. MATERIALS AND METHODS: The proband was a boy aged 1 year and 2 months at presentation. Newborn hearing screening test by automated auditory brainstem response generated "pass" results for both ears. His reaction to sound deteriorated by 9 months. Average pure tone threshold at 0.5, 1, and 2 kHz was 55 dB by conditioned orientation response audiometry. His father had congenital hearing loss, and his mother had progressive hearing loss since childhood. Invader assays and Sanger sequencing were performed to investigate genetic causes of the hearing loss in the proband, and heteroplasmy was assessed by PCR-restriction fragment length polymorphism, Sanger sequencing, and pyrosequencing. Additionally, mitochondrial function was evaluated by measurement of the oxygen consumption rate of patient skin fibroblasts. RESULTS: An m.7445A > G mitochondrial DNA mutation and a heterozygous c.235delC (p.L79Cfs*3) mutation of GJB2 were detected in the proband. His mother carried the m.7445A > G mitochondrial DNA mutation, and his father was a compound heterozygote for GJB2 mutations (c.[235delC]; [134G > A; 408C > A]). Tissue samples from both the proband and his mother exhibited a high degree of heteroplasmy. Fibroblasts from the proband exhibited markedly reduced oxygen consumption rates. These data indicate that the proband had impaired mitochondrial function, resulting in hearing loss. CONCLUSION: This research demonstrates that hearing loss in a proband who presented in infancy and that of his mother resulted from a high level of heteroplasmy for the m.7445A > G mitochondrial DNA mutation, indicating that this alteration can cause hearing loss in infancy.

Prevalence of TECTA mutation in patients with mid-frequency sensorineural hearing loss.

BACKGROUND: To date, 102 genes have been reported as responsible for non-syndromic hearing loss, some of which are associated with specific audiogram features. Four genes have been reported as causative for mid-frequency sensorineural hearing loss (MFSNHL), among which TECTA is the most frequently reported; however, the prevalence of TECTA mutations is unknown. To elucidate the prevalence of TECTA mutation in MFSNHL and clarify genotype-phenotype correlations, we analyzed the genetic and clinical features of patients with MFSNHL. METHODS: Subjects with bilateral non-syndromic hearing loss were prescreened for GJB2 and m.1555A > G and m.3243A > G mitochondrial DNA mutations, and patients with inner ear malformations were excluded. We selected MFSNHL patients whose audiograms met the U-shaped criterion proposed by the GENDEAF study group, along with those with shallow U-shaped audiograms, for TECTA analysis. All TECTA exons were analyzed by Sanger sequencing. Novel missense variants were classified as possibly pathogenic, non-pathogenic, and variants of uncertain significance, based on genetic data. To evaluate novel possibly pathogenic variants, we predicted changes in protein structure by molecular modeling. RESULTS: Pathogenic and possibly pathogenic variants of TECTA were found in 4 (6.0%) of 67 patients with MFSNHL. In patients with U-shaped audiograms, none (0%) of 21 had pathogenic or possibly pathogenic variants. In patients with shallow U-shaped audiograms, four (8.7%) of 46 had pathogenic or possibly pathogenic variants. Two novel possibly pathogenic variants were identified and two previously reported mutations were considered as variant of unknown significance. The clinical features of patients with pathogenic and possibly pathogenic variants were consistent with those in previous studies. Pathogenic or possibly pathogenic variants were identified in 3 of 23 families (13.0%) which have the family histories compatible with autosomal dominant and 1 of 44 families (2.3%) which have the family histories compatible with sporadic or autosomal recessive. CONCLUSIONS: TECTA mutations were identified in 6.0% of MFSNHL. These mutations were more frequent in patients with shallow U-shaped audiograms than those with U-shaped audiograms, and in families which have the family histories compatible with autosomal dominant than those with the family histories compatible with sporadic or autosomal recessive.

The Improvement of the Hepatic Histological Findings in a Patient with Non-alcoholic Steatohepatitis with Type 2 Diabetes after the Administration of the Sodium-glucose Cotransporter 2 Inhibitor Ipragliflozin.

The patient was a 67-year-old woman with type 2 diabetes and non-alcoholic steatohepatitis (NASH). The administration of the sodium-glucose cotransporter 2 (SGLT2) inhibitor, ipragliflozin improved her liver dysfunction clinically and histologically. The serum alanine aminotransferase (ALT) and ferritin levels decreased to normal limits after treatment for four months. Type IV collagen and hyaluronic acid, both of which were serum fibrotic markers, decreased after treatment. Ultrasonography and computed tomography showed a decrease in the fat deposits in her liver. Her liver sample showed marked improvement, especially in steatosis, inflammation, and ballooning. The SGLT2 inhibitor ipragliflozin may be useful as a specific therapeutic drug for NASH.

The first sporadic case of DFNA11 identified by next-generation sequencing.

We report the first sporadic case of nonsyndromic autosomal dominant hearing loss (DFNA11). The patient was a 5-year-old boy with moderate bilateral hearing loss. Targeted next-generation sequencing analysis of patient DNA identified a known heterozygous DFNA11 mutation, c.689C > T, in MYO7A, encoding p.Ala230Val. The mutation was not detected in the parents of the patient and is considered to be de novo. This mutation is identical to the one reported previously in an Italian family. Accumulation of mutation data increases the feasibility of identifying autosomal dominant mutations in sporadic sensorineural hearing loss.

Clinical practice guidelines for the diagnosis and management of otitis media with effusion (OME) in children in Japan, 2015.

OBJECTIVE: To (1) indicate the definition, the disease state, methods of diagnosis, and testing for otitis media with effusion (OME) in childhood (<12 years); and (2) recommend methods of treatment in accordance with the evidence-based consensus reached by the Subcommittee of Clinical Practice Guideline for Diagnosis and Management of OME in Children. METHODS: We produced Clinical Questions (CQs) concerning the treatment of OME and searched the literature published until April 2014 according to each theme including CQ, the definition, the disease state, the method of diagnosis, and examination. The recommendations are based on the results of the literature review and the expert opinion of the Subcommittee. RESULTS: Because children with Down's syndrome and cleft palate are susceptible to OME, we categorized OME into low-risk and high-risk groups (e.g., Down's syndrome and cleft palate), and recommended the appropriate treatment for each group. CONCLUSION: In the clinical management of OME in children, Japanese Clinical Practice Guidelines recommend management not only of OME itself, such as effusion in the middle ear and pathological changes in the tympanic membrane, but also pathological abnormality in surrounding organs, such as infectious or inflammatory diseases.

Efficacy and safety of oral propranolol for infantile hemangioma in Japan.

BACKGROUND: There have been few reports on the efficacy and safety of oral propranolol at 3 mg/kg/day for infantile hemangioma (IH) in Japanese patients. METHODS: A multicenter, open-label phase III study was conducted to evaluate the efficacy and safety of oral propranolol solution in Japanese infants aged 35-150 days with proliferating IH. Thirty-two patients were enrolled in the study, received propranolol solution for 24 weeks at 3 mg/kg/day, and completed the study. RESULTS: The success rate (complete or nearly complete resolution) at week 24 (primary endpoint) was 78% (95%CI: 60-91%). The improvement rate since the previous visit was 100% (32/32) after week 5. Overall, the IH surface area, maximum diameter, and color intensity all decreased over time. Consistency in assessment between the centralized and the investigator on-site assessments was observed in 26 patients. Of the 32 patients, 11 needed further treatment other than the study drug. The incidence of adverse events (AE) and drug-related AE was 97% and 31%, respectively. AE that occurred in ≥two patients were either typical of propranolol use (such as blood pressure decrease) or common events in infants. AE that resulted in dose reduction were observed in two patients, but no serious AE or AE that led to study drug discontinuation were observed. CONCLUSION: Oral propranolol solution at 3 mg/kg/day is effective and safe in Japanese IH patients.