[Research progress on hereditary endocrine and metabolic diseases associated with sensorineural hearing loss].

Hereditary endocrine and metabolic diseases , caused by genetic factors, exhibit complex and diverse symptoms, including the possibility of concurrent sensorineural deafness. Currently, there is a limited clinical understanding of hereditary endocrine and metabolic diseases that manifest with deafness, the pathogenesis remains unclear,and there is a lack of effective diagnostic and treatment methods. This article summarizes the research progress of hereditary endocrine and metabolic diseases complicated with deafness from the pathogenesis, clinical phenotype, diagnosis and treatment. Understanding the current research progress and integrating genetic analysis into clinical practice are crucial for accurate diagnosis and treatment, evaluating clinical efficacy, and providing effective genetic counseling for these diseases.

[Advances in studies on genetics of syndromes combining sensorineural hearing loss with scoliosis].

Sensorineural hearing loss and scoliosis are common in several disease groups, such as hereditary connective tissue syndrome, hereditary motor and sensory neuropathy, lysosomal storage syndrome and endocrine disorders. These diseases have significant phenotypic diversity and genetic heterogeneity, different subtypes show inconsistent characteristics of deafness. Moreover, subtypes with similar clinical manifestations have different genetic mechanisms. Using new generation sequencing technology, considerable progress has been achieved in these diseases. This paper reviews clinical manifestations and genetic mechanism of syndromes combining sensorineural hearing loss and scoliosis.

Discovery of sensorineural hearing loss and ossicle deformity in a Chinese Li nationality family with spondyloepiphyseal dysplasia congenita caused by p.G504S mutation of COL2A1.

BACKGROUND: Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant chondrodysplasia characterized by disproportionate short stature, abnormal epiphyses, and flattened vertebral bodies. COL2A1 has been confirmed as the pathogenic gene. Hearing loss represents an infrequent manifestation for 25-30% of patients with SEDC. The characteristics of the hearing impairment were rarely documented. METHODS: Audiological, ophthalmic, imaging examinations were conducted on the family members. The whole exome sequencing (WES) was performed to detect the candidate gene, and the Sanger sequencing was used to confirm the causative variation. RESULTS: COL2A1 c.1510G>A (p.G504S), a hot spot variation, was identified as the disease-causing mutation of the Chinese Li nationality family with SEDC. This variation was co-segregated with the SEDC phenotype in the family and was absent in the 1000 Genomes Project, ESP and ExAC. Clinically, several manifestations were first demonstrated in SEDC patients caused by p.G504S, including sensorineural hearing loss, auditory ossicles deformity, retinal detachment, sacrum cracked and elbow and wrist joints deformity. Other classical SEDC manifestations such as bones and joints pain, midfacial dysplasia, disproportionate short stature, spinal deformity, thoracocyllosis, coxa arthropathy, myopia and waddling gait were also showed in the family patients. CONCLUSION: We first identified the mutation p.G504S in COL2A1 gene as the pathogenesis in a Chinese Li nationality family and reported the correlation between p.G504S and atypical clinical phenotypes including sensorineural hearing loss, auditory ossicles deformity, retinal detachment, sacrum cracked and elbow and wrist joints deformity. Our findings would extend the phenotypic spectrum of SEDC and deepen clinicians' understanding of genotype-phenotype correlation of the disease.

Esophageal peripheral T-cell lymphoma treated with radiotherapy: A case report.

RATIONALE: The clinical prognosis of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) patients is poor. Therefore, effective treatment is still a challenge at present. Moreover, little is known about the value of radiotherapy in the treatment of PTCL-NOS. PATIENT CONCERNS: A 55-year-old male patient with eating difficulties and progressive exacerbation for 3 months was diagnosed as non-Hodgkin's lymphoma. Airway compression occurred after 2 cycles of first line treatment with cyclophosphamide-Adriamycin-vincristine-prednisone regimen, radiotherapy (48Gy/24f) was given as the second line therapy. DIAGNOSIS: After radiotherapy, the patient complained that mild intermittent dysphagia still existed. Endoscopic biopsy of the upper digestive tract confirmed necrotic material and superficial squamous epithelial mucosa, suggesting esophageal stricture after radiotherapy, which was indistinguishable from tumor residue. INTERVENTIONS: The patient received anti-inflammatory treatment outside the hospital and did not receive any other special treatment. OUTCOMES: The symptoms of dysphagia disappeared and the focus showed complete response (CR). As of October 1, 2020, the patient has been diagnosed with PTCL-NOS for more than 57 months and the overall survival (OS) have not been achieved. LESSONS: Radiotherapy has obvious and rapid anti-tumor effect on cyclophosphamide-Adriamycin-vincristine-prednisone refractory PTCL-NOS. At the same time, hollow organs after radiotherapy can lead to lumen stenosis and the symptoms of suspected recurrence which is difficult to distinguish only from the imaging findings.

Analysis of thyroid dysfunction in patients with sudden sensorineural hearing loss.

BACKGROUND: Sudden sensorineural hearing loss (SSHL) refers to the sudden occurrence of unexplained sensorineural hearing loss. The present study showed that different systemic diseases had different influence on the occurrence and hearing outcome of SSHL. Thyroid hormone is one of the important factors for the development of fetal ear and auditory function. However, the distribution of thyroid dysfunction in SSHL patients and the effect of thyroid dysfunction on the occurrence and hearing outcome of SSHL has not been studied. METHODS: In this study, a retrospective analysis had been done in 676 patients with SSHL. We had described the distribution of thyroid function in patients with SSHL in detail, and by the statistical method, analyzed the relationship between the hearing outcome and thyroid dysfunction, respectively. RESULTS: In all patients, 24.41% (165/676) had abnormal thyroid function testing results. The onset age of SSHL in FT3 abnormal group (including low and high group) was younger than that in normal FT3 group. Recovery group had more patients with lower-than-normal T3 level as compared to non-recovery patients. Significant associations between T3 levels and hearing outcome were observed in the subgroup with longer time elapse between symptom onset and treatment (≥14 d). CONCLUSION: The incidence of thyroid dysfunction in SSHL is significantly higher than in the general population. There was obvious relationship between T3 and FT3 item of thyroid dysfunction and the onset time and hearing outcome of SSHL, which indicated that T3 or FT3 indicator may be one of the affecting factors for the SSHL. Early screening and diagnosis of thyroid dysfunction, especial T3 level, may help to evaluate the prognosis in SSHL patients.

[Identification of a novel mutation of CEACAM16 gene in a Chinese family with autosomal dominant nonsyndromic hearing loss].

Objective:To explore the genetic cause of a Chinese autosomal dominant nonsyndromic hearing loss family and investigate the clinical features and molecular genetic characteristics of this family. Method:Detailed medical history and systematic audiology tests were carried out in the family members, and they were subjected to comprehensive genetic analyses using massively parallel sequencing, which targeted 139 known deafness genes and 6 mitochondrial DNA mutations associated with hearing loss. Result:This family's hearing loss was consistent with autosomal dominant nonsyndromic hearing loss. The affected family members appeared to have developed a high-frequency hearing loss with the onset of twenties. We identified a heterozygous missense mutation, c.418A>G/p. Thr140Ala in the CEACAM16 gene, segregating with the deafness in this family. Conclusion:In this study, we identified a new mutation of CEACAM16 gene, which was the second mutation identified in Chinese hearing loss population. It has enriched the mutation spectrum of this gene.

Weighted correlation gene network analysis reveals a new stemness index-related survival model for prognostic prediction in hepatocellular carcinoma.

In this study, we constructed a new survival model using mRNA expression-based stemness index (mRNAsi) for prognostic prediction in hepatocellular carcinoma (HCC). Weighted correlation network analysis (WGCNA) of HCC transcriptome data (374 HCC and 50 normal liver tissue samples) from the TCGA database revealed 7498 differentially expressed genes (DEGs) that clustered into seven gene modules. LASSO regression analysis of the top two gene modules identified ANGPT2, EMCN, GLDN, USHBP1 and ZNF532 as the top five mRNAsi-related genes. We constructed our survival model with these five genes and tested its performance using 243 HCC and 202 normal liver samples from the ICGC database. Kaplan-Meier survival curve and receive operating characteristic curve analyses showed that the survival model accurately predicted the prognosis and survival of high- and low-risk HCC patients with high sensitivity and specificity. The expression of these five genes was significantly higher in the HCC tissues from the TCGA, ICGC, and GEO datasets (GSE25097 and GSE14520) than in normal liver tissues. These findings demonstrate that a new survival model derived from five strongly correlating mRNAsi-related genes provides highly accurate prognoses for HCC patients.

Hand-foot syndrome and survival in patients with advanced non-small-cell lung cancer receiving anlotinib: a subgroup analysis of data from the ALTER 0303 study.

BACKGROUND: The ALTER 0303 study showed that anlotinib can significantly improve overall survival (OS) compared with the placebo in advanced non-small-cell lung cancer (NSCLC). Hand-foot syndrome (HFS) is a common anlotinib-related adverse event. The aim of this study was to assess the association of HFS with clinical benefit. METHODS: A subgroup analysis of patients treated with anlotinib from the ALTER 0303 study was performed. Our analysis assessed if the appearance of anlotinib-related HFS in the first 42 days (second-cycle HFS) and at any time could produce better clinical benefits. RESULTS: In this study, 294 patients were treated with anlotinib. Of which, 129 patients had HFS at any time, and 76 patients developed HFS in the first 2 cycles. Patients who received anlotinib and developed HFS had significantly prolonged OS, progression-free survival (PFS) compared to those who did not develop HFS in the first 2 cycles (13.5 vs 8.7 months, p = 0.001; adjusted hazard ratio (HR) 0.63 (95% confidence interval [CI] 0.44-0.89), p = 0.009; 5.8 vs 4.5 months, p = 0.001; adjusted HR, 0.59 [0.43-0.81], p = 0.001). The significant OS and PFS benefits for patients with HFS versus without were seen at any time (14.5 vs 7.3 months, p = 0.000; adjusted HR, 0.50 [0.36-0.67], p = 0.000; 5.8 vs 4.2 months, p = 0.000; adjusted HR, 0.49 [0.37-0.65], p = 0.000). In addition, the grade of severity of HFS was strongly correlated with OS (p = 0.000). CONCLUSION: Presence of HFS may be a potential clinical marker for the treatment of NSCLC with anlotinib.

Methylation­driven genes PMPCAP1, SOWAHC and ZNF454 as potential prognostic biomarkers in lung squamous cell carcinoma.

Of the different types of lung cancer, lung squamous cell cancer (LUSC) has the second highest rates of morbidity and mortality, which have been increasing in recent years. Epigenetic abnormalities may serve as potential biomarkers and diagnostic and/or therapeutic targets, which may help to monitor and improve the prognosis of patients with cancer. In the present study, data were obtained from The Cancer Genome Atlas database and survival and joint survival analyses were conducted using the R MethylMix package. Peptidase, mitochondrial processing a subunit pseudogene 1 (PMPCAP1), sosondowah ankyrin repeat domain family member C (SOWAHC) and zinc finger protein (ZNF) 454 were identified as independent prognosis­related hub methylation­driven genes (MDGs). Of these three genes, PMPCAP1 and SOWAHC, characterized by hypomethylation and high expression levels, were associated with poor prognosis in patients with LUSC, whilst ZNF454 was associated with an improved prognosis. In addition, pathway enrichment analysis suggested that PMPCAP1, SOWAHC and ZNF454 were primarily involved in gene expression or transcription pathways. Furthermore, 5, 1 and 10 key methylation sites of PMPCAP1, SOWAHC and ZNF454, respectively, were confirmed to be significantly relevant to gene expression, establishing a basis for further investigation into the mechanisms and more precise targets of these 3 genes. In conclusion, the MDGs PMPCAP1, SOWAHC and ZNF454 may be potential prognostic biomarkers of LUSC for guiding diagnosis and therapy options, as well as providing a theoretical basis for further investigation.

Identification of methylation-driven genes related to prognosis in clear-cell renal cell carcinoma.

With the participation of the existing treatment methods, the prognosis of advanced clear-cell renal cell carcinoma (ccRCC) is poor. More evidence indicates the presence of methylation in ccRCC cancer cells, but there is a lack of studies on methylation-driven genes in ccRCC. We analyzed the open data of ccRCC in The Cancer Genome Atlas database to obtain ccRCC-related methylation-driven genes, and then carried out pathway enrichment, survival, and joint survival analyses. More important, we deeply explored the correlation between differential methylation sites and the expression of these driving genes. Finally, we screened 29 methylation-driven genes via MethylMix, of which six were significantly associated with the survival of ccRCC patients. This study demonstrated that the effect of hypermethylation or hypomethylation on prognosis is different, and the level of methylation of key methylation sites is associated with gene expression. We identified methylation-driven genes independently predicting prognosis in ccRCC, which offers theoretical support in bioinformatics for the study of methylation in ccRCC and a new perspective for the epigenetic study of ccRCC.

Clinical Auditory Phenotypes Associated with GATA3 Gene Mutations in Familial Hypoparathyroidism-deafness-renal Dysplasia Syndrome.

BACKGROUND: Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is an autosomal dominant disorder primarily caused by haploinsufficiency of GATA binding protein 3 (GATA3) gene mutations, and hearing loss is the most frequent phenotypic feature. This study aimed at identifying the causative gene mutation for a three-generation Chinese family with HDR syndrome and analyzing auditory phenotypes in all familial HDR syndrome cases. METHODS: Three affected family members underwent otologic examinations, biochemistry tests, and other clinical evaluations. Targeted genes capture combining next-generation sequencing was performed within the family. Sanger sequencing was used to confirm the causative mutation. The auditory phenotypes of all reported familial HDR syndrome cases analyzed were provided. RESULTS: In Chinese family 7121, a heterozygous nonsense mutation c.826C>T (p.R276*) was identified in GATA3. All the three affected members suffered from sensorineural deafness and hypocalcemia; however, renal dysplasia only appeared in the youngest patient. Furthermore, an overview of thirty HDR syndrome families with corresponding GATA3 mutations revealed that hearing impairment occurred earlier in the younger generation in at least nine familial cases (30%) and two thirds of them were found to carry premature stop mutations. CONCLUSIONS: This study highlights the phenotypic heterogeneity of HDR and points to a possible genetic anticipation in patients with HDR, which needs to be further investigated.

Reproductive management through integration of PGD and MPS-based noninvasive prenatal screening/diagnosis for a family with GJB2-associated hearing impairment.

A couple with a proband child of GJB2 (encoding the gap junction protein connexin 26)-associated hearing impairment and a previous pregnancy miscarriage sought for a reproductive solution to bear a healthy child. Our study aimed to develop a customized preconception-to-neonate care trajectory to fulfill this clinical demand by integrating preimplantation genetic diagnosis (PGD), noninvasive prenatal testing (NIPT), and noninvasive prenatal diagnosis (NIPD) into the strategy. Auditory and genetic diagnosis of the proband child was carried out to identify the disease causative mutations. The couple then received in-vitro-fertilization treatment, and eight embryos were obtained for day 5 biopsy. PGD was performed by short-tandem-repeat linkage analysis and Sanger sequencing of GJB2 gene. Transfer of a GJB2c.235delC heterozygous embryo resulted in a singleton pregnancy. At the 13th week of gestation, genomic DNA (gDNA) from the trio family and cell-free DNA (cfDNA) from maternal plasma were obtained for assessment of fetal chromosomal aneuploidy and GJB2 mutations. NIPT and NIPD showed the absence of chromosomal aneuploidy and GJB2-associated disease in the fetus, which was later confirmed by invasive procedures and postnatal genetic/auditory diagnosis. This strategy successfully prevented the transmission of hearing impairment in the newborn, thus providing a valuable experience in reproductive management of similar cases and potentially other monogenic disorders.

[The curative effect analysis of combined medical therapy for auditory neuropathy spectrum disorder].

OBJECTIVE: To investigate the efficacy of combined medical treatment on auditory neuropathy spectrum disorder and the effect of related factors on the prognosis. METHOD: Eleven cases (22 ears) diagnosed as auditory neuropathy spectrum disorder using multiple criteria including pure tone auditory threshold, impedance audiometry, acoustic reflexes, distortion products otoacoustic emission (DPOAE) and auditory brainstem response (ABR) were subjected to combined medical treatment . Eleven auditory neuropathy spectrum disorder patients diagnosed during the corresponding period but refused treatment were selected as control group. The change of pure tone auditory threshold and speech discrimination score after treatment or follow-up were evaluated for both 2 groups, and the relationship between the patients' gender, age, accompanying symptoms and curative effect were also analyzed. Data were analyzed by SPSS 19.0 statistical software using pared-sample t-test, independent-sample test and Pearson's chi-square test. RESULT: The effective rate of combined medical therapy was 59.09% (13/22) in the therapy group. PTA levels before and after-treatment were (53.92 +/- 18.86) dB HL and (47.44 +/- 14.98) dB HL respectively in 22 ears with the combined medical therapy, the improvement of which showed statistically significance (t = 5.20, P < 0.05). No obvious hearing change was noted in the 11 patients who refused therapy (P > 0.05). Speech discrimination score before and after-treatment were (29.20 +/- 25.80)% and (41.60 +/- 22.90)% respectively for the treatment group. The average improvement of speech discrimination score was (12.40 +/- 13.80)% with statistically significant difference (t = 4.02, P < 0.05). Patients accompanied with tinnitus had relatively poorer effect compared with individuals without tinnitus (t = -3.85, P < 0.05). Age is negatively correlated with the prognosis (r = -6.72, P < 0.05). Gender had no effect on the prognosis (P > 0.05). CONCLUSION: The combined medical therapy with glucocorticoids helps improving the pure tone auditory threshold and speech discrimination score of auditory neuropathy spectrum disorder. In light of our findings we support the combined medical therapy as an option for patients with auditory neuropathy spectrum disorder.

[Clinical analysis of in-patients with large vestibular aqueduct syndrome].

OBJECTIVE: This study is to investigate the clinical materials of in-patients with the large vestibular aqueduct syndrome (LVAS), and explore the feature, diagnosis and treatment measures of the disease. METHOD: A retrospective review was conducted including the medical history, audiological examinations, vestibular function examinations, imaging examinations and treatment methods of 44 in patients (87 ears) suffering LVAS admitted to our hospital in the past 4 years(from 2008 to 2012). RESULT: ln the 44 in patients, there were 24 male cases and 20 female cases, and the male-female ratio was 1.2 :1. The average of the onset age was 3.39 years. Five cases (11. 36%) had related familial history. The profound hearing loss was found in 67 ears (77.01%), and the severe hearing loss was found in 20 ears (22.99%). After systemic treatment,the hearing of 38 ears improved effectively,but that of 49 ears did not improve obviously. The analysis found that patients suffering sudden hearing loss got better curative effect than those with progressive hearing loss. Patients received combined drug therapy improving arterial circulation as well as venous reflux got better therapeutic effect. There was a significant difference on effect between the patients with course of treatment more than 7 days and those less than 7 days. There was no significant correlation between therapeutic effect and other factors. CONCLUSION: In part of LVAS patients,the hearing level can be effectively improved through a standard internal medicine treatment. We can improve the personalized and standardized treatment strategy for this disease through analysis of diagnosis and treatment of in-patients with complete clinical data.