Critical analysis of moderate and severe retractions in the pars tensa and pars flaccida of the tympanic membrane.

OBJECTIVES: Analyze the prevalence of retractions in different areas of the Tympanic Membrane (TM), the correlations between the involvement of the Pars Tensa (PT) and Pars Flaccida (PF), and the air-bone gaps. METHODS: A cross-sectional study. Patients with moderate and/or severe TM retraction of 2200 consecutive patients with chronic otitis media between August 2000 and January 2019 were included. Ears with previous surgery were excluded. Ears were classified as isolated PF and PT retractions and association of both. The degrees of severity and presence of effusion were evaluated. The data were analyzed using the SPSS Statistics software program. RESULTS: 661 ears were included. The prevalence of isolated atical retractions was 24.9%, of isolated posterior quadrants was 10.6%, and of association of quadrants was 64%. There was no correlation between the retractions in the different areas of the TM (posterior and attic quadrants: r = 0.13; p = 0.041; anterior and posterior quadrants: r = 0.23; p = 0.013, anterior and attic quadrants: r = 0.06; p = 0.043). Effusion was present in 30.7% of the ears. ABG median was lower in ears with PF retraction (6.25 dB HL) than PT retraction, isolated (15 dB HL) or not (13.75 dB HL; p < 0.05); 72% of the ears had an ABG ≤ 20 dB HL. For severity of the retraction of PF, the ABG was similar across groups. For the PT, there was a global difference in the medians of ABG in terms of the degree of severity, with a moderate correlation. CONCLUSION: The prevalence of moderate and severe retractions was 24.5%; 64% of the ears had an association of affected regions. There was no correlation between the retraction in the different areas of the TM. We found a significant correlation between the severity of retraction and the worsening of ABG threshold, only for PT. EVIDENCE LEVEL: 4.

Audiometric Pattern in Moderate and Severe Tympanic Membrane Retraction.

OBJECTIVE: To evaluate the audiometric pattern in moderate/severe retractions of the tympanic membrane and correlate it with the severity of the otoscopy findings. STUDY DESIGN: Cross-sectional study. SETTING: Tertiary hospital. PATIENTS: Consecutive patients with moderate or severe tympanic membrane retraction in at least one ear (451 ears) between August 2000 and January 2019, and no surgical history or effusion (mean [standard deviation] age, 32.8 [20.2] yr; 54% female and 42.4% children). INTERVENTION: Pure-tone audiometry. MAIN OUTCOME MEASURES: Air conduction (AC) and bone conduction thresholds, and air-bone gap (ABG) measured at the four-frequency pure-tone average. RESULTS: The median in decibel hearing level (dB HL) (minimum-maximum) of the AC, BC, and ABG were 25 dB HL (0-120 dB HL), 10 dB HL (0-75 dB HL), and 12.5 dB HL (0-55 dB HL), respectively. Seventy-two percent of the ears had an ABG ≤ 20 dB HL. For severity of the retraction of pars flaccida (PF), the AC, bone conduction, and ABG were similar across groups, with a weak correlation. For the pars tensa (PT), there was a global difference in the medians of AC and ABG in terms of the degree of severity, with a moderate correlation. Retraction in PF and PT at the same time was observed in 6 4% of the ears. ABG median was lower in ears with PF retraction (6.25 dB HL) than PT retraction, isolated (15 dB HL) or not (13.75 dB HL; p < 0.05). CONCLUSION: The ABG pure-tone average median was higher when PT was involved. We found a significant correlation between the retraction severity and worsening of AC and ABG thresholds, only for PT.

Comparative analysis of moderate and severe tympanic membrane retractions in children and adults.

OBJECTIVE: Owing to the limited literature demonstrating the correlation between the degree of severity of retractions and the degree of hearing loss in children and adults, the study aimed to compare the differences in the location, the severity, and the air-bone gap (ABG) of tympanic membrane (TM) retractions in children and adults. METHODS: Cross-sectional study, in a tertiary hospital. Consecutive patients with moderate or severe TM retractions (661 ears) between August 2000 and January 2019 were evaluated. The average age (mean ± standard deviation) was 11.7 ± 3.3 years among pediatric patients (42.4%) and 46.4 ± 5 years among adults (57.6%). Video-otoscopy and pure tone audiometry were performed in all patients. The main outcome measures were the locations of retractions, their prevalence, and their severity; ABG thresholds measured at the 4-frequency pure-tone average (PTA). RESULTS: The prevalence of pars flaccida (PF) retractions was higher in adults, while that of pars tensa (PT) was higher in children (p = 0.00). The degree of severity was similar between children and adults for isolated PF and PT retractions (p = 0.37 and p = 0.10, respectively). Effusion was similar in children (27.8%) and adults (33.3%). The median decibel hearing level (dB HL) (minimum-maximum) of the ABG PTA was 13.75 dB (0-57.5 dB HL) in children and 13.75 dB (0-58.7 dB) in adults (p = 0.48). There was no difference in the size of the ABG PTA between children and adults (p = 0.71), and in ABG size for isolated PF retractions (p = 0.14), PT retractions (p = 0.35), and association of PF and PT retractions (p = 0.56). CONCLUSION: PT retractions were more prevalent in children and PF retractions in adults. There was no difference between the two groups based on the severity of the retraction. The size of the air-bone gaps was similar in children and adults.

Coexistence of beta-thalassemia and hereditary hemochromatosis in homozygosity: a possible synergic effect?

A few considerations, which we found in the literature, inspired us to reevaluate patients previously investigated [characterized for beta-thalassemia (beta-thal) and hereditary hemochromatosis (HH) genes] by our department at Medical Genetics, School of Medicine, University of Foggia, Italy.

Screening of mutations of hemophilia A in 40 Italian patients: a novel G-to-A mutation in intron 10 of the F8 gene as a putative cause of mild hemophilia A in southern Italy.

Hemophilia A is an X-linked bleeding disorder caused by widespread mutations in the human coagulation factor 8 gene. We have searched for mutations in factor 8 gene DNAs from 40 unrelated Italian patients with hemophilia A. All patients came from the same region (Calabria) and were followed-up at the same hemophilia center. Of the 40 patients, 20 (50%) had severe hemophilia A, 19 (47.5%) had moderate hemophilia A, and one (2.5%) had mild hemophilia A. All patients were first screened for the common intron 22 and intron 1 inversions. Inversion-negative samples were screened for point mutations by direct sequencing of all coding regions and intron-exon boundaries of the factor 8 gene. Mutations previously reported as causative of hemophilia A were identified in 14 of the 40 patients. These included five (12.5%) intron 22 inversions, one (2.5%) small deletion, one (2.5%) small insertion and seven (17.5%) point mutations. In all patients with moderate and mild hemophilia A, a nucleotide change in the c.1538 -18G>A in intron 10, not reported in the HAMSTeRS factor 8 mutation database (http://europium.csc.mrc.ac.uk/), was found. The G-to-A change predicts the appearance of a new acceptor splice site. We have also demonstrated that all patients share a common haplotype, suggesting that the mutation probably occurred in a single ancestor. In conclusion, we suggest that the c.1538-18G>A transition can be the putative mutation, which probably occurred in a common ancestor and then spread in neighbours, in patients with moderate-mild hemophilia A investigated in the present study.

Critical analysis of moderate and severe retractions in the pars tensa and pars flaccida of the tympanic membrane,

Abstract Objectives: Analyze the prevalence of retractions in different areas of the Tympanic Membrane (TM), the correlations between the involvement of the Pars Tensa (PT) and Pars Flaccida (PF), and the air-bone gaps. Methods: A cross-sectional study. Patients with moderate and/or severe TM retraction of 2200 consecutive patients with chronic otitis media between August 2000 and January 2019 were included. Ears with previous surgery were excluded. Ears were classified as isolated PF and PT retractions and association of both. The degrees of severity and presence of effusion were evaluated. The data were analyzed using the SPSS Statistics software program. Results: 661 ears were included. The prevalence of isolated atical retractions was 24.9%, of isolated posterior quadrants was 10.6%, and of association of quadrants was 64%. There was no correlation between the retractions in the different areas of the TM (posterior and attic quadrants: r = 0.13; p = 0.041; anterior and posterior quadrants: r = 0.23; p = 0.013, anterior and attic quadrants: r = 0.06; p = 0.043). Effusion was present in 30.7% of the ears. ABG median was lower in ears with PF retraction (6.25 dB HL) than PT retraction, isolated (15 dB HL) or not (13.75 dB HL; p < 0.05); 72% of the ears had an ABG ≤ 20dB HL. For severity of the retraction of PF, the ABG was similar across groups. For the PT, there was a global difference in the medians of ABG in terms of the degree of severity, with a moderate correlation. Conclusion: The prevalence of moderate and severe retractions was 24.5%; 64% of the ears had an association of affected regions. There was no correlation between the retraction in the different areas of the TM. We found a significant correlation between the severity of retraction and the worsening of ABG threshold, only for PT. Evidence level: 4.

Phenylalanine hydroxylase deficiency in south Italy: Genotype-phenotype correlations, identification of a novel mutant PAH allele and prediction of BH4 responsiveness.

We investigated the mutation spectrum of the phenylalanine hydroxylase gene (PAH) in a cohort of patients from 33 Italian PKU families. Mutational screening of the known coding region, including conventional intron splice sites, was performed by direct sequencing of the patients' genomic DNA. Thirty-three different disease causing mutations were identified in our patient group, including 19 missense, 6 splicing, 3 nonsense, 5 deletions, with a detection rate of 100%. The most prevalent mutation was the IVS10-11G>A, accounting for 12.1% of PKU alleles studied. Other frequent mutations were: p.R261Q (9.1%), p.P281L (7.6%), and p.R408W (6.1%). We also identified one novel missense mutation, p.H290Q. A spectrum of 31 different genotypes was observed and a genotype based predictions of BH4-responsiveness were assessed. Among all genotypes, 13 were predicted to be BH4-responsive represented by thirteen PKU families. In addition, genotype-phenotype correlations were performed. This study reveals the importance of a full genotyping of PKU patients and the prediction of BH4-responsiveness, not only because of the definitive diagnosis and prediction of the optimal diet, but also to point out those patients that could benefit from new therapeutic approach. They may potentially benefit from BH4 therapy which, combined with a less strict diet, or eventually in special cases as monotherapy, may contribute to reduce nutritional deficiencies and minimize neurological and psychological dysfunctions.

Intra-familiar discordant PKU phenotype explained by mutation analysis in three pedigrees.

Classical phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP) are two phenotypes of phenylalanine hydroxylase (PAH) deficiency with different degrees of severity. We have analyzed three families in which classical PKU, MHP and a normal phenotype occurred within each family due to the different combinations of three mutations segregating within the family. Indeed, sequence PAH analysis revealed three different alleles segregating in each family. This report suggests that when discordant phenotypes occur in a family, complete analysis of the PAH gene may be performed in order to support the diagnosis and assist in accurate genetic counseling and patient management. We further support the marked heterogeneity of hyperphenylalaninemia primarily due to allelic heterogeneity at the PAH locus.

Mutation analysis in hyperphenylalaninemia patients from South Italy.

BACKGROUND: Mutations in the gene encoding phenylalanine hydroxylase (PAH, EC 1.14.16.1) are associated with various degrees of hyperphenylalaninemia (HPA), including classical phenylketonuria (PKU). OBJECTIVE: The aim of the study was to determine the mutations responsible for mild forms of HPA and to relate different clinical phenotypes of HPA patients to their PAH genotypes in order to better predict the clinical phenotype and implement optimal dietary therapy and prognosis in newborns with the disease. METHODS: Phenylalanine hydroxylase (PAH) gene mutations have been analyzed by direct DNA sequencing in 30 HPA patients (Phe levels ranging from 2 to 6mg/dL) from Southern Italy who were identified in a neonatal screening program and a genotype-phenotype correlation was performed. RESULTS: PAH gene mutation was identified in 39 out of 60 alleles with a mutation detection rate of 65%. Eighteen mutations, 2 undescribed, were observed (13 missense mutations, 1 deletion, 4 splice site mutations). Using the "in vitro" predicted residual activity, a good genotype-phenotype correlation was obtained also in a new mild HPA case, a PAH compound heterozygote, previously undetected. CONCLUSION: A marked genetic heterogeneity was found in HPA patients from Southern Italy and a good genotype-phenotype correlation was obtained. Identification of PAH gene mutations responsible for PAH deficiency will therefore be useful in the prediction of biochemical and clinical phenotypes in HPA patients.

Outcome of patients with splanchnic venous thrombosis presenting without overt MPN: a role for the JAK2 V617F mutation re-evaluation.

INTRODUCTION: Although investigation for JAK2 V617F mutation is recommended in patients presenting with splanchnic venous thrombosis (SVT), no specific clinical advice is given to SVT patients presenting without myeloproliferative neoplasms (MPN) and JAK2 V617F mutation. In MPN-free SVT patients, to investigate the clinical outcome, the clinical impact of re-evaluation for the JAK2 V617F mutation, and relationships with the occurrence and time to diagnosis of MPN. MATERIALS AND METHODS: A cohort of non-cirrhotic SVT patients, enrolled at a single centre and prospectively analyzed. RESULTS: In 121 SVT patients prospectively followed from 1994 to 2012, a MPN was present in 28 (23.1%). Additional 13 patients (10.7%) showed only the JAK2 V617F mutation. During the follow-up, the JAK2 V617F mutation and/or MPN were identified in 8 patients (median time of development: 21 months, range 6-120), whereas 72 remained (MPN and JAK2 V617F)-free until the end of the observation. The mortality rate was higher among patients presenting with MPN and/or the JAK2 V617F mutation than in patients who developed later or remained disease-free (p=0.032). The thrombosis-free survival was lower in patients with (p=0.04) or developing later MPN and the JAK2 V617F mutation (p=0.005) than in patients (MPN and JAK2 V617F)-free. The incidence of bleeding was similar among groups. CONCLUSIONS: MPN with or without circulating positive clones for JAK2 V617F mutation can occur long after a SVT, identifying at risk patients for new thrombotic events. If confirmed in other studies, re-evaluation for JAK2 V617F mutation may be of help in early MPN detection and clinical management of SVT patients.

Detection of new deletions in a group of Italian patients with Hemophilia A by multiplex ligation-dependent probe amplification.

AIM: Hemophilia A is an X-linked bleeding disorder caused by mutations widespread in the human coagulation F8 gene. Apart from common intrachromosomal translocations, most of the mutations in the F8 gene are detectable using genomic sequencing analysis. However, deletions of one or more exons or deletion encompassing the entire gene can go undetected, especially in heterozygous females. RESULTS: The multiplex ligation-dependent probe amplification is an efficient tool, new and fast, for discovering these rearrangements. In this study different deletions, which were detected using multiplex ligation-dependent probe amplification assay on 25 patients affected by severe hemophilia A, were classified as "mutation negative" by sequencing analysis. CONCLUSIONS: These data suggest that this screening could be systematically included in genetic screening of patients with Hemophilia A.