Phenotype in 18 Danish subjects with genetically verified CHARGE syndrome.

CHARGE (coloboma of the eye, heart defects, choanal atresia, retarded growth and development, genital hypoplasia and ear anomalies and/or hearing loss) syndrome is a rare genetic, multiple-malformation syndrome. About 80% of patients with a clinical diagnose, have a mutation or a deletion in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7). Genotype-phenotype correlation is only partly known. In this nationwide study, phenotypic characteristics of 18 Danish CHD7 mutation positive CHARGE individuals (N = 18) are presented. We studied patient records, clinical photographs, computed tomography, and magnetic resonance imaging (MRI). Information was not available for all traits in all subjects. Therefore, the results are presented as fractions. The following prevalence of cardinal symptoms were found: coloboma, 16/17; heart defects, 14/18; choanal atresia, 7/17; retarded growth and development, 11/13; genital abnormalities, 5/18; ear anomalies, 15/17 and sensorineural hearing loss, 14/15. Vestibular dysfunction (10/13) and swallowing problems (12/15) were other frequent cranial nerve dysfunctions. Three-dimensional reconstructions of MRI scans showed temporal bone abnormalities in >85%. CHARGE syndrome present a broad phenotypic spectrum, although some clinical features are more frequently occurring than others. Here, we suggest that genetic testing for CHD7 mutation should be considered in neonates with a specific combination of several clinical symptoms.

A possible association between early apical resorption of primary teeth and ectodermal characteristics of the permanent dentition.

The hypothesis of this study is that children with unexpected early apical resorption of the primary teeth are also predisposed to resorption in the permanent dentition. Accordingly, the aim was to perform a longitudinal study focussing on the permanent teeth in children with unexpected early apical resorption in the primary dentition. Panoramic radiographs of 12 children (7 boys and 5 girls) aged 6 years 4 months to 8 years 9 months with unexpected early apical resorption of primary teeth were identified from a dental archive of 588 patients. After written request, follow-up radiographs were obtained (2-15 year interval between early and follow-up radiographs). The radiographs were examined in order to verify the abnormal resorption pattern of the primary teeth and dental deviations in the permanent teeth, known to predispose for root resorption (i.e. invaginations, narrow crowns, abrupt root deflections, slender roots, short roots, taurodontia, agenesis, deviant pattern of eruption). Primary dentition: Two phenotypically different resorption groups were identified: group I, eight patients (resorption of the roots only), and group II, four patients (resorption of root and crown). Permanent dentition: In all 12 children, dental deviations in the permanent dentition were observed. Additionally, idiopathic external apical resorption of the permanent teeth was seen in three children, two of whom had received orthodontic treatment.

Unexpected early apical resorption of primary molars and canines.

AIM: This was to examine the resorption pattern of primary molars and canines in dentitions with advanced apical resorption even though the permanent successor had barely begun root formation and to verify the resorption process histologically. STUDY DESIGN: Panoramic or bite-wing radiographs were selected from a dentition archive of radiographs from 142 children with deviant resorption patterns. METHODS: There were 14 patients (10 boys, 4 girls) aged 6 years 2 months to 8 years 1 month selected. In 11 patients abnormal resorption occurred only in the roots (group I). In 3 patients resorption occurred in the roots as well as in the crown (group II). The degree of resorption was evaluated using Haavikko's five resorption stages, and the degree of development of the permanent successor was evaluated using Haavikko's ten formation stages [Haavikko, 1973]. For histologic study 7 teeth were decalcified, paraffin-embedded, sectioned and stained with hematoxylin and eosin and examined microscopically. RESULTS: Group I: in 5 patients severe root resorption occurred before crown formation of the permanent successor was completed. In 6 children the abnormal resorption pattern was less severe. Group II: in 3 subjects full resorption of the root complex was observed as well as partial resorption of the crown. A histological analysis confirmed the resorption process. CONCLUSION: This is the first study focussing on unexpected early resorption of primary molars and canines in 14 patients without agenesis. The study showed an abnormal resorption pattern of roots and crown of primary teeth before the permanent successor had barely begun root formation. This indicates that resorption of primary molars and canines may occur independently from eruptional processes in the succeeding permanent tooth.

Contribution of the N-acetyltransferase 2 polymorphism NAT2*6A to age-related hearing impairment.

BACKGROUND: Age-related hearing impairment (ARHI) is the most common sensory impairment in older people, affecting 50% of those aged 80 years. The proportion of older people is increasing in the general population, and as a consequence, the number of people affected with ARHI is growing. ARHI is a complex disorder, with both environmental and genetic factors contributing to the disease. The first studies to elucidate these genetic factors were recently performed, resulting in the identification of the first two susceptibility genes for ARHI, NAT2 and KCNQ4. METHODS: In the present study, the association between ARHI and polymorphisms in genes that contribute to the defence against reactive oxygen species, including GSTT1, GSTM1 and NAT2, was tested. Samples originated from seven different countries and were combined into two test population samples, the general European population and the Finnish population. Two distinct phenotypes for ARHI were studied, Z(low) and Z(high), representing hearing in the low and high frequencies, respectively. Statistical analysis was performed for single polymorphisms (GSTM1, GSTT1, NAT2*5A, NAT2*6A, and NAT2*7A), haplotypes, and gene-environment and gene-gene interactions. RESULTS: We found an association between ARHI and GSTT1 and GSTM1 in the Finnish population sample, and with NAT2*6A in the general European population sample. The latter finding replicates previously published data. CONCLUSION: As replication is considered the ultimate proof of true associations in the study of complex disorders, this study provides further support for the involvement of NAT2*6A in ARHI.

Familial aggregation of tinnitus: a European multicentre study.

INTRODUCTION AND AIM: Tinnitus is a common condition affecting approximately 20% of the older population. There is increasing evidence that changes in the central auditory system following cochlear malfunctioning are responsible for tinnitus. To date, few investigators have studied the influence of genetic factors on tinnitus. The present report investigates the presence of a familial effect in tinnitus subjects. METHODS: In a European multicentre study, 198 families were recruited in seven European countries. Each family had at least 3 siblings. Subjects were screened for causes of hearing loss other than presbyacusis by clinical examination and a questionnaire. The presence of tinnitus was evaluated with the question "Nowadays, do you ever get noises in your head or ear (tinnitus) which usually last longer than five minutes". Familial aggregation was tested using three methods: a mixed model approach, calculating familial correlations, and estimating the risk of a subject having tinnitus if the disorder is present in another family member. RESULTS: All methods demonstrated a significant familial effect for tinnitus. The effect persisted after correction for the effect of other risk factors such as hearing loss, gender and age. The size of the familial effect is smaller than that for age-related hearing impairment, with a familial correlation of 0.15. CONCLUSION: The presence of a familial effect for tinnitus opens the door to specific studies that can determine whether this effect is due to a shared familial environment or the involvement of genetic factors. Subsequent association studies may result in the identification of the factors responsible. In addition, more emphasis should be placed on the effect of role models in the treatment of tinnitus.

Autosomal dominant optic atrophy associated with hearing impairment and impaired glucose regulation caused by a missense mutation in the WFS1 gene.

Autosomal dominant optic atrophy (ADOA) is genetically heterogeneous, with OPA1 on 3q28 being the most prevalently mutated gene. Additional loci are OPA3, OPA4, and OPA5, located at 19q13.2, 18q12.2, and 22q12.1-q13.1, respectively. Mutations in the WFS1 gene, at 4p16.3, are associated with either optic atrophy (OA) as part of the autosomal recessive Wolfram syndrome or with autosomal dominant progressive low frequency sensorineural hearing loss (LFSNHL) without any ophthalmological abnormalities. Linkage and sequence mutation analyses of the ADOA candidate genes OPA1, OPA3, OPA4, and OPA5, including the genes WFS1, GJB2, and GJB6 associated with recessive inherited OA or dominant LFSNHL, were performed. We identified one novel WFS1 missense mutation E864K, c.2590G-->A in exon 8 that co-segregates with ADOA combined with hearing impairment and impaired glucose regulation. This is the first example of autosomal dominant optic atrophy and hearing loss associated with a WFS1 mutation, supporting the notion that mutations in WFS1 as well as in OPA1 may lead to ADOA combined with impaired hearing.

Two families with phenotypically different hereditary low frequency hearing impairment: longitudinal data and linkage analysis.

Two families with low frequency hearing impairment have been described previously. Family A (Danish) presented a sensorineural hearing impairment most pronounced for frequencies below 2 kHz and a pedigree typical for an autosomal dominant trait with complete penetrance (Königsmark type). Family B, originating from the Faroe Islands, showed conflicting audiological test results, making a valid classification impossible. The pedigree suggested autosomal dominant inheritance with incomplete penetrance. The objectives of the present study are to acquire longitudinal audiometric data, to clarify the mode of transmission, and to localize the mutant gene by reevaluation of the two families. The methods used are evaluation of the family history, audiological examination and linkage analysis. In family A, update of the pedigree fitted the assumption of an autosomal dominant mode of transmission. In six examined subjects audiological data were available from the previous study. The median progression over a 13-21-year period was 13.8 dB HL for the thresholds, averaged across 0.5, 1, 2 and 4 kHz and 17.5 dB HL for the thresholds, averaged across 2 and 4kHz. In family B, the probable mode of transmission is autosomal dominant with reduced penetrance. In this family no progression of the hearing impairment was found. Linkage analysis of family A showed a lod score of 3.53, indicating significant linkage to the loci DFNA6 and DFNA14 on chromosome 4, previously found to be involved in low frequency hearing impairment. Family B was not linked to the region on chromosome 4, further adding to the genetic heterogeneity in low frequency sensorineural hearing impairment.

Cystic hygroma of the head and neck--a long-term follow-up of 44 cases.

Cystic hygroma of the neck is a relatively rare congenital malformation usually diagnosed during the first years of infancy. Complete surgical extirpation may be impossible without sacrificing important neurovascular structures. This paper reports the long-term outcome of surgical treatment during a 35-year period. A follow-up examination of 44 patients (24 males and 20 females) treated in our departments during the last 35 years was performed. Median age at first operation was 1.5 years (0-28 years) The observation period ranged between 1 and 36 years, median 16.2 years. Indications for operation were space occupying lesion, haemorrhage, dysphagia, difficulties in pronunciation or breathing and infection or nerve lesions. Fifty percent of the patients revealed residual or recurrent hygroma at the time of follow-up. Forty-four percent suffered from impaired speech, food intake, breathing or swallowing. Thirty-six percent were cosmetically bothered, and only 11% reported reduced quality of life. A significant correlation was noted between the extension of the lesion and (i) the number of operations performed and (ii) the rate of recurrent or residual hygroma. The rate of residual or recurrent hygroma was statistically higher for the suprahyoid lesions compared with the infrahyoid lesions. The localization and extent of the lesion is related to the surgical outcome. Surgical intervention should be centralized and should be considered carefully. Neurovascular structures should not be damaged in an attempt to effect complete removal. The above-mentioned results lead to a search for a new therapeutic modality, and the authors have recently taken up the Japanese way of treating hygromas by intralesional injection of OK-432. The first two patients treated by this technique had total regression of the lesion, and the method seems to be promising as an alternative to surgery.

Clinical study of a digital vs an analogue hearing aid.

Digital signal processing in hearing instruments has brought new perspectives to the compensation of hearing impairment and may result in alleviation of the adverse effects of hearing problems. This study compares a commercially available digital signal processing hearing aid (HA) (Senso) with a modern analogue HA with programmable fitting (Logo). The HAs tested are identical in appearance and, in spite of a different mode of operation, the study design ensured blinding of the test subjects. Outcome parameters were: improvements in speech recognition score in noise (deltaSRSN) with the HAs; overall preference for HA; overall satisfaction; and various measures of HA performance evaluated by a self-assessment questionnaire. A total of 28 experienced HA users with sensorineural hearing impairment were included and 25 completed the trial. No significant differences were found in deltaSRSN between the two HAs. Eleven subjects indicated an overall preference for the digital HA, 10 preferred the analogue HA and 4 had no preference. Concerning overall satisfaction, 8 subjects rated the digital HA superior to the analogue one, whereas 7 indicated a superior rating for the analogue HA and 10 rated the HAs equal. Acceptability of noise from traffic was the only outcome parameter which gave a significant difference between the HAs in favour of the digital HA. It is concluded that there are no significant differences in outcome between the digital and analogue signal processing HAs tested by these experienced HA-users.

Peritonsillar infiltration with low-dose tenoxicam after tonsillectomy.

We have compared the effect of peritonsillar infiltration with tenoxicam 5 mg and placebo on postoperative pain after tonsillectomy. Fifty patients undergoing bilateral elective tonsillectomy under general anaesthesia were allocated randomly to receive peritonsillar infiltration with tenoxicam 5 mg in 8 ml of normal saline (4 ml per tonsil) or normal saline only, before tracheal extubation. Median time to first request for morphine (30 min in each group, P = 0.83), cumulative morphine requirements from 0 to 2 h after surgery (two and one doses, P = 0.50), and from 2 to 24 h after surgery (one dose in each group, P = 0.17) were similar. There were no significant differences between groups in VAS scores at rest or when drinking 100 ml of water at any time. The power of detecting a reduction in VAS scores of 20 mm was 90% at the 5% significance level.

[Bone-anchored auricular prosthesis]. / Knogleforankret aurikelprotese.

During the period February 1989-September 1991, 15 patients with absent or defective pinna were treated with a bone-anchored auricular prosthesis at the ENT-department, Rigshospitalet, Copenhagen. These patients were followed up from the hospital records and by means of a questionnaire. Altogether 40 titanium implants have been inserted, of which one implant was found not to be integrated at the time of the second-stage surgery. Five patients underwent additional surgery, one patient because of non-integration of a screw, and four patients on account of soft-tissue reactions. From the questionnaire replies it appears that all patients found the cosmetic result and the technique concerning mounting of the prosthesis very satisfactory. Nearly half the patients found that the care of the skin around the abutments caused considerable problems. Three patients had experienced unintended losses of the prosthesis. In conclusion, treatment with a bone anchored auricular prosthesis has considerable advantages compared to treatment with a prosthesis attached by adhesive. Furthermore the use of a bone-anchored prosthesis should be considered a viable alternative to surgical reconstruction because of the outstanding aesthetic result and because the surgical procedure puts less strain on the patient. The disadvantage of the method is the lifelong daily care of the skin and the dependence on the health services.

Bonding of enamel-dentin crown fragments after crown fracture. An experimental study using bonding agents.

Previous experimental studies into the use of dentin bonding agents for reattachment of enamel-dentin crown fragments have demonstrated fracture strength about 50-60% of that of intact teeth. In the clinic this has been reflected in the frequent need of repeated bonding of the treated incisors due to refracture. Recently newer bonding agents have been developed which can bond equally well with enamel and dentin. Employing the same experimental model, these bonding agents (All-Bond 2, Scotchbond MP) were used to reattach crown fragments to the remaining portion of sheep incisors. Loading of teeth bonded with these agents in an Instron testing machine at a speed of 1 mm/min demonstrated similar fracture strengths as those previously achieved with Gluma, Scotchbond 2 or Tenure. A second study was carried out whereby fragments were bonded with Scotchbond MP and loaded at various speeds. The results demonstrated that the fracture strength decreased exponentially with increased loading speed. By extrapolation, it was concluded that the strength was nil at a loading speed of approximately 2 m/min. It was concluded that the weak link in the bond between tooth fragment and remaining tooth structure is the bonding resin. Theoretically, a resin which is slightly elastic might act as a shock absorber to withstand functional stress. However, studies carried out with resins of varying moduli of elasticity gave disappointing results probably due to their low flexural strength.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum tryptophan levels in alcoholics.

An oral load of L-tryptophan was administered to alcoholics and non-alcoholic control subjects in order to determine whether prolonged ethanol consumption influences serum tryptophan levels. Both samples were taken under fasting conditions and after the load. No differences in fasting serum tryptophan levels were noted. In alcohol addicts and in alcoholics treated with disulfiram (Antabuse) serum tryptophan levels were below normal after the load. No differences were observed in serum tryptophan levels between treated alcoholics not receiving disulfiram and control subjects. The findings suggest that chronic consumption of ethanol-containing beverages can enhance removal of tryptophan from the blood. Explanations to account for this finding are considered.