von Hippel-Lindau disease: deafness due to a non-MRI-visible endolymphatic sac tumor despite targeted screening.

OBJECTIVE: Endolymphatic sac tumours (ELSTs) of the inner ear occur in 16% of patients with the hereditary tumor syndrome von Hippel-Lindau disease (vHL). ELSTs of all sizes can cause irreversible hearing loss which can, however, be prevented through early diagnosis and treatment. We aim to emphasize the challenges of prophylactic ELST screening and to explore the role of audiometry in pre-symptomatic ELST screening. DESIGN: For a period of 17 years our patient was screened for ELSTs with inner-ear MRI (magnetic resonance imaging), audiometry, and clinical interviews. STUDY SAMPLE: A male vHL patient who became deaf in one ear due to a radiologically undetectable ELST. RESULTS: Despite annual MRIs, the ELST was not visible until four months after onset of deafness when it appeared as a 1.4 × 1.4 mm tumor mass. Although his hearing was objectively within normal limits for the first 14 years, a distinct pattern of low-frequency hearing loss could retrospectively be seen at all audiometries. CONCLUSIONS: Audiometry is a candidate screening tool for detection of non-symptomatic pre-MRI-visible ELSTs, and we have initiated an international collaborative study to further determine its application. At present, we suggest an ELST screening protocol of yearly audiological assessment and inner ear MRI.

von Hippel-Lindau disease: Updated guideline for diagnosis and surveillance.

von Hippel Lindau disease (vHL) is caused by a hereditary predisposition to multiple neoplasms, especially hemangioblastomas in the retina and CNS, renal cell carcinomas (RCC), pheochromocytomas, neuroendocrine pancreatic tumours (PNET) and endolymphatic sac tumours. Evidence based approaches are needed to ensure an optimal clinical care, while minimizing the burden for the patients and their families. This guideline is based on evidence from the international vHL literature and extensive research of geno- and phenotypic characteristics, disease progression and surveillance effect in the national Danish vHL cohort. We included the views and preferences of the Danish vHL patients, ensured consensus among Danish experts and compared with international recommendations. RECOMMENDATIONS: vHL can be diagnosed on clinical criteria, only; however, in most cases the diagnosis can be supported by identification of a pathogenic or likely pathogenic variant in VHL. Surveillance should be initiated in childhood in persons with, or at risk of, vHL, and include regular examination of the retina, CNS, inner ear, kidneys, neuroendocrine glands, and pancreas. Treatment of vHL manifestations should be planned to optimize the chance of cure, without unnecessary sequelae. Most manifestations are currently treated by surgery. However, belzutifan, that targets HIF-2α was recently approved by the U.S. Food and Drug Administration (FDA) for adult patients with vHL-associated RCC, CNS hemangioblastomas, or PNETs, not requiring immediate surgery. Diagnostics, surveillance, and treatment of vHL can be undertaken successfully by experts collaborating in multidisciplinary teams. Systematic registration, collaboration with patient organisations, and research are fundamental for the continuous improvement of clinical care and optimization of outcome with minimal patient inconvenience.

von Hippel-Lindau disease: surveillance strategy for endolymphatic sac tumors.

PURPOSE: : Up to 16% of patients with the hereditary von Hippel-Lindau disease develop endolymphatic sac tumors of the inner ear. Early diagnosis and treatment of endolymphatic sac tumors can prevent audiovestibular morbidity, but optimal endolymphatic sac tumor surveillance strategy has yet to be determined. We aimed to evaluate endolymphatic sac tumor surveillance to determine the best surveillance strategy. METHODS: : In a national prospective study, 40 VHL mutation carriers were interviewed about audiovestibular symptoms and had audiological examinations and magnetic resonance imaging of the inner ear. Further, we performed a meta-analysis including all reported endolymphatic sac tumor von Hippel-Lindau disease cases in the literature (N = 140 with 156 endolymphatic sac tumors). RESULTS: : In the prospective study, endolymphatic sac tumors were suspected based on audiovestibular symptoms, audiometry, and magnetic resonance imaging in 34%, 30%, and 12.5% of subjects, respectively. In total, more than 90% of radiologically diagnosed endolymphatic sac tumors were associated with abnormal audiometric findings. No endolymphatic sac tumor genotype-phenotype correlations were found. CONCLUSION: : We recommend annual audiometry as a first-line endolymphatic sac tumor screening tool, and in countries where periodic surveillance magnetic resonance imaging of the central nervous system is performed, specific images of the inner ear should be included. Audiometric abnormalities in patients with von Hippel-Lindau disease without magnetic resonance imaging-visible endolymphatic sac tumors could be due to microscopic endolymphatic sac tumors. Determination of audiometric endolymphatic sac tumor characteristics could further target screening and improve endolymphatic sac tumor diagnosis.

Branchio-oto-renal syndrome: detection of EYA1 and SIX1 mutations in five out of six Danish families by combining linkage, MLPA and sequencing analyses.

The branchio-oto-renal (BOR) syndrome is an autosomal-dominant disorder characterized by hearing loss, branchial and renal anomalies. BOR is genetically heterogeneous and caused by mutations in EYA1 (8q13.3), SIX1 (14q23.1), SIX5 (19q13.3) and in an unidentified gene on 1q31. We examined six Danish families with BOR syndrome by assessing linkage to BOR loci, by performing EYA1 multiplex ligation-dependent probe amplification (MLPA) analysis for deletions and duplications and by sequencing of EYA1, SIX1 and SIX5. We identified four EYA1 mutations (c.920delG, IVS10-1G>A, IVS12+4A>G and p.Y591X) and one SIX1 mutation (p.W122R), providing a molecular diagnosis in five out of the six families (83%). The present, yet preliminary, observation that renal and temporal bone malformations are less frequent in SIX1-related disease suggests a slightly different clinical profile compared to EYA1-related disease. Unidentified mutations impairing mRNA expression or further genetic heterogeneity may explain the lack of mutation finding in one family despite LOD score indications of EYA1 involvement.

[The type of traumatic sensorineural hearing loss affects diagnostic and medico-legal assessment].

Traumatic sensorineural hearing loss (TSHN) is mostly a high-frequency loss resembling noise-induced hearing loss (NIHL). However, approx. 25% of TSHN audiograms differ from NIHL in being of the slope, flat or low-frequency type. The physical properties of the trauma influence the audiogram shape, and the great individual variation of susceptibility to TSHN indicates the importance of genetic factors as well. As TSHN, like NIHL, predominantly is of a metabolic rather than a mechanical nature, its magnitude and configuration may change considerably during the first weeks after the causative incident.

[Diagnostics on noise-induced hearing loss]. / Diagnostik af støjbetinget hørenedsættelse.

Occupational noise-induced hearing loss (NIHL) may qualify to compensation and must be distinguished from the ski slope hearing loss (SKI) which is a hereditary type of hearing loss. By combining the NIHL and presbyacusis tables of ISO 1999 it was concluded that in a hearing loss caused solely by noise and ageing the median threshold at 2 kHz is never poorer than 35 dB, and that the ratio between the actual 3 kHz threshold and the average 2-4 kHz threshold does not exceed 1.3. Thus, the audiometric characteristics of the 2-3 kHz segment can distinguish between NIHL and SKI.

Von Hippel-Lindau disease (vHL). National clinical guideline for diagnosis and surveillance in Denmark. 3rd edition.

These clinical guidelines outline the criteria and recommendations for diagnostic and genetic work-up of families suspected of von Hippel-Lindau disease (vHL), as well as recommendations for prophylactic surveillance for vHL patients. The guideline has been composed by the Danish Coordination Group for vHL which is comprised of Danish doctors and specialists interested in vHL. The recommendations are based on longstanding clinical experience, Danish original research, and extensive review of the international literature. vHL is a hereditary multi-tumour disease caused by germline mutations in the VHL gene. vHL is inherited in an autosomal dominant manner. Predisposed individuals are advised to undergo prophylactic examinations, as they are at lifelong risk of developing multiple cysts and tumours, especially in the cerebellum, the spinal cord, the retina (hemangioblastomas), the kidneys (renal cell carcinoma), the adrenal glands (pheochromocytoma), the pancreas, as well as in other organs. As many different organs can be affected, several medical specialities often take part in both diagnosis and treatment of manifestations. vHL should be suspected in individuals with a family history of the disease, and/or in individuals with a vHL-associated manifestation; i.e. a hemangioblastoma in the retina or the central nervous system, familial or bilateral pheochromocytomas, familial, multiple, or early onset renal cell carcinomas, and in individuals with an endolymphatic sac tumour in the inner ear. Individuals suspected of vHL should be referred to a department of clinical genetics for genetic work-up and counselling as well as have a clinical work-up to identify any undiagnosed vHL-associated manifestations. This guideline describes the elements of the clinical diagnostic work-up, as well as the genetic work-up, counselling, and mutation screening. Individuals who are affected with vHL, individuals at risk of vHL, and VHL-mutation carriers are advised to follow the surveillance program which consists of regular prophylactic examinations relevant to different age groups. The examinations are recommended to start in infancy with annual paediatric examinations and ophthalmoscopy until the age of five years. From five to 14 years, annual plasma-metanephrine and plasma-normetanephrine tests, as well as annual hearing examinations are added. Also, an MRI (Magnetic Resonance Imaging) examination of the CNS and abdomen should be done between the ages of eight and 14 years. After the age of 15 years, individuals should be referred to: a) annual ophthalmoscopy in dilation, b) annual neurological examination, c) every two years: MRIs of the CNS, including the inner ear, d) annual ultrasound/MRI of the abdomen, e) annual plasma-metanephrine, plasma-normetanephrine, and plasma-chromogranin A tests, and f) annual hearing examination at a department of audiology. It is advised that one doctor takes on the responsibility of coordination of and referral to the many examinations, and the communication with the patient. To facilitate the coordination, and especially for the patients' own use, a mobile chart can be used. In 2012, the Danish vHL Coordination Group established a national vHL database comprising individuals with vHL and their relatives, as well as individuals examined for vHL. The database is designated to be a treatment and diagnostic instrument, as well as a tool in future vHL research in Denmark.

[Use of hearing aids five years after issue]. / Brug af høreapparater fem år efter tildelingen.

INTRODUCTION: With an annual issue of 100,000 hearing aids in Denmark it is of interest to quantify their use and non-use. METHODS: Adult reapplicants (n = 1003) with five-year-old hearing aids (median) were interviewed about their hearing aid use, and those possessing unused aids (n = 182) were contacted a year later with a postal questionnaire. The data were compared with 683 returned International Outcome Inventory - Hearing Aid (IOI-HA) questionnaires from a national quality control project conducted in the same period which had been mailed to 1125 of our patients from a central site. RESULTS: Of the 1003 hearing-aid users, 83% wore an aid for at least 3-4 hours daily while 13% never wore any. In the IOI-HA-survey, non-use was reported by only 2%. Among the 182 who were contacted a year later, the proportion of users tripled to 67%. Non-use was predominantly (70%) due to unpleasant sound quality, lack of benefit, or a poorly fitting ear mould/shell. Hearing aid usage increased with increasing hearing loss and with the patients' level of experience. Conversely, non-use seemed to increase with the length of the observation period. CONCLUSION: Although only 13% had stopped using their aids after five years, this represents a considerable loss which can be reduced through active follow up. The reported that the 2% non-use rate in the IOI-HA-clientele can be ascribed to the fact that the survey took place only 2-3 months post issue, but it may also reflect a non-response bias.