Christoph Brase

Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs approximately US

Head and neck paragangliomas: clinical and molecular genetic classification

2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age <or=40 years (OR, 4.0), and male gender (OR, 3.5). By screening only preselected cases and a stepwise approach, 60% cost reduction can be achieved, with 91.8% sensitivity and 94.5% negative predictive value. Our data give evidence that clinical parameters can predict for mutation and help prioritize gene testing to reduce costs in HNP. Such strategy is cost-saving in the practice of genetics-based personalized health care.

Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention

Head and neck paragangliomas are tumors arising from specialized neural crest cells. Prominent locations are the carotid body along with the vagal, jugular, and tympanic glomus. Head and neck paragangliomas are slowly growing tumors, with some carotid body tumors being reported to exist for many years as a painless lateral mass on the neck. Symptoms depend on the specific locations. In contrast to paraganglial tumors of the adrenals, abdomen and thorax, head and neck paragangliomas seldom release catecholamines and are hence rarely vasoactive. Petrous bone, jugular, and tympanic head and neck paragangliomas may cause hearing loss. The internationally accepted clinical classifications for carotid body tumors are based on the Shamblin Class I–III stages, which correspond to postoperative permanent side effects. For petrous-bone paragangliomas in the head and neck, the Fisch classification is used. Regarding the molecular genetics, head and neck paragangliomas have been associated with nine susceptibility genes: NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2 (SDH5), and TMEM127. Hereditary HNPs are mostly caused by mutations of the SDHD gene, but SDHB and SDHC mutations are not uncommon in such patients. Head and neck paragangliomas are rarely associated with mutations of VHL, RET, or NF1. The research on SDHA, SDHAF2 and TMEM127 is ongoing. Multiple head and neck paragangliomas are common in patients with SDHD mutations, while malignant head and neck paraganglioma is mostly seen in patients with SDHB mutations. The treatment of choice is surgical resection. Good postoperative results can be expected in carotid body tumors of Shamblin Class I and II, whereas operations on other carotid body tumors and other head and neck paragangliomas frequently result in deficits of the cranial nerves adjacent to the tumors. Slow growth and the tendency of hereditary head and neck paragangliomas to be multifocal may justify less aggressive treatment strategies.

Function-preserving therapy for jugulotympanic paragangliomas: A retrospective analysis from 2000 to 2010†

Importance Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. Objective To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. Design, Setting, and Patients This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. Main Outcomes and Measures Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. Results Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001). Conclusions and Relevance The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

Involvement of the anterior semicircular canal in posttraumatic benign paroxysmal positioning vertigo.

Treatment for jugulotympanic paragangliomas (JTPs) is shifting from radical toward function‐preserving surgery. Alternative primary treatments are available, such as stereotactic radiotherapy (SRT) and radiosurgery. The aim of this study was to analyze the results after primary function‐preserving surgery with or without adjuvant radiotherapy, or primary SRT, in the treatment of JTPs.

Treatment of cervical paragangliomas: Is surgery the only way?

Objective: To study the involvement of the different semicircular canals in posttraumatic benign paroxysmal positioning vertigo (BPPV) with special reference to the anterior canal (AC). Study Design: Retrospective review. Setting: Tertiary referral center. Patients: Seventy-four BPPV patients. Interventions: Neurotologic assessment with video-oculography; treatment of BPPV with the canalith repositioning procedure appropriate for the affected semicircular canal. Main Outcome Measures: Number of patients with AC, posterior canal (PC), horizontal canal (HC), and multiple-canal involvement in posttraumatic versus idiopathic BPPV. Results: 85.1% of patients were classified as idiopathic BPPV, whereas 14.9% had a history of posttraumatic BPPV. The prevalence of AC BPPV was significantly higher in the posttraumatic group (27.3%) compared with that in the idiopathic group (3.2%; Fishers exact test: p = 0.021). Multiple-canal (combined) BPPV was observed more frequently after head trauma (27.3%) compared with the idiopathic form of the disorder (1.6%; p = 0.009). In particular, the risk for combined AC/PC BPPV was greater in posttraumatic than idiopathic cases (odds ratio, 13.78; 95% confidence interval, 1.13-167.8). No significant differences were observed for the involvement of the PC and HC between the two groups. Two cases of combined AC/PC BPPV are presented with particular respect to the underlying trauma mechanism. Conclusion: Head trauma is a risk factor for AC and combined BPPV, in particular AC/PC BPPV. Involvement of the AC should especially be considered in patients who experienced head trauma resulting in a nonupright position of the body.

First experience with a new titanium clip stapes prosthesis and a comparison with the earlier model used in stapes surgery

PURPOSE To analyze the results after surgery or stereotactic radiotherapy (SRT) in the treatment of cervical paragangliomas. Against this background, the decision-making algorithm used in the treatment of carotid body tumors (CBTs) and vagal paragangliomas (VPs) was reevaluated relative to the existing literature on the topic. MATERIALS AND METHODS Retrospective study between 2000 and 2012. A total of 27 CBTs and nine VPs in 32 patients were treated. Shamblin class I: 59.3% (n=16); class II: 29.6% (n=8); class III: 11.1% (n=3). Treatment modalities were surgery, radiotherapy, or observation. The end points for analysis were long-term tumor control and integrity of the cranial nerves. RESULTS 21 CBTs and seven VPs underwent surgery; SRT was performed in three CBTs and two VPs. Three CBTs were clinically observed. Permanent nerve paresis followed after surgery for CBTs in five patients (20%) and in all patients with VPs. No impaired cranial nerve function resulted after SRT. The median follow-up period was 4.7 years. The tumor control rate after therapy for CBTs and VPs was 100%. One CBT that received clinical observation showed slow tumor progression. CONCLUSIONS A surgical procedure should be regarded as the treatment of choice in patients with small CBTs. In larger CBTs, particularly in elderly patients with unimpaired cranial nerves, radical surgery should be regarded critically. As surgery for VPs caused regularly impairment of cranial nerves with functional disturbances of various degrees a comprehensive consultation with the patient is mandatory and nonsurgical strategies should be discussed.

Bone conduction after stapes surgery: comparison of CO2 laser and manual perforation.

The aim of the study was to gain the first clinical experience with a new titanium clip prosthesis in stapes surgery, and to compare this model with its predecessor. We placed particular emphasis on the practicability of fixing the prosthesis to the long process of the incus and on the postoperative improvement in hearing.

Results obtained with a new superelastic nitinol stapes prosthesis in stapes surgery.

Objective To compare bone conduction after 2 different ways of perforating the stapes footplate during stapedotomy in patients with otosclerosis. Study Design Retrospective clinical study. Setting Tertiary reference center. Materials and Methods This study evaluated data from 302 patients (61.2% women) who had undergone primary surgery for stapedial ankylosis between 2000 and 2010. Bone conduction thresholds at 0.5, 1, 2, and 4 kHz were determined on the first and fourth postoperative days in all patients; 280 patients were followed up after 1 month and 125 after 1 year. Audiograms were compared with preoperative bone conduction. A laser was used to open the stapes footplate in 180 patients; manual perforation was performed in 122. Results Immediately postoperatively the bone conduction threshold was significantly worse at almost all frequencies. At lower frequencies (0.5 and 1 kHz), it improved to baseline within the first 4 days. At 2 kHz, the threshold on Day 4 remained significantly worse than baseline and improved only after 1 month, then exceeding the preoperative value. Bone conduction at 4 kHz still tended to be worse than baseline 1 month after surgery, but the difference was no longer statistically significant 1 year later. A direct comparison with classic stapedotomy showed a trend in favor of the laser technique, but the difference was not statistically significant. Conclusion Both laser and classic techniques can be used successfully in stapes surgery without causing long-term damage to the inner ear. Direct comparison shows a trend in favor of laser stapedotomy.

First experience with the fiber-enabled CO2 laser in stapes surgery and a comparison with the "one-shot" technique.

Objective The trimmable nitinol-polytetrafluoroethylene stapes prosthesis is a novel prosthesis that features a band-shaped nitinol loop. Unlike the SMart prosthesis, which uses the heat-activated self-crimping property of the alloy for fixation to the long process of the incus, this new prosthesis uses the property of superelasticity. The objective of the present study was to assess the hearing outcomes and intraoperative handling of the first 31 prostheses to be implanted in a primary stapes operation and to compare the results and experience thus obtained with those previously achieved with SMart prostheses. Study Design Retrospective clinical study. Setting Tertiary reference center. Patients The results obtained in the first 31 patients (16 women and 15 men) in whom a nitinol prosthesis was implanted in a primary stapes operation between May 2009 and April 2010 were assessed and compared with those obtained in the first 31 patients (23 women and 8 men) to receive a SMart prosthesis between October 2004 and September 2005. Intervention Primary stapes surgery. Main Outcome Measures Audiometry was performed preoperatively, and after a mean follow-up period of 26.9 days (standard deviation [SD], ±16 d) in the nitinol group and 26.2 days (SD, ±22 d) in the SMart group. Audiometry was repeated in 18 patients in the nitinol group and in 21 patients in the SMart group after a mean period of 480 days (SD, ±118 d) and 495 days (SD, ±160 d), respectively. Results All the nitinol-polytetrafluoroethylene prostheses were implanted without problem. Fixation was simpler than with the SMart piston prosthesis. In the nitinol group, mean ABG3000 and ABG4000 were 9.5 dB (SD, ±5.7 dB) and 10.7 dB (SD, ±6.1 dB), respectively, with an improvement of 21.8 dB (SD, ±8.0 dB) and 21.7 dB (SD, ±7.9 dB), respectively. The corresponding values in the SMart piston group were 8.9 dB (±4.3 dB) and 10.0 dB (±5.2 dB), respectively, with an improvement of 21.2 ± 8.2 dB and 20.8 ± 8.3 dB, respectively. At the second follow-up, the values in the nitinol group were 4.4 dB (SD, ±3.1 dB) for ABG3000 and 6.5 dB (SD, ±4.3 dB) for ABG4000, with a mean improvement of 27.9 ± 6.0 dB and 27.0 ± 6.9 dB, respectively, whereas in the SMart group, the values were 5.7 ± 5.0 dB for ABG3000 and 6.4 ± 4.0 dB for ABG4000, with a mean improvement of 24.9 ± 7.2 and 24.7 ± 7.9 dB, respectively. These results did not differ to a statistically significant extent between the 2 groups. Conclusion The hearing outcomes obtained with the new superelastic nitinol prosthesis were similar to those that we had obtained previously with the SMart prosthesis. The fixation mechanism is simpler than with other types of prosthesis; however, the loop of the prosthesis seems not to be equally suitable for all diameters of the long process of the incus.