Delayed facial nerve palsy after vestibular schwannoma resection: risk factors, extent and prognosis.

INTRODUCTION: Facial nerve palsies may develop during the postoperative period of microsurgical removal of vestibular schwannomas (VSs), even after normal facial function for days or weeks after surgery. The aim of this study was to identify the pathomechanism and predictive factors of delayed palsy. MATERIAL AND METHOD: The clinical data of 193 patients who underwent vestibular schwannoma surgery between 2012 and 2021 were retrospectively analyzed. A total of 134 patients were included. The patients showed intact facial nerve function up to 24 h after surgery. All patients (n = 20) with palsy from postoperative day 4 were included and collectively referred to as delayed facial nerve palsy (DFNP). Various factors were checked using a binomial regression analysis. RESULTS: The mean age of patients with DFNP was 57.8 years (55% female, 45% male). 70% had VS with KOOS ≥ 3, and 60% underwent surgery via a translabyrinthine approach Among the 16 patients with DFNP-related neurotropic pathogens, 25% were seropositive for herpes simplex virus. Most patients (n = 9/20) experienced onset of palsy between postoperative days 6 and 10. Of the four variables included in the significance test, three were significant: KOOS ≥ 3 (p < .04), ipsilateral vestibular organ failure (p < .05), and age group (p < .03). After therapy, 100% of patients recovered almost complete facial nerve function. The parameters mentioned above (KOOS classification and ipsilateral vestibular dysfunction) could be proven risk factors for the occurrence of DFNP.

[Traumatology of the lateral skull base]. / Traumatologie der Laterobasis.

The most common cause of lateral skull base fractures are still road traffic accidents, followed by falls. The radiologic classification into otic capsule-sparing or otic capsule-violating fractures correlates well with an increased risk of injury to the sensitive structures of the middle ear with otic capsule-violating fractures. In case of immediate onset complete facial nerve paralysis, decompression surgery is generally recommended if bony impingement can be demonstrated on high-resolution CT of the temporal bone. For many other facials nerve complications, recent publications have achieved good to excellent facial nerve recovery rates with watchful waiting under conservative treatment with prednisolone administration.

New software for three-dimensional visualization and calculation of volume of living cells.

We investigated the physical properties of head and neck cancer cells to develop new cell-selective treatment strategies for squamous cell carcinoma. For better characterization and subsequent differentiation of cancerous and healthy cells, we developed MATLAB-based software to analyze image stacks obtained using a confocal laser-scanning microscope. A confocal laser-scanning microscope was used for three-dimensional (3-D) imaging of a cell line from the head and neck area. The volume of cell organelles of interest was calculated using our newly developed software. Our software enables 3-D visualization and volume calculation as well as data analysis associated with cell morphology. Using filter and semi-automatic segmentation algorithms, our software recognizes individual cell organelles in each slice of an image stack. It matches the corresponding cell cross section areas to produce a 3-D image and to determine the volume of the imaged organelles. We calculated the volume of the nucleus, actin filaments and microtubules in relation to total cell volume. Our software enables 3-D visualization and calculation of organelle volume, which improves cell characterization and comparison of healthy and cancerous cell lines. Differences between cell lines can be observed in detail and used to develop new cancer treatment strategies.

Retrospective in silico evaluation of optimized preoperative planning for temporal bone surgery.

PURPOSE: Robot-assisted surgery at the temporal bone utilizing a flexible drilling unit would allow safer access to clinical targets such as the cochlea or the internal auditory canal by navigating along nonlinear trajectories. One key sub-step for clinical realization of such a procedure is automated preoperative surgical planning that incorporates both segmentation of risk structures and optimized trajectory planning. METHODS: We automatically segment risk structures using 3D U-Nets with probabilistic active shape models. For nonlinear trajectory planning, we adapt bidirectional rapidly exploring random trees on Bézier Splines followed by sequential convex optimization. Functional evaluation, assessing segmentation quality based on the subsequent trajectory planning step, shows the suitability of our novel segmentation approach for this two-step preoperative pipeline. RESULTS: Based on 24 data sets of the temporal bone, we perform a functional evaluation of preoperative surgical planning. Our experiments show that the automated segmentation provides safe and coherent surface models that can be used in collision detection during motion planning. The source code of the algorithms will be made publicly available. CONCLUSION: Optimized trajectory planning based on shape regularized segmentation leads to safe access canals for temporal bone surgery. Functional evaluation shows the promising results for both 3D U-Net and Bézier Spline trajectories.

i3PosNet: instrument pose estimation from X-ray in temporal bone surgery.

PURPOSE: Accurate estimation of the position and orientation (pose) of surgical instruments is crucial for delicate minimally invasive temporal bone surgery. Current techniques lack in accuracy and/or line-of-sight constraints (conventional tracking systems) or expose the patient to prohibitive ionizing radiation (intra-operative CT). A possible solution is to capture the instrument with a c-arm at irregular intervals and recover the pose from the image. METHODS: i3PosNet infers the position and orientation of instruments from images using a pose estimation network. Said framework considers localized patches and outputs pseudo-landmarks. The pose is reconstructed from pseudo-landmarks by geometric considerations. RESULTS: We show i3PosNet reaches errors [Formula: see text] mm. It outperforms conventional image registration-based approaches reducing average and maximum errors by at least two thirds. i3PosNet trained on synthetic images generalizes to real X-rays without any further adaptation. CONCLUSION: The translation of deep learning-based methods to surgical applications is difficult, because large representative datasets for training and testing are not available. This work empirically shows sub-millimeter pose estimation trained solely based on synthetic training data.

Patient quality of life after vestibular schwannoma removal: possibilities and limits to measuring different domains of patients' wellbeing.

PURPOSE: Since the 1980s, health-related quality of life (HRQOL) has been recognized in the assessment of medical treatment. To determine the health-related quality of life (HRQOL) of vestibular schwannoma (VS) patients, a specific questionnaire that has been validated in different languages is essential. METHODS: The Short Form-36 Health Survey (SF-36) and PANQOL questionnaires in German were evaluated in patients after removal of a VS via the translabyrinthine approach. Descriptive statistics of a comparison of the SF-36 results to those of a normal sample are illustrated. Criterion validity was investigated using Spearman's rank test to correlate the PANQOL domains with the SF-36 domains. A confirmatory factor analysis of the PANQOL was performed to determine the stability of the factor structure of the PANQOL questionnaire for our cohort. RESULTS: The criterion validity of the German PANQOL questionnaire is comparable to that of the original English version. The SF-36 domains values ranged from 49.31/100 (role physical) to 66.46/100 (physical functioning). Compared to the normal population, patients who underwent surgical removal of a VS showed a significantly reduced quality of life, mainly in domains such as physical and social functioning, as well as psychological wellbeing. CONCLUSION: The German PANQOL has been validated and is now available. Post-surgical treatment should be focused not only on physiological rehabilitation but also on improving the quality of life, especially aspects of psychological and social wellbeing.

High-precision evaluation of electromagnetic tracking.

PURPOSE: Navigation in high-precision minimally invasive surgery (HP-MIS) demands high tracking accuracy in the absence of line of sight (LOS). Currently, no tracking technology can satisfy this requirement. Electromagnetic tracking (EMT) is the best tracking paradigm in the absence of LOS despite limited accuracy and robustness. Novel evaluation protocols are needed to ensure high-precision and robust EMT for navigation in HP-MIS. METHODS: We introduce a novel protocol for EMT measurement evaluation featuring a high-accuracy phantom based on LEGO[Formula: see text], which is calibrated by a coordinate measuring machine to ensure accuracy. Our protocol includes relative sequential positions and an uncertainty estimation of positioning. We show effects on distortion compensation using a learned interpolation model. RESULTS: Our high-precision protocol clarifies properties of errors and uncertainties of EMT for high-precision use cases. For EMT errors reaching clinically relevant 0.2 mm, our design is 5-10 times more accurate than previous protocols with 95% confidence margins of 0.02 mm. This high-precision protocol ensures the performance improvement in compensated EMT by 0.05 mm. CONCLUSION: Our protocol improves the reliability of EMT evaluations because of significantly lower protocol-inherent uncertainties. To reduce patient risk in HP-MIS and to evaluate magnetic field distortion compensation, more high-accuracy protocols such as the one proposed here are required.

Toward an automatic preoperative pipeline for image-guided temporal bone surgery.

PURPOSE: Minimally invasive surgery is often built upon a time-consuming preoperative step consisting of segmentation and trajectory planning. At the temporal bone, a complete automation of these two tasks might lead to faster interventions and more reproducible results, benefiting clinical workflow and patient health. METHODS: We propose an automatic segmentation and trajectory planning pipeline for image-guided interventions at the temporal bone. For segmentation, we use a shape regularized deep learning approach that is capable of automatically detecting even the cluttered tiny structures specific for this anatomy. We then perform trajectory planning for both linear and nonlinear interventions on these automatically segmented risk structures. RESULTS: We evaluate the usability of segmentation algorithms for planning access canals to the cochlea and the internal auditory canal on 24 CT data sets of real patients. Our new approach achieves similar results to the existing semiautomatic method in terms of Dice but provides more accurate organ shapes for the subsequent trajectory planning step. The source code of the algorithms is publicly available. CONCLUSION: Automatic segmentation and trajectory planning for various clinical procedures at the temporal bone are feasible. The proposed automatic pipeline leads to an efficient and unbiased workflow for preoperative planning.

Cochlear Implantation in Patients With Single-sided Deafness After the Translabyrinthine Resection of the Vestibular Schwannoma-Presented at the Annual Meeting of ADANO 2016 in Berlin.

OBJECTIVE: To evaluate effectiveness of the cochlear implant (CI) to facilitate single-sided deafness (SSD) rehabilitation following translabyrinthine resection of the vestibular schwannoma. STUDY DESIGN: Retrospective patient review. SETTING: Single center, University hospital. PATIENTS: Patients with SSD who underwent translabyrinthine resection of a vestibular schwannoma with anatomical preservation of the cochlear nerve and subsequent CI on the same ear. INTERVENTIONS: CI at post-translabyrinthine resection of the acoustic neuroma to treat SSD, and evaluation by retrospective individual case review in a period from 2009 to 2016. MAIN OUTCOME MEASURES: Individual patients' clinical outcome and speech understanding. RESULTS: Thirteen patients were provided CI. In all cases, complete removal of the tumor was achieved and the cochlear nerve was preserved; in one case, the CI was implanted simultaneously. In most cases, the follow-up interval was 2 years. In 9 of 13 cases, the implanted ear achieved capability to understand and discriminate monosyllabic words at 65 dB. Level of speech understanding of over 50% at 65 dB was possible in 7 patients at 12 months after the first fitting of CI. CONCLUSIONS: Under certain conditions, CI was an effective solution to restore hearing in patients with SSD following translabyrinthine access to the skull base. Study with prospective design is required to provide more significant results.

The Wnt-Driven Mll1 Epigenome Regulates Salivary Gland and Head and Neck Cancer.

We identified a regulatory system that acts downstream of Wnt/ß-catenin signaling in salivary gland and head and neck carcinomas. We show in a mouse tumor model of K14-Cre-induced Wnt/ß-catenin gain-of-function and Bmpr1a loss-of-function mutations that tumor-propagating cells exhibit increased Mll1 activity and genome-wide increased H3K4 tri-methylation at promoters. Null mutations of Mll1 in tumor mice and in xenotransplanted human head and neck tumors resulted in loss of self-renewal of tumor-propagating cells and in block of tumor formation but did not alter normal tissue homeostasis. CRISPR/Cas9 mutagenesis and pharmacological interference of Mll1 at sequences that inhibit essential protein-protein interactions or the SET enzyme active site also blocked the self-renewal of mouse and human tumor-propagating cells. Our work provides strong genetic evidence for a crucial role of Mll1 in solid tumors. Moreover, inhibitors targeting specific Mll1 interactions might offer additional directions for therapies to treat these aggressive tumors.

Influence of patient-specific anatomy on medical computed tomography and risk evaluation of minimally invasive surgery at the otobasis.

PURPOSE: With the increasing use of new minimally invasive approaches in temporal bone surgery, the need arises for evaluation of the risk of injury to sensitive anatomical structures. The factors that influence the measurement uncertainty (variation in representation of position and shape of anatomical structures) of imaging are of relevance. We investigate the effect of patients' anatomy on the measurement uncertainty of medical CT. METHODS: Six formalin-fixed temporal bones were used, fiducial markers were bone-implanted, and 20 CT scans of each temporal bone were generated. Surgically threatened anatomical structures of importance were defined. Manual segmentation was performed to create 3D surface models, and different Gaussian filters were applied. Analysis points were established along the border of the superior semicircular canal to determine the deviation between the 3D images of the labyrinth. The standard uncertainty was calculated, and one-way analysis of variance was performed (significance level = 5%) to evaluate the effect of certain factors (patient, side, Gaussian filter) on the measurement uncertainty. RESULTS: The influence of patient-specific anatomy on the measurement uncertainty of medical CT (p = 0.049) was demonstrated for the first time. The applied Gaussian filter (p = 0.622) and the patient's side (p = 0.341) showed no significant effect. CONCLUSION: The applied method and the results of the statistical analysis suggest that the patient's individual anatomical conditions affect the measurement uncertainty of medical CT. Thus, the patient's anatomy must be considered as an important influencing factor during risk evaluation concerning minimally invasive and image-guided surgery.

Surgery of Small Anterior Skull Base Meningiomas by Endoscopic 5-Aminolevulinic Acid Fluorescence Guidance: First Clinical Experience.

BACKGROUND: Minimally invasive surgery of small skull base meningiomas is technically challenging. We report the role of endoscopic 5-aminolevulinic acid fluorescence guidance (e-5-ALA-FGS) for small and deep-seated anterior skull base meningiomas. METHODS: We report the cases of 2 patients. The first case was a small olfactory groove meningioma resected via a trans-eyebrow, subfrontal approach. The second case was a clinoid meningioma with invasion of the optic canal resected via a small frontolateral approach. Intraoperative documentation demonstrated the usefulness of 5-ALA endoscopy. In either case, residual fluorescing tumor tissue was detected. No complication was encountered. The clinical and radiological outcomes were good. No regrowth had occurred after 54 and 17 months of follow-up, respectively. RESULTS: Residual meningioma tissue on the far side of a keyhole approach (e.g., in the olfactory groove or at the optic canal) can be difficult to visualize. Visualization can be improved by use of an endoscope. To date, fluorescence guidance with a microscope was limited by insufficient fluorescence signals in deep corridors. With a specially equipped 5-ALA fluorescence endoscope, one can combine the advantages of both endoscopic vision and fluorescence guidance. The results of present report have demonstrated the usefulness of 5-ALA endoscopy for difficult to visualize areas. CONCLUSION: Endoscopic 5-ALA fluorescence guidance was shown to be feasible when resecting small and deep-seated skull base meningiomas via minimally invasive approaches. Based on this proof of principle, we encourage its evaluation for the middle or posterior fossa (e.g., internal auditory canal) and other difficult areas (e.g., behind neurovascular structures or the brainstem). The sensitivity and specificity of this method should be prospectively and systematically investigated.

Continuous and Dynamic Facial Nerve Mapping During Surgery of Cerebellopontine Angle Tumors: Clinical Pilot Series.

OBJECTIVE: To evaluate a new surgical tool combining suction and monopolar neurostimulation (stimulation sucker) for cerebellopontine angle (CPA) tumors. The usefulness for continuous (time) and dynamic (space) facial nerve mapping was studied. METHODS: Patients operated on with the stimulation sucker for a CPA tumor between April 2016 and May 2017 in a tertiary care center were identified. Clinical charts were retrospectively evaluated. The minimum follow-up time of patients was 12 months. RESULTS: The study population included 17 patients with tumor (6 women and 11 men). The age range was from 2 to 77 years (mean age, 45.7 years; standard error of the mean, 22.7 years). Most CPA tumors were large (Koos grade 4) vestibular schwannomas (n = 10); other pathologies included petrous meningioma (n = 1), metastasis (n = 1), medulloblastoma (n = 2), ependymoma (n = 2), and pilocytic astrocytoma (n = 1). One patient with trigeminal neuralgia served as the normal control subject. No complications because of the stimulation sucker were encountered. Clinical and radiologic outcomes compared favorably with institutional experience and literature. The stimulation sucker allowed for continuous (time) mapping of the facial nerve at the site of resection (space). This real-time feedback allowed early identification of the facial nerve. Handling and ergonomy were excellent and workflow improved. The shortcomings compared with a bayonet-shaped bipolar probe were decreased visibility of neurovascular structures and lower spatial discrimination. The new device did not simplify delicate at the brainstem and on the nerve. We think it should be considered as a complementary tool in the surgeon's armamentarium. CONCLUSIONS: Until now, nerve damage as assessed by neuromonitoring (e.g., facial nerve electromyography, motor evoked potential) served as surrogate for nerve function. This concept should be challenged. The studied stimulation sucker detected the facial nerve earlier than conventional techniques, preventing harm by surgical trauma. A larger, prospective study is warranted to better define its role in CPA surgery.

Quality of Life After Translabyrinthine Vestibular Schwannoma Resection-Reliability of the German PANQOL Questionnaire.

OBJECTIVE: To quantify the postoperative quality of life (QOL) of patients after translabyrinthine surgery for vestibular schwannoma (VS) using the German version of the Penn acoustic neuroma quality-of-life questionnaire (PANQOL) in a university hospital. METHODS: The PANQOL questionnaire was administered to 72 patients who were treated in our department with translabyrinthine surgery for VS between January 2007 and January 2017. Descriptive evaluations of results were performed in addition to analyses of the reliability and convergent validity of the results and a subgroup analysis. RESULTS: For the first time, QOL was measured in German-speaking VS patients after translabyrinthine surgery. Cronbach's alpha for internal consistency and Guttman's split half, used as measures of reliability, showed values between 0.39 and 0.92 (raw alpha) and 0.58 and 0.98 (Lambda 4), respectively. DESCRIPTIVE STATISTICS: The mean total PANQOL score of patients after translabyrinthine VS resection was 61.96. The domain "hearing" had the lowest score (50.87), while "facial dysfunction" had the highest score (74.88). Subgroup analysis showed that neither preoperative tumor size nor elapsed time postoperatively significantly influenced QOL outcomes. CONCLUSIONS: Depending on the different domains the German PANQOL questionnaire showed poor to good internal consistency, reliability, and convergent validity. Moreover, some VS patients suffer from reduced QOL for a long time after the translabyrinthine procedure, thus psycho-oncological care should be recommended in these cases.

Mutational and Functional Analysis of FANCB as a Candidate Gene for Sporadic Head and Neck Squamous Cell Carcinomas.

BACKGROUND/AIM: Head and neck squamous cell carcinomas (HNSCCs) form a heterogeneous tumor entity located throughout the oral cavity, pharynx and larynx that is caused predominantly by chemically or virally induced carcinogenesis. Heterozygous germline mutations in cancer susceptibility genes might also lead to increased incidence of HNSCCs. As DNA stability is typically impaired in HNSCC cells and genes of the Fanconi anemia/BRCA DNA repair pathway can be mutated or down-regulated in HNSCCs, we investigated here whether germline mutations occur in the X-chromosomal FANCB as candidate gene. MATERIALS AND METHODS: Germline DNA of 85 consecutive HNSCC patients was sequenced. Missense alterations in FANCB were functionally tested in reference cells. RESULTS AND CONCLUSION: Four single nucleotide polymorphisms were identified, three of which were located in untranslated regions of FANCB (rs2188383, rs2375729, rs2905223) and predicted to be associated with normal function. One missense alteration, c.1004G>A resulting in p.G335E (rs41309679), in exon 4 was detected in five men in homozygous and in five women in heterozygous state. Four in silico prediction programs uniformally predicted p.G335E to be associated with loss-of-function of the protein. To clarify these predictions, we expressed the FANCB p.G335E protein in primary human FANCB deficient fibroblasts. Cell cycle analysis of these fibroblasts established that the FANCB p.G335E was functionally indistinguishable from the wildtype FANCB protein. Thus, functional studies in genetically defined cells showed that the p.G335E germline alteration in FANCB is not associated with impaired function.

[Hearing rehabilitation with the cochlea implant following translabyrinthine CPA tumor removal ?] / Hörrehabilitation durch Cochlea-Implantation nach Vestibularisschwannom-Entfernung?

We present a quality analysis of 10 patients with an individual treatment trial for a simultaneous or consecutive cochlea implantation after translabyrinthine removal of a neurinoma at the cerebellopontine angle. The results show that most of the patients benefit from the cochlea implantation after unilateral deafness. Through a careful surgical preparation technique at the inner ear canal and its surroundings the morphological and functional integrity of the neurovascular structures can be guaranteed.

Multistep translation and cultural adaptation of the Penn acoustic neuroma quality-of-life scale for German-speaking patients.

BACKGROUND: Monitoring the health-related quality of life (HRQOL) for patients with vestibular schwannoma (VS) has garnered increasing interest. In German-speaking countries, there is no disease-specific questionnaire available similar to the "Penn Acoustic Neuroma Quality-of-life Scale" (PANQOL). METHOD: We translated the PANQOL for German-speaking patients based on a multistep protocol that included not only a forward-backward translation but also linguistic and sociocultural adaptations. The process consists of translation, synthesis, back translation, review by an expert committee, administration of the prefinal version to our patients, submission and appraisal of all written documents by our research team. The required multidisciplinary team for translation comprised head and neck surgeons, language professionals (German and English), a professional translator, and bilingual participants. A total of 123 patients with VS underwent microsurgical procedures via different approaches at our clinic between January 2007 and January 2017. Among these, 72 patients who underwent the translabyrinthine approach participated in the testing of the German-translated PANQOL. RESULT: The first German version of the PANQOL questionnaire was created by a multistep translation process. The responses indicate that the questionnaire is simple to administer and applicable to our patients. CONCLUSION: The use of a multistep process to translate quality-of-life questionnaires is complex and time-consuming. However, this process was performed properly and resulted in a version of the PANQOL for assessing the quality of life of German-speaking patients with VS.

The Youngest Reported and Successfully Treated Patient with a Dermoid Cyst of the Parotid Gland: A Rare Pediatric Case.

Dermoid cysts (DCs) are rare benign, epithelial-lined lesions. Up to 7% of them are found in the head and neck region and 80% of those predominantly occur in the orbit, in the nose, and in the floor of the mouth. The average age of presentation is around the age of six. Dermoid cysts located in the parotid gland have only been published in 19 cases so far. Interestingly, the mean age of occurrence in the parotid gland was much higher (31 years). We report on a four-year-old girl being the youngest patient who had ever been diagnosed with this disease.

Challenges in Histologic Diagnosis of Nonchordomatous Lesions of the Clivus.

IMPORTANCE: Nonchordomatous clival lesions are rare and represent a wide range of different benign and malignant pathologies. For an accurate and specific final diagnosis, biopsy procedures and/or resections followed by histologic examination are mandatory. OBJECTIVE: To illustrate the challenges in obtaining a final histologic diagnosis in patients with various types of clival lesions. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective analysis of medical records of 24 patients who underwent endonasal endoscopic biopsy of the clivus between February 1, 2005, and June 1, 2013, in 2 medical university hospitals. Analysis was conducted between January 1 and August 15, 2014. INTERVENTIONS: All patients underwent endoscopic biopsy of the clivus. MAIN OUTCOMES AND MEASURES: The number of biopsies performed to establish a diagnosis in clival lesions and the problems encountered when analyzing the radiologic findings and histologic results. RESULTS: In 14 of 24 patients (58%), a conclusive histologic diagnosis of the nonchordomatous clival lesion could be determined. Despite up to 3 endonasal endoscopic biopsies, the histologic result could not be clearly specified in the remaining 10 patients (42%). No major complications occurred. Treatment based on the testing results included endonasal endoscopic surgery, radiotherapy or radiochemotherapy, and/or follow-up examination. CONCLUSIONS AND RELEVANCE: Challenges can occur in the radiologic evaluation and pathologic differentiation of diverse bone lesions with overlapping morphologic features as well as in the differentiation between neoplastic, reactive, inflammatory, and metabolic bone lesions and developmental disorders. Despite more than 1 biopsy, histologic classification will not always lead to a definitive diagnosis. In such cases, an interdisciplinary team should decide whether additional biopsies should be performed or whether clinical, endoscopic, and radiologic controls are sufficient.

AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia.

Fanconi anemia (FA) is a rare inherited disorder clinically characterized by congenital malformations, progressive bone marrow failure and cancer susceptibility. At the cellular level, FA is associated with hypersensitivity to DNA-crosslinking genotoxins. Eight of 17 known FA genes assemble the FA E3 ligase complex, which catalyzes monoubiquitination of FANCD2 and is essential for replicative DNA crosslink repair. Here, we identify the first FA patient with biallelic germline mutations in the ubiquitin E2 conjugase UBE2T. Both mutations were aluY-mediated: a paternal deletion and maternal duplication of exons 2-6. These loss-of-function mutations in UBE2T induced a cellular phenotype similar to biallelic defects in early FA genes with the absence of FANCD2 monoubiquitination. The maternal duplication produced a mutant mRNA that could encode a functional protein but was degraded by nonsense-mediated mRNA decay. In the patient's hematopoietic stem cells, the maternal allele with the duplication of exons 2-6 spontaneously reverted to a wild-type allele by monoallelic recombination at the duplicated aluY repeat, thereby preventing bone marrow failure. Analysis of germline DNA of 814 normal individuals and 850 breast cancer patients for deletion or duplication of UBE2T exons 2-6 identified the deletion in only two controls, suggesting aluY-mediated recombinations within the UBE2T locus are rare and not associated with an increased breast cancer risk. Finally, a loss-of-function germline mutation in UBE2T was detected in a high-risk breast cancer patient with wild-type BRCA1/2. Cumulatively, we identified UBE2T as a bona fide FA gene (FANCT) that also may be a rare cancer susceptibility gene.