Fabry disease is a rare X-linked lysosomal storage disorder that affects multiple organ systems, including the gastrointestinal tract. The aims were to characterize the prevalence, characteristics, and severity of gastrointestinal symptoms in patients with Fabry disease compared to the general population, and to investigate the relationships between these gastrointestinal symptoms with clinical outcomes, including disease severity (DS3), health-related quality of life, psychological distress, and pain. A cross-sectional study design was used. Adults (≥ 18 years) with Fabry disease attending regular follow-up appointments at Oslo University Hospital, Norway, were recruited. Participants completed validated measures in Norwegian language of gastrointestinal symptoms [Rome III and the Irritable Bowel Syndrome Severity Scoring System (IBS-SSS)], Short-Form Health Survey-36 (SF-36v2), Hospital Anxiety and Depression scale, and Brief Pain Inventory. Thirty-five adults with Fabry disease participated (mean age = 48 years; 54

Introduction::Choanal atresia (CA) is a congenital narrowing or obliteration of the posterior nasal aperture. The condition is rare with an incidence of approximately 1 in 5000 to 9000 live births.Objective::The aim of this work was to assess the results of treating this condition at the Otolaryngology Department in Oslo University Hospital‐Rikshospitalet.Methods::Retrospective review of patients treated at Oslo University Hospital‐Rikshospitalet between 2005 and 2015 were performed. The review consisted of surgical techniques and outcomes, types of atresia, uses of stent and mitomycin C, age at operation, laterality of atresia, and associated anomalies.Results::Thirty‐one patients with CA were referred to Oslo University Hospital‐Rikshospitalet during the mentioned observation period. Nine (29%) of the cases had bilateral CA and 22 (71%) had unilateral CA. Ten patients (32%) had bony atresia, 12 (39%) had membranous and eight (26%) had mixed type of atresia. Twenty‐one patients (68%) needed revision surgery because of complete or partial restenosis after primary surgery. Stents were applied in 16 cases (52%) of patients and Mitomycin C was only used in the primary surgery of three patients. In the bilateral group, eight of the nine patients were operated on within the first 9 days of life. Sixteen patients (45%) had associated anomalies.Conclusions::According to the observations in our sample, the restenosis problem is expected more and may need more revisions in bilateral CA than the unilateral type. The presence of other anomalies is associated with higher incidence of restenosis. Stenting is not essential in preventing restenosis.

Background: The estimated prevalence of tracheobronchomalacia (TBM) in children is about 1:2100. Tracheomalacia (TM) prevalence is higher in patients with chronic lung disease such as bronchiectasis and cystic fibrosis (CF) and may contribute to increased morbidity. Objective: To determine the prevalence and assess clinical features of TM, TBM and bronchomalacia (BM) in patients with primary ciliary dyskinesia (PCD). Methods: We performed a retrospective case-note review of all children with a confirmed or highly likely diagnosis of PCD attending Oslo University Hospital between 2000-2021. We selected those who had undergone flexible fiberoptic bronchoscopy (FB) and in whom the presence of TBM was assessed. We retrieved demographic and clinical data, including airway symptoms, PCD-diagnostic criteria, indication for bronchoscopy, the presence of lobar atelectasis, bacteriology and the descriptive and unblinded video-recorded results of FB. Complications occurring during and after bronchoscopy were noted. Results: Of 71 children with PCD, 32 underwent FB and were included in the review. The remaining 39 were included for TBM prevalence calculation only. Median age at FB was 6.0 y (3.1 – 11.9). Twenty-two children (69%) had intrathoracic airway malacia. Four (13%) had isolated TM, seven (22%) had TBM, and 11 (34%) had isolated BM affecting either main (n=4) or lobar bronchi (n=7) (LBM), including four with associated lobar atelectasis. FB related complications, one major, 12 minor, were documented in 13 children (41%). Conclusion: We found a high prevalence of TBM among children with PCD undergoing FB. This may represent a significant comorbidity and have implications for patient management.

Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type– and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.

Objectives:The objective of this study was twofold: to determine the prevalence of arterial and venous thromboembolic events in the Norwegian Hereditary Hemorrhagic Telangiectasia (HHT) population, and to explore potential factors linked to such events, with particular emphasis on FVIII. Methods:Patients with an HHT diagnosis attending the Otorhinolaryngology Department at Oslo University Hospital-Rikshospitalet were included consecutively between April 2021 and November 2022. We recorded the participants' medical history with an emphasis on thromboembolic events. Measurements of blood constituents, including FVIII, FIX, vWF, hemoglobin, iron, ferritin, and CRP were performed. Results:One hundred and thirty-four patients were included in the study. The total prevalence of thromboembolic events among the participants was 23.1%. FVIII levels were high (>150 IU/dL) in the majority of HHT patients (n = 84) (68.3%) and were significantly associated with thromboembolic events (p < .001), as was age. Of the patients with high FVIII levels, 28 (33%) had experienced a thromboembolic event. Furthermore, FVIII levels were measured consecutively in 51 patients and were found to fluctuate above or below 150 IU/dL in 25% of these cases. Conclusion:Thromboembolic events are highly prevalent in the Norwegian HHT population and are significantly associated with FVIII levels. FVIII levels can fluctuate, and measurements should be repeated in HHT patients to assess the risk of thromboembolic events. Level of Evidence:4.

Abstract Background The randomised double-blinded placebo-controlled EXIST-1–3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms in patients with tuberous sclerosis complex (TSC), although evidence of outcomes in clinical practice remains limited. This study aimed to investigate, in clinical practice, the effectiveness and safety of everolimus for epilepsy, renal angiomyolipoma (rAML), and subependymal giant cell astrocytoma (SEGA) in patients with TSC. Results The study included 64 patients with TSC (median age: 19, range 0.9–54 years) receiving everolimus treatment (Norway: n = 35; Denmark: n = 29). Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment. Nineteen (42%) patients changed their anti-seizure medications (ASMs). Responders were more common among patients < 18 years (46%) than among patients ≥ 18 years (14%, p = 0.03). In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% and 59%, respectively, after a mean treatment duration of 37 months. SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months. Adverse effects were reported in 61 of 64 patients (95%) after a median treatment duration of 31 months (range 0–106), with oral ulceration/stomatitis (63%) and upper respiratory tract infections (38%) being the most common. The most common laboratory abnormalities were increased cholesterol (41%), anaemia (30%), and leucopoenia (25%). Grade 3–4 adverse effects were reported in 36% of cases, and life-threatening conditions were reported in two patients. Nine patients discontinued everolimus treatment. Conclusions Seizure reduction in this study sample was consistent with results from EXIST, but might be lower than expected, given that changes in concomitant ASMs are part of clinical practice. Seizure reduction was associated with younger age. As with EXIST, everolimus reduced or stabilised rAML size in most patients. SEGA volume was reduced in all three patients. Close follow-up is needed for this group, especially for children and patients who may not be able to report adverse effects.

Craniosynostosis (CS) is a common congenital anomaly defined by premature fusion of one or more cranial sutures. Syndromic CS involves additional organ anomalies or neurocognitive deficits and accounts for 25%-30% of the cases. In a recent population-based study by our group, 84% of the syndromic CS cases had a genetically verified diagnosis after targeted analyses. A number of different genetic causes were detected, confirming that syndromic CS is highly heterogeneous. In this study, we performed whole-exome sequencing of 10 children and parents from the same cohort where previous genetic results were negative. We detected pathogenic, or likely pathogenic, variants in four additional genes (NFIA, EXTL3, POLR2A, and FOXP2) associated with rare conditions. In two of these (POLR2A and FOXP2), CS has not previously been reported. We further detected a rare predicted damaging variant in SH3BP4, which has not previously been related to human disease. All findings were clustered in genes involved in the pathways of osteogenesis and suture patency. We conclude that whole-exome sequencing expands the list of genes associated with syndromic CS, and provides new candidate genes in osteogenic signaling pathways.

Abstract Background Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by multiorgan dysfunction. Since individuals with FD usually experience progressive clinical disease manifestations, their health-related quality of life (HRQOL) is expected to change over time. However, there is limited longitudinal research examining HRQOL outcomes in individuals with FD. We aimed to: assess longitudinal outcomes in HRQOL in adults with FD; examine the physical- and mental HRQOL trajectories at the initial registration (baseline), 3–5 year, and 7–13 year follow-ups; and evaluate the possible associations of age, sex and medical complications with the physical- and mental HRQOL trajectories. Methods Forty-three individuals with FD (53% female) who were aged 18 to 81 years at baseline attended clinical follow-up visits between 2006 and 2020. Medical records were extracted retrospectively. Demographics and the 36-item Short-Form Health Survey (SF-36) were recorded at scheduled visits, except for the last data collection which was prospectively obtained in 2020. The physical (PCS) and mental (MCS) composite scores (SF-36) were chosen as outcome measures. Results The eight SF-36 domain scores were stable over a span of 13 years, and only physical- and social functioning domains worsened clinically over this follow-up period. Mean baseline SF-36 domain scores were all significantly lower (decreased HRQOL) in the FD sample compared with Norwegian population norms. Two hierarchical linear models were run to examine whether demographics and medical complications (measured at the last clinical visit) predicted physical and mental HRQOL trajectories. Age above 47 years (p < 0.001), male sex (p = 0.027), small fibre neuropathy (p < 0.001), renal dysfunction (p < 0.001), and cerebrovascular events (p = 0.003) were associated with lower HRQOL over time. No significant interactions were found between the time of follow up and the abovementioned predictors of HRQOL. Conclusions Overall HRQOL trajectories remained stable between baseline, 3–5 year, and 7–13 year follow-ups, with the majority of individuals reporting decreased physical and mental HRQOL. Medical complications in combination with older age and male sex are important predictors of lower HRQOL in FD. Awareness of this relationship is valuable both for health care providers and for patients. The findings provide indicators that can guide treatment decisions to improve physical and mental HRQOL outcomes.

This study aimed to compare histological features of familial and sporadic testicular germ cell tumors (TGCTs) and surrounding parenchyma, since discriminating features might be etiologically relevant and clinically useful. The study of parenchyma was prompted by reports claiming a higher prevalence of testicular microlithiasis in familial cases. Histological features of TGCTs and surrounding parenchyma of 296 sporadic and 305 familial cases were compared. For each case, one representative hematoxylin and eosin-stained slide was available. Slides were independently scored by two expert pathologists using a semi-quantitative data abstract. Discrepancies were resolved by consensus. A logistic regression model was used to assess the ability to discriminate between sporadic and familial GCT. The histological composition of a tumor, amount of lymphocytic infiltration, amount of germ cell neoplasia in situ (GCNIS), and presence of testicular microlithiasis (TM) did not discriminate between sporadic and familial GCT (area under the curve 0.56, 95%CI 0.51–0.61). Novel observations included increasing lymphocytic infiltration and decreasing GCNIS and TM with increasing age at diagnosis. The presence of tubules with infiltrating lymphocytes was mainly associated with pure seminomas and nonseminomas with a seminoma component. Among seminomas, tubules with infiltrating lymphocytes decreased with increasing age. No discernable differences between sporadic and familial TGCTs were found. The age-related changes in the tumors and surrounding parenchyma in these groups combined are consistent with a host response building up over time predominantly affecting seminomas, the seminoma-component of nonseminomas and GCNIS. TM may gradually dissolve with age. Our hypothesis that histological differences between sporadic and familial TGCT might identify genetically distinct disease subsets was not supported.

Health-related quality of life (HRQOL) is reduced in Fabry disease (FD) and associated with clinical disease manifestations, but few have used Fabry-specific severity scores to study how disease burden interferes with quality of life. We investigated how the Fabry DS3, consisting of four somatic domains and one patient-reported item, associates with HRQOL, while also evaluating fatigue, pain and psychological distress as possible predictors. Thirty-six adults with FD completed the Short-form Health Survey (SF-36), the hospital anxiety and depression scale (HADS), the brief pain inventory (BPI) and reported fatigue on a visual analog scale. Clinical data were collected from the last multidisciplinary hospital visit. Using correlation and hierarchical linear regression analyses, we examined associations between demographic, clinical and self-reported predictors and the SF-36 physical (PCS) and mental (MCS) component summary scores. Males scored lower than the general population in all SF-36 domains (P < .05). General health and social functioning were reduced in females. Before including self-reported symptom scores, DS3 showed associations with PCS (P = .009). Our fully adjusted model explained 66% of the variation in PCS, where education (P = .040) and fatigue (P = .002) retained significance. With HADS depression score (P = .001) as the sole significant factor, our regression model explained 56% of the variation in MCS. The DS3 score has implications for HRQOL in FD. Low education and fatigue represent major barriers to physical well-being, while depression strongly influences mental quality of life. Fatigue should be recognized as an important endpoint in future FD trials. Increased efforts to diagnose and treat affective disorders are warranted.

An accurate diagnosis of syndromic craniosynostosis (CS) is important for personalized treatment, surveillance, and genetic counselling. We describe detailed clinical criteria for syndromic CS and the distribution of genetic diagnoses within the cohort. The prospective registry of the Norwegian National Unit for Craniofacial Surgery was used to retrieve individuals with syndromic CS born between 1 January 2002 and 30 June 2019. All individuals were assessed by a clinical geneticist and classified using defined clinical criteria. A stepwise approach consisting of single-gene analysis, comparative genomic hybridization (aCGH), and exome-based high-throughput sequencing, first filtering for 72 genes associated with syndromic CS, followed by an extended trio-based panel of 1570 genes were offered to all syndromic CS cases. A total of 381 individuals were registered with CS, of whom 104 (27%) were clinically classified as syndromic CS. Using the single-gene analysis, aCGH, and custom-designed panel, a genetic diagnosis was confirmed in 73% of the individuals (n = 94). The diagnostic yield increased to 84% after adding the results from the extended trio-based panel. Common causes of syndromic CS were found in 53 individuals (56%), whereas 26 (28%) had other genetic syndromes, including 17 individuals with syndromes not commonly associated with CS. Only 15 individuals (16%) had negative genetic analyses. Using the defined combination of clinical criteria, we detected among the highest numbers of syndromic CS cases reported, confirmed by a high genetic diagnostic yield of 84%. The observed genetic heterogeneity encourages a broad genetic approach in diagnosing syndromic CS.

OBJECTIVE:The authors present population-based epidemiological data for craniosynostosis regarding incidence, age at diagnosis, sex differences, and frequency of syndromic and familial cases. METHODS:The prospective registry of the Norwegian National Unit for Craniofacial Surgery was used to retrieve data on all individuals with craniosynostosis treated between 2003 and 2017. The cohort was divided into three 5-year groups based on year of birth: 2003-2007, 2008-2012, and 2013-2017. RESULTS:The authors identified 386 individuals with craniosynostosis. Of these, 328 (85%) consented to be registered with further information. The incidence increased significantly during the study period and was 5.5 per 10,000 live births (1/1800) in the last 5-year period. The increase was seen almost exclusively in the nonsyndromic group. Syndromic craniosynostosis accounted for 27% of the cases, and the incidence remained stable throughout the three 5-year periods. Both syndromic and nonsyndromic craniosynostosis were highly suture specific. There was a male preponderance (male/female ratio 2:1), and males accounted for 75% of the individuals with midline synostosis. Overall, 9.5% were index individuals in families with more than one affected member; of these, 73% were nonsyndromic cases. CONCLUSIONS:The incidence of craniosynostosis increased during the study period, and the observed incidence is among the highest reported. The authors attribute this to increasing awareness among healthcare professionals. The number of syndromic cases was high, likely due to a broader definition compared to the majority of earlier reports. The study revealed a high number of familial cases in both syndromic and nonsyndromic craniosynostosis, thus highlighting the importance of genetics as an underlying cause of craniosynostosis.

Background: The estimated prevalence of tracheobronchomalacia (TBM) in the general population is about 1:2100 and is reported to be increased in patients with cystic fibrosis. We could find no reports of TBM prevalence in primary ciliary dyskinesia (PCD). Aims: To study the prevalence of TBM in children with PCD aged <18 years. Methods: We performed a retrospective review of all children with confirmed or highly likely PCD at Oslo University Hospital undergoing transnasal flexible bronchoscopy (FB) between 2012–2019 for suspected TBM, atelectasis or diagnostic work-up, and who were assessed for TBM. TBM and lobar bronchomalacia (LBM) were defined as a subjective reduction of >50% in the airway cross-sectional area during quiet respiration or coughing. Results: We identified 22 (10F) patients, median (range) age 6.0 (0.4-15.3) yr who underwent FB; TBM was diagnosed in 7 (32%). 6 patients had LBM affecting at least one lobe, including 2 of 7 with TBM. In a further 8 patients with middle lobe atelectasis, LBM affecting the same lobe was present in 4. Excluding patients with atelectasis in whom LBM may be secondary, TBM or LBM was present in 10 (2:8, F:M) children (45%). One patient (no TBM/LBM) had chronic Pseudomonas Aeruginosa (PA) infection. Method: The high prevalence of TBM/LBM may partly be due to selection bias. Even allowing for bias, the prevalence was higher than expected and was not associated with chronic PA infection. These findings should be confirmed in larger studies.

Background Head and neck paragangliomas (HNPG) are rare and predominantly benign tumours, originating from the neuroendocrine paraganglionic system. A considerable proportion of HNPGs are hereditary, depending on the population. Aims/objectives The purpose of this study was to estimate the rate of hereditary HNPGs in a Scandinavian (Norwegian) population, report long-term experience with HNPGs and offer all patients diagnosed an updated follow-up, with emphasis on identifying hereditary HNPGs through genetic screening and multifocality by 18 F-2-fluorodeoxyglucose positron emission tomography/computed tomography (F-18-FDG PET/CT). Material and methods Our study was a partly retrospective and partly prospective cohort study. It included patients with HNPG diagnosed at Oslo University Hospital (OUH), Rikshospitalet between 1990 and 2017. The patients underwent genetic testing, F-18-FDG PET/CT and measurement of catecholamines and meta-nephrines in the plasma. All resection specimens and biopsies were subjected to histopathological review. The genetic testing protocol consisted of testing for mutations in the following genes; SDHD, SDHB, SDHC, VHL and RET. Results Sixty-three patients were included in the study with a median age of 49 years (range 12 - 80). Cranial nerve dysfunction was present upon diagnosis in 13%, and 14% had multifocal paraganglioma (PG) disease. Fifty-six patients (89% of all the patients) underwent genetic testing, and 29% of these had a PG related mutation. Seven of the eight patients (88%) with multifocal PGs who underwent genetic testing had a mutation. In two of the patients, the F-18-FDG PET/CT revealed unknown and subclinical multifocality. Conclusions and significance This is the first study with systematic genetic workup and PET/CT imaging in Scandinavia of HNPG patients. The mutation rate was within the lower range reported in the literature with respect to HNPGs. Combining genetic testing and PET/CT imaging in the diagnostic workup of HNPGs is valuable.

BackgroundEpistaxis is the most common symptom in patients with hereditary hemorrhagic telangiectasia (HHT), with the greatest negative impact on quality of life (QoL). Repeated intranasal submucosal bevacizumab injections (RISBI) is a relatively new treatment option for moderate or severe grades of epistaxis in HHT. However, the effect of RISBI on QoL is not fully evaluated.Study DesignProspective, non‐comparative study.Materials and MethodsPatients treated by RISBI for HHT‐associated epistaxis between June 2011 and August 2013 were prospectively invited to the present study. The end of follow‐up was October 2013. The patients were requested to answer QoL questionnaires before the first treatment, and 6‐8 weeks after the last treatment. Three levels of QoL were assessed: Overall QoL using Cantril's Self‐Anchoring Ladder; Health‐related QoL using Short Form 36 (SF‐36), and Disease‐specific QoL. Psychological distress was measured with the Hospital Anxiety and Depression scale (HADS).ResultsThirty‐three patients were treated with RISBI during the period referred to above. Twenty‐three patients completed the QoL questionnaires. The average number of treatments per patient was 2.15 ± 1.3 (Range: 1–5). The mean overall QoL improved from 6.47 ± 1.9 to 7.26 ± 1.6 (P < .05). Several dimensions measured by SF‐36 were significantly improved with a medium to strong effect size. HADS demonstrated a significant decrease in psychological distress after the last treatment.ConclusionHHT patients treated by RISBI improved in several aspects of quality of life, and psychological distress decreased. RISBI was an effective treatment option for moderate and severe grades of HHT‐associated epistaxis.Level of Evidence4 (case series).Laryngoscope, 130:E284–E288, 2020

Purpose The purpose of this study was to characterize current clinical and genetic knowledge of patients with inherited retinal disease in Norway and give an estimate of the prevalence. These data are necessary to identify patients eligible for new personalized medicines, to facilitate genetic counselling for their families and to plan clinical follow-up. Methods A patient registry including clinical and genetic data was established. Clinical data were retrieved during 2003-2018. Genetic testing was performed in the period 2007-2018. Results The material included 866 patients with 41 clinical diagnoses at the cut-off date. The most prevalent diseases were as follows: retinitis pigmentosa (54%), Stargardt macular dystrophy (6.5%) and Leber congenital amaurosis (5.2%). A genetic diagnosis was identified in 32% of patients. In total, 207 disease-causing variants in 56 genes were reported. The most commonly reported disease-causing genes were ABCA4, USH2A and BEST1. The estimated adjusted minimum prevalence of inherited retinal disease in the south-east region of Norway was 1: 3,856 (2.6/10 000). Conclusion This population-based study demonstrated an estimated prevalence for all inherited retinal diseases in south-east Norway and described the distribution of clinical diagnoses, onset of symptoms, inheritance patterns and genetic data and thereby expands our knowledge of inherited retinal disease in Norway. The newly established registry and biobank will support patient feasibility for future clinical trials, treatment selection and counselling of families.