Craniosynostosis constitutes one of the most common congenital cranial malformations, affecting approximately 6/10,0000 live births. A genetic etiology has long been known for several forms of syndromic craniosynostosis, including pathogenic variants in TWIST1 and FGFR3 in children with Saethre-Chotzen and Muenke syndrome. Over the last decade, reports of genetic aberrations in TCF12 in children with craniosynostosis have emerged, in particular in cases with premature closure of the coronal suture(s). In this study, we, therefore, systematically reviewed the rapidly growing knowledge of TCF12-related coronal craniosynostosis, clearly illustrating its high degree of genotype and phenotype variability. With the two novel cases presented, at least 113 cases of TCF12-related coronal craniosynostosis have currently been reported. By pooling data from several prospectively collected undifferentiated craniosynostosis cohorts (ntotal = 770), we estimate a prevalence of pathogenic TCF12 variants of at least 2

OBJECTIVE Subfrontal meningiomas grow insidiously in areas with high cerebral compliance and a relative scarcity of eloquent function. Symptoms develop progressively, are nonspecific, and include anosmia, changes in personality and cognition, depressive symptoms, headaches, visual disturbances, and seizures. Patients with subfrontal meningiomas carry the highest risk of developing psychological symptoms, which makes patient-reported outcome in terms of long-term health-related quality of life (HRQOL), anxiety, and depression of particular importance. This observational study aimed to investigate long-term HRQOL, anxiety, and depression in patients with subfrontal meningiomas who underwent a bifrontal craniotomy (subfrontal) approach between 2008 and 2017 at a single tertiary center. Correlations between preoperative, perioperative, and postoperative factors and HRQOL, anxiety, and depression were analyzed to detect prognostic factors. METHODS Seventy-seven consecutive patients who underwent operations at Rigshospitalet, Copenhagen, Denmark, between 2008 and 2017 were retrospectively analyzed. Patients were prospectively invited to respond to the Functional Assessment of Cancer Therapy-General, Functional Assessment of Cancer Therapy-Brain, and Hospital Anxiety and Depression Scale. Information regarding preoperative, perioperative, and postoperative factors were collected from the patients' medical records and scans. RESULTS Patients with subfrontal meningiomas exhibited better HRQOL and lower levels of anxiety and depression than general populations and other meningioma and glioblastoma cohorts. The only statistically significant prognostic factors for long-term HRQOL were number of symptoms at diagnosis and whether patients were discharged home or to a local hospital postoperatively. Tumor and peritumoral brain edema volumes were not prognostic factors. CONCLUSIONS Patients with subfrontal meningiomas exhibited better long-term postoperative HRQOL and were less likely to have anxiety or depression than the reference populations. This information on long-term prognosis is very valu-able for patients, next of kin, and neurosurgeons and has not been previously studied in detail.

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.

Objective: To assess improvement of soft-tissue facial symmetry in children surgically treated for unicoronal synostosis (UCS) in infancy, to correlate pre- and postsurgical facial asymmetry and to evaluate whether the improvement was visually recognizable. Design: Case-controlled follow-up. Patients/Settings: Eleven Danish children diagnosed with UCS were included, 3 of whom had tested positive for Muenke mutation. Preoperative computed tomography scans and postoperative 3dMD surfaces were available for measurements. A control group of healthy children matched for age and sex was employed. Main Outcome Measures: Pre- and postsurgical facial asymmetry was analyzed using a computerized method capable of objective and spatially detailed quantification in 3-dimension (transverse, vertical, and sagittal directions). Asymmetry was evaluated in the facial region and 6 subregions (forehead, mouth, eyes, nose, cheek, and chin). Results: The largest significant improvement was seen in the sagittal direction of the facial (1.9 mm), forehead (2.0 mm), and cheek (3.4 mm) regions. Small but significant improvements were also seen in the mouth, chin, and eye regions. No significant improvement was seen in the nose region. Significant correlations were found between the pre- and postsurgically calculated facial asymmetry and between calculated asymmetry and clinical validation scores. Conclusions: All patients presented with improved facial symmetry after surgery and the improvements were visually recognizable. However, only 1 (9.1%) of the 11 patients reached a level of facial asymmetry as low as that seen in the control group. The best outcome was, in general, seen in cases with mild facial asymmetry presurgically.

Complete resection is the treatment of choice for most pediatric brain tumors, but early postoperative MRI for detection of residual tumor may be misleading because of MRI signal changes caused by the operation. PET imaging with amino acid tracers in adults increases the diagnostic accuracy for brain tumors, but the literature in pediatric neurooncology is limited. A hybrid PET/MRI system is highly beneficial in children, reducing the number of scanning procedures, and this is to our knowledge the first larger study using PET/MRI in pediatric neurooncology. We evaluated if additional postoperative 18F-fluoro-ethyl-tyrosine (18F-FET) PET in children and adolescents would improve diagnostic accuracy for the detection of residual tumor as compared with MRI alone and would assist clinical management. Methods: Twenty-two patients (7 male; mean age, 9.5 y; range, 0–19 y) were included prospectively and consecutively in the study and had 27 early postoperative 18F-FET PET exams performed preferentially in a hybrid PET/MRI system (NCT03402425). Results: Using follow-up (93%) or reoperation (7%) as the reference standard, PET combined with MRI discriminated tumor from treatment effects with a lesion-based sensitivity/specificity/accuracy (95% confidence intervals) of 0.73 (0.50–1.00)/1.00 (0.74–1.00)/0.87 (0.73–1.00) compared with MRI alone: 0.80 (0.57–1.00)/0.75 (0.53–0.94)/0.77 (0.65–0.90); that is, the specificity for PET/MRI was 1.00 as compared with 0.75 for MRI alone (P = 0.13). In 11 of 27 cases (41%), results from the 18F-FET PET scans added relevant clinical information, including one scan that directly influenced clinical management because an additional residual tumor site was identified. 18F-FET uptake in reactive changes was frequent (52%), but correct interpretation was possible in all cases. Conclusion: The high specificity for detecting residual tumor suggests that supplementary 18F-FET PET is relevant in cases where reoperation for residual tumor is considered.

Intracranial germinoma (WHO grade IV) has a good prognosis as over 90% can be cured with chemo- and radiotherapy, while intracranial nongerminomatous germ cell tumors (NGGCT) also have a good although somewhat less favorable outcome. We evaluated the use of 18F-fluoro-ethyltyrosine (18F-FET) positron emission tomography (PET) for response assessment in intracranial germinoma and NGGCT. Six patients (5 males, age 13-17 years) diagnosed with intracranial germinoma (n=4) or NGGCT (elevated alpha-fetoprotein (AFP)) (n=2) were included and 18F-FET PET scans were performed at baseline and after 9-12 weeks of chemotherapy (treated according to SIOP CNS GCT 2). One germinoma patient declined follow-up 18F-FET PET. All germinoma and one NGGCT patients had partial or complete response on MRI and were subsequently treated with proton radiation therapy, and are in clinical complete response (cCR). The second NGGCT patient had normalisation of AFP but progression on MRI; he was subsequently operated where histology showed only residual teratoma. He received further chemo- and radiotherapy and is in cCR. All patients with follow-up PET showed marked decrease of 18F-FET activity uptake after chemotherapy. Maximal tumor-to-background ratio decreased from 2.2 ± 0.4 before chemotherapy to 1.4 ± 0.3, p=0.001 (paired t-test). In five patients treated successfully for intracranial germ cell tumors, 18F-FET PET showed a marked decrease in activity uptake in response to chemotherapy. The results are promising for further studies of the use of 18F-FET PET in response assessment in this disease, possibly to assist radiation therapy dosing with the aim to reduce late effects.

Positron Emission Tomography (PET) with 18F-fluoro-ethyltyrosine (18F-FET) improves diagnostic accuracy in adult patients with gliomas but the literature in pediatric neuro-oncology is still scarce. We aimed 1) to collect a material of various pediatric brain tumors 2) to determine sensitivity and specificity for tumor using 18F-FET PET versus MRI alone 3) to test the clinical impact of the scans. Eighty patients with primary pediatric CNS-tumors was included and a total of 121 hybrid 18F-FET PET/MRI or PET/CT scans have been performed. Clinical impact was assessed as minor (change of diagnosis) or major (change of treatment plan). Minor impact was seen in 28% of all scans and major impact in 9%. In the 27 cases, when a PET scan had beforehand been regarded clinically indicated, 38% showed minor impact and 35% showed major impact. A high uptake was seen in pilocytic astrocytoma and in high grade gliomas, while lower uptake was seen in e.g. AT/RT (atypical teratoid/rhabdoid tumor), ependymoma, germinomas. No increased uptake was seen in e.g. non-contrast enhancing low grade glioma. In 24 early postoperative 18F-FET PET scans conducted primarily within 72 hours after surgery, minor impact was seen in 42% and major impact in 4% of cases. Based on a consensus reading for residual tumor of follow-up scans (up to 24 months), we found the following lesion-based sensitivity/specificity/accuracy for diagnosing residual tumor: MRI alone: 80%/64%/72%. PET/MRI: 73%/100%/86%. The addition of 18F-FET PET to MRI for imaging of pediatric CNS-tumors has a major impact on the clinical management in 9% of all scans and in 35% of the clinically indicated scans. The addition of 18F-FET PET for early postoperative imaging seems to increase the specificity for residual tumor and should be considered when radical surgery is of high priority, especially if MRI is equivocal.

Objective: Quantitatively assess 3D spatially detailed soft-tissue facial asymmetry in children who had undergone craniofacial reconstruction for Unicoronal Synostosis (UCS), and compare the facial asymmetry to control patients. It was hypothesized that there would be no significant differences in the facial asymmetry between the groups.Design: Clinical, retrospective follow-up study. Methodological study.Setting: Primary care center.Patients/Participants: Twenty-two children with UCS were selected after review of records. Inclusion criteria: isolated UCS; surgically treated for UCS within the first 19 months of life, without secondary reconstruction; and DNA analysis for the Muenke mutation. An age- and sex-matched control group was employed.Interventions: The UCS group had undergone bilateral craniotomy of the frontal bone with unilateral supraorbital rim advancement.Main Outcome Measure(s): Using 3D surface scanning, a detailed map of 3D asymmetry presenting the amount of asymmetry in the sagittal, vertical, and transverse directions was calculated for six facial subregions.Results: The facial asymmetry in the UCS group was significantly larger than in the control group for all regions, to the largest extent in the sagittal direction (level of significance: 5%). The regions with the most pronounced asymmetry were cheeks (mean: 5.45 mm; SD: 1.83 mm), forehead (mean: 5.00 mm; SD: 1.57 mm), and eyes (mean: 4.26 mm; SD: 1.44 mm).Conclusions: Ninety percent of the UCS patients in the study had significant facial asymmetry throughout the facial area. The study demonstrates a methodology of facial asymmetry quantification well suited for soft-tissue surgical outcome evaluations and long-term follow-up studies in patients with craniofacial anomalies.

assessed by receiver-operating-characteristic curve analyses using histology or clinical course as a reference. Results: In patients with newly diagnosed cerebral lesions, the highest accuracy (77%) to detect neoplastic tissue (19/26 patients) was obtained when the maximum TBR was 1.7 or greater (area under the curve, 0.80 ± 0.09; sensitivity, 79%; specificity, 71%; positive predictive value, 88%; P 5 0.02). For diagnosing tumor progression or recurrence, the highest accuracy (82%) was obtained when curve patterns 2 or 3 were present (area under the curve, 0.80 ± 0.11; sensitivity, 75%; specificity, 90%; positive predictive value, 90%; P 5 0.02). During chemotherapy, ad ecrease of TBRs was associated with a stable clinical course, and in 2 patients PET detected residual tumor after presumably complete tumor resection. Conclusion: Our findings suggest that 18 F-FET PET

Medulloblastoma is the most common malignant brain tumor in childhood. Radical surgery in the non-metastatic stage is an important factor with respect to overall survival. In this case, 5-aminolevulinic acid (5-ALA) was used at second-look surgery in order to improve surgical results.

BACKGROUND: Experience regarding the use of dynamic O-(2-[18F]-fluoroethyl)-L-tyrosine (18F-FET) PET in children and adolescents with brain tumors is limited. METHODS: Sixty-nine 18F-FET PET scans of 49 patients (median age, 13 years; range, 1-18 years) were analyzed retrospectively. Patients had been referred for: (A) assessment of newly diagnosed cerebral lesions (26 scans in 26 patients), (B) diagnosing tumor progression/recurrence (24 scans in 18 patients), (C) monitoring of chemotherapy effects (8 scans in 4 patients), and (D) the detection of residual tumor tissue after resection (11 scans in 10 patients). Maximum and mean tumor/brain ratios (TBRmax/mean) of 18F-FET uptake were determined (20-40 min p.i.) and time-activity curves were generated and assigned to one of the following patterns: (1) constantly increasing uptake, (2) uptake peaking at a midway point (>20-40 min) followed by a plateau, and (3) uptake peaking early (≤20 min) followed by a constant descent. The diagnostic values of TBRs and kinetic parameters to detect neoplastic tissue or diagnose tumor progression/recurrence were assessed using ROC analyses. Diagnoses were confirmed histologically and/or by clinical course. RESULTS: In patients with newly diagnosed cerebral lesions, highest accuracy (77%) to detect neoplastic tissue (7 of 26 patients) was obtained when TBRmax was >1.7 (AUC, 0.80 ± 0.09; sensitivity, 79%; specificity, 71%, PPV, 88%; P = 0.02). For diagnosing tumor progression/recurrence, highest accuracy (82%) was obtained when curve patterns 2 or 3 were present (AUC, 0.80 ± 0.11; sensitivity, 75%; specificity, 90%, PPV, 90%; P = 0.02). During chemotherapy, a decrease of TBRs was associated with a stable clinical course at least for 6 months. In patients after complete tumor resection (2 of 10 patients), 18F-FET PET detected metabolically active tumor (TBRmax ≥ 1.7). CONCLUSIONS: Our findings suggest that 18F-FET PET can add valuable information for clinical decision-making in pediatric brain tumor patients.

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.

Experience regarding O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) PET in children and adolescents with brain tumors is limited. Methods: Sixty-nine 18F-FET PET scans of 48 children and adolescents (median age, 13 y; range, 1–18 y) were analyzed retrospectively. Twenty-six scans to assess newly diagnosed cerebral lesions, 24 scans for diagnosing tumor progression or recurrence, 8 scans for monitoring of chemotherapy effects, and 11 scans for the detection of residual tumor after resection were obtained. Maximum and mean tumor-to-brain ratios (TBRs) were determined at 20–40 min after injection, and time–activity curves of 18F-FET uptake were assigned to 3 different patterns: constant increase; peak at greater than 20–40 min after injection, followed by a plateau; and early peak (≤20 min), followed by a constant descent. The diagnostic accuracy of 18F-FET PET was assessed by receiver-operating-characteristic curve analyses using histology or clinical course as a reference. Results: In patients with newly diagnosed cerebral lesions, the highest accuracy (77%) to detect neoplastic tissue (19/26 patients) was obtained when the maximum TBR was 1.7 or greater (area under the curve, 0.80 ± 0.09; sensitivity, 79%; specificity, 71%; positive predictive value, 88%; P = 0.02). For diagnosing tumor progression or recurrence, the highest accuracy (82%) was obtained when curve patterns 2 or 3 were present (area under the curve, 0.80 ± 0.11; sensitivity, 75%; specificity, 90%; positive predictive value, 90%; P = 0.02). During chemotherapy, a decrease of TBRs was associated with a stable clinical course, and in 2 patients PET detected residual tumor after presumably complete tumor resection. Conclusion: Our findings suggest that 18F-FET PET can add valuable information for clinical decision making in pediatric brain tumor patients.

INTRODUCTION The first edition of this national clinical guideline was published in 2002 after an extensive review of the international literature and the long standing Danish experience and praxis performed by a working group of Danish doctors and other specialists interested in vHL. The second revised edition came in 2005. Since then, Denmark has hosted “The 8th International Medical Symposium on von Hippel-Lindau disease”, Roskilde 2008, original Danish literature on vHL has been published [1-4], and the working group has been formalized as The Danish vHL Coordination group. The present third edition of the clinical guideline is the result of a thorough revision. The diagnostic criteria have been changed: There is no longer a distinction between major and minor criteria, the analysis of catecholamines in urine has been replaced by analysis of plasma-metanephrines, recommendations regarding prophylactic screening for endolymphatic sac tumours (ELSTs) have been added, and prophylactic screening in families with an isolated case of central nervous system (CNS) hemangioblastoma are no longer recommended. Many individuals predisposed to vHL have to take several days off from work to attend the screening examinations. For many this is inconvenient, and it may cause some to refrain from surveillance. It is an ambition of the working group to optimize the coordination of the screening examinations, for example by establishing interdisciplinary vHL clinics.