Jugular foramen stenosis in external hydrocephalus in infants.

OBJECTIVE: To measure the size of jugular foramina in infants affected by external hydrocephalus (EH) and in a control group, to support the hypothesis that a jugular foramen (JF) stenosis may determine dural venous sinus alterations and increased venous outflow resistance as main pathophysiological factor. METHODS: Minimum, maximum, and mean values of JF areas were measured in a series of phase-contrast magnetic resonance venous angiography (angio MRV PCA3D) performed on 81 infants affected by EH. Results were compared with a group of 54 controls. RESULTS: Smaller JF area was significantly smaller in patients versus controls (43.1 ± 14.6 vs. 52.7 ± 17.8; p < 0.001) resulting in a significantly smaller mean JF areas in patients vs. controls (51.6 ± 15.8 vs. 57.0 ± 18.3; p = 0.043). In patients, smaller JF areas were significantly associated with higher venous obstruction grading score (VOGS) both on the right (p = 0.018) and on the left side (p = 0.005). Positional plagiocephaly (cranial vault asymmetry index > 3.5%) was more frequent among EH patients than controls (38/17) but the difference was not significant (p = 0.07). In the 38 plagiocephalic patients, JF area was smaller on the flattened side than the contralateral in a significant number of cases both in right (21/7) and left (9/1) plagiocephaly (p < 0.0005) as well as the mean area (48.2 + 16.4 mm2 vs. 57.5 + 20.7 mm2, p = 0.002) and VOGS was significantly higher on the plagiocephalic side than on the contralateral side (1.6 ± 1.1 vs. 1.1 ± 0.9, p = 0.019). CONCLUSION: In this series of infants affected by EH, the mean size of the ostium of both JF resulted significantly smaller than controls. JF stenosis was significantly associated with higher degrees of venous obstruction on both sides, suggesting a direct extrinsic effect of JF size on dural sinus lumen and possible consequent effect on venous outflow resistance. Positional plagiocephaly, when present, was associated with a decreased JF area and increased VOGS on the flattened side.

Biobank for craniosynostosis and faciocraniosynostosis, rare pediatric congenital craniofacial disorders: a study protocol.

PURPOSE: Craniosynostosis (CRS) is a rare congenital cranial malformation in which 1 or more cranial or facial sutures are fused in utero or rapidly fused in early infancy. The cranial sutures separate the skull bone plates and enable rapid growth of the skull in the first 2 years of life, in which growth is largely dictated by growth of the brain. CRS is a rare disease that occurs in 1 in 2100 to 1 in 2500 births and may be either nonsyndromic (also referred to as isolated) or syndromic. In syndromic CRS, other birth defects are present next to the CRS. The distinction between nonsyndromic and syndromic manifestations is made on the basis of dysmorphologic evaluation and genetic evaluation. Owing to advances in genetic diagnostics, nonsyndromic patients are increasingly recognized as syndromic patients. CRS treatment is almost entirely surgical and is sometimes paired with postoperative helmet therapy for maintenance. Corrective procedures are complex, long, and associated with the risk of numerous complications, including heavy blood loss and its sequelae. Although surgery may restore a normal appearance, even in nonsyndromic patients, patients may experience persistent deficits in intellectual ability and cognitive function. The European Commission (EC) has prioritized rare diseases in recent horizon European research programs; indeed, collections or even individual samples may be extremely valuable for research. METHODS AND RESULTS: Here, we present a study protocol in which the combined expertise of clinicians and researchers will be exploited to generate a biobank dedicated to CRS. The generation of the CRS biobank presented in this study will include the collection of different types of biological materials as well as advanced radiological images available to the scientific community. CONCLUSION: The activation of a CRS biobank will provide an opportunity to improve translational research on CRS and to share its benefits with the scientific community and patients and their families.

Unravelling the pathogenesis of foramen magnum stenosis in patients with severe achondroplasia: a CT-based comparison with age-matched controls and FGFR3 craniosynostosis syndromes.

OBJECTIVE: Foramen magnum(FM) stenosis can be responsible for acute and chronic damage to the cervicomedullary junction in children with achondroplasia. The bony anatomy and patterns of suture fusion of the FM in this context are incompletely understood, yet becoming increasingly important in the light of novel medical therapies for achondroplasia. The objective of this study was to describe and quantify bony anatomy and fusion patterns of FM stenosis in patients with achondroplasia using CT scans, comparing them to age-matched controls and other FGFR3 craniosynostosis patients. METHODS: Patients with achondroplasia and severe FM stenosis, classified as achondroplasia foramen magnum score(AFMS) grades 3 and 4, were identified from a departmental operative database. All had pre-operative CT scans of the craniocervical junction. Measurements obtained comprised sagittal diameter (SD), transverse diameter (TD), foramen magnum area, and opisthion thickness. Anterior and posterior interoccipital synchondroses (AIOS and PIOS) were graded by the extent of fusion. These measurements were then compared with CT scans from 3 age-matched groups: the normal control group, children with Muenke syndrome, and children with Crouzon syndrome with acanthosis nigricans (CSAN). RESULTS: CT scans were reviewed in 23 cases of patients with achondroplasia, 23 normal controls, 20 Muenke, and 15 CSAN. Children with achondroplasia had significantly smaller sagittal diameter (mean 16.2 ± 2.4 mm) compared to other groups (control 31.7 ± 2.4 mm, p < 0.0001; Muenke 31.7 ± 3.5 mm, p < 0.0001; and CSAN 23.1 ± 3.4 mm, p < 0.0001) and transverse diameters (mean 14.3 ± 1.8 mm) compared with other groups (control 26.5 ± 3.2 mm, p < 0.0001; Muenke 24.1 ± 2.6 mm, p < 0.0001; CSAN 19.1 ± 2.6 mm, p < 0.0001). This translated into a surface area which was 3.4 times smaller in the achondroplasia group compared with the control group. The median grade of the AIOS fusion achondroplasia group was 3.0 (IQR 3.0-5.0), which was significantly higher compared with the control group (1.0, IQR 1.0-1.0, p < 0.0001), Muenke group (1.0, IQR 1.0-1.0, p < 0.0001), and CSAN (2.0, IQR 1.0-2.0, p < 0.0002). Median PIOS fusion grade was also highest in the achondroplasia group (5.0, IQR 4.0-5.0) compared with control (1.0, IQR 1.0-1.0, p < 0.0001), Muenke (2.5, IQR 1.3-3.0, p < 0.0001), and CSAN (4.0, IQR 4.0-4.0, p = 0.2). Distinct bony opisthion spurs projecting into the foramen magnum were seen in achondroplasia patients but not others, resulting in characteristic crescent and cloverleaf shapes. CONCLUSION: Patients with AFMS stages 3 and 4 have significantly reduced FM diameters, with surface area 3.4 times smaller than age-matched controls. This is associated with premature fusion of the AIOS and PIOS in comparison with controls and other FGFR3-related conditions. The presence of thickened opisthion bony spurs contributes to stenosis in achondroplasia. Understanding and quantifying bony changes at the FM of patients with achondroplasia will be important in the future quantitative evaluation of emerging medical therapies.

Risk factors for endocrine complications in transfusion-dependent thalassemia patients on chelation therapy with deferasirox: a risk assessment study from a multi-center nation-wide cohort.

Transfusion-dependent patients typically develop iron-induced cardiomyopathy, liver disease, and endocrine complications. We aimed to estimate the incidence of endocrine disorders in transfusiondependent thalassemia (TDT) patients during long-term iron-chelation therapy with deferasirox (DFX). We developed a multi-center follow-up study of 426 TDT patients treated with once-daily DFX for a median duration of 8 years, up to 18.5 years. At baseline, 118, 121, and 187 patients had 0, 1, or ≥2 endocrine diseases respectively. 104 additional endocrine diseases were developed during the follow-up. The overall risk of developing a new endocrine complication within 5 years was 9.7% (95% Confidence Interval [CI]: 6.3-13.1). Multiple Cox regression analysis identified three key predictors: age showed a positive log-linear effect (adjusted hazard ratio [HR] for 50% increase 1.2, 95% CI: 1.1-1.3, P=0.005), the serum concentration of thyrotropin showed a positive linear effect (adjusted HR for 1 mIU/L increase 1.3, 95% CI: 1.1-1.4, P<0.001) regardless the kind of disease incident, while the number of previous endocrine diseases showed a negative linear effect: the higher the number of diseases at baseline the lower the chance of developing further diseasess (adjusted HR for unit increase 0.5, 95% CI: 0.4-0.7, P<0.001). Age and thyrotropin had similar effect sizes across the categories of baseline diseases. The administration of levothyroxine as a covariate did not change the estimates. Although in DFX-treated TDT patients the risk of developing an endocrine complication is generally lower than the previously reported risk, there is considerable risk variation and the burden of these complications remains high. We developed a simple risk score chart enabling clinicians to estimate their patients' risk. Future research will look at increasing the amount of variation explained from our model and testing further clinical and laboratory predictors, including the assessment of direct endocrine magnetic resonance imaging.

Neuroimaging of paediatric pineal, sellar and suprasellar tumours: a guide to differential diagnosis.

INTRODUCTION: Pineal, sellar and suprasellar tumours in children comprise a wide range of diseases with different biological behaviours and clinical management. Neuroimaging plays a critical role in the diagnosis, treatment planning and follow up of these patients, but imaging interpretation can prove challenging due to the significant overlap in radiological features. MATERIALS AND METHOD: A review of the literature was performed by undertaking a search of the MEDLINE and EMBASE databases for appropriate MeSH terminology. Identified abstracts were screened for inclusion and articles meeting the objectives of the review were included. RESULTS AND CONCLUSION: In this article, we review radiological appearances of common and uncommon pineal, sellar and suprasellar tumours occurring in the paediatric population. We discuss the importance of anatomical localization, clinical information and cerebrospinal fluid tumour markers, and propose a practical approach to differential diagnosis. Lastly, we discuss future directions and prospective new imaging strategies to support state-of-the-art patient care.

Magnetic resonance features and cranial nerve involvement in pediatric head and neck rhabdomyosarcomas.

PURPOSE: Rhabdomyosarcoma (RMS) is a malignant tumor frequent in children. The frequency and characteristics of cranial nerve involvement in pediatric head and neck (H&N) RMS have been scarcely reported. The aim of this study is to review a large cohort of pediatric head and neck RMS with an emphasis on cranial nerve involvement. METHODS: We retrospectively reviewed H&N RMS cases from 3 tertiary hospitals over a 10-year period. Cranial nerve involvement was defined as radiologically apparent tumor extension along a nerve and/or the presence of secondary signs. Scans were reviewed by two pediatric neuroradiologists, blinded to clinical data. RESULTS: A total of 52 patients met the inclusion criteria. Histologically, 39/52 were embryonal RMS, while 13/52 were alveolar RMS. Regional lymph nodes metastases were present in 19.2%. Cranial nerve involvement was present in 36.5%. Nerves were mainly involved as a direct extension of the mass through skull base foramina or after invasion of cavernous sinus, Meckel's cave, orbital apex, or stylomastoid foramen. CONCLUSION: Cranial nerve involvement is frequent in pediatric head and neck RMS and occurs secondary to "geographic" invasion due to direct extension through skull base foramina or cavernous sinus. These tumors never showed distant perineural metastatic disease as is seen in cases of adult head and neck carcinomas. This implies a different biological interaction between the nerves and these tumors in comparison to adult H&N tumors.

Life-Threatening Drug-Induced Liver Injury in a Patient with ß-Thalassemia Major and Severe Iron Overload on Polypharmacy.

A 20-year-old male affected by transfusion-dependent ß-thalassemia (ß-thal), was prescribed intensive chelation therapy with deferoxamine (DFO) and deferiprone (DFP) because of severe hepatic and cardiac iron overload and ß-blocker and warfarin to manage a previous event of atrial fibrillation (AFib) and heart failure. After a few months, he developed critical liver failure, renal tubulopathy and severe electrolyte imbalance. Laboratory and instrumental evaluations were performed to carry out differential diagnosis of acute liver failure and an exclusion diagnosis of drug induced liver injury (DILI) was made. The cholestatic pattern suggested warfarin as the main causative agent and polypharmacy, liver iron overload and heart failure as aggravating factors. Warfarin is a drug commonly prescribed in thalassemia patients who often need polypharmacy for the management of anemia- and iron-related complications. Strict monitoring and multidisciplinary approaches are mandatory to avoid preventable mortality in this fragile population.

Neuroimaging in Nonsyndromic Craniosynostosis: Key Concepts to Unlock Innovation.

Craniosynostoses (CRS) are caused by the premature fusion of one or more cranial sutures, with isolated nonsyndromic CRS accounting for most of the clinical manifestations. Such premature suture fusion impacts both skull and brain morphology and involves regions far beyond the immediate area of fusion. The combined use of different neuroimaging tools allows for an accurate depiction of the most prominent clinical-radiological features in nonsyndromic CRS but can also contribute to a deeper investigation of more subtle alterations in the underlying nervous tissue organization that may impact normal brain development. This review paper aims to provide a comprehensive framework for a better understanding of the present and future potential applications of neuroimaging techniques for evaluating nonsyndromic CRS, highlighting strategies for optimizing their use in clinical practice and offering an overview of the most relevant technological advancements in terms of diagnostic performance, radiation exposure, and cost-effectiveness.

Intraoperative MRI Assessment of the Tissue Damage during Laser Ablation of Hypothalamic Hamartoma.

Laser ablation for treatment of hypothalamic hamartoma (HH) is a minimally invasive and effective technique used to destroy hamartomatous tissue and disconnect it from the functioning brain. Currently, the gold standard to evaluate the amount of tissue being "burned" is the use of heat maps during the ablation procedure. However, these maps have low spatial resolution and can be misleading in terms of extension of the tissue damage. The aim of this study is to use different MRI sequences immediately after each laser ablation and correlate the extension of signal changes with the volume of malacic changes in a long-term follow-up scan. During the laser ablation procedure, we imaged the hypothalamic region with high-resolution axial diffusion-weighted images (DWI) and T2-weighted images (T2WI) after each ablation. At the end of the procedure, we also added a post-contrast T1-weighted image (T1WI) of the same region. We then correlated the product of the maximum diameters on axial showing signal changes (acute oedema on T2WI, DWI restriction rim, DWI hypointense core and post-contrast T1WI rim) with the product of the maximum diameters on axial T2WI of the malacic changes in the follow-up scan, both as a fraction of the total area of the hamartoma. The area of the hypointense core on DWI acquired immediately after the laser ablation statistically correlated better with the final area of encephalomalacia, while the T2WI, hyperintense oedema, DWI rim and T1WI rim of enhancement tended to overestimate the encephalomalacic damage. In conclusion, the use of intraoperative sequences (in particular DWI) during laser ablation can give surgeons valuable information in real time about the effective heating damage on the hamartomatous tissue, with better spatial resolution in comparison to the thermal maps.

Extra-neural metastases in pediatric diffuse midline gliomas, H3 K27-altered: presentation of two cases and literature review.

Introduction: Pediatric diffuse midline gliomas (DMG), H3 K27- altered, are the most aggressive pediatric central nervous system (CNS) malignancies. Disease outcome is dismal with a median survival of less than one year. Extra-neural metastases are an unusual occurrence in DMG and have been rarely described. Methods and results: Here, we report on two pediatric patients affected by DMG with extra-neural dissemination. Their clinical, imaging, and molecular characteristics are reported here. An 11-year-old male 5 months after the diagnosis of diffuse intrinsic pontine glioma (DIPG) developed metastatic osseous lesions confirmed with computed tomography (CT) guided biopsy of the left iliac bone. The patient died one month after the evidence of metastatic progression. Another 11-year-old female was diagnosed with a cerebellar H3K27- altered DMG. After six months, she developed diffuse sclerotic osseous lesions. A CT-guided biopsy of the right iliac bone was non-diagnostic. She further developed multifocal chest and abdominal lymphadenopathy and pleural effusions. Droplet digital polymerase chain reaction (ddPCR) on pleural effusion revealed the presence of H3.3A mutation (c.83A>T, p.K28M). The patient died 24 months after the diagnosis of DMG and 3 months after the evidence of metastatic pleural effusion. Discussion: Extra-neural metastasis of DMG is a rare event and no standard therapy exists. An accurate and early diagnosis is necessary in order to develop a personalized plan of treatment. Further research is needed to gain further insights into the molecular pathology of DMG, H3K27- altered and improve the quality of life and the final outcome of patients with this deadly disease.

DICER1 Syndrome: A Multicenter Surgical Experience and Systematic Review.

DICER1 syndrome is a rare genetic disorder that predisposes patients to the development of malignant and non-malignant diseases. Presently, DICER1 syndrome diagnosis still occurs late, usually following surgical operations, affecting patients' outcomes, especially for further neoplasms, which are entailed in this syndrome. For this reason, herein we present a multicenter report of DICER1 syndrome, with the prospective aim of enhancing post-surgical surveillance. A cohort of seven patients was collected among the surgical registries of Pediatric Surgery at the University of Pisa with the General and Oncologic Surgery of Federico II, University of Naples, and the Pediatric Surgery, Regina Margherita Hospital, University of Turin. In each case, the following data were analyzed: sex, age at diagnosis, age at first surgery, clinical features, familial, genetic investigations, and follow-up. A comprehensive literature review of DICER1 cases, including case reports and multicenter studies published from 1996 to June 2022, was performed. Eventually, the retrieved data from the literature were compared with the data emerging from our cohort of patients.

A 40-Year Cohort Study of Evolving Hypothalamic Dysfunction in Infants and Young Children (<3 years) with Optic Pathway Gliomas.

Despite high survival, paediatric optic pathway hypothalamic gliomas are associated with significant morbidity and late mortality. Those youngest at presentation have the worst outcomes. We aimed to assess presenting disease, tumour location, and treatment factors implicated in the evolution of neuroendocrine, metabolic, and neurobehavioural morbidity in 90 infants/children diagnosed before their third birthday and followed-up for 9.5 years (range 0.5-25.0). A total of 52 (57.8%) patients experienced endo-metabolic dysfunction (EMD), the large majority (46) of whom had hypothalamic involvement (H+) and lower endocrine event-free survival (EEFS) rates. EMD was greatly increased by a diencephalic syndrome presentation (85.2% vs. 46%, p = 0.001)), H+ (OR 6.1 95% CI 1.7-21.7, p 0.005), radiotherapy (OR 16.2, 95% CI 1.7-158.6, p = 0.017) and surgery (OR 4.8 95% CI 1.3-17.2, p = 0.015), all associated with anterior pituitary disorders. Obesity occurred in 25% of cases and was clustered with the endocrinopathies. Neurobehavioural deficits occurred in over half (52) of the cohort and were associated with H+ (OR 2.5 95% C.I. 1.1-5.9, p = 0.043) and radiotherapy (OR 23.1 C.I. 2.9-182, p = 0.003). Very young children with OPHG carry a high risk of endo-metabolic and neurobehavioural comorbidities which deserve better understanding and timely/parallel support from diagnosis to improve outcomes. These evolve in complex, hierarchical patterns over time whose aetiology appears predominantly determined by injury from the hypothalamic tumour location alongside adjuvant treatment strategies.

Posterior Fossa Tumours in the First Year of Life: A Two-Centre Retrospective Study.

Posterior fossa tumours (PFTs) in infants are very rare, and information on these tumours is scarce in the literature. This retrospective study reports their pathological characteristics and describes surgical aspects and treatment outcomes. A two-centre cohort of infants with PFTs treated from 2007 to 2018 was retrospectively reviewed. Patient characteristics, clinical, and treatment data were reviewed. Survival curves for progression-free survival (PFS) and overall survival (OS) were generated. Thirty-three infants were retrieved. There were 11 low grade and 22 high-grade tumours. The most common presenting symptom was intracranial hypertension. Fifteen children out of thirty-three progressed. Five-year PFS was significantly lower in children with high-grade tumours (38.3%) than those with low-grade tumours (69.3%), p = 0.030. High-grade pathology was the only predictor of progression (HR 3.7, 95% CI 1.1-13.31), p = 0.045. Fourteen children with high-grade tumours died, with a 5-year OS of 55.25%. PFTs in children below one year of age still represent a unique challenge. Infants with high-grade tumours display the worst outcomes and the lowest survival, indicating that more effective strategies are needed.

Diencephalic Syndrome Due to Optic Pathway Gliomas in Pediatric Patients: An Italian Multicenter Study.

Diencephalic syndrome (DS) is a rare pediatric condition associated with optic pathway gliomas (OPGs). Since they are slow-growing tumors, their diagnosis might be delayed, with consequences on long-term outcomes. We present a multicenter case series of nine children with DS associated with OPG, with the aim of providing relevant details about mortality and long-term sequelae. We retrospectively identified nine children (6 M) with DS (median age 14 months, range 3-26 months). Four patients had NF1-related OPGs. Children with NF1 were significantly older than sporadic cases (median (range) age in months: 21.2 (14-26) versus 10 (3-17); p = 0.015). Seven tumors were histologically confirmed as low-grade astrocytomas. All patients received upfront chemotherapy and nutritional support. Although no patient died, all of them experienced tumor progression within 5.67 years since diagnosis and were treated with several lines of chemotherapy and/or surgery. Long-term sequelae included visual, pituitary and neurological dysfunction. Despite an excellent overall survival, PFS rates are poor in OPGs with DS. These patients invariably present visual, neurological or endocrine sequelae. Therefore, functional outcomes and quality-of-life measures should be considered in prospective trials involving patients with OPGs, aiming to identify "high-risk" patients and to better individualize treatment.

Removal of Koos IV acoustic neuroma and auditory brainstem implant in NF2 patient.

The authors present the case of removal of a Koos grade IV right acoustic neuroma in a neurofibromatosis type 2 (NF2) patient, already operated on for left cerebellopontine angle meningioma at 7 years of age and a left acoustic neuroma at 16 years of age. A transpetrosal approach allowed cochlear sensor implantation to detect residual hearing. An enlarged retrosigmoid approach then allowed subtotal microsurgical removal of the lesion; consequently, the authors illustrate the technical nuances of an auditory brainstem implant (ABI). One month after surgery, the ABI was successfully switched on, giving back hearing perception to the patient. The video can be found here: https://stream.cadmore.media/r10.3171/2021.7.FOCVID2188.

Natural History of Scoliosis in Children with NF1: An Observation Study.

(1) Background. Scoliosis is the most common musculoskeletal manifestation of Neurofibromatosis type 1 (NF1), and it might be dystrophic (D) or non-dystrophic (ND) depending on the presence of dysplastic changes of the spine. The aim of our study was to describe the characteristics and natural history of patients with NF1 and scoliosis. (2) Methods. We retrospectively reviewed records from patients with NF1 and scoliosis. Scoliosis was classified as D if at least two dystrophic changes were documented at imaging. (3) Results. Of the 438 patients reviewed, 43 fulfilled inclusion criteria; 17 were classified in D group and 26 in ND. The groups did not differ in age and localization of scoliosis curvature. Surgery was needed more often in D group, but the between-group difference was not significant. Male-to-female ratios of 3:1 and 4:1 were reported in surgically treated NF1 patients with ND and D scoliosis, respectively. (4) Conclusions. Our data suggests independently by the presence of dysplastic changes affecting the spine that males with NF1 are more often affected by scoliosis that requires surgery.

Auditory cortex hypoperfusion: a metabolic hallmark in Beta Thalassemia.

BACKGROUND: Sensorineural hearing loss in beta-thalassemia is common and it is generally associated with iron chelation therapy. However, data are scarce, especially on adult populations, and a possible involvement of the central auditory areas has not been investigated yet. We performed a multicenter cross-sectional audiological and single-center 3Tesla brain perfusion MRI study enrolling 77 transfusion-dependent/non transfusion-dependent adult patients and 56 healthy controls. Pure tone audiometry, demographics, clinical/laboratory and cognitive functioning data were recorded. RESULTS: Half of patients (52%) presented with high-frequency hearing deficit, with overt hypoacusia (Pure Tone Average (PTA) > 25 dB) in 35%, irrespective of iron chelation or clinical phenotype. Bilateral voxel clusters of significant relative hypoperfusion were found in the auditory cortex of beta-thalassemia patients, regardless of clinical phenotype. In controls and transfusion-dependent (but not in non-transfusion-dependent) patients, the relative auditory cortex perfusion values increased linearly with age (p < 0.04). Relative auditory cortex perfusion values showed a significant U-shaped correlation with PTA values among hearing loss patients, and a linear correlation with the full scale intelligence quotient (right side p = 0.01, left side p = 0.02) with its domain related to communication skills (right side p = 0.04, left side p = 0.07) in controls but not in beta-thalassemia patients. Audiometric test results did not correlate to cognitive test scores in any subgroup. CONCLUSIONS: In conclusion, primary auditory cortex perfusion changes are a metabolic hallmark of adult beta-thalassemia, thus suggesting complex remodeling of the hearing function, that occurs regardless of chelation therapy and before clinically manifest hearing loss. The cognitive impact of perfusion changes is intriguing but requires further investigations.

Juvenile erythrocytosis in children after liver transplantation: prevalence, risk factors and outcome.

Most reports of post-transplant erythrocytosis have involved kidney recipients and, so far, there have been no large studies of onset of erythrocytosis after orthotopic liver transplantation (OLT) in children. We present a long-term survey of pediatric liver recipients, evaluating prevalence, outcome and the main potential causes of erythrocytosis, including a comprehensive mutational analysis of commonly related genes (mutations of HBB and HBA, JAK2, EPOR, VHL, EPAS1 and EGLN1). Between 2000 and 2015, 90 pediatric OLT recipients were observed for a median period of 8.7 years (range 1-20.4 [IQR 4.9-13.6] years). Five percent of the study population (4 males and 1 female) developed erythrocytosis at 8.5 years post OLT (range 4.1-14.9 [IQR 4.7-14.7]) at a median age of 16.6 years (range 8.2-18.8 [IQR 11.7-17.7]). Erythrocytosis-free survival after OLT was 98.6% at 5 years, 95% at 10 years, and 85% at 15 years, with an incidence rate of 6/1000 person-years. No cardiovascular events or thrombosis were reported. No germinal mutation could be clearly related to the development of erythrocytosis. One patient, with high erythropoietin levels and acquired multiple bilateral renal cysts, developed clinical hyper-viscosity symptoms, and was treated with serial phlebotomies. In conclusion, this prospective longitudinal study showed that erythrocytosis is a rare complication occurring several years after OLT, typically during adolescence. Erythrocytosis was non-progressive and manageable. Its pathogenesis is still not completely understood, although male gender, pubertal age, and renal cysts probably play a role.