Drug-induced thrombocytopenia in a patient with colorectal cancer: A case report.

Drug-induced thrombocytopenia is an adverse reaction characterized by accelerated platelet destruction. The present study described a case of thrombocytopenia that occurred during treatment with panitumumab. A female patient aged 49 years with metastatic rectal adenocarcinoma was treated with 9 out of 12 cycles of therapy with the standard of care, 5-fluorouacil (5-FU), oxaliplatin and folic acid, in association with panitumumab. During cycle 10, the patient developed severe thrombocytopenia, so the therapy was adjusted to a lower dosage; however, during cycle 11, after administration of panitumumab and before administration of 5-FU or oxaliplatin, the patient again presented with severe thrombocytopenia, with a platelet count <2×109/l. Immunology test results were negative apart from anti-nucleus antibodies (titration, 1:160). Naranjo's algorithm was used to establish the relationship between the use of panitumumab and thrombocytopenia onset and a score of 6 ('probable') was found. The temporal link between the onset of symptoms and administration of therapy, the relapse of thrombocytopenia after re-administration of the drug during cycle 11 (positive rechallenge) and Naranjo score of 6 ('probable') are crucial elements for establishing the causal relationship and the probability that thrombocytopenia was related to the administration of panitumumab. The patient then underwent two cycles of therapy with 5-FU, folic acid and irinotecan, in association with bevacizumab, experiencing again the same adverse event. Treatment with monoclonal antibodies was suspended altogether in favor of a switch to trifluridine/tipiracil. No other serious adverse events were reported.

Altered plasma levels of apixaban in major gastrointestinal tract surgery: A case report and review of the literature.

Altered direct oral anticoagulant (DOAC) plasma levels can lead either to spontaneous hemorrhagic or thrombotic complications. We describe a case of suspected altered apixaban disposition in a patient with an upper gastrointestinal cancer resection treated with apixaban for non-valvular atrial fibrillation. Diagnosis of ischemic stroke for left hemiparesis was confirmed due to recent emergence of a hypodense area in the posterior capsular nucleus of ischemic reference in a context of binuclear capsular lacunar lesions. Thus, apixaban underexposure was suspected from anamnestic data and oral anticoagulation was switched to parenteral at the next scheduled dose for stroke recurrence. Before switching apixaban pharmacokinetic analysis was performed and unexpectedly showed apixaban plasma overexposure. After 3 days from the switch, the patient experienced spontaneous bleeding complications, for which the risk-benefit profile of continuing anticoagulant treatment for stroke recurrences warranted treatment discontinuation. Unexpected DOAC plasma exposure may present in special patient populations with thrombotic and bleeding complications. Though universally recognized therapeutic ranges have yet to be established for DOACs, periodic drug monitoring may aid in guiding optimization of DOAC therapy and reduce the risk of adverse events in special patient populations.

Prescriptive Appropriateness: Inhospital Adherence to Proton Pump Inhibitors Deprescription Flow Chart.

The prescriptive appropriateness of Proton Pump Inhibitors (PPIs) in polypharmacy is controversial. PPIs are often overprescribed and the risk of prescribing errors and adverse drug reactions increases for each additional drug added to therapy. Hence, guided deprescription should be considered and easily implementable in ward practice. This observational prospective study evaluated the implementation of a validated PPIs deprescription flow chart to real-life internal ward activity through the presence of a clinical pharmacologist as an enhancing additional factor by assessment of inhospital prescriber's adherence to the proposed flow chart. Patients' demographics and prescribing trends of PPIs prescriptions were analyzed by descriptive statistics. The final analysis of data included ninety-eight patients (forty-nine male and forty-nine female), aging 75.6 ± 10.6 years; 55.1% of patients had home-PPIs prescriptions, while 44.9% received inhospital-PPIs prescriptions. Evaluation of prescriber's adherence to the flow chart revealed that the percentage of patients with a prescriptive/deprescriptive pathway conforming to that of the flow chart was 70.4%, with low symptomatologic recurrences. The clinical pharmacologists' presence and influence in ward activity may have contributed to this finding, since continuous training of the prescribing physicians is deemed a success-related factor in the deprescribing strategy. Multidisciplinary management of PPIs deprescription protocols shows high adherence by prescribers in real-life hospital settings and low recurrence events.

Biallelic variants in NSUN6 cause an autosomal recessive neurodevelopmental disorder.

PURPOSE: 5-methylcytosine RNA modifications are driven by NSUN methyltransferases. Although variants in NSUN2 and NSUN3 were associated with neurodevelopmental diseases, the physiological role of NSUN6 modifications on transfer RNAs and messenger RNAs remained elusive. METHODS: We combined exome sequencing of consanguineous families with functional characterization to identify a new neurodevelopmental disorder gene. RESULTS: We identified 3 unrelated consanguineous families with deleterious homozygous variants in NSUN6. Two of these variants are predicted to be loss-of-function. One maps to the first exon and is predicted to lead to the absence of NSUN6 via nonsense-mediated decay, whereas we showed that the other maps to the last exon and encodes a protein that does not fold correctly. Likewise, we demonstrated that the missense variant identified in the third family has lost its enzymatic activity and is unable to bind the methyl donor S-adenosyl-L-methionine. The affected individuals present with developmental delay, intellectual disability, motor delay, and behavioral anomalies. Homozygous ablation of the NSUN6 ortholog in Drosophila led to locomotion and learning impairment. CONCLUSION: Our data provide evidence that biallelic pathogenic variants in NSUN6 cause one form of autosomal recessive intellectual disability, establishing another link between RNA modification and cognition.

Deprescribing Strategies: A Prospective Study on Proton Pump Inhibitors.

Proton pump inhibitors (PPIs) are among the most controversially prescribed drugs in polypharmacy. This observational prospective study assessed the PPI prescriptive trend during hospitalization before and after implementation of a prescribing/deprescribing algorithm in a real-life hospital setting and the related clinical-economic benefit at discharge. PPI prescriptive trends were compared between three quarters of 2019 (9 months) and the same period of 2018 by a chi-square test with a Yate's correction. The proportions of treated patients in the two years (1120 discharged patients in 2018 and 1107 in 2019) were compared by the Cochran-Armitage trend test. DDDs (defined daily doses) were compared between 2018 and 2019 by the non-parametric Mann-Whitney test and normalizing DDD/DOT (days of therapy) and DDD/100 bd (bed days) for each patient. Multivariate logistic regression was performed on PPI prescriptions at discharge. The distribution of patients with PPIs at discharge was significantly different in the two years (p = 0.0121). There was a downward trend in the number of PPI prescriptions (29.9%) in the third trimester of 2019 compared to the others of the same year (first trimester: 34.1%, second trimester: 36.0%) and by contrast with the same periods of 2018 (29.4, 36.0, and 34.7%) (p = 0.0124). DDDs/patient did not differ between 2018 and 2019 nor across the three trimesters. However, both DDD/DOT and DDD/100 bd showed a decrease in the third trimester of 2019, with a marked difference for DDD/DOT (p = 0.0107). The reduction in consumption detected in the last phase of 2019 in terms of DDD/DOT was 0.09 with a consequent containment of pharmaceutical spending. The development and implementation of multidisciplinary prescribing/deprescribing protocols in both hospital and community settings could lead to a reduction in the misuse of PPIs, with significant savings in healthcare resources.

Precision fluoropyrimidines dosing in a compound heterozygous variant carrier of the DPYD gene: a case report.

BACKGROUND: Fluoropyrimidines (FPs) form still nowadays the backbone of chemotherapic schemes in colorectal cancer (CRC). Inter-patient variability of the toxicity profile of FPs may be partially accounted for by variable expression of dihydropyrimidine dehydrogenase (DPD). DPD rate activity is genetically determined by its extremely polymorphic coding gene DPYD. In spite of pharmacogenetic guideline-directed-dosing of FPs based regimens treating carrier of multiple variants of DPYD gene remains still challenging. CASE PRESENTATION: We present a case of a 48-year-old Caucasian man, compound heterozygous variant carrier of the DPYD gene (HapB3 and c.2194G>A) who had a diagnosis of adenocarcinoma of the left colon and was safely treated with a pharmacogenetic-guided 25% dose reduction of the standard CAP adjuvant treatment. Compound heterozygosis may have been responsible for an earlier over exposure to CAP resulting into low-grade toxicity with an anticipated median time to toxicity of the c.2194G>A variant to the 4th vs. 6th cycles. Some haplotypes of DPYD variants may have an advantage in terms of survival compared to wild-type patients. Our patient may also have benefitted from compound heterozygosis, as shown by no evidence of disease (NED) at 6-month follow-up. CONCLUSION: Pharmacogenetic-guided dosing of DPYD intermediate metabolizer compound heterozygous HapB3 and c.2194G>A variant carries should be managed by a multidisciplinary team with a dose reduction ranging from 25 to 50% to maintain effectiveness and close clinical monitoring for early detection of ADRs.

Development and Validation of a Novel LC-MS/MS Method for a TDM-Guided Personalization of HSCT Conditioning with High-Dose Busulfan in Children.

Personalization of busulfan (Bu) exposure via therapeutic drug monitoring (TDM) is recommended for patients treated with high-dose conditioning regimens. Several laboratories' developed methods are available in the literature with a lack of standardization. The aim of this study is to develop a new standardized LC-MS/MS method and validate it according to the international ICH M10 (EMA) guidelines. Our method is based on rapid protein precipitation from 50 µL plasma followed by separation on a reversed-phase C-18 UHPLC column after the addition of deuterated internal standard and has been tested on real samples from pediatric patients treated with myeloablative conditioning regimens, including Bu, before autologous or allogeneic hematopoietic stem cell transplantation (HSCT). The validated LC-MS/MS method is linear over wide concentration ranges (125-2000 ng/mL), accurate, and reproducible in the absence of matrix effects, allowing for the specific and rapid quantification of Bu and allowing next-dose recommendations to be made in a timely fashion to answer clinicians' needs. Given the lack of data on the stability of Bu in real clinical samples, stability was assessed both on quality controls and on real samples to set up a robust protocol in real-life conditions. This novel LC-MS/MS method is suitable for application to the TDM-guided personalization of conditioning treatments with high-dose busulfan in pediatric patients undergoing HSCT.

Antitumor Potential of Antiepileptic Drugs in Human Glioblastoma: Pharmacological Targets and Clinical Benefits.

Glioblastoma (GBM) is characterized by fast-growing cells, genetic and phenotypic heterogeneity, and radio-chemo-therapy resistance, contributing to its dismal prognosis. Various medical comorbidities are associated with the natural history of GBM. The most disabling and greatly affecting patients' quality of life are neurodegeneration, cognitive impairment, and GBM-related epilepsy (GRE). Hallmarks of GBM include molecular intrinsic mediators and pathways, but emerging evidence supports the key role of non-malignant cells within the tumor microenvironment in GBM aggressive behavior. In this context, hyper-excitability of neurons, mediated by glutamatergic and GABAergic imbalance, contributing to GBM growth strengthens the cancer-nervous system crosstalk. Pathogenic mechanisms, clinical features, and pharmacological management of GRE with antiepileptic drugs (AEDs) and their interactions are poorly explored, yet it is a potentially promising field of research in cancer neuroscience. The present review summarizes emerging cooperative mechanisms in oncogenesis and epileptogenesis, focusing on the neuron-to-glioma interface. The main effects and efficacy of selected AEDs used in the management of GRE are discussed in this paper, as well as their potential beneficial activity as antitumor treatment. Overall, although still many unclear processes overlapping in GBM growth and seizure onset need to be elucidated, this review focuses on the intriguing targeting of GBM-neuron mutual interactions to improve the outcome of the so challenging to treat GBM.

Simultaneous Quantification of Ivacaftor, Tezacaftor, and Elexacaftor in Cystic Fibrosis Patients' Plasma by a Novel LC-MS/MS Method.

The new breakthrough cystic fibrosis (CF) drug combination of ivacaftor (IVA), tezacaftor (TEZ), and elexacaftor (ELX), namely "caftor" drugs, directly modulates the activity and trafficking of the defective CF transmembrane conductance regulator protein (CFTR) underlying the CF disease. The role of therapeutic drug monitoring (TDM) of caftor drugs in clinical settings has recently been established. The availability of reliable and robust analytical methods for the quantification of IVA, TEZ, and ELX is essential to support dose-concentration-effect studies. We have developed and validated a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the rapid and simultaneous quantification of IVA, TEZ, and ELX from the plasma of CF patients. The method was based on a rapid extraction protocol from 50 µL human plasma and separation on a reversed-phase C-18 HPLC column after the addition of deuterated internal standards. Accurate analyte quantification using multiple reaction monitoring (MRM) detection was then obtained using a Thermofisher Quantiva triple-quadrupole MS coupled to an Ultimate 3000 UHPLC. The method has been validated following international (EMA) guidelines for bioanalytical method validation and has been tested on plasma samples from 62 CF patients treated with the three-drug combination IVA/TEZ/ELX, marketed as Kaftrio® or Trikafta®, in steady-state condition. The assay was linear over wide concentration ranges (0.008-12 mg/L) in plasma for IVA, TEZ, and ELX, suitable for a broad range of plasma concentrations, and accurate and reproducible in the absence of matrix effects. The stability of analytes for at least 30 days at room temperature could allow for cost-effective shipment and storage. On the same day of sample collection, a sweat test was evaluated for 26 associated patients' samples, FEV1 (%) for 58, and BMI was calculated for 62. However, Spearman correlation showed no correlation between Cthrough plasma concentrations of analytes (IVA, TEZ, ELX) and sweat test, FEV1 (%), or BMI. Our method proved to be suitable for TDM and could be helpful in assessing dose-concentration-response correlations in larger studies.

Long-Term Neuroradiological and Clinical Evaluation of NBIA Patients Treated with a Deferiprone Based Iron-Chelation Therapy.

Neurodegeneration with brain iron accumulation (NBIA) comprises various rare clinical entities with brain iron overload as a common feature. Magnetic resonance imaging (MRI) allows diagnosis of this condition, and genetic molecular testing can confirm the diagnosis to better understand the intracellular damage mechanism involved. NBIA groups disorders include: pantothenate kinase-associated neurodegeneration (PKAN), mutations in the gene encoding pantothenate kinase 2 (PANK2); neuroferritinopathy, mutations in the calcium-independent phospholipase A2 gene (PLA2G6); aceruloplasminemia; and other subtypes with no specific clinical or MRI specific patterns identified. There is no causal therapy, and only symptom treatments are available for this condition. Promising strategies include the use of deferiprone (DFP), an orally administered bidentate iron chelator with the ability to pass through the blood-brain barrier. This is a prospective study analysis with a mean follow-up time of 5.5 ± 2.3 years (min-max: 2.4-9.6 years) to define DFP (15 mg/kg bid)'s efficacy and safety in the continuous treatment of 10 NBIA patients through clinical and neuroradiological evaluation. Our results show the progressive decrease in the cerebral accumulation of iron evaluated by MRI and a substantial stability of the overall clinical neurological picture without a significant correlation between clinical and radiological findings. Complete ferrochelation throughout the day appears to be of fundamental importance considering that oxidative damage is generated, above, all by non-transferrin-bound iron (NTBI); thus, we hypothesize that a (TID) administration regimen of DFP might better apply its chelating properties over 24 h with the aim to also obtain clinical improvement beyond the neuroradiological improvement.

A case of anti-HMGCR myopathy triggered by sodium/glucose co-transporter 2 (SGLT2) inhibitors.

Inflammatory myopathies, including immune-mediated necrotizing myopathy (IMNM), are a rare and heterogeneous group of autoimmune diseases which can even involve extramuscular districts and seriously impact patients' quality of life. We report the case of a 76-year-old woman who developed muscle weakness, fatigue, and increased CK, following treatment with dapagliflozin, a sodium/glucose co-transporter 2 (SGLT2) inhibitor, and metformin. Neurophysiology, muscle biopsy, and antibody dosage confirmed the diagnosis of IMNM. The temporal correlation between the onset of clinical manifestations and the increase in the dosage of antidiabetic drugs, the improvement of symptoms with the dechallenge of dapagliflozin, and the exclusion of other possible causes triggering myopathy suggests that this may be the first case of dapagliflozin-induced myopathy, different from the former one associated with the use of SGLT2 inhibitors.

Evaluation of Pharmacokinetics and Pharmacodynamics of Deferasirox in Pediatric Patients.

BACKGROUND: Deferasirox (DFX) is commonly used to reduce the chronic iron overload (IO) in pediatric patients. However, the drug is characterized by a large pharmacokinetic variability and approximately 10% of patients may discontinue the treatment due to toxicities. Therefore, the present retrospective study investigated possible correlations between DFX pharmacokinetics and drug-associated toxicities in 39 children (26 males), aged 2-17 years, who underwent an allogeneic hematopoietic stem cell transplantation. METHODS: IO was diagnosed by an abdominal magnetic resonance imaging and DFX was started at a median dose of 500 mg/day. DFX plasma concentrations were measured by a high performance liquid chromatographic method with UV detection and they were analysed by nonlinear mixed-effects modeling. RESULTS: The pharmacometric analysis demonstrated that DFX pharmacokinetics were significantly influenced by lean body mass (bioavailability and absorption constant), body weight (volume of distribution), alanine and aspartate transaminases, direct bilirubin, and serum creatinine (clearance). Predicted DFX minimum plasma concentrations (Ctrough) accounted for 32.4 ± 23.2 mg/L (mean ± SD), and they were significantly correlated with hepatic/renal and hematological toxicities (p-value < 0.0001, T-test and Fisher's exact tests) when Ctrough threshold values of 7.0 and 11.5 mg/L were chosen, respectively. CONCLUSIONS: The population pharmacokinetic model described the interindividual variability and identified Ctrough threshold values that were predictive of hepatic/renal and hematological toxicities associated with DFX.

Pharmacokinetics of Non-ß-Lactam ß-Lactamase Inhibitors.

The growing emergence of drug-resistant bacterial strains is an issue to treat severe infections, and many efforts have identified new pharmacological agents. The inhibitors of ß-lactamases (BLI) have gained a prominent role in the safeguard of beta-lactams. In the last years, new ß-lactam-BLI combinations have been registered or are still under clinical evaluation, demonstrating their effectiveness to treat complicated infections. It is also noteworthy that the pharmacokinetics of BLIs partly matches that of ß-lactams companions, meaning that some clinical situations, as well as renal impairment and renal replacement therapies, may alter the disposition of both drugs. Common pharmacokinetic characteristics, linear pharmacokinetics across a wide range of doses, and known pharmacokinetic/pharmacodynamic parameters may guide modifications of dosing regimens for both ß-lactams and BLIs. However, comorbidities (i.e., burns, diabetes, cancer) and severe changes in individual pathological conditions (i.e., acute renal impairment, sepsis) could make dose adaptation difficult, because the impact of those factors on BLI pharmacokinetics is partly known. Therapeutic drug monitoring protocols may overcome those issues and offer strategies to personalize drug doses in the intensive care setting. Further prospective clinical trials are warranted to improve the use of BLIs and their ß-lactam companions in severe and complicated infections.

Pharmacokinetics and pharmacodynamics of antibiotics in cystic fibrosis: a narrative review.

Cystic fibrosis affects several organs, predisposing patients to severe bacterial respiratory infections, including those caused by methicillin-resistant Staphylococcus aureus. Cystic fibrosis is also associated with a wide spectrum of pathological changes that can significantly affect the absorption, distribution, metabolism, and/or elimination of several drugs, including antibacterial agents. Therefore, awareness of the pharmacokinetic derangements in patients with cystic fibrosis is mandatory for the optimisation of antibiotic therapy. This review discusses the basic principles of pharmacokinetics and the pathophysiology of the pharmacokinetics changes associated with cystic fibrosis; it also provides an update of available data for the most widely used antibiotics. Evidence accumulated in the last few years has clearly shown that a significant number of cystic fibrosis patients treated with conventional dosing schemes have sub-therapeutic antibiotic concentrations, increasing their risk of therapeutic failure and/or the emergence of resistant pathogens. Some proposals to optimise antibiotic therapies in this clinical setting based on therapeutic drug monitoring are also discussed.

Ophthalmic phenotypes associated with biallelic loss-of-function PCDH12 variants.

Individuals carrying biallelic loss-of-function mutations in PCDH12 have been reported with three different conditions: the diencephalic-mesencephalic junction dysplasia syndrome 1 (DMJDS1), a disorder characterized by global developmental delay, microcephaly, dystonia, and a midbrain malformation at the diencephalic-mesencephalic junction; cerebral palsy combined with a neurodevelopmental disorder; and cerebellar ataxia with retinopathy. We report an additional patient carrying a homozygous PCDH12 frameshift, whose anamnesis combines the most recurrent DMJDS1 clinical features, that is, global developmental delay, microcephaly, and ataxia, with exudative vitreoretinopathy. This case and previously published DMJDS1 patients presenting with nonspecific visual impairments and ophthalmic disorders suggest that ophthalmic alterations are an integral part of clinical features associated with PCDH12 loss-of-function.

De Novo Frameshift Variants in the Neuronal Splicing Factor NOVA2 Result in a Common C-Terminal Extension and Cause a Severe Form of Neurodevelopmental Disorder.

The neuro-oncological ventral antigen 2 (NOVA2) protein is a major factor regulating neuron-specific alternative splicing (AS), previously associated with an acquired neurologic condition, the paraneoplastic opsoclonus-myoclonus ataxia (POMA). We report here six individuals with de novo frameshift variants in NOVA2 affected with a severe neurodevelopmental disorder characterized by intellectual disability (ID), motor and speech delay, autistic features, hypotonia, feeding difficulties, spasticity or ataxic gait, and abnormal brain MRI. The six variants lead to the same reading frame, adding a common proline rich C-terminal part instead of the last KH RNA binding domain. We detected 41 genes differentially spliced after NOVA2 downregulation in human neural cells. The NOVA2 variant protein shows decreased ability to bind target RNA sequences and to regulate target AS events. It also fails to complement the effect on neurite outgrowth induced by NOVA2 downregulation in vitro and to rescue alterations of retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in zebrafish. Our results suggest a partial loss-of-function mechanism rather than a full heterozygous loss-of-function, although a specific contribution of the novel C-terminal extension cannot be excluded.

Novel IQCE variations confirm its role in postaxial polydactyly and cause ciliary defect phenotype in zebrafish.

Polydactyly is one of the most frequent inherited defects of the limbs characterized by supernumerary digits and high-genetic heterogeneity. Among the many genes involved, either in isolated or syndromic forms, eight have been implicated in postaxial polydactyly (PAP). Among those, IQCE has been recently identified in a single consanguineous family. Using whole-exome sequencing in patients with uncharacterized ciliopathies, including PAP, we identified three families with biallelic pathogenic variations in IQCE. Interestingly, the c.895_904del (p.Val301Serfs*8) was found in all families without sharing a common haplotype, suggesting a recurrent mechanism. Moreover, in two families, the systemic phenotype could be explained by additional pathogenic variants in known genes (TULP1, ATP6V1B1). RNA expression analysis on patients' fibroblasts confirms that the dysfunction of IQCE leads to the dysregulation of genes associated with the hedgehog-signaling pathway, and zebrafish experiments demonstrate a full spectrum of phenotypes linked to defective cilia: Body curvature, kidney cysts, left-right asymmetry, misdirected cilia in the pronephric duct, and retinal defects. In conclusion, we identified three additional families confirming IQCE as a nonsyndromic PAP gene. Our data emphasize the importance of taking into account the complete set of variations of each individual, as each clinical presentation could finally be explained by multiple genes.

Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual Disability and Dysmorphic Features and Lead to P-Body Defects and RNA Dysregulation.

The human RNA helicase DDX6 is an essential component of membrane-less organelles called processing bodies (PBs). PBs are involved in mRNA metabolic processes including translational repression via coordinated storage of mRNAs. Previous studies in human cell lines have implicated altered DDX6 in molecular and cellular dysfunction, but clinical consequences and pathogenesis in humans have yet to be described. Here, we report the identification of five rare de novo missense variants in DDX6 in probands presenting with intellectual disability, developmental delay, and similar dysmorphic features including telecanthus, epicanthus, arched eyebrows, and low-set ears. All five missense variants (p.His372Arg, p.Arg373Gln, p.Cys390Arg, p.Thr391Ile, and p.Thr391Pro) are located in two conserved motifs of the RecA-2 domain of DDX6 involved in RNA binding, helicase activity, and protein-partner binding. We use functional studies to demonstrate that the first variants identified (p.Arg373Gln and p.Cys390Arg) cause significant defects in PB assembly in primary fibroblast and model human cell lines. These variants' interactions with several protein partners were also disrupted in immunoprecipitation assays. Further investigation via complementation assays included the additional variants p.Thr391Ile and p.Thr391Pro, both of which, similarly to p.Arg373Gln and p.Cys390Arg, demonstrated significant defects in P-body assembly. Complementing these molecular findings, modeling of the variants on solved protein structures showed distinct spatial clustering near known protein binding regions. Collectively, our clinical and molecular data describe a neurodevelopmental syndrome associated with pathogenic missense variants in DDX6. Additionally, we suggest DDX6 join the DExD/H-box genes DDX3X and DHX30 in an emerging class of neurodevelopmental disorders involving RNA helicases.

What is known about deferasirox chelation therapy in pediatric HSCT recipients: two case reports of metabolic acidosis.

To date, in pediatric field, various hematological malignancies are increasingly treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Iron overload and systemic siderosis often occur in this particular cohort of patients and are associated with poor prognosis. We describe herein the case of two allo-HSCT patients, on treatment with deferasirox; they showed histopathological elements compatible with venoocclusive disease or vanishing bile duct syndrome in ductopenic evolution before deferasirox started. The first patient developed drug-induced liver damage with metabolic acidosis and the second one a liver impairment with Fanconi syndrome. After withdrawing deferasirox treatment, both patients showed improvement. Measurements of drug plasma concentrations were performed by HPLC assay. The reduction and consequent disappearance of symptoms after the suspension of deferasirox substantiate its role in inducing hepatic damage, probably enabling the diagnosis of drug-induced liver damage. But the difficulties in diagnosing drug-related toxicity must be underlined, especially in compromised subjects. For these reasons, in patients requiring iron-chelating therapy, close and careful drug therapeutic monitoring is strongly recommended.