Hypomorphic FANCA mutations correlate with mild mitochondrial and clinical phenotype in Fanconi anemia

Fanconi anemia is a rare disease characterized by congenital malformations, aplastic anemia, and predisposition to cancer. Despite the consolidated role of the Fanconi anemia proteins in DNA repair, their involvement in mitochondrial function is emerging. The purpose of this work was to assess whether the mitochondrial phenotype, independent of genomic integrity, could correlate with patient phenotype. We evaluated mitochondrial and clinical features of 11 affected individuals homozygous or compound heterozygous for p.His913Pro and p.Arg951Gln/Trp, the two residues of FANCA that are more frequently affected in our cohort of patients. Although p.His913Pro and p.Arg951Gln proteins are stably expressed in cytoplasm, they are unable to migrate in the nucleus, preventing cells from repairing DNA. In these cells, the electron transfer between respiring complex I-III is reduced and the ATP/AMP ratio is impaired with defective ATP production and AMP accumulation. These activities are intermediate between those observed in wild-type and FANCA-/- cells, suggesting that the variants at residues His913 and Arg951 are hypomorphic mutations. Consistent with these findings, the clinical phenotype of most of the patients carrying these mutations is mild. These data further support the recent finding that the Fanconi anemia proteins play a role in mitochondria, and open up possibilities for genotype/phenotype studies based on novel mitochondrial criteria

Acute pediatric cerebellitis and mutism. Case report and review of the literature

Acute cerebellitis (AC) is a rare syndrome characterized by an inflammatory involvement of the cerebellum which can complicate infections or vaccinations. AC can be a life-threatening condition, presenting with speech disorders including longlasting mutism, usually followed by dysarthria. Clinical examination, laboratory findings and Magnetic Resonance Imaging are essential for establishing an early diagnosis and initiating prompt and adequate treatment, thereby reducing morbidity and mortality. We report a case of a child with AC complicated by mutism and we present a review of the literature of pediatric cases with this condition

Nerve growth factor eye drop administration improves visual function in a patient with optic glioma

BACKGROUND: Spontaneous visual improvement in people with an optic glioma (OG) of the anterior or retrochiasmatic optic pathways is rare. OBJECTIVE: To evaluate the effects on visual function of nerve growth factor (NGF) eye drop administration in a patient with severe visual impairment due to a low-grade OG. METHODS: A 45-year-old woman with OG and long-standing optic nerve atrophy was assessed before and after 2 NGF treatment courses. The drug used was 2.5S murine NGF. One milligram of NGF, diluted in saline solution, was administered onto the conjunctiva of both eyes for 10 consecutive days 3 times a day for each treatment. The follow-up was performed by clinical, neuroradiologic, and electrophysiological tests (electroretinogram and visual evoked potentials [VEPs]) at the end of each treatment and 30 and 60 days later. RESULTS: A repeated subjective and objective improvement of visual function (>3 lines visual acuity; >40\ub0 visual field; >50% VEP amplitude increase, Wilcoxon test P < .01) was recorded after NGF treatment. These measures tended to deteriorate toward baseline values 60 days from the end of each NGF treatment. No ocular or systemic side effects were observed throughout treatment. CONCLUSIONS: Conjunctival NGF may be a beneficial adjunct therapy for visual loss in patients with OG, possibly exerting its effects on residual viable optic pathways

Current practice and recent advances in pediatric pain management

Differently from the adult patients, in pediatric age it is more difficult to assess and treat efficaciously the pain and often this symptom is undertreated or not treated. In children, selection of appropriate pain assessment tools should consider age, cognitive level and the presence of eventual disability, type of pain and the situation in which it is occurring. Improved understanding of developmental neurobiology and paediatric analgesic drugs pharmacokinetics should facilitate a better management of childhood pain

Current practice and recent advances in pediatric pain management

Differently from the adult patients, in pediatric age it is more difficult to assess and treat efficaciously the pain and often this symptom is undertreated or not treated. In children, selection of appropriate pain assessment tools should consider age, cognitive level and the presence of eventual disability, type of pain and the situation in which it is occurring. Improved understanding of developmental neurobiology and paediatric analgesic drugs pharmacokinetics should facilitate a better management of childhood pain

Utility of intranasal Ketamine and Midazolam to perform gastric aspirates in children: a double-blind, placebo controlled, randomized study

We performed a prospective, randomized, placebo-controlled study aimed to evaluate the efficacy and safety of a sedation protocol based on intranasal Ketamine and Midazolam (INKM) administered by a mucosal atomizer device in uncooperative children undergoing gastric aspirates for suspected tuberculosis

Effects of nerve growth factor in experimental model of focal microgyria

The effects on neural repair of intraparenchymal nerve growth factor (NGF) administration were evaluated in neonate Wistar rats with experimentally induced focal microgyria

Acute lymphoblastic leukemia in the context of RASopathies

International audienceNoonan syndrome is associated with a range of malignancies including acute lymphoblastic leukemia (ALL). However, little information is available regarding the frequency, natural history, characteristics and prognosis of ALL in Noonan syndrome or RASopathies in general. Cross-referencing data from a large prospective cohort of 1176 patients having a molecularly confirmed RASopathy with data from the French childhood cancer registry allowed us to identify ALL in 6 (0.5%) patients including 4/778 (0.5%) with a germline PTPN11 mutation and 2/94 (2.1%) with a germline SOS1 mutation. None of the patients of our series with CFC syndrome (with germline BRAF or MAP2K1/MAP2K2 mutation - n = 121) or Costello syndrome (with HRAS mutation - n = 35) had an ALL. A total of 19 Noonan-ALL were gathered by adding our patients to those of the International Berlin-Munster-Frankfurt (I-BFM) study group and previously reported patients. Strikingly, all Noonan-associated ALL were B-cell precursor ALL, and high hyperdiploidy with more than 50 chromosomes was found in the leukemia cells of 13/17 (76%) patients with available genetics data. Our data suggest that children with Noonan syndrome are at higher risk to develop ALL. Like what is observed for somatic PTPN11 mutations, NS is preferentially associated with the development of hyperdiploid ALL that will usually respond well to chemotherapy. However, Noonan syndrome patients seem to have a propensity to develop post therapy myelodysplasia that can eventually be fatal. Hence, one should be particularly cautious when treating these patients

Platinum compounds in children with cancer: toxicity and clinical management

Platinum compounds are widely used in the treatment of pediatric tumors such as neuroblastoma, germ-cell tumors, osteosarcoma, retinoblastoma, hepatoblastoma, brain tumors (low-grade gliomas and medulloblastoma/PNET), and relapsed and refractory lymphomas. The three major platinum compounds (cisplatin, carboplatin, and oxaliplatin) have a similar pharmacokinetics profile and mechanism of action, but the differences in their chemical structure are responsible for their different antitumor activity and toxicity. In this review, we have described the main characteristics of cisplatin, carboplatin, and oxaliplatin, focusing on their toxic effects and possible strategies to prevent them to improve the clinical outcomes in pediatric cancer patients. The underlying mechanism of each platinum-related toxicity is shown together with the clinical manifestations. Furthermore, possible preventive strategies are suggested to reduce the negative impact of platinum compounds on the quality of life of children with cancer. Cisplatin seems to be mostly ototoxic and nephrotoxic, carboplatin mainly produces myelosuppression, whereas oxaliplatin induces predominantly peripheral sensory neurotoxicity. In contrast, nausea and vomiting can be linked to all platinum compounds, although cisplatin exerts the strongest emetic effect. A correct knowledge of pharmacokinetics and toxicological profile of platinum compounds may aid physicians prevent their toxicity on auditory, nervous, renal, and bone marrow function, improving the quality of life of pediatric cancer patients

Autoimmune Neutropenia and Immune-Dysregulation in a Patient Carrying a TINF2 Variant

In recent years, the knowledge about the immune-mediated impairment of bone marrow precursors in immune-dysregulation and autoimmune disorders has increased. In addition, immune-dysregulation, secondary to marrow failure, has been reported as being, in some cases, the most evident and early sign of the disease and making the diagnosis of both groups of disorders challenging. Dyskeratosis congenita is a disorder characterized by premature telomere erosion, typically showing marrow failure, nail dystrophy and leukoplakia, although incomplete genetic penetrance and phenotypes with immune-dysregulation features have been described. We report on a previously healthy 17-year-old girl, with a cousin successfully treated for acute lymphoblastic leukemia, who presented with leukopenia and neutropenia. The diagnostic work-up showed positive anti-neutrophil antibodies, leading to the diagnosis of autoimmune neutropenia, a slightly low NK count and high TCR-&alpha;&beta;+-double-negative T-cells. A next-generation sequencing (NGS) analysis showed the 734C&gt;A variant on exon 6 of the TINF2 gene, leading to the p.Ser245Tyr. The telomere length was short on the lymphocytes and granulocytes, suggesting the diagnosis of an atypical telomeropathy showing with immune-dysregulation. This case underlines the importance of an accurate diagnostic work-up of patients with immune-dysregulation, who should undergo NGS or whole exome sequencing to identify specific disorders that deserve targeted follow-up and treatment