Publications by authors named "Paolo Picco"

51 Publications

Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy.

Brain 2021 Apr 15. Epub 2021 Apr 15.

Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, 611-0011, Japan.

Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health. We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in vivo. In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized by predominant gut dysmotility, encephalopathy, and neuromuscular abnormalities. Bonora et al. identify a new mitochondrial recessive disorder caused by biallelic variants in the LIG3 gene encoding DNA ligase III, which is responsible for mitochondrial DNA repair. Clinical signs include gut dysmotility and neurological features such as leucoencephalopathy, epilepsy and stroke-like episodes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awab056DOI Listing
April 2021

Oral Administration of S-Adenosylmethionine (SAMe) and Lactobacillus Plantarum HEAL9 Improves the Mild-To-Moderate Symptoms of Depression: A Randomized, Double-Blind, Placebo-Controlled Study.

Prim Care Companion CNS Disord 2020 Jun 25;22(4). Epub 2020 Jun 25.

Nutrilinea SRL, Varese, Italy.

Objective: To assess the effects of the combination of SAMe (S-adenosylmethionine) 200 mg and Lactobacillus plantarum (L. plantarum) HEAL9 1 × 10⁹ CFU for the overall symptomatology of mild-to-moderate depression.

Methods: This 6-week randomized, double-blind, placebo-controlled study included subjects aged 18-60 years with mild-to-moderate depression (according to ICD-10 diagnostic criteria) recruited from September 17, 2018, to October 5, 2018. Difference between groups in change from baseline to treatment week 6 on the Zung Self-Rating Depression Scale (Z-SDS) was the primary outcome. Comparisons between groups in change from baseline to treatment week 2 of the Z-SDS and from baseline to treatment weeks 2 and 6 of other scales (related to insomnia, anxiety, irritable bowel syndrome, and health status) were also analyzed.

Results: Ninety patients were randomized to SAMe plus L. plantarum HEAL9 (n = 46) or placebo (n = 44) groups. A greater reduction for the new combination compared to placebo was seen at treatment week 6 in the Z-SDS total score (P = .0165) and the core depression subdomain (P = .0247). A significant reduction in favor of the combination was shown at treatment week 2 for the Z-SDS total score (P = .0330), the cognitive and anxiety subdomains (P = .0133 and P = .0459, respectively), and the anxiety questionnaire (P = .0345). No treatment-related adverse events occurred.

Conclusions: Supplementation of SAMe and L. plantarum HEAL9 in adults with subthreshold or mild-to-moderate symptoms of depression resulted in fast and clinically relevant effects after 2 weeks. The combination was safe and significantly improved symptoms of depression, anxiety, and cognitive and somatic components. The effect of this novel product is independent from the severity of the symptoms unlike traditional antidepressants available on the market that have minimal benefits for subthreshold or mild-to-moderate symptoms.

Trial Registration: ClinicalTrials.gov identifier: NCT03932474.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4088/PCC.19m02578DOI Listing
June 2020

The expanding pathways of autoinflammation: a lesson from the first 100 genes related to autoinflammatory manifestations.

Adv Protein Chem Struct Biol 2020 12;120:1-44. Epub 2019 Dec 12.

Autoinflammatory Diseases and Immunodeficiencies Centre, IRCCS Istituto Giannina Gaslini, Genova, GE, Italy.

AutoInflammatory Diseases (AIDs) are a group of innate immune system disorders characterized by sterile inflammation without evidence of pathogenic autoantibodies or auto-reactive T lymphocytes. An expanding spectrum of genes and molecular pathways are associated with AIDs. Inflammasomopathies are secondary to dysregulation of multi-protein complexes, called inflammasomes, leading to an excessive maturation and secretion of IL1β and IL18. Patients present with persistent or recurrent systemic inflammation, abdominal and chest pain, skin rashes and are sensible to IL1 inhibitors. Unfolded proteins response causes a small number of AIDs that we propose to call immuno-proteinopathies, characterized by recurrent fevers and deep tissues inflammation. Other inflammatory conditions can occur in case of abnormalities of actin polymerization and the term of immuno-actinopathies is proposed. Generalized pustular psoriasis is a marker of autoinflammation mainly affecting the keratinocytes. Specific treatment targeting the p40 subunit of IL12 and IL23 or IL-17 are usually effective. Granulomatous inflammation characterizes AIDs related to NOD2 signaling defects. Defects in the ubiquitin-proteasome system cause a group of relopathies and some interferonopathies related to defect of the proteasome function (CANDLE syndrome). Gain of function of proteins regulating the production of type I interferons lead to severe inflammatory conditions, called interferonopathies. The JAK/STAT inhibitors are usually effective in these latter conditions. In conclusions, the identification of the main intracellular pathways involved in rare monogenic AIDs allows not only the proper classification of different conditions, but also highlight a pivotal role of possible novel therapeutic targets for the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/bs.apcsb.2019.11.001DOI Listing
February 2021

Anti-GAD epileptic encephalopathy in a toddler with Parry-Romberg syndrome.

Neurol Sci 2020 Mar 11;41(3):705-708. Epub 2019 Dec 11.

Department of Paediatrics, Institute Giannina Gaslini, Genoa, Italy.

Parry-Romberg syndrome (PRS) is a progressive facial hemiatrophy often associated with severe epilepsy. Although an immune-mediated vasculitic pathogenesis is widely assumed, no CNS-specific autoantibody has been described so far. A 2-year-old boy was admitted for a status epilepticus preceded by fever, restlessness, insomnia, and left facial rash. Cerebrospinal fluid was positive for glutamic acid decarboxylase (GAD)-antibodies. Brain MRI revealed FLAIR hyperintensities on left mediotemporal areas. He was successfully treated with intravenous methylprednisolone. One month later, seizures and facial rash reappeared and steroids were satisfactorily repeated. However, left hemifacial rash reappeared 5 months later, slowly followed by sclerotic skin lesions on frontal scalp and hemifacial sub-atrophy, leading to a diagnosis of PRS. Three years later, and despite chronic immunosuppression, new MRI lesions on left white matter are seen and left hemifacial atrophy has progressed. For the first time, we describe GAD autoantibodies in a PRS patient with epileptic encephalopathy. Epileptic syndromes with GAD autoantibodies are frequently described though with a questionable pathogenic significance. Given the clinical and MRI similarities of PRS with both Morphea and Rasmussen's encephalitis, we suggest that, in our patient, the initial facial skin vasculitis spread into CNS vessels through perforating arteries, inducing neuronal MHC-class I presentation of GAD epitopes, ultimately causing CD8-mediated neuronal cytotoxicity and the epileptic encephalopathy. GAD autoantibodies might represent the missing pathophysiological link between PRS and neuropsychiatric manifestations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10072-019-04187-6DOI Listing
March 2020

A child with a novel ACAN missense variant mimicking a septic arthritis.

Ital J Pediatr 2019 Nov 20;45(1):148. Epub 2019 Nov 20.

Pediatric Rheumatology Clinic, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147, Genova, Italy.

Heterozygous mutations of the ACAN gene have been associated with a broad spectrum of non-lethal skeletal dysplasias, called Aggrecanopathies. We report a case of a child with severe inflammatory elbow involvement mimicking septic arthritis who carried the new ACAN missense variant c.6970 T > C, p.Trp2324Arg. The comprehensive clinical evaluation of the patient and his family, focused on the associated clinical features (facial dysmorphisms, short stature, brachydactily), led us to suspect a hereditary condition. Our findings suggest that Aggrecanopathies should be considered in children with familial short stature, poor growth spurt and joint involvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13052-019-0719-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868685PMC
November 2019

Next generation sequencing panel in undifferentiated autoinflammatory diseases identifies patients with colchicine-responder recurrent fevers.

Rheumatology (Oxford) 2020 02;59(2):344-360

Autoinflammatory Diseases and Immunodeficiencies Centre, Pediatric Rheumatology Clinic, IRCCS Giannina Gaslini Institute, University of Genoa.

Objectives: The number of innate immune system disorders classified as systemic autoinflammatory diseases (SAID) has increased in recent years. More than 70% of patients with clinical manifestations of SAID did not receive a molecular diagnosis, thus being classed as so-called undifferentiated or undefined SAID (uSAID). The aim of the present study was to evaluate a next-generation sequencing (NGS)-based clinically oriented protocol in patients with uSAID.

Methods: We designed a NGS panel that included 41 genes clustered in seven subpanels. Patients with uSAID were classified into different groups according to their clinical features and sequenced for the coding portions of the 41 genes.

Results: Fifty patients were enrolled in the study. Thirty-four patients (72%) displayed recurrent fevers not consistent with a PFAPA phenotype. Sixteen patients displayed a chronic inflammatory disease course. A total of 100 gene variants were found (mean 2 per patient; range 0-6), a quarter of which affected suspected genes. Mutations with a definitive diagnostic impact were detected in two patients. Patients with genetically negative recurrent fevers displayed a prevalent gastrointestinal, skin and articular involvement. Patients responded to steroids on demands (94%) and colchicine, with a response rate of 78%.

Conclusion: Even with a low molecular diagnostic rate, a NGS-based approach is able to provide a final diagnosis in a proportion of uSAID patients with evident cost-effectiveness. It also allows the identification of a subgroup of genetically negative patients with recurrent fever responding to steroid on demand and colchicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/kez270DOI Listing
February 2020

Early onset PFAPA-like syndrome in a child with microduplication of the 7q11.23.

Clin Exp Rheumatol 2019 Nov-Dec;37 Suppl 121(6):163. Epub 2019 Jul 2.

Paediatric Rheumatology Clinic, IRCCS Istituto Giannina Gallini, Genoa, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
January 2020

Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome.

J Clin Immunol 2019 07 29;39(5):476-485. Epub 2019 May 29.

U.O.C. Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Objectives: Mutations affecting the TMEM173 gene cause STING-associated vasculopathy with onset in infancy (SAVI). No standard immunosuppressive treatment approach is able to control disease progression in patients with SAVI. We studied the efficacy and safety of targeting type I IFN signaling with the Janus kinase inhibitor, ruxolitinib.

Methods: We used DNA sequencing to identify mutations in TMEM173 in patients with peripheral blood type I IFN signature. The JAK1/2 inhibitor ruxolitinib was administered on an off-label basis.

Results: We identified three patients with SAVI presenting with skin involvement and progressive severe interstitial lung disease. Indirect echocardiographic signs of pulmonary hypertension were present in one case. Following treatment with ruxolitinib, we observed improvements of respiratory function including increased forced vital capacity in two patients, with discontinuation of oxygen therapy and resolution of echocardiographic abnormalities in one case. Efficacy was persistent in one patient and only transitory in the other two patients. Clinical control of skin complications was obtained, and one patient discontinued steroid treatment. One patient, who presented with kidney involvement, showed resolution of hematuria. One patient experienced increased recurrence of severe viral respiratory infections. Monitoring of peripheral blood type I interferon signature during ruxolitinib treatment did not show a stable decrease.

Conclusions: We conclude that targeting type I IFN receptor signaling may represent a promising therapeutic option for a subset of patients with SAVI syndrome and severe lung involvement. However, the occurrence of viral respiratory infection might represent an important cautionary note for the application of such form of treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-019-00645-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086512PMC
July 2019

Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.

EMBO J 2018 12 12;37(23). Epub 2018 Nov 12.

Department of Genetics, Assistance Publique des Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France.

A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the () mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/embj.2018100540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276871PMC
December 2018

T-cell defects in patients with germline mutations account for combined immunodeficiency.

Blood 2018 11 25;132(22):2362-2374. Epub 2018 Sep 25.

Department of Pediatrics & Department of Microbiology-Immunology, Dalhousie University, Halifax, NS, Canada.

ARPC1B is a key factor for the assembly and maintenance of the ARP2/3 complex that is involved in actin branching from an existing filament. Germline biallelic mutations in have been recently described in 6 patients with clinical features of combined immunodeficiency (CID), whose neutrophils and platelets but not T lymphocytes were studied. We hypothesized that ARPC1B deficiency may also lead to cytoskeleton and functional defects in T cells. We have identified biallelic mutations in in 6 unrelated patients with early onset disease characterized by severe infections, autoimmune manifestations, and thrombocytopenia. Immunological features included T-cell lymphopenia, low numbers of naïve T cells, and hyper-immunoglobulin E. Alteration in ARPC1B protein structure led to absent/low expression by flow cytometry and confocal microscopy. This molecular defect was associated with the inability of patient-derived T cells to extend an actin-rich lamellipodia upon T-cell receptor (TCR) stimulation and to assemble an immunological synapse. ARPC1B-deficient T cells additionally displayed impaired TCR-mediated proliferation and SDF1-α-directed migration. Gene transfer of in patients' T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In 2 of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In 1 revertant patient, memory CD8 T cells expressing normal levels of ARPC1B displayed improved T-cell migration. Inherited ARPC1B deficiency therefore alters T-cell cytoskeletal dynamics and functions, contributing to the clinical features of CID.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2018-07-863431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265646PMC
November 2018

ABCC6 mutations and early onset stroke: Two cases of a typical Pseudoxanthoma Elasticum.

Eur J Paediatr Neurol 2018 Jul 12;22(4):725-728. Epub 2018 Apr 12.

Rare Disease Unit, Istituto Giannina Gaslini, Genoa, Italy.

Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterized by fragmented and mineralized elastic fibers in the mid-dermis of the skin, eye, digestive tract and cardiovascular system. Clinical presentation includes typical skin lesions, ocular angioid streaks, and multisystem vasculopathy. The age of onset varies considerably from infancy to old age, but the diagnosis is usually made in young adults due to frequent absence of pathognomonic skin and ocular manifestations in early childhood. We report two children with PXE presenting with isolated multisystem vasculopathy and early-onset stroke. In the first patient, diagnosis was delayed until typical dermatologic alterations appeared; in the second patient, next-generation sequencing (NGS) study led to early diagnosis and specific follow-up, underlying the crucial role in idiopathic pediatric stroke of early genetic testing using NGS-based panels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2018.04.002DOI Listing
July 2018

CD70 Deficiency due to a Novel Mutation in a Patient with Severe Chronic EBV Infection Presenting As a Periodic Fever.

Front Immunol 2017 29;8:2015. Epub 2018 Jan 29.

Clinica Pediatria e Reumatologia, Istituto Giannina Gaslini, Genova, Italy.

Primary immunodeficiencies with selective susceptibility to EBV infection are rare conditions associated with severe lymphoproliferation. We followed a patient, son of consanguineous parents, referred to our center for recurrent periodic episodes of fever associated with tonsillitis and adenitis started after an infectious mononucleosis and responsive to oral steroid. An initial diagnosis of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome was done. In the following months, recurrent respiratory infections and episodes of keratitis were also observed, together with a progressive reduction of immunoglobulin levels and an increase of CD20 cells. Cell sorting and EBV PCR showed 25,000 copies for 100,000 leukocytes with predominant infection of B lymphocytes. Lymph node's biopsy revealed reactive lymphadenopathy with paracortical involvement consistent with a chronic EBV infection. Molecular analysis of , and genes did not detect any pathogenic mutation. The patients underwent repeated courses of anti-CD20 therapy with only a partial control of the disease, followed by stem cell transplantation with a complete normalization of clinical and immunological features. Whole exome sequencing of the trio was performed. Among the variants identified, a novel loss of function homozygous c.163-2A>G mutation of the gene, affecting the exon 2 AG-acceptor splice site, fit the expected recessive model of inheritance. Indeed, deficiency of both CD27, and, more recently, of its ligand CD70, has been reported as a cause of EBV-driven lymphoproliferation and hypogammaglobulinemia. Cell surface analysis of patient-derived PHA-T cell blasts and EBV-transformed lymphoblastoid cell lines confirmed absence of CD70 expression. In conclusion, we describe a case of severe chronic EBV infection caused by a novel mutation of CD70 presenting with recurrent periodic fever.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2017.02015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796890PMC
January 2018

Type I interferon-mediated autoinflammation due to DNase II deficiency.

Nat Commun 2017 12 19;8(1):2176. Epub 2017 Dec 19.

Pathology Department, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France.

Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-017-01932-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736616PMC
December 2017

Type I interferon pathway activation in COPA syndrome.

Clin Immunol 2018 02 10;187:33-36. Epub 2017 Oct 10.

Clinica Pediatrica e Reumatologia, Istituto Giannina Gaslini, Genova, Italy. Electronic address:

Mutations of the COPA gene cause an immune dysregulatory disease characterised by polyarticular arthritis and progressive interstitial lung disease with pulmonary haemorrhages. We report the case of a young girl that presented at age 3 with polyarticular arthritis, chronic cough and high titer rheumatoid factor. Radiologic imaging showed interstitial lung disease with tree-in-a-bud nodules and air-filled cysts. Targeted genetic analysis of COPA gene showed the reported c.698G>A mutation. The patient was lost to follow up for 3years during which therapy was discontinued with the development of joint damage and deformities. Analysis of peripheral blood showed activation of type 1 interferon pathway, which was also confirmed in 4 previously reported COPA patients. Our observations underline the importance of early treatment in COPA disease to avoid loss of joint function. Furthermore, our results suggest a role for type 1 interferon in disease pathogenesis opening the possibility for targeted therapeutic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clim.2017.10.001DOI Listing
February 2018

ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study.

Ann Rheum Dis 2017 10 18;76(10):1648-1656. Epub 2017 May 18.

Division of Human Genetics, G. Gaslini Institute, Genova, Italy.

Objectives: To analyse the prevalence of mutations in patients diagnosed with early onset livedo reticularis and/or haemorrhagic/ischaemic strokes in the context of inflammation or polyarteritis nodosa (PAN). Forty-eight patients from 43 families were included in the study.

Methods: Direct sequencing of was performed by Sanger analysis. Adenosine deaminase 2 (ADA2) enzymatic activity was analysed in monocyte isolated from patients and healthy controls incubated with adenosine and with or without an ADA1 inhibitor.

Results: Biallelic homozygous or compound heterozygous mutations were detected in 15/48 patients. A heterozygous disease-associated mutation (p.G47V) was observed in two affected brothers. The mean age of onset of the genetically positive patients was 24 months (6 months to 7 years). Ten patients displayed one or more cerebral strokes during their disease course. Low immunoglobulin levels were detected in six patients. Thalidomide and anti-TNF (tumour necrosis factor) blockers were the most effective drugs. Patients without mutations had a later age at disease onset, a lower prevalence of neurological and skin manifestations; one of these patients displayed all the clinical features of adenosine deaminase 2deficiency (DADA2) and a defective enzymatic activity suggesting the presence of a missed mutation or a synthesis defect.

Conclusions: DADA2 accounts for paediatric patients diagnosed with PAN-like disease and strokes and might explain an unrecognised condition in patients followed by adult rheumatologist. Timely diagnosis and treatment with anti-TNF agents are crucial for the prevention of severe complications of the disease. Functional assay to measure ADA2 activity should complement genetic testing in patients with non-confirming genotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2016-210802DOI Listing
October 2017

Critical role of STIR MRI in early detection of post-streptococcal periostitis with dysproteinaemia (Goldbloom's syndrome).

Clin Exp Rheumatol 2017 May-Jun;35(3):516-517. Epub 2017 Mar 23.

2nd Department of Paediatrics, Giannina Gaslini Institute, Genova, Italy.

Objectives: In 1966, Goldbloom et al. described two children who developed a peculiar clinical picture characterized by intermittent daily bone pain in the lower limbs, fever spikes, increased acute phase reactants and dysproteinaemia. The syndrome occurred two weeks after a group A β-haemolytic streptococcus infection. So far, only a few cases have been reported in the medical literature in English.

Methods: We report two further cases of Goldbloom's syndrome with a review of the literature in English.

Results: Our two patients lived in the same Italian region and presented their syndrome onset a week apart. Early use of STIR MRI revealed an atypical metaphyseal hyperintensity in the femurs and tibias. X-ray showed periosteal hyperostosis. A short cycle of corticosteroids led to rapid recovery of symptoms and disappearance of bone changes.

Conclusions: The reported cases highlight a likely under-recognised post-streptococcal inflammatory periosteal reaction and emphasise the diagnostic utility of the newer imaging modalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
August 2017

Widening the Heterogeneity of Leigh Syndrome: Clinical, Biochemical, and Neuroradiologic Features in a Patient Harboring a NDUFA10 Mutation.

JIMD Rep 2017 1;37:37-43. Epub 2017 Mar 1.

Rare Diseases Unit, Istituto Giannina Gaslini, Genoa, Italy.

Leigh syndrome (LS) is an early-onset progressive neurodegenerative disorder, characterized by a wide clinical and genetic heterogeneity, and is the most frequent disorder of mitochondrial energy production in children. Beside its great variability in clinical, biochemical, and genetic features, LS is pathologically uniformly characterized by multifocal bilateral and symmetric spongiform degeneration of the basal ganglia, brainstem, thalamus, cerebellum, spinal cord, and optic nerves. Isolated complex I deficiency is the most common defect identified in Leigh syndrome. In 2011, the first child with a mutation of NDUFA10 gene, coding for an accessory subunits of complex I, was described. Here, we present an additional description of a child with Leigh syndrome harboring a homozygous mutation in NDUFA10, providing insights in clinical, biochemical, and neuroradiologic features for future earlier recognition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/8904_2017_9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740043PMC
March 2017

Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial.

Lancet 2017 03 3;389(10072):909-916. Epub 2017 Feb 3.

Istituto Giannina Gaslini, Genoa, Italy; Università degli Studi di Genova, Genoa, Italy.

Background: Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases the efficacy of intra-articular corticosteroid therapy.

Methods: We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70.

Findings: Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32%) patients assigned to intra-articular corticosteroids alone and 39 (37%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0·48). Adverse events were recorded for 20 (17%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event.

Interpretation: Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis.

Funding: Italian Agency of Drug Evaluation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(17)30065-XDOI Listing
March 2017

Interstitial 18q22.3q23 deletion: clinical, neuroradiological and molecular characterization of a new case and review of the literature.

Mol Cytogenet 2016 10;9:78. Epub 2016 Oct 10.

Istituto Giannina Gaslini, Genoa, Italy.

Background: Deletions of the long arm of chromosome 18 cause a common autosomal syndrome clinically characterized by a protean clinical phenotype.

Case Presentation: We report on a 16-month-old male infant affected by fever attacks apparently unrelated with any infectious or inflammatory symptoms, growth retardation, bilateral vertical talus, congenital aural atresia, dysmorphisms, mild psychomotor delay, and peculiar neuroradiological features. Array-CGH analysis revealed one of the smallest 18q22.3q23 interstitial deletions involving five genes: , , and .

Conclusions: Herein we focus on previously unreported heralding symptoms and neuroradiological abnormalities which enlarge the spectrum of 18q deletion syndrome demonstrating that a small deletion can determine a complex phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13039-016-0285-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5057431PMC
October 2016

Juvenile eosinophilic fasciitis: three case reports with review of the literature.

Clin Exp Rheumatol 2016 May-Jun;34(3):527-30. Epub 2016 May 30.

UOC Pediatria II, Reumatologia, Istituto Giannina Gaslini, Genoa, Italy.

Objectives: Eosinophilic fasciitis is an uncommon scleroderma-like disorder characterised by induration and thickening of skin and soft tissue, usually associated with peripheral eosinophilia, poorly characterised in childhood.

Methods: We report 3 paediatric cases of eosinophilic fasciitis showing unusual clinical and histopathological features with a review of the literature.

Results: All cases presented progressive motility impairment started from upper limbs with no skin abnormalities. All cases showed systemic inflammatory involvement and 2 patients had acute complications. Two patients developed disabling outcomes despite appropriate treatments.

Conclusions: Eosinophilic fasciitis may present unusual clinical and histopathological features during childhood and requires early recognition in order to prevent acute complications and disabling outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
August 2016

Type I interferonopathies in pediatric rheumatology.

Pediatr Rheumatol Online J 2016 Jun 4;14(1):35. Epub 2016 Jun 4.

U.O. Pediatria 2, Istituto Giannina Gaslini, Genoa, Italy.

Defective regulation of type I interferon response is associated with severe inflammatory phenotypes and autoimmunity. Type I interferonopathies are a clinically heterogenic group of Mendelian diseases with a constitutive activation of this pathway that might present as atypical, severe, early onset rheumatic diseases. Skin vasculopathy with chilblains and livedo reticularis, interstitial lung disease, and panniculitis are common. Recent studies have implicated abnormal responses to nucleic acid stimuli or defective regulation of downstream effector molecules in disease pathogenesis. As observed for IL1-β and autoinflammatory diseases, knowledge of the defects responsible for type I interferonopathies will likely promote the development of targeted therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12969-016-0094-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893274PMC
June 2016

A Long-Term Psychological Observation in an Adolescent Affected with Gardner Diamond Syndrome.

Indian J Psychol Med 2016 Jan-Feb;38(1):74-7

Department of Child Pediatrics, G. Gaslini Institute, Genoa, Italy.

Gardner-Diamond syndrome (GDS) is an uncommon disease clinically characterized by a wide spectrum of psycho-emotive symptoms associated with painful ecchymoses/purpuric lesions and positivity of auto-erythrocyte sensitization skin test. Herein, a perspective clinical and psychological observation of an adolescent GDS is firstly reported focusing on her psychological features long-term monitored for a 1-year period. The administration of a standardized tools battery allowed us to define psychological features of the young patient over time and to monitored clinical course and response to treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/0253-7176.175129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782453PMC
March 2016

Disease activity accounts for long-term efficacy of IL-1 blockers in pyogenic sterile arthritis pyoderma gangrenosum and severe acne syndrome.

Rheumatology (Oxford) 2016 07 17;55(7):1325-35. Epub 2016 Mar 17.

Pediatrics II Unit and Laboratory of Immunology of Pediatric Rheumatology, G. Gaslini IRCCS, Genoa, Italy.

Objective: To provide a rationale for anti-IL-1 treatment in pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) by defining whether IL-1β secretion is enhanced; requires NLRP3; and correlates with proline-serine-threonine phosphatase-interacting protein 1 mutations, disease activity and/or the clinical picture in PAPA.

Methods: Monocytes were isolated from 13 patients and 35 healthy donors and studied at baseline and following activation. Secretion pattern of IL-1β, IL-1α, IL-1Ra, IL-6, IL-18 and TNF-α was assessed in supernatants by ELISA. The NLRP3 requirement for IL-1β secretion was investigated by silencing technique in PAPA and healthy donor monocytes. Long-term follow-up (mean 26 months, range 4-38) was performed in five patients enrolled in an anti-IL-1 regimen.

Results: IL-1β secretion in PAPA is increased, requires NLRP3 and correlates with disease activity. Patients with a history of osteoarticular flares release more IL-1β, IL-6 and TNF-α compared with those with predominant cutaneous recurrences. Monocytes from patients in anti-IL-1 treatment dramatically reduced IL-1β secretion after ex vivo activation, and long-term follow-up demonstrated decreased frequency of flares and normalization of acute phase reactants in all the patients. A straightforward correlation between genotype and IL-1β signalling was not observed suggesting that factors other than mutation itself may play a role in regulating IL-1β secretion and response to treatment in PAPA.

Conclusion: PAPA patients with active lesions display increased NLRP3-mediated IL-1β secretion, and long-term efficacy of IL-1 blockade was demonstrated. Even if other mechanisms related to the complex proline-serine-threonine phosphatase-interacting protein 1 protein networking might play additional roles, this study further supports the potential of IL-1 blockade as an effective therapeutic strategy in PAPA syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/kew031DOI Listing
July 2016

Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome.

Nat Commun 2015 Jul 28;6:7870. Epub 2015 Jul 28.

Division of Epigenomics and Development, Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.

The life-threatening Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) syndrome is a genetically heterogeneous autosomal recessive disorder. Twenty percent of patients cannot be explained by mutations in the known ICF genes DNA methyltransferase 3B or zinc-finger and BTB domain containing 24. Here we report mutations in the cell division cycle associated 7 and the helicase, lymphoid-specific genes in 10 unexplained ICF cases. Our data highlight the genetic heterogeneity of ICF syndrome; however, they provide evidence that all genes act in common or converging pathways leading to the ICF phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms8870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519989PMC
July 2015

Dissecting the heterogeneity of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.

J Rheumatol 2015 Jun 15;42(6):994-1001. Epub 2015 Apr 15.

From the Istituto Giannina Gaslini, Genoa, Italy; Karolinska University Hospital Solna, Stockholm, Sweden; Gulhane Military Medical Faculty, Ankara, Turkey; Royal Children's Hospital, Melbourne, Australia; Bakırkoy Maternity and Children Education and Research Hospital, Istanbul, Turkey; King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Policlinico Università di Catania, Catania, Italy; Hospital Universitário Clementino Fraga Filho, Rio de Janeiro, Brazil; Universitaetsklinik fuer Kinderheilkunde, Inselspital, Berne, Switzerland; Ospedale Policlinico, Chieti, Italy; Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico; University of Messina, Messina, Italy; Carolinas HealthCare System, Charlotte, North Carolina; Women and Children's Hospital, Buffalo, New York, USA; Zentrum fuer Allgemeine Paediatrie und Neonatologie, Sankt Augustin, Germany; Stanford School of Medicine, Palo Alto, California, USA; Department for Immunology and Rheumatology, Children's Hospital of Zagreb, Zagreb, Croatia; Steven and Alexandra Cohen Children's Hospital of New York, New York, New York, USA; IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy; University of Latvia, Riga, Latvia; Hospital das Clínicas, Botucatu, Brazil; King Fahad National Guard Hospital, Riyadh, Saudi Arabia; Arkansas Children's Hospital, Little Rock, Arkansas, USA; Kyriakou Children's Hospital of Athens, Athens, Greece; The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Children's University Hospital, Riga, Latvia; Hospital Universitario 12 de Octubre, Madrid, Spain; M. Iashvili Children's Central Clinic, Tbilisi, Georgia; Azienda Ospedaliera Universitaria Ospedali Riuniti, Ancona, Italy; Gazi University, Ankara, Turkey; Università degli Studi di Genova, Genoa, Italy; University of Alabama at Birmingham, Birmingham, Alabama, USA.F. Minoia, MD; S. Davì, MD, Istituto Giannina Gaslini; A. Horne, M

Objective: To seek insights into the heterogeneity of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) through the analysis of a large patient sample collected in a multinational survey.

Methods: International pediatric rheumatologists and hemato-oncologists entered their patient data, collected retrospectively, in a Web-based database. The demographic, clinical, laboratory, histopathologic, therapeutic, and outcome data were analyzed in relation to (1) geographic location of caring hospital, (2) subspecialty of attending physician, (3) demonstration of hemophagocytosis, and (4) severity of clinical course.

Results: A total of 362 patients were included by 95 investigators from 33 countries. Demographic, clinical, laboratory, and histopathologic features were comparable among patients seen in diverse geographic areas or by different pediatric specialists. Patients seen in North America were given biologics more frequently. Patients entered by pediatric hemato-oncologists were treated more commonly with biologics and etoposide, whereas patients seen by pediatric rheumatologists more frequently received cyclosporine. Patients with demonstration of hemophagocytosis had shorter duration of sJIA at MAS onset, higher prevalence of hepatosplenomegaly, lower levels of platelets and fibrinogen, and were more frequently administered cyclosporine, intravenous immunoglobulin (IVIG), and etoposide. Patients with severe course were older, had longer duration of sJIA at MAS onset, had more full-blown clinical picture, and were more commonly given cyclosporine, IVIG, and etoposide.

Conclusion: The clinical spectrum of MAS is comparable across patients seen in different geographic settings or by diverse pediatric subspecialists. There was a disparity in the therapeutic choices among physicians that underscores the need to establish uniform therapeutic protocols.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3899/jrheum.141261DOI Listing
June 2015

Whole-body MRI as an unconventional diagnostic tool in a pediatric patient with systemic infection.

Acta Radiol Short Rep 2014 Dec 4;3(11):2047981614549571. Epub 2014 Dec 4.

2nd Pediatric Division, IRCCS Giannina Gaslini Insitute and University of Genoa, Genova, Italy.

Anaplasma phagocytophilum, an obligate intracellular bacterium, is the causative agent of human granulocytic anaplasmosis (HGA), a tickborne infection usually manifesting as fever, malaise, cytopenia, spleen enlargement, and hepatitis. Herein, we report a case of a 14-year-old girl with HGA whose whole-body magnetic resonance imaging (MRI) disclosed an unusual picture characterized by small, widespread punctuate millimetric nodules, hypointense on T1-weighted and hyperintense on STIR sequences. This firstly reported finding may represent an alternative tool for identifying atypical infectious diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2047981614549571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271715PMC
December 2014