Daniele De Brssi
@santobonopausilipon.it
Department of Pediatrics
AORN Santobono Pausilipon
RESEARCH INTERESTS
Clinical Genetics, Medical Genetics, Human Genetics, Pedaitrics
Scopus Publications
Scopus Publications
Paolo Quitadamo and Daniele De Brasi
Associazione Culturale Pediatri
In recent years, many evidences have shown the importance of genetics in inflammatory bowel disease (IBD). It is well known that from an etiopathogenetic point of view, IBDs are multifactorial diseases, likely due to a complex interaction between genetic predisposition, intestinal microbiota, and other environmental factors. Regarding genetic factors, these, in terms of IBD-associated gene variants, are believed to influence only 20% of cases. Conversely, in recent years, there is increasing evidence of a role of epigenetic modifications associated with environmental modifiers underlying the onset of IBD and its recurrence. In particular, the role of DNA methylation and noncoding RNAs in disease expression, relapse, and tumor complications appears increasingly clear.
Manuela Morleo, Rossella Venditti, Evangelos Theodorou, Lauren C. Briere, Marion Rosello, Alfonsina Tirozzi, Roberta Tammaro, Nour Al-Badri, Frances A. High, Jiahai Shi,et al.
Elsevier BV
Simona Amenta, Giuseppe Marangi, Daniela Orteschi, Silvia Frangella, Fiorella Gurrieri, Elisa Paccagnella, Annalaura Torella, Gerarda Cappuccio, Francesco Musacchia, Margherita Mutarelli,et al.
Springer Science and Business Media LLC
M. Cesana, L. Vaccaro, M. J. Larsen, M. Kibæk, L. Micale, S. Riccardo, P. Annunziata, C. Colantuono, L. Di Filippo, D. De Brasi,et al.
Springer Science and Business Media LLC
AbstractThe application of next-generation sequencing (NGS) to clinical practice is still hampered by the ability to interpret the clinical relevance of novel variants and the difficulty of evaluating their effect in specific tissues. Here, we applied integrated genomic approaches for interrogating blood samples of two unrelated individuals with neurodevelopmental disorders and identified a novel neuro-pathogenic role for the Mitogen-Activated Protein Kinase 4 gene (MAP4K4). In particular, we identified two novel frameshift variants in coding exons expressed in the blood and neuronal isoforms. Both variants were predicted to generate non-sense-mediated decay. By transcriptome analysis, we simultaneously demonstrated the deleterious effect of the identified variants on the splicing activity and stability of MAP4K4 mRNA. Therefore, we propose MAP4K4 as a novel causative gene for non-syndromic and syndromic neurodevelopmental disorders. Altogether, we prove the efficacy of an integrated approach of exome and transcriptome sequencing in the resolution of undiagnosed cases by leveraging the analysis of variants in genes expressed in peripheral blood.
Paolo Quitadamo and Daniele De Brasi
Associazione Culturale Pediatri
Inflammatory bowel diseases (IBD) are chronic diseases of the gastrointestinal tract that have been steadily increasing in recent years, particularly in pediatric age. The clinical manifestations of IBD differ according to the forms (Crohn’s m., ulcerative rectocolitis, undifferentiated colitis), and can be distinguished into intestinal and extra-intestinal. The laboratory contributes at various levels in the diagnosis of IBD, from the use of inflammation markers, to the most commonly used serologic markers (ASCA and p-ANCA), to fecal markers (calprotectin). Ultrasonography of the bowel loops is the most recommended noninvasive instrumental investigation to date because of its noninvasiveness, safety, and low cost. The major limitation of ultrasonography is operator-dependent variability, although recently, the use of new technique, SICUS (small intestine contrast ultrasonography), has been shown to greatly improve the sensitivity of the examination and reduce inter-operator variability. Endoscopic investigation coupled with histologic analysis of biopsy specimens is, to date, the gold standard for making a diagnosis of IBD, playing a key role in the diagnosis and therapy of these conditions. The primary goals of pediatric IBD therapy are to induce and maintain a sustained remission with prevention of clinical relapse, optimize growth and pubertal development, and improve the patient’s quality of life. The importance of the genetic and epigenetic component in the phenotypic expression of IBD is increasingly widely demonstrated. These aspects will be the subject of a forthcoming contribution.
Laura Pignata, Francesco Cecere, Fabio Acquaviva, Emilia D’Angelo, Daniela Cioffi, Valeria Pellino, Orazio Palumbo, Pietro Palumbo, Massimo Carella, Angela Sparago,et al.
Frontiers Media SA
Imprinting disorders are congenital diseases caused by dysregulation of genomic imprinting, affecting growth, neurocognitive development, metabolism and cancer predisposition. Overlapping clinical features are often observed among this group of diseases. In rare cases, two fully expressed imprinting disorders may coexist in the same patient. A dozen cases of this type have been reported so far. Most of them are represented by individuals affected by Beckwith–Wiedemann spectrum (BWSp) and Transient Neonatal Diabetes Mellitus (TNDM) or BWSp and Pseudo-hypoparathyroidism type 1B (PHP1B). All these patients displayed Multilocus imprinting disturbances (MLID). Here, we report the first case of co-occurrence of BWS and PHP1B in the same individual in absence of MLID. Genome-wide methylation and SNP-array analyses demonstrated loss of methylation of the KCNQ1OT1:TSS-DMR on chromosome 11p15.5 as molecular cause of BWSp, and upd(20)pat as cause of PHP1B. The absence of MLID and the heterodisomy of chromosome 20 suggests that BWSp and PHP1B arose through distinct and independent mechanism in our patient. However, we cannot exclude that the rare combination of the epigenetic defect on chromosome 11 and the UPD on chromosome 20 may originate from a common so far undetermined predisposing molecular lesion. A better comprehension of the molecular mechanisms underlying the co-occurrence of two imprinting disorders will improve genetic counselling and estimate of familial recurrence risk of these rare cases. Furthermore, our study also supports the importance of multilocus molecular testing for revealing MLID as well as complex cases of imprinting disorders.
Alessandro De Falco, Daniele De Brasi, Matteo Della Monica, Claudia Cesario, Stefano Petrocchi, Antonio Novelli, Giuseppe D’Alterio, Achille Iolascon, Mario Capasso, and Carmelo Piscopo
MDPI AG
Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder that affects many organs. The diagnosis of this condition is primarily clinical and it can be confirmed by molecular analysis of the genes known to cause this disease, although about 30% of CdLS patients are without a genetic diagnosis. Here we report clinical and genetic findings of a patient with CdLS type 4, a syndrome of which the clinical features of only 30 patients have been previously described in the literature. The index patient presented with clinical characteristics previously associated with CdLS type 4 (short nose, thick eyebrow, global development delay, synophrys, microcephaly, weight < 2DS, small hands, height < 2DS). She also presented cardiac anomalies, cleft palate and laryngomalacia, which was never described before. The index patient was diagnosed with a novel de novo RAD21 variant (c.1722_1723delTG, p.Gly575SerfsTer2): segregation analysis, bioinformatic analysis, population data and in silico structural modelling indicate the pathogenicity of the novel variant. This report summarizes previously reported clinical manifestations of CdLS type 4 but also highlights new clinical symptoms, which will aid correct counselling of future CdLS type 4 cases.
M. A. Siano, R. Pivonello, M. Salerno, M. Falco, C. Mauro, D. De Brasi, A. Klain, S. Sestito, A. De Luca, V. Pinna,et al.
Frontiers Media SA
Background and ObjectivesEndocrine complications have been described in patients affected by RASopathies but no systematic assessment has been reported. In this study, we investigate the prevalence of endocrine disorders in a consecutive unselected cohort of patients with RASopathies.Study Design72 patients with a genetically confirmed RASopathy (Noonan syndrome [NS], N=53; 29 LEOPARD syndrome [LS], N=2; cardiofaciocutaneous syndrome [CFCS], N=14; subjects showing co-occurring pathogenic variants in PTPN11 and NF1, N=3) and an age- and sex-matched healthy controls were included in the study. Endocrine system involvement was investigated by assessing the thyroid function, pubertal development, auxological parameters, adrenal function and bone metabolism.ResultsShort stature was detected in 40% and 64% of the NS and CFCS subcohorts, respectively. Patients showed lower Z-scores at DXA than controls (p&lt;0.05) when considering the entire case load and both NS and CFCS groups. Vitamin D and Calcitonin levels were significantly lower (p&lt; 0.01), Parathormone levels significantly higher (p&lt;0.05) in patients compared to the control group (p&lt;0.05). Patients with lower BMD showed reduced physical activity and joint pain. Finally, anti-TPO antibody levels were significantly higher in patients than in controls when considering the entire case load and both NS and CFCS groups.ConclusionsThe collected data demonstrate a high prevalence of thyroid autoimmunity, confirming an increased risk to develop autoimmune disorders both in NS and CFCS. Reduced BMD, probably associated to reduced physical activity and inflammatory cytokines, also occurs. These findings are expected to have implications for the follow-up and prevention of osteopenia/osteoporosis in both NS and CFCS.
Francesco Passaretti, Laura Pignata, Giuseppina Vitiello, Viola Alesi, Gemma D’Elia, Francesco Cecere, Fabio Acquaviva, Daniele De Brasi, Antonio Novelli, Andrea Riccio,et al.
MDPI AG
Silver–Russell syndrome is an imprinting disorder characterised by pre- and post-natal growth retardation and several heterogeneous molecular defects affecting different human genomic loci. In the majority of cases, the molecular defect is the loss of methylation (LOM) of the H19/IGF2 differentially methylated region (DMR, also known as IC1) at the telomeric domain of the 11p15.5 imprinted genes cluster, which causes the altered expression of the growth controlling genes, IGF2 and H19. Very rarely, the LOM also affects the KCNQ1OT1 DMR (also known as IC2) at the centromeric domain, resulting in an SRS phenotype by an unknown mechanism. In this study, we report on two cases with SRS features and a LOM of either IC1 and IC2. In one case, this rare and complex epimutation was secondary to a de novo mosaic in cis maternal duplication, involving the entire telomeric 11p15.5 domain and part of the centromeric domain but lacking CDKN1C. In the second case, neither the no 11p15.5 copy number variant nor the maternal-effect subcortical maternal complex (SCMC) variant were found to be associated with the epimutation, suggesting that it arose as a primary event. Our findings further add to the complexity of the molecular genetics of SRS and indicate how the LOM in both 11p15.5 DMRs may result from different molecular mechanisms.
Marcello Scala, Masashi Nishikawa, Hidenori Ito, Hidenori Tabata, Tayyaba Khan, Andrea Accogli, Laura Davids, Anna Ruiz, Pietro Chiurazzi, Gabriella Cericola,et al.
Oxford University Press (OUP)
Abstract Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G &gt; C p.G12R, c.179G &gt; A p.G60D, c.186_188delGGA p.E62del, c.187G &gt; A p.D63N, c.191A &gt; G p.Y64C and c.348G &gt; C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes.
Giuseppe Limongelli, Stefano Iucolano, Emanuele Monda, Pasquale Elefante, Chiara De Stasio, Imma Lubrano, Martina Caiazza, Marialuisa Mazzella, Fabio Fimiani, Maria Galdo,et al.
Oxford University Press (OUP)
Abstract Background The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period. Methods To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period. Results Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P &lt; 0.001 and 37 versus 349, P &lt; 0.001, respectively) and 2018 (117 versus 389, P &lt; 0.001 and 37 versus 282, P &lt; 0.001, respectively). Eighty-two among 98 rare disease experts completed the questionnaire. Diagnostic success (95%), access to diagnosis (80%) and follow-up (72%), lack of Personal Protective Equipment (60%), lack of Covid-19 guidelines (50%) and the need for home therapy (78%) were the most important issues raised during Covid-19 outbreak. Conclusions This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.
Thea Giacomini, Marcello Scala, Giulia Nobile, Mariasavina Severino, Domenico Tortora, Lino Nobili, Andrea Accogli, Annalaura Torella, Valeria Capra, Maria Margherita Mancardi,et al.
Elsevier BV
Maria Simona Sabbatino, Federica De Seta, Daniele De Brasi, Claudio Santoro, Francesco Esposito, and Paolo Siani
Edizioni Minerva Medica
Paolo Quitadamo, Giusy Ranucci, Stefania Ragozzino, Sonia Tamasi, Marcella Giugliano, Giovanni Gaglione, Daniele De Brasi, Augusto Mastrominico, and Giovanni Di Nardo
Elsevier BV
Angela Pepe, Angelo Colucci, and Lucia Nazzaro
Associazione Culturale Pediatri
DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) is a complex and potentially life-threatening drug induced hypersensitivity reaction. It is characterized by a massive skin reaction associated with multiorgan involvement, lymphadenopathy, eosinophilia. Here we describe a case of DRESS syndrome with acute liver failure in an 11-year-old boy triggered by Valproic Acid. We emphasize the importance of differential diagnosis on the basis of clinical, anamnestic and laboratory data.
Francesca Orlando, Germana Nardini, and Daniele De Brasi
Associazione Culturale Pediatri
Knowledge in the genetic field of autoinflammatory diseases has progressively increased over the last decade. Starting from the genetic knowledge on a few initially known diseases (Familial Mediterranean Fever, Periodic Syndrome Associated with Tumor Necrosis Factor Receptor 1, Mevalonate Kinase Deficiency, Cryopyrinopathies), at least 40 genes associated with these conditions have been identified, and more than 100 genes are currently being tested with Next Generation Sequencing (NGS) technologies. Indeed, starting recommendations for the genetic diagnosis of autoinflammatory diseases were limited to a gene-by-gene diagnosis strategy, based on the Sanger method, and restricted to a few prototypic recurrent fevers. More recently, improvement of genetic technologies, in particular NGS, allowed identification of genetic variants among involved genes in an easier and more rapid way. Detection of more and more genetic variants made interpretation of results more complicated, and often a genetic diagnosis is not achieved. On the other hand, other mechanisms, namely somatic mosaicisms, epigenetic modifications, digenic inheritance, allow to explain some not genetically defined cases. Eventually, further genetic and non-genetic mechanisms will be probably identified in near future to explain underlying basis of autoinflammatory diseases, especially in a still large part of patients without a clearcut genetic basis.
Francesca Di Candia, Paolo Fontana, Pamela Paglia, Mariateresa Falco, Carmen Rosano, Carmelo Piscopo, Gerarda Cappuccio, Maria Anna Siano, Daniele De Brasi, Claudia Mandato,et al.
Springer Science and Business Media LLC
AbstractKabuki syndrome (KS) is a well-recognized disorder characterized by postnatal growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability. The syndrome is caused by KMT2D gene mutations or less frequently KDM6A gene mutations or deletions. We report a systematic evaluation of KS patients from Campania region of Italy; data were also compared with literature ones. We collected data of 15 subjects (8 males and 7 females with age range 10–26 years; mean age 16.9 years) with confirmed diagnosis of KS, representing the entire cohort of patients from Campania Region. Each patient performed biochemical testing and instrumental investigation. Neuro-intellectual development, cranio-facial dysmorphisms, and multisystem involvement data were collected retrospectively. For each category, type of defects and frequency of the anomalies were analyzed. Our observation shows that KS patients from Campania region have some particular and previously underscored, neurological and immunological findings. We found high prevalence of EEG’s abnormalities (43%) and MRI brain abnormalities (60%). Microcephaly resulted more common in our series (33%), if compared with major cohorts described in literature. Biochemical features of immunodeficiency and autoimmune diseases including thyroid autoimmunity, polyserositis, and vitiligo were observed with high prevalence (54.5%). Low immunoglobulins levels were a frequent finding. Lymphocyte class investigation showed significantly reduced CD8 levels in one patient.Conclusions: These data confirm great heterogeneity of clinical manifestations in KS and suggest to introduce further clinical diagnostic criteria in order to perform a correct and precocious diagnosis. What is Known• Kabuki syndrome is characterized by growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability• Immune dysfunction is a common finding but autoimmune diseases are rarely seen• Neurological features are common What is New• Some particular facial features could help gestalt diagnosis (hypertelorism, broad nasal bridge, micrognathia, tooth agenesis, cutaneous haemangiomas and strabismus)• Higher prevalence of autoimmune disorders than previously reported• Particular neurological features are present in this cohort (EEG and MRI brain abnormalities)
M. A. Siano, V. Marchetti, S. Pagano, F. Di Candia, M. Alessio, D. De Brasi, A. De Luca, V. Pinna, S. Sestito, D. Concolino,et al.
Springer Science and Business Media LLC
Abstract Background Abnormalities of the immune system are rarely reported in patients affected by RASopathies. Aim of the current study was to investigate the prevalence of immune system dysfunction in a cohort of patients affected by RASopathies. Study design A group of 69 patients was enrolled: 60 at the Federico II University, Naples, 7 at University Magna Graecia of Catanzaro, 2 at “Scuola Medica Salernitana”, Salerno. An age- and sex-matched control group was also enrolled. Autoimmune disorders were investigated according to international consensus criteria. Immune framework was also evaluated by immunoglobulin levels, CD3, CD4, CD8, CD19, CD56 lymphocyte subpopulations, autoantibodies levels and panel of inflammatory molecules, in both patients and controls. Results Frequent upper respiratory tract infections were recorded in 2 patients; pneumonia, psoriasis and alopecia in single patients. Low IgA levels were detected in 8/44 patients (18.18%), low CD8 T cells in 13/35 patients (37.14%). Anti-tg and anti-TPO antibodies were detected in 3/24 patients (12.5%), anti r-TSH in 2 cases (8.33%), all in euthyroidism. Serum IgA and CD8 levels were significantly lower in patients than in controls (p 0.00685; p 0.000656 respectively). All tested patients showed increased inflammatory molecules compared to controls. These findings may anticipate the detection of overt autoimmune disease. Conclusions Patients affected by RASopathies are at risk to develop autoimmune disorders. Routine screening for autoimmunity is recommended in patients with RASopathy.
Alessandra Verde, Angelina Grammegna, Emma Petrone, Augusto Mastrominico, Daniele De Brasi, Claudia Mandato, Giusy Ranucci, Maria Simona Sabbatino, Michelina Sibilio, and Paolo Quitadamo
Oxford University Press (OUP)
Chiara Delehaye, Marida Della Corte, Giusy Ranucci, Elio Prestipino, Daniele De Brasi, and Antonio Varone
Elsevier BV
Daniele De Brasi, Francesca Orlando, Valeria Gaeta, Maria De Liso, Fabio Acquaviva, Luigi Martemucci, Augusto Mastrominico, and Maja Di Rocco
MDPI AG
Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic condition characterized by extraskeletal bone formation. Most of the musculoskeletal characteristics of FOP are related to dysregulated chondrogenesis, with heterotopic ossification being the most typical feature. Activating mutations of activin receptor A type I (ACVR1), a bone morphogenetic protein (BMP) type I receptor, are responsible for the skeletal and nonskeletal features. The clinical phenotype is always consistent, with congenital bilateral hallux valgus malformation and early-onset heterotopic ossification occurring spontaneously or, more frequently, precipitated by trauma. Painful, recurrent soft-tissue swellings (flare-ups) precede localized heterotopic ossification that can occur at any location, typically affecting regions near the axial skeleton and later progressing to the appendicular bones. A diagnosis of FOP is suspected in a proband presenting with hallux valgus malformation, heterotopic ossification, and confirmed by the identification of a heterozygous pathogenic variant in the ACVR1/ALK2 gene. Avoiding unnecessary surgical procedures, prescribing prophylactic corticosteroids, preventing falls, and using protective headgear represent essential interventions for care management. Different classes of medications to contain acute inflammation flare-ups have been proposed, with high dose corticosteroids and nonsteroidal anti-inflammatory drugs usually utilized. Here, we report on two FOP patients, with typical clinical features summarizing the principal aspects of FOP, and we aim to provide comprehensive information outlining some unusual findings, possibly contributing to FOP’s definition and management.
Pia Bernardo, Mauro Budetta, Ferdinando Aliberti, Maria Luisa Carpentieri, Daniele De Brasi, Livio Sorrentino, Carmela Russo, Alessandra D’amico, Giuseppe Cinalli, Claudia Santoro,et al.
Springer Science and Business Media LLC
Temporal lobe abnormalities and focal epilepsy have been documented in FGFR3-related clinical condition, including hypochondroplasia and Muenke syndrome. FGFR3 is expressed in the brain during development and could play a role in nervous system development and hippocampal formation. These observations suggest a non-casual association between temporal malformation, epilepsy, and FGFR3 mutations. Herein, we report clinical, electroclinical, and neuroimaging findings of three additional cases of focal epilepsy and temporal lobe malformations occurring in children with FGFR3 gene mutations.
Marco Sarno, Francesco Maria Rosanio, Daniele De Brasi, Claudio Santoro, Andrea Lo Vecchio, Francesco Esposito, Paolo Siani, Pietro Vajro, and Claudia Mandato
Ovid Technologies (Wolters Kluwer Health)
Diagnosis of systemic cat scratch disease may be challenging. Here, we describe a case of an immunocompetent girl exhibiting fever and multifocal hepatosplenic abscesses. Diagnostic tests for Bartonella henselae infection (enzyme immunoassay and polymerase chain reaction) were found steadily negative and the diagnosis, suspected on the basis of the Margilet's criteria, was finally confirmed by indirect immunofluorescent antibodies.
Claudia Ciaccio, Valentina Duga, Chiara Pantaleoni, Silvia Esposito, Isabella Moroni, Michele Pinelli, Raffaele Castello, Vincenzo Nigro, Luisa Chiapparini, Stefano D'Arrigo,et al.
Elsevier BV