Publications by authors named "Isabella Ceccherini"

152 Publications

Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients.

Genes (Basel) 2021 Aug 24;12(9). Epub 2021 Aug 24.

UOSD Laboratory of Genetics and Genomics of Rare Diseases, IRCCS Istituto Giannina Gaslini, 16148 Genoa, Italy.

Inborn errors of immunity (IEI) include a large group of inherited diseases sharing either poor, dysregulated, or absent and/or acquired function in one or more components of the immune system. Next-generation sequencing (NGS) has driven a rapid increase in the recognition of such defects, though the wide heterogeneity of genetically diverse but phenotypically overlapping diseases has often prevented the molecular characterization of the most complex patients. Two hundred and seventy-two patients were submitted to three successive NGS-based gene panels composed of 58, 146, and 312 genes. Along with pathogenic and likely pathogenic causative gene variants, accounting for the corresponding disorders (37/272 patients, 13.6%), a number of either rare (probably) damaging variants in genes unrelated to patients' phenotype, variants of unknown significance (VUS) in genes consistent with their clinics, or apparently inconsistent benign, likely benign, or VUS variants were also detected. Finally, a remarkable amount of yet unreported variants of unknown significance were also found, often recurring in our dataset. The NGS approach demonstrated an expected IEI diagnostic rate. However, defining the appropriate list of genes for these panels may not be straightforward, and the application of unbiased approaches should be taken into consideration, especially when patients show atypical clinical pictures.
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http://dx.doi.org/10.3390/genes12091299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469131PMC
August 2021

Type I interferon activation in RAS-associated autoimmune leukoproliferative disease (RALD).

Clin Immunol 2021 Oct 26;231:108837. Epub 2021 Aug 26.

Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, Genoa, Italy; DINOGMI, Università di Genova, Genoa, Italy. Electronic address:

RAS-associated autoimmune leukoproliferative disease (RALD) is a rare immune dysregulation syndrome caused by somatic gain-of-function mutations of either NRAS or KRAS gene in hematopoietic cells. We describe a 27-year-old patient presenting at 5 months of age with recurrent infections and generalized lymphadenopathy who developed a complex multi-organ autoimmune syndrome with hypogammaglobulinemia, partially controlled with oral steroids, hydroxichloroquine, mofetil mycophenolate and IVIG prophylaxis. Activation of type I interferon pathway was observed in peripheral blood. Since 18 years of age, the patient developed regenerative nodular hyperplasia of the liver evolving into hepatopulmonary syndrome. Whole exome sequencing analysis of the peripheral blood DNA showed the NRAS p.Gly13Asp mutation validated as somatic. Our report highlights the possibility of detecting somatic NRAS gene mutations in patients with inflammatory immune dysregulation and type I interferon activation.
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http://dx.doi.org/10.1016/j.clim.2021.108837DOI Listing
October 2021

The Association among Pyoderma Gangrenosum, Ulcerative Colitis, and Hidradenitis Suppurativa and the Syndromic Hidradenitis Suppurativa Network: A Case Report.

Skin Appendage Disord 2021 Apr 4;7(3):227-230. Epub 2021 Mar 4.

Section of Dermatology and Infectious Diseases, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.

Hidradenitis suppurativa (HS), together with other inflammatory diseases, is involved in a syndromic network where different combinations of signs and symptoms characterize the definition. The observation of the concurrent occurrence of HS, pyoderma gangrenosum (PG), and inflammatory bowel disease (IBD), in detail ulcerative colitis (UC), led the authors to describe a new association. The patient, a 36-year-old woman, who saw IBD as the first appearing condition, shortly followed by HS and PG, was referred because of a clinical situation quickly worsening. A severe aggravation of both GI symptoms and general systemic situation total led to total colectomy. Surprisingly, shortly after the radical surgical treatment of UC, the cutaneous manifestations of HS and PG with no specific treatment almost completely disappeared suggesting the existence of a common etiopathogenetic mechanism and possibly an inductor role of UC on the other disorders. The presentation of this case offers the opportunity to deal with the fact that the resolution of one of the associated conditions may lead to the clearance of one or more of the others. It confirms a pathogenetic link between them and the pivotal role of one of them, in this case colitis.
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http://dx.doi.org/10.1159/000513639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138252PMC
April 2021

Genetic screening of children with marrow failure. The role of primary Immunodeficiencies.

Am J Hematol 2021 09 2;96(9):1077-1086. Epub 2021 Jun 2.

Hematology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

The differential diagnosis of marrow failure (MF) is crucial in the diagnostic work-up, since genetic forms require specific care. We retrospectively studied all patients with single/multi-lineage MF evaluated in a single-center to identify the type and incidence of underlying molecular defects. The diepoxybutane test was used to screen Fanconi Anemia. Other congenital MFs have been searched using Sanger and/or Next Generation Sequencing analysis, depending on the available tools over the years. Between 2009-2019, 97 patients (aged 0-32 years-median 5) with single-lineage (29%) or multilineage (68%) MF were evaluated. Fifty-three (54%) and 28 (29%) were diagnosed with acquired and congenital MF, respectively. The remaining 16 (17%), with trilinear (n=9) and monolinear (n=7) MF, were found to have an underlying primary immunodeficiency (PID) and showed clinical and biochemical signs of immune-dysregulation in 10/16 (62%) and in 14/16 (87%) of cases, respectively. Clinical signs were also found in 22/53 (41%) and 8/28 (28%) patients with idiopathic and classical cMF, respectively. Eight out of 16 PIDs patients were successfully transplanted, four received immunosuppression, two did not require treatment, and the remaining two died. We show that patients with single/multi-lineage MF may have underlying PIDs in a considerable number of cases and that MF may represent a relevant clinical sign in patients with PIDs, thus widening their clinical phenotype. An accurate immunological work-up should be performed in all patients with MF, and PID-related genes should be considered when screening MF in order to identify disorders that may receive targeted treatments and/or appropriate conditioning regimens before transplant.
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http://dx.doi.org/10.1002/ajh.26242DOI Listing
September 2021

Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia.

Brain 2021 06;144(5):1422-1434

Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.
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http://dx.doi.org/10.1093/brain/awab041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219359PMC
June 2021

Paired-like homeobox gene (PHOX2B) nonpolyalanine repeat expansion mutations (NPARMs): genotype-phenotype correlation in congenital central hypoventilation syndrome (CCHS).

Genet Med 2021 09 6;23(9):1656-1663. Epub 2021 May 6.

Department of Pediatrics, Division of Autonomic Medicine, Center for Autonomic Medicine in Pediatrics (CAMP), Ann & Robert H. Lurie Children's Hospital of Chicago and Stanley Manne Children's Research Institute, Chicago, IL, USA.

Purpose: CCHS is an extremely rare congenital disorder requiring artificial ventilation as life support. Typically caused by heterozygous polyalanine repeat expansion mutations (PARMs) in the PHOX2B gene, identification of a relationship between PARM length and phenotype severity has enabled anticipatory management. However, for patients with non-PARMs in PHOX2B (NPARMs, ~10% of CCHS patients), a genotype-phenotype correlation has not been established. This comprehensive report of PHOX2B NPARMs and associated phenotypes, aims at elucidating potential genotype-phenotype correlations that will guide anticipatory management.

Methods: An international collaboration (clinical, commercial, and research laboratories) was established to collect/share information on novel and previously published PHOX2B NPARM cases. Variants were categorized by type and gene location. Categorical data were analyzed with chi-square and Fisher's exact test; further pairwise comparisons were made on significant results.

Results: Three hundred two individuals with PHOX2B NPARMs were identified, including 139 previously unreported cases. Findings demonstrate significant associations between key phenotypic manifestations of CCHS and variant type, location, and predicted effect on protein function.

Conclusion: This study presents the largest cohort of PHOX2B NPARMs and associated phenotype data to date, enabling genotype-phenotype studies that will advance personalized, anticipatory management and help elucidate pathological mechanisms. Further characterization of PHOX2B NPARMs demands longitudinal clinical follow-up through international registries.
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http://dx.doi.org/10.1038/s41436-021-01178-xDOI Listing
September 2021

The Gene Is Involved in Hirschsprung Associated Enterocolitis Susceptibility through an Altered Downstream Signaling.

Int J Mol Sci 2021 Apr 7;22(8). Epub 2021 Apr 7.

Health Science Department (DISSAL), Biostatistics Unit, Università di Genova, Via Pastore 1, 16132 Genova, Italy.

Hirschsprung (HSCR) Associated Enterocolitis (HAEC) is a common life-threatening complication in HSCR. HAEC is suggested to be due to a loss of gut homeostasis caused by impairment of immune system, barrier defense, and microbiome, likely related to genetic causes. No gene has been claimed to contribute to HAEC occurrence, yet. Genetic investigation of HAEC by Whole-Exome Sequencing (WES) on 24 HSCR patients affected (HAEC) or not affected (HSCR-only) by enterocolitis and replication of results on a larger panel of patients allowed the identification of the HAEC susceptibility variant p.H187Q in the Oncostatin-M receptor () gene (14.6% in HAEC and 5.1% in HSCR-only, = 0.0024). Proteomic analysis on the lymphoblastoid cell lines from one HAEC patient homozygote for this variant and one HAEC patient not carrying the variant revealed two well distinct clusters of proteins significantly up or downregulated upon OSM stimulation. A marked enrichment in immune response pathways ( < 0.0001) was shown in the HAEC H187 cell line, while proteins upregulated in the HAEC Q187 lymphoblasts sustained pathways likely involved in pathogen infection and inflammation. In conclusion, p.H187Q is an HAEC susceptibility variant and perturbates the downstream signaling cascade necessary for the gut immune response and homeostasis maintenance.
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http://dx.doi.org/10.3390/ijms22083831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067804PMC
April 2021

The challenge of early diagnosis of autoimmune lymphoproliferative syndrome in children with suspected autoinflammatory/autoimmune disorders.

Rheumatology (Oxford) 2021 Apr 28. Epub 2021 Apr 28.

Center for Autoinflammatory diseases and Immunodeficiencies, IRCCS G. Gaslini.

Objectives: To test the usefulness of an extended panel of lymphocyte subsets (LS) in combination with Oliveira's diagnostic criteria for the identification of autoimmune lymphoproliferative syndrome (ALPS) in children referred to a pediatric rheumatology center.

Methods: patients referred from 2015 to 2018 to our Rheumatology Unit for an autoimmune or autoinflammatory condition were retrospectively analyzed. Oliveira's required criteria (chronic lymphoproliferation and elevated DNT) were applied as first screening. Flow cytometry study included double negative CD4-CD8-TCR αβ+T lymphocytes (DNT), CD25+CD3+, HLA-DR+CD3+T cells, B220+T cells, and CD27+B cells. Data were analyzed with an univariate logistic regression analysis, followed by a multivariate analysis. Sensitivity and specificity of the Oliveira's required criteria were calculated.

Results: 264 patients were included in the study and classified as: i) autoimmune diseases (26); ii) juvenile idiopathic arthritis (JIA) (35) iii) monogenic systemic autoinflammatory disease (SAID) (27); iv) PFAPA syndrome (100); v) systemic undefined recurrent fever (SURF) (45); vi) undetermined-SAID (14); vii) ALPS (17). Oliveira's required criteria displayed a sensitivity of 100% and specificity of 79%. When compared with other diseases the TCRαβ+B220+ lymphocytes were significantly increased in ALPS patients. The multivariate analysis revealed 5 clinical/laboratory parameters positively associated to ALPS: splenomegaly, female gender, arthralgia, elevated DNT and TCRαβ+B220+lymphocytes.

Conclusions: Oliveira's required criteria are useful for the early suspicion of ALPS. TCRαβ+B220+ lymphocytes should be added in the diagnostic work-up of patients referred to pediatric rheumatology unit for a suspected autoimmune or autoinflammatory condition, providing a relevant support in the early diagnosis of ALPS.
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http://dx.doi.org/10.1093/rheumatology/keab361DOI Listing
April 2021

Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy.

Brain 2021 06;144(5):1451-1466

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

Congenital anomalies of the kidney and urinary tract in a cohort of 280 consecutive patients with Hirschsprung disease.

Pediatr Nephrol 2021 Oct 9;36(10):3151-3158. Epub 2021 Apr 9.

Pediatric Surgery, Umberto Bosio Center for Digestive Diseases, The Children Hospital, AO SS Antonio e Biagio e Cesare Arrigo, Alessandria, EU, Italy.

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) have been underestimated in Hirschsprung disease (HSCR). This paper aims at reporting results of patients with HSCR who underwent kidney and urinary tract assessment.

Methods: Patients seen between December 2005 and November 2020 underwent a complete kidney and urinary tract diagnostic workup. Data regarding CAKUT, gender, length of aganglionosis, familial history, HSCR-associated enterocolitis (HAEC), RET genotype, and outcome were collected.

Results: Out of 472 patients, 280 completed the workup and represented the focus. Male to female ratio was 3.24:1. Familial cases accounted for 9.8% of patients. RET mutations were detected in 19.8%. We encountered a total of 61 patients with 70 nephrological issues (21.8%), including 28 hypoplasia/dysplasia, 12 hydronephrosis, 11 vesicoureteric reflux, 7 duplex collecting system, 2 kidney agenesis, 2 horseshoe kidney, and 8 miscellanea, involving 91 kidneys without side preponderance (50 right, 41 left). Of these 61 patients, 20 (7.1% of the whole series) required medical or surgical treatment. When comparing patients with and without CAKUT, familial history proved to occur with a significantly lower frequency in the former as did better patient perspectives of outcome.

Conclusions: We confirmed that all diagnostic workups in HSCR should include a complete kidney and urinary tract diagnostic workup. Our study suggests that genes other than RET could play a role in determining CAKUT. Given worse patient perspectives of outcome, CAKUT seems to significantly interfere with quality of life thus confirming the need for early diagnosis and tailored prevention strategies.
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http://dx.doi.org/10.1007/s00467-021-05061-4DOI Listing
October 2021

Spectrum of Systemic Auto-Inflammatory Diseases in India: A Multi-Centric Experience.

Front Immunol 2021 19;12:630691. Epub 2021 Mar 19.

Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

Systemic autoinflammatory diseases (SAID) are rare inherited disorders involving genes regulating innate immune signaling and are characterized by periodic or chronic multi-systemic inflammation. To describe spectrum of clinical, immunological, molecular features, and outcomes of patients with SAID in India. Request to share data was sent to multiple centers in India that are involved in care and management of patients with Inborn Errors of Immunity. Six centers provided requisite data that were compiled and analyzed. Data on 107 patients with SAID were collated-of these, 29 patients were excluded due to unavailability of complete information. Twelve patients (15%) had type 1 interferonopathies, 21 (26%) had diseases affecting inflammasomes, 30 patients (41%) had non-inflammasome related conditions and 1five patients (19%) had Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA). Type1 interferonopathies identified in the cohort included patients with Deficiency of Adenosine Deaminase 2 ( (six patients; five families); STING-associated vasculopathy infantile-onset (SAVI) (three patients, one family); Spondyloenchondro-dysplasia with Immune Dysregulation (SPENCD) (two patients). Diseases affecting inflammasomes include Mevalonate Kinase Deficiency (eight patients); Cryopyrin-Associated Periodic Syndromes (CAPS) (seven patients); NLR Family, Pyrin domain-containing 12 NLRP12) (two patients); Familial Mediterranean fever (FMF) (two patients); Autoinflammation and PLCG-associated antibody deficiency and immune dysregulation (APLAID) (two patients). TNF receptor-associated periodic syndrome (TRAPS) (three patients); A20 haploinsufficiency (four patients); Deficiency of Interleukin 1 Receptor Antagonist (DIRA) (two patients) were categorized as non-inflammasome related conditions. There were significant delays in diagnosis Corticosteroids and other immunosuppressive agents were used for treatment as anti-IL-1 drugs and other biological agents were and still are not available in India. Eight (16.3%) patients had so far succumbed to their illness. This is the first nationwide cohort of patients with SAID from India. Clinical manifestations were diverse. Overlapping of clinical features with other relatively common rheumatological disorders often resulted in delays in diagnosis. More nationwide efforts are needed to enhance awareness of SAID among health care professionals and there is an urgent need to make targeted immunotherapies universally available.
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http://dx.doi.org/10.3389/fimmu.2021.630691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017183PMC
September 2021

A Common 3'UTR Variant of the Gene Is Associated With Infant Life-Threatening and Sudden Death Events in the Italian Population.

Front Neurol 2021 19;12:642735. Epub 2021 Mar 19.

Laboratorio di Genetica e Genomica delle Malattie Rare, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Giannina Gaslini, Genoa, Italy.

Heterozygous mutations in the Paired like homeobox 2b () gene are causative of congenital central hypoventilation syndrome (CCHS), a rare monogenic disorder belonging to the family of neurocristopathies and due to a defective development of the autonomic nervous system. Most patients manifest sudden symptoms within 1 year of birth, mainly represented by central apnea and cyanosis episodes. The sudden appearance of hypoxic manifestations in CCHS and their occurrence during sleep resemble two other unexplained perinatal disorders, apparent life-threatening event (ALTE) and sudden and unexpected infant death (SUID), among which the vast majority is represented by sudden infant death syndrome (SIDS). Differently from CCHS, characterized by Mendelian autosomal dominant inheritance, ALTE and SIDS are complex traits, where common genetic variants, together with external factors, may exert an additive effect with symptoms likely manifesting only over a "threshold." Given the similarities observed among the three abovementioned perinatal disorders, in this work, we have analyzed the frequency of common variants in two groups of Italian idiopathic ALTE (IALTE) and SUIDs/SIDS patients. Here, we report that the c161G>A (rs114290493) SNP of the 3'UTR (i) became overrepresented in the two sets of patients compared to population matched healthy controls, and (ii) associated with decreased gene expression, likely mediated by miR-204, a microRNA already known to bind the 3'UTR of the gene. Overall, these results suggest that, at least in the Italian population, the SNP c161G>A (rs114290493) does contribute, presumably in association with others mutations or polymorphisms, to confer susceptibility to sudden unexplained perinatal life-threatening or fatal disorders by increasing the effect of miR-204 in inducing expression down-regulation. However, these are preliminary observations that need to be confirmed on larger cohorts to achieve a clinical relevance.
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http://dx.doi.org/10.3389/fneur.2021.642735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017182PMC
March 2021

Underlying CTLA4 Deficiency in a Patient With Juvenile Idiopathic Arthritis and Autoimmune Lymphoproliferative Syndrome Features Successfully Treated With Abatacept-A Case Report.

J Pediatr Hematol Oncol 2021 Nov;43(8):e1168-e1172

Haematology Unit.

Background: Functional variants of the cytotoxic T-lymphocyte antigen-4 (CTLA4) could contribute to the pathogenesis of disorders characterized by abnormal T-cell responses.

Case Presentation: We report a case of a 13-year-old girl who first presented with polyarticular juvenile idiopathic arthritis poorly responsive to treatment. During the following years the patient developed cytopenias, chronic lymphoproliferation, high values of T-cell receptor αβ+ CD4- CD8- double-negative T cells and defective Fas-mediated T cells apoptosis. Autoimmune lymphoproliferative syndrome was diagnosed and therapy with mycophenolate mofetil was started, with good hematological control. Due to the persistence of active polyarthritis, mycophenolate mofetil was replaced with sirolimus. In the following months the patient developed hypogammaglobulinemia and started having severe diarrhea. Histologically, duodenitis and chronic gastritis were present. Using the next generation sequencing-based gene panel screening, a CTLA4 mutation was detected (p.Cys58Serfs*13). At the age of 21 the patient developed acute autoimmune hemolytic anemia; steroid treatment in combination with abatacept were started with clinical remission of all symptoms, even arthritis.

Conclusions: Targeted immunologic screening and appropriate genetic tests could help in the diagnosis of a specific genetically mediated immune dysregulation syndrome, allowing to select those patients who can take advantage of target therapy, as in the case of abatacept in CTLA4 deficiency.
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http://dx.doi.org/10.1097/MPH.0000000000002120DOI Listing
November 2021

Hemolysis and Neurologic Impairment in PAMI Syndrome: Novel Characteristics of an Elusive Disease.

Pediatrics 2021 03;147(3)

Pediatric Hematology/Oncology Department, Istituto di Ricovero e Cura a Carattere Scientifico, Istituto G. Gaslini, Genova, Italy.

PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a rare early-onset autoinflammatory disease associated with various hematologic findings, including chronic neutropenia and pancytopenia. We report a unique case of PAMI syndrome in a toddler with transfusion-dependent hemolytic anemia, hepatosplenomegaly, failure to thrive, developmental delay, and multiple malformations. Because of acute inflammatory-driven decompensation, anakinra was started with dramatic improvement of both the hematologic and neurologic involvement. A customized next-generation sequencing panel later identified a de novo pathogenic variant in the gene, confirming the diagnosis. Our case illustrates the broad spectrum of phenotypes associated with PAMI syndrome, which should be considered in any case of unexplained cytopenias associated with autoinflammatory stigmata. It is also one of the few reports of neurologic involvement in -associated inflammatory diseases. Increased awareness of this rare disease and early performance of genetic testing can correctly diagnose PAMI syndrome and prevent disease complications.
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http://dx.doi.org/10.1542/peds.2020-0784DOI Listing
March 2021

Alexander Disease Modeling in Zebrafish: An In Vivo System Suitable to Perform Drug Screening.

Genes (Basel) 2020 12 11;11(12). Epub 2020 Dec 11.

Department of Earth, Environment and Life Sciences (DISTAV), University of Genoa, 16132 Genoa, Italy.

Alexander disease (AxD) is a rare astrogliopathy caused by heterozygous mutations, either inherited or arising de novo, on the glial fibrillary acid protein (GFAP) gene (17q21). Mutations in the GFAP gene make the protein prone to forming aggregates which, together with heat-shock protein 27 (HSP27), αB-crystallin, ubiquitin, and proteasome, contribute to form Rosenthal fibers causing a toxic effect on the cell. Unfortunately, no pharmacological treatment is available yet, except for symptom reduction therapies, and patients undergo a progressive worsening of the disease. The aim of this study was the production of a zebrafish model for AxD, to have a system suitable for drug screening more complex than cell cultures. To this aim, embryos expressing the human gene carrying the most severe p.R239C under the control of the zebrafish gene promoter underwent functional validation to assess several features already observed in in vitro and other in vivo models of AxD, such as the localization of mutant GFAP inclusions, the ultrastructural analysis of cells expressing mutant GFAP, the effects of treatments with ceftriaxone, and the heat shock response. Our results confirm that zebrafish is a suitable model both to study the molecular pathogenesis of mutations and to perform pharmacological screenings, likely useful for the search of therapies for AxD.
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http://dx.doi.org/10.3390/genes11121490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764705PMC
December 2020

Novel ACTG2 variants disclose allelic heterogeneity and bi-allelic inheritance in pediatric chronic intestinal pseudo-obstruction.

Clin Genet 2021 03 14;99(3):430-436. Epub 2020 Dec 14.

UOSD Genetica e Genomica delle Malattie Rare, IRCCS Istituto Giannina Gaslini, Genoa, Italia, Italy.

Variants in the ACTG2 gene, encoding a protein crucial for correct enteric muscle contraction, have been found in patients affected with chronic intestinal pseudo-obstruction, either congenital or late-onset visceral myopathy, and megacystis-microcolon-intestinal hypoperistalsis syndrome. Here we report about ten pediatric and one adult patients, from nine families, carrying ACTG2 variants: four show novel still unpublished missense variants, including one that is apparently transmitted according to a recessive mode of inheritance. Four of the remaining five probands carry variants affecting arginine residues, that have already been associated with a severe phenotype. A de novo occurrence of the variants could be confirmed in six of these families. Since a genotype-phenotype correlation is affected by extrinsic factors, such as, diagnosis delay, quality of clinical management, and intra-familial variability, we have undertaken 3D molecular modeling to get further insights into the effects of the variants here described. The present findings and further ACTG2 testing of patients presenting with intestinal pseudo-obstruction, will improve our understanding of visceral myopathies, including implications in the prognosis and genetic counseling of this set of severe disorders.
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http://dx.doi.org/10.1111/cge.13895DOI Listing
March 2021

Late-onset and long-lasting autoimmune neutropenia: an analysis from the Italian Neutropenia Registry.

Blood Adv 2020 11;4(22):5644-5649

Hematology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)-Istituto Giannina Gaslini, Genoa, Italy.

Primary autoimmune neutropenia (pAN) is typified by onset in early infancy and a mild/moderate phenotype that resolves within 3 years of diagnosis. In contrast, secondary AN is classically an adult disease associated with malignancy, autoimmunity, immunodeficiency, viral infection, or drugs. This study describes a cohort of 79 children from the Italian Registry who, although resembling pAN, did not fully match the criteria for pAN because neutropenia either appeared after age 5 years (LO-Np) or lasted longer than 3 years (LL-Np). These 2 categories compared with classical pAN showed a far inferior rate of resolution (P < .001), lower severity of neutropenia (P = .03), leukopenia (P < .001), lymphopenia (P < .001) with low B+ (P = .001), increased need of granulocyte colony-stimulating factor (P = .04), and increased frequency of autoimmunity over the disease course (P < .001). A paired comparison between LO-Np and LL-Np suggested that LO-Np had a lower rate of resolution (P < .001) and lower white blood cell (P < .001) and lymphocyte (P < .001) values, higher occurrence of apthae (P = .008), and a stronger association with autoimmune diseases/markers (P = .001) than LL-Np, thus suggesting a more pronounced autoimmune signature for LO-Np. A next-generation sequencing panel applied in a small subgroup of LO-Np and LL-Np patients identified variants related to immune dysregulations. Overall, these findings indicate that there are important differences among pAN LL-Np and LO-Np. Forms rising after 3 years of age, with low tendency to resolution, require tight monitoring and extensive immune investigations aimed to early identify underlying immunologic disease.
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http://dx.doi.org/10.1182/bloodadvances.2020002793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686904PMC
November 2020

A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease.

PLoS Genet 2020 11 5;16(11):e1009106. Epub 2020 Nov 5.

Center of Medical Research, Medical Faculty Mannheim, Mannheim, Germany.

Hirschsprung disease (HSCR, OMIM 142623) involves congenital intestinal obstruction caused by dysfunction of neural crest cells and their progeny during enteric nervous system (ENS) development. HSCR is a multifactorial disorder; pathogenetic variants accounting for disease phenotype are identified only in a minority of cases, and the identification of novel disease-relevant genes remains challenging. In order to identify and to validate a potential disease-causing relevance of novel HSCR candidate genes, we established a complementary study approach, combining whole exome sequencing (WES) with transcriptome analysis of murine embryonic ENS-related tissues, literature and database searches, in silico network analyses, and functional readouts using candidate gene-specific genome-edited cell clones. WES datasets of two patients with HSCR and their non-affected parents were analysed, and four novel HSCR candidate genes could be identified: ATP7A, SREBF1, ABCD1 and PIAS2. Further rare variants in these genes were identified in additional HSCR patients, suggesting disease relevance. Transcriptomics revealed that these genes are expressed in embryonic and fetal gastrointestinal tissues. Knockout of these genes in neuronal cells demonstrated impaired cell differentiation, proliferation and/or survival. Our approach identified and validated candidate HSCR genes and provided further insight into the underlying pathomechanisms of HSCR.
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http://dx.doi.org/10.1371/journal.pgen.1009106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643938PMC
November 2020

Guidelines for diagnosis and management of congenital central hypoventilation syndrome.

Orphanet J Rare Dis 2020 09 21;15(1):252. Epub 2020 Sep 21.

Karolinska University Hospital, Stockholm, Sweden.

Background: Congenital Central Hypoventilation Syndrome (CCHS) is a rare condition characterized by an alveolar hypoventilation due to a deficient autonomic central control of ventilation and a global autonomic dysfunction. Paired-like homeobox 2B (PHOX2B) mutations are found in most of the patients with CCHS. In recent years, the condition has evolved from a life-threatening neonatal onset disorder to include broader and milder clinical presentations, affecting children, adults and families. Genes other than PHOX2B have been found responsible for CCHS in rare cases and there are as yet other unknown genes that may account for the disease. At present, management relies on lifelong ventilatory support and close follow up of dysautonomic progression. BODY: This paper provides a state-of-the-art comprehensive description of CCHS and of the components of diagnostic evaluation and multi-disciplinary management, as well as considerations for future research.

Conclusion: Awareness and knowledge of the diagnosis and management of this rare disease should be brought to a large health community including adult physicians and health carers.
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http://dx.doi.org/10.1186/s13023-020-01460-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503443PMC
September 2020

A case report of a novel compound heterozygous mutation in a Brazilian patient with deficiency of Interleukin-1 receptor antagonist (DIRA).

Pediatr Rheumatol Online J 2020 Aug 20;18(1):67. Epub 2020 Aug 20.

Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Giannina Gaslini, Genoa, Italy.

Background: Deficiency of the natural antagonist of interleukin-1 was first described in 2009 and so far 20 patients has been reported. In Brazil just two cases have been reported both carrying the same homozygous 15 bp deletion. Blocking interleukin-1 has changed rate survival for DIRA patients. The use of anakinra and rilonacept has been reported safe and efficient, whereas the selective blockade of interleukin-1 beta, using the monoclonal antibody canakinumab has been reported in a single case only.

Case Presentation: Here we report a case of a 7 years old Brazilian boy that presented with recurrent episodes of systemic inflammation with severe disabling osteomyelitis with mild pustular skin rash. A Next Generation Sequencing gene panel allowed to detect two pathogenic mutations in the IL1RN gene, described in compound heterozygosity. Corticosteroids was effective in controlling inflammation and anti-IL1 beta blocker triggered disease flare. Complete clinical control could be achieved using IL-1 receptor antagonist.

Conclusions: DIRA is a severe, life threatening autoinflammatory condition with low numbers of patients described all over the world. The mutation p.Asp72_Ile76del in IL1RN is presented in all Brazilian DIRA patients already described and p.Q45* (rs1019766125) is a new mutation affecting the IL1RN gene. Following the pathogenesis of DIRA, blocking both subunits of interleukin one as well as antagonizing the receptor using anakinra or rilonacept seems to be effective. There is just one report using canakinumab for the treatment of DIRA and this is the first report of disease flare using this drug.
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http://dx.doi.org/10.1186/s12969-020-00454-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439677PMC
August 2020

Targeted re-sequencing in pediatric and perinatal stroke.

Eur J Med Genet 2020 Nov 18;63(11):104030. Epub 2020 Aug 18.

U.O.C. Medicina Fisica e Riabilitazione, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy.

Pediatric and perinatal stroke can present as an early symptom in undiagnosed syndromes characterized by simple Mendelian inheritance. In order to diagnose those patients affected with a monogenic disorder in which an arterial cerebrovascular event or arteriopathy may have preceded any other specific symptom, we aimed to establish and validate a targeted gene panel, and to determine its diagnostic yield and clinical utility. To this end, thirty-eight patients were selected with heterogeneous cryptogenic stroke phenotypes, mostly including multiple and recurrent ischemic or hemorrhagic arterial strokes and porencephalies, variably associated with calcifications, intracranial or systemic steno-occlusive arteriopathies, positive family history, and syndromic conditions. Clinical and neuroradiological data were collected for every patient enrolled in the study, and DNA samples were tested by means of a customized gene panel including 15 genes associated with known genetic diseases related to pediatric stroke. In four patients (10.5%) the analyses unraveled pathogenetic variants in ABCC6 and COL4A1 genes, leading to a definite genetic diagnosis with a great beneficial impact on patients management, while results were null in the remaining patients. These findings suggest a high complexity and variability of the included stroke phenotypes, that could not be fully accounted for by the genes tested in the present study. A wider gene panel or an unbiased genomic approach may be better suited and advisable to explain a greater proportion of pediatric and perinatal stroke events.
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http://dx.doi.org/10.1016/j.ejmg.2020.104030DOI Listing
November 2020

Dysregulation in B-cell responses and T follicular helper cell function in ADA2 deficiency patients.

Eur J Immunol 2021 01 28;51(1):206-219. Epub 2020 Aug 28.

Unità Operativa Semplice Dipartimentale Centro Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genova, Italy.

Adenosine deaminase 2 deficiency (DADA2) is an autoinflammatory disease characterized by inflammatory vasculopathy, early strokes associated often with hypogammaglobulinemia. Pure red cell aplasia, thrombocytopenia, and neutropenia have been reported. The defect is due to biallelic loss of function of ADA2 gene, coding for a protein known to regulate the catabolism of extracellular adenosine. We therefore investigated immune phenotype and B- and T-cell responses in 14 DADA2 patients to address if ADA2 mutation affects B- and T-cell function. Here, we show a significant decrease in memory B cells, in particular class switch memory, and an expansion of CD21 B cells in DADA2 patients. In vitro stimulated B lymphocytes were able to secrete nonfunctional ADA2 protein, suggesting a cell intrinsic defect resulting in an impairment of B-cell proliferation and differentiation. Moreover, CD4 and CD8 T cells were diminished; however, the frequency of circulating T follicular helper cells was significantly increased but they had an impairment in IL-21 production possibly contributing to an impaired B cell help. Our findings suggest that ADA2 mutation could lead to a B-cell intrinsic defect but also to a defective Tfh cell function, which could contribute to the immunodeficient phenotype reported in DADA2 patients.
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http://dx.doi.org/10.1002/eji.202048549DOI Listing
January 2021

Multidisciplinary study of sudden unexpected infant death in Liguria (Italy): an nine-year report.

Minerva Pediatr 2020 Apr 2. Epub 2020 Apr 2.

Department of Pediatric Emergency - Sudden Infant Death Syndrome Liguria Centre, Istituto Giannina Gaslini, Genoa, Italy.

We conducted a retrospective analysis of cases of SUID referred to the SIDS-ALTE Center of the Liguria Region (Italy) from 2010 to 2018. In all cases, the death scene was inspected and a multidisciplinary post-mortem evaluation was conducted. Our aim was to analyze the epidemiological data and etiological distribution. We examined 15 cases initially classified as sudden infant death. In all cases, the death was initially unexplained. Seven cases involved males and eight involved females. Their mean age was 67,47 days; the youngest victim was 2 days old, while the oldest was 8.5 months (253 days). In 7 cases, the post-mortem analysis showed an infection of lung. In 4 cases, the prone position of the infant during sleep was identified as a risk factor. In only one case did the cause of death remain unexplained and it was classified as sudden infant death syndrome II according to San Diego classification. In the forensic approach to cases of SUID, it is always important to conduct a thorough multidisciplinary investigation. In order to avoid procedural errors that might compromise the post- mortem investigation, it is necessary to consider the medical and social history of both mother and child, in addition to the circumstances of the death. Moreover, a complete pediatric post-mortem examination and multidisciplinary discussion are required in order to identify potentially important causative or contributory factors.
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http://dx.doi.org/10.23736/S0026-4946.20.05599-1DOI Listing
April 2020

ISSAID/EMQN Best Practice Guidelines for the Genetic Diagnosis of Monogenic Autoinflammatory Diseases in the Next-Generation Sequencing Era.

Clin Chem 2020 04;66(4):525-536

Department of Medical Genetics, Rare Diseases and Personalized Medicine, Reference Center CEREMAIA, CHU Montpellier, University of Montpellier, Montpellier, France.

Background: Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses, and are characterized by sterile systemic inflammatory episodes. Since symptoms can overlap within this rapidly expanding disease category, accurate genetic diagnosis is of the utmost importance to initiate early inflammation-targeted treatment and prevent clinically significant or life-threatening complications. Initial 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 the 4 prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes). The development of best practices guidelines integrating critical recent discoveries has become essential.

Methods: The preparatory steps included 2 online surveys and pathogenicity annotation of newly recommended genes. The current guidelines were drafted by European Molecular Genetics Quality Network members, then discussed by a panel of experts of the International Society for Systemic Autoinflammatory Diseases during a consensus meeting.

Results: In these guidelines, we combine the diagnostic strength of next-generation sequencing and recommendations to 4 more recently identified genes (ADA2, NOD2, PSTPIP1, and TNFAIP3), nonclassical pathogenic genetic alterations, and atypical phenotypes. We present a referral-based decision tree for test scope and method (Sanger versus next-generation sequencing) and recommend on complementary explorations for mosaicism, copy-number variants, and gene dose. A genotype table based on the 5-category variant pathogenicity classification provides the clinical significance of prototypic genotypes per gene and disease.

Conclusions: These guidelines will orient and assist geneticists and health practitioners in providing up-to-date and appropriate diagnosis to their patients.
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http://dx.doi.org/10.1093/clinchem/hvaa024DOI Listing
April 2020

Unusual Late-onset Enteropathy in a Patient With Lipopolysaccharide-responsive Beige-like Anchor Protein Deficiency.

J Pediatr Hematol Oncol 2020 11;42(8):e768-e771

Haematology Unit.

In recent years, monogenic causes of immune dysregulation syndromes, with variable phenotypes, have been documented. Mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) protein are associated with common variable immunodeficiency, autoimmunity, chronic enteropathy, and immune dysregulation disorders. The LRBA protein prevents degradation of cytotoxic T-lymphocyte antigen 4 (CTLA4) protein, thus inhibiting immune responses. Both LRBA and CTLA4 deficiencies usually present with immune dysregulation, mostly characterized by autoimmunity and lymphoproliferation. In this report, we describe a patient with an atypical clinical onset of LRBA deficiency and the patient's response to abatacept, a fusion protein-drug that mimics the action of CTLA4.
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http://dx.doi.org/10.1097/MPH.0000000000001708DOI Listing
November 2020

A Novel Mutation of Causing Adult-Onset Alexander Disease.

Front Neurol 2019 6;10:1124. Epub 2019 Nov 6.

Department of Neurology and Laboratory of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Auxologico Italiano, Milan, Italy.

Alexander disease (AxD) is a rare, autosomal dominant neurological disorder. Three clinical subtypes are distinguished based on age at onset: infantile (0-2 years), juvenile (2-13 years), and adult (>13 years). The three forms differ in symptoms and prognosis. Rapid neurological decline with a fatal course characterizes the early-onset forms, while symptoms are milder and survival is longer in the adult forms. Currently, the sole known cause of AxD is mutations in the gene, which encodes a type III intermediate filament protein that is predominantly expressed in astrocytes. A wide spectrum of mutations comprising point mutations, small insertions, and deletions is associated with the disease. The genotype-phenotype correlation remains unclear. The considerable heterogeneity in severity of disease among individuals carrying identical mutations suggests that other genetic or environmental factors probably modify age at onset or progression of AxD. Describing new cases is therefore important for establishing reliable genotype-phenotype correlations and revealing environmental factors able to modify age at onset or progression of AxD. We report the case of a 54-year-old Caucasian woman, previously diagnosed with ovarian cancer and treated with surgery and chemotherapy, who developed dysarthria, ataxia, and spastic tetraparesis involving mainly the left side. Cerebral and spinal magnetic resonance imaging (MRI) revealed a peculiar tadpole-like atrophy of the brainstem. Genetic analysis of the gene detected a heterozygous mutation in exon 1 (c.219G>C), resulting in an amino acid exchange from methionine to isoleucine at codon 73 (p.M73I). The expression of this mutant affected the formation of the intermediate filament network. Thus, we have identified a new mutation in a patient with an adult form of AxD.
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http://dx.doi.org/10.3389/fneur.2019.01124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851058PMC
November 2019

Copy number variations in candidate genomic regions confirm genetic heterogeneity and parental bias in Hirschsprung disease.

Orphanet J Rare Dis 2019 11 25;14(1):270. Epub 2019 Nov 25.

U.O.C. Genetica Medica, IRCCS, Istituto Giannina Gaslini, 16148, Genoa, Italy.

Background: Hirschsprung Disease (HSCR) is a congenital defect of the intestinal innervations characterized by complex inheritance. Many susceptibility genes including RET, the major HSCR gene, and several linked regions and associated loci have been shown to contribute to disease pathogenesis. Nonetheless, a proportion of patients still remains unexplained. Copy Number Variations (CNVs) have already been involved in HSCR, and for this reason we performed Comparative Genomic Hybridization (CGH), using a custom array with high density probes.

Results: A total of 20 HSCR candidate regions/genes was tested in 55 sporadic patients and four patients with already known chromosomal aberrations. Among 83 calls, 12 variants were experimentally validated, three of which involving the HSCR crucial genes SEMA3A/3D, NRG1, and PHOX2B. Conversely RET involvement in HSCR does not seem to rely on the presence of CNVs while, interestingly, several gains and losses did co-occur with another RET defect, thus confirming that more than one predisposing event is necessary for HSCR to develop. New loci were also shown to be involved, such as ALDH1A2, already found to play a major role in the enteric nervous system. Finally, all the inherited CNVs were of maternal origin.

Conclusions: Our results confirm a wide genetic heterogeneity in HSCR occurrence and support a role of candidate genes in expression regulation and cell signaling, thus contributing to depict further the molecular complexity of the genomic regions involved in the Enteric Nervous System development. The observed maternal transmission bias for HSCR associated CNVs supports the hypothesis that in females these variants might be more tolerated, requiring additional alterations to develop HSCR disease.
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http://dx.doi.org/10.1186/s13023-019-1205-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878652PMC
November 2019

A Metagenomics Study on Hirschsprung's Disease Associated Enterocolitis: Biodiversity and Gut Microbial Homeostasis Depend on Resection Length and Patient's Clinical History.

Front Pediatr 2019 9;7:326. Epub 2019 Aug 9.

Department, of Biology, University of Florence, Firenze, Italy.

Since 2010, several researches demonstrated that microbiota dynamics correlate and can even predispose to Hirschsprung (HSCR) associated enterocolitis (HAEC). This study aims at assessing the structure of the microbiota of HSCR patients in relation to extent of aganglionosis and HAEC status. All consecutive HSCR patients admitted to Gaslini Institute (Genova, Italy) between May 2012 and November 2014 were enrolled. Institutional review board (IRB) approval was obtained. Stools were sampled and 16S rDNA V3-V4 regions were sequenced using the Illumina-MiSeq. Taxonomy assignments were performed using QIIME RDP. Alpha diversity indexes were analyzed by Shannon and Simpson Indexes, and Phylogenetic Diversity. We enrolled 20 patients. Male to female ratio was 4:1. Six patients suffered from Total Colonic Aganglionosis (TCSA). Considering sample site (i.e., extent of aganglionosis), we confirmed the known relationship between sample site and both biodiversity and composition of intestinal microbiota. Patients with TCSA showed lower biodiversity and increased Proteobacteria/Bacteroidetes relative abundance ratio. When addressing biodiversity, composition and dynamics of TCSA patients we could not find any significant relationship with regard to HAEC occurrences. The composition of HAEC predisposing microbiota is specific to each patient. We could confirm that total colon resections can change the composition of intestinal microbiota and to dramatically reduce microbial diversity. The subsequent reduction of system robustness could expose TCSA patients to environmental microbes that might not be part of the normal microbiota. Future long-term studies should investigate both patients and their family environment, as well as their disease history.
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http://dx.doi.org/10.3389/fped.2019.00326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696876PMC
August 2019

Causative and common PHOX2B variants define a broad phenotypic spectrum.

Clin Genet 2020 01 30;97(1):103-113. Epub 2019 Aug 30.

U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, Genova, Italy.

Paired Like homeobox 2B (PHOX2B) is a gene crucial for the differentiation of the neural lineages of the autonomic nervous system (ANS), whose coding mutations cause congenital central hypoventilation syndrome (CCHS). The vast majority of PHOX2B mutations in CCHS is represented by expansions of a polyalanine region in exon 3, collectively defined PARMs (PolyAlanine Repeat Mutations), the minority being frameshift, missense and nonsense mutations, defined as NPARMs (Non-PARMs). While PARMs are nearly exclusively associated with isolated CCHS, most of NPARMs is detected in syndromic CCHS, presenting with neuroblastoma and/or Hirschsprung disease. More recently, evidence of a complex role of PHOX2B in the pathogenesis of a wider spectrum of ANS disorders has emerged. Indeed, common and hypomorphic PHOX2B variants, including synonymous, polyalanine-contractions, gene deletions may influence the occurrence of either apparent life-threatening event (ALTE), Sudden Infant Death Syndrome (SIDS), neuroblastoma, or isolated HSCR, likely through small effects on PHOX2B expression levels. After an introduction to the role of PHOX2B in the ANS development, causative mutations, common variants, and gene expression deregulation of the PHOX2B gene are discussed, though the involvement of synonymous variants and contractions requires further confirmations with respect to ANS disorders and molecular mechanisms underlying the PHOX2B phenotypic heterogeneity.
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http://dx.doi.org/10.1111/cge.13633DOI Listing
January 2020
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