Publications by authors named "Giuseppe Zampino"

112 Publications

Contactless: a new personalised telehealth model in chronic pediatric diseases and disability during the COVID-19 era.

Ital J Pediatr 2021 Feb 12;47(1):29. Epub 2021 Feb 12.

Pediatric Neurology Unit, Fondazione Policlinico A Gemelli -IRCCS, Università Cattolica del Sacro Cuore, Largo Gemelli 8, 00168, Rome, Italy.

Background: Suspending ordinary care activities during the COVID-19 pandemic made it necessary to find alternative routes to comply with care recommendations not only for acute health needs but also for patients requiring follow-up and multidisciplinary visits. We present the 'Contactless' model, a comprehensive operational tool including a plurality of services delivered remotely, structured according to a complexity gradient, aimed to cover diagnostic procedures and monitor disease progression in chronic pediatric patients.

Methods: A multidisciplinary and multiprofessional project team was recruited, in collaboration with patients' associations, to map a panel of available Evidence-Based solutions and address individual needs in full respect of the concept of personalized medicine. The solutions include a number of services from videoconsultations to more structure videotraining sessions.

Results: A modular framework made up of four three Macro-levels of complexity - Contactless Basic, Intermediate and Advanced - was displayed as an incremental set of services and operational planning establishing each phase, from factors influencing eligibility to the delivery of the most accurate and complex levels of care.

Conclusion: The multimodal, multidisciplinary 'Contactless' model allowed the inclusion of all Units of our Pediatric Department and families with children with disability or complex chronic conditions. The strengths of this project rely on its replicability outside of pediatrics and in the limited resources needed to practically impact patients, caregivers and professionals involved in the process of care. Its implementation in the future may contribute to reduce the duration of hospital admissions, money and parental absence from work.
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http://dx.doi.org/10.1186/s13052-021-00975-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880513PMC
February 2021

Recognition Memory in Noonan Syndrome.

Brain Sci 2021 Jan 29;11(2). Epub 2021 Jan 29.

Laboratory of Clinical and Behavioral Neurology, Santa Lucia Foundation, 00179 Rome, Italy.

Noonan syndrome (NS) and the clinically related NS with multiple lentiginous (NMLS) are genetic conditions characterized by upregulated RAS mitogen activated protein kinase (RAS-MAPK) signaling, which is known to impact hippocampus-dependent memory formation and consolidation. The aim of the present study was to provide a detailed characterization of the recognition memory of children and adolescents with NS/NMLS. We compared 18 children and adolescents affected by NS and NMLS with 22 typically developing (TD) children, matched for chronological age and non-verbal Intelligence Quotient (IQ), in two different experimental paradigms, to assess familiarity and recollection: a Process Dissociation Procedure (PDP) and a Task Dissociation Procedure (TDP). Differences in verbal skills between groups, as well as chronological age, were considered in the analysis. Participants with NS and NSML showed reduced recollection in the PDP and impaired associative recognition in the TDP, compared to controls. These results indicate poor recollection in the recognition memory of participants with NS and NSML, which cannot be explained by intellectual disability or language deficits. These results provide evidence of the role of mutations impacting RAS-MAPK signaling in the disruption of hippocampal memory formation and consolidation.
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http://dx.doi.org/10.3390/brainsci11020169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910957PMC
January 2021

Musculo-skeletal phenotype of Costello syndrome and cardio-facio-cutaneous syndrome: insights on the functional assessment status.

Orphanet J Rare Dis 2021 Jan 22;16(1):43. Epub 2021 Jan 22.

Center for Rare Diseases and Birth Defects, Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Gemelli 8, 00168, Rome, Italy.

Background: Costello syndrome (CS) and cardio-facio-cutaneous syndrome (CFCS) belong to the RASopathies, a group of neurodevelopmental disorders with skeletal anomalies. Due to their rarity, the characterization of the musculo-skeletal phenotype in both disorders has been poorly characterized.

Patients And Methods: Herein we reported data on orthopedic findings and functional status of a large sample of CS and CFCS patients. Thirty-four patients (CS = 17 and CFCS = 17) were recruited. Functional and disability evaluations were performed by assessing the 6-min walking test (6MWT) and Pediatric Outcomes Data Collection Instrument (PODCI). Genotype/phenotype correlation was also provided.

Results: Orthopedic manifestations are highly prevalent in CS and CFCS and overlap in the two disorders. Overall, patients with CS harboring the recurrent HRAS Gly12Ser substitution show a more severe skeletal phenotype compared to patients carrying the Gly12Ala and Gly13Cys variants. Among CFCS patients, those with the MAP2K1/2 variant show different skeletal characteristics compared to BRAF variants, with a higher prevalence of orthopedic abnormalities. Functional assessment showed that patients with CS and CFCS reached lower values compared to the general population, with CFCS patients displaying the lowest scores.

Conclusions: Orthopedic manifestations appear universal features of CS and CFCS and they can evolve across patients' life. Longitudinal assessment of disability status by using 6MWT and PODCI could be useful to evaluate the functional impact of orthopedic manifestations on patients' outcome and help planning a tailored treatment of these comorbidities.
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http://dx.doi.org/10.1186/s13023-021-01674-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821553PMC
January 2021

De Novo Partial 13q22-q34 Trisomy with Typical Neurological and Immunological Findings: A Case Report with New Genetic Insights.

Brain Sci 2020 Dec 26;11(1). Epub 2020 Dec 26.

Pediatric Unit, Fondazione Policlinico Universitario "A. Gemelli", IRCSS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.

The partial trisomy 13q encompasses an extensive variability of phenotypic and radiological findings including leukoencephalopathy and brain malformations such as holoprosencephaly, callosal dysgenesis, hippocampal hypoplasia, olfactory hypoplasia, and vermian hypoplasia. We report for the first time a case of a 23-year-old patient affected by de novo partial 13q22.1q34 trisomy (41.7 Mb, 72,365,975-114,077,122x3) presenting with hemiparesis related to both ischemic and haemorrhagic cerebral lesions compatible with cerebral vasculitis due to a possible combination of genetic and immunological interaction.
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http://dx.doi.org/10.3390/brainsci11010021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823677PMC
December 2020

Adult phenotype in Koolen-de Vries/ haploinsufficiency syndrome.

J Med Genet 2020 Dec 24. Epub 2020 Dec 24.

Dipartimento Universitario Scienze della Vita e Sanità Pubblica, Sezione di Medicina Genomica, Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Roma, Italy

Background: Koolen-de Vries syndrome (KdVS) is a multisystem neurodevelopmental disorder caused by 17q21.31 deletions or mutations in . It was mainly described in children.

Methods: A retrospective study on 9 subjects aged 19-45 years and revision of 18 literature patients, with the purpose to get insights into the phenotypic evolution with time, and into the clinical manifestations in adulthood.

Results: Seven patients had a 17q21.31 deletion and two a point mutation in . All had intellectual disability, which was mild in five (56%) and moderate in four (44%). Epilepsy was diagnosed in four subjects (44%), with onset from 1 to 7 years and full remission before 9 years in 3/4 patients. Scoliosis affected seven individuals (77.7%) and it was substantially stable with age in 5/7 patients, allowing for simple daily activities. Two subjects had severely progressive scoliosis, which was surgically corrected. Overweight or true obesity did occur after puberty in six patients (67%). Behaviour abnormalities were recorded in six patients (67%). The facial phenotype slightly evolved with time to include thick eyebrows, elongated nose and pronounced pointed chin. Despite behaviour abnormalities, happy disposition and sociable attitudes were common. Half of patients had fluent language and were good at writing and reading. Rich language, although limited to single words or short sentences, and very limited or absent skills in writing and reading were observed in the remaining patients. Autonomy in daily activities and personal care was usually limited.

Conclusions: Distinctive features in adult KdVS subjects include intellectual disability, overweight/obesity, behaviour abnormalities with preserved social interest, ability in language, slight worsening of the facial phenotype and no seizures.
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http://dx.doi.org/10.1136/jmedgenet-2020-107225DOI Listing
December 2020

Rare and de novo coding variants in chromodomain genes in Chiari I malformation.

Am J Hum Genet 2021 01 21;108(1):100-114. Epub 2020 Dec 21.

Department of Neurosurgery, Washington University, St. Louis, MO 63110, USA; Department of Neurology, Washington University, St. Louis, MO 63110, USA; Department of Genetics, Washington University, St. Louis, MO 63110, USA. Electronic address:

Chiari I malformation (CM1), the displacement of the cerebellum through the foramen magnum into the spinal canal, is one of the most common pediatric neurological conditions. Individuals with CM1 can present with neurological symptoms, including severe headaches and sensory or motor deficits, often as a consequence of brainstem compression or syringomyelia (SM). We conducted whole-exome sequencing (WES) on 668 CM1 probands and 232 family members and performed gene-burden and de novo enrichment analyses. A significant enrichment of rare and de novo non-synonymous variants in chromodomain (CHD) genes was observed among individuals with CM1 (combined p = 2.4 × 10), including 3 de novo loss-of-function variants in CHD8 (LOF enrichment p = 1.9 × 10) and a significant burden of rare transmitted variants in CHD3 (p = 1.8 × 10). Overall, individuals with CM1 were found to have significantly increased head circumference (p = 2.6 × 10), with many harboring CHD rare variants having macrocephaly. Finally, haploinsufficiency for chd8 in zebrafish led to macrocephaly and posterior hindbrain displacement reminiscent of CM1. These results implicate chromodomain genes and excessive brain growth in CM1 pathogenesis.
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http://dx.doi.org/10.1016/j.ajhg.2020.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820723PMC
January 2021

Basedow-Graves' disease in a pediatric patient with Sticlker syndrome, a new endocrine finding to improve personalized treatment.

Ital J Pediatr 2020 Dec 1;46(1):178. Epub 2020 Dec 1.

Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.

Background: Stickler syndrome is a connective tissue disorder with predominantly autosomal dominant inheritance, with ocular, auditory and joint involvement. Thyroid dysfunction was not described as part of alterations in Stickler syndrome and in particular, the association between Stickler's syndrome and Graves' disease has never been previously reported in literature. Moreover, the presence of Graves' disease is uncommon in the pediatric age (especially in children younger than 6 years old).

Case Presentation: We report the case of a 5-years old child affected by Stickler syndrome who received the diagnosis of Graves's disease, in absence of suggestive symptoms, during health supervision.

Conclusions: This is the first evidence of thyroid dysfunction and autoimmune pattern for Sticker syndrome. Further clinical reports are expected before suggesting the implementation of new clinical skills for Stickler syndrome, but this paper may contribute to improve personalized management of this rare disorder.
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http://dx.doi.org/10.1186/s13052-020-00945-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706036PMC
December 2020

Children with special health care needs attending emergency department in Italy: analysis of 3479 cases.

Ital J Pediatr 2020 Nov 23;46(1):173. Epub 2020 Nov 23.

Department of Pediatrics, ASST-Lariana, Hospital "Sant'Anna", Como, Italy.

Background: Although children with special health care needs (CSHCN) represent a minority of the population, they go through more hospitalizations, more admissions to the Emergency Department (ED), and receive a major number of medical prescriptions, in comparison to general pediatric population. Objectives of the study were to determine the reasons for admission to the ED in Italian CSHCN, and to describe the association between patient's demographic data, clinical history, and health services requirements.

Methods: Ad hoc web site was created to collect retrospective data of 3479 visits of CSHCN to the ED in 58 Italian Hospitals.

Results: Seventy-two percent of patients admitted to ED were affected by a previously defined medical condition. Most of the ED admissions were children with syndromic conditions (54%). 44.2% of the ED admissions were registered during the night-time and/or at the weekends. The hospitalization rate was of 45.6% among patients admitted to the ED. The most common reason for admission to the ED was the presence of respiratory symptoms (26.6%), followed by gastrointestinal problems (21.3%) and neurological disorders (18.2%). 51.4% of the access were classified as 'urgent', with a red/yellow triage code. Considering the type of ED, 61.9% of the visits were conducted at the Pediatric EDs (PedEDs), 33.5% at the Functional EDs (FunEDs) and 4.6% at the Dedicated EDs (DedEDs). Patients with more complex clinical presentation were more likely to be evaluated at the PedEDs. CSHCN underwent to a higher number of medical procedures at the PedEDs, more in comparison to other EDs. Children with medical devices were directed to a PedED quite exclusively when in need for medical attention. Subjects under multiple anti-epileptic drug therapy attended to PedEDs or FunEDs generally. Patients affected by metabolic diseases were more likely to look for medical attention at FunEDs. Syndromic patients mostly required medical attention at the DedEDs.

Conclusions: Access of CSHCN to an ED is not infrequent. For this reason, it is fundamental for pediatricians working in any kind of ED to increase their general knowledge about CHSCN and to gain expertise in the management of such patients and their related medical complexity.
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http://dx.doi.org/10.1186/s13052-020-00937-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685641PMC
November 2020

De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment.

Am J Hum Genet 2020 12 12;107(6):1129-1148. Epub 2020 Nov 12.

Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK; Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK. Electronic address:

The endosomal sorting complexes required for transport (ESCRTs) are essential for multiple membrane modeling and membrane-independent cellular processes. Here we describe six unrelated individuals with de novo missense variants affecting the ATPase domain of VPS4A, a critical enzyme regulating ESCRT function. Probands had structural brain abnormalities, severe neurodevelopmental delay, cataracts, growth impairment, and anemia. In cultured cells, overexpression of VPS4A mutants caused enlarged endosomal vacuoles resembling those induced by expression of known dominant-negative ATPase-defective forms of VPS4A. Proband-derived fibroblasts had enlarged endosomal structures with abnormal accumulation of the ESCRT protein IST1 on the limiting membrane. VPS4A function was also required for normal endosomal morphology and IST1 localization in iPSC-derived human neurons. Mutations affected other ESCRT-dependent cellular processes, including regulation of centrosome number, primary cilium morphology, nuclear membrane morphology, chromosome segregation, mitotic spindle formation, and cell cycle progression. We thus characterize a distinct multisystem disorder caused by mutations affecting VPS4A and demonstrate that its normal function is required for multiple human developmental and cellular processes.
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http://dx.doi.org/10.1016/j.ajhg.2020.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820634PMC
December 2020

Point of view of the Italians pediatric scientific societies about the pediatric care during the COVID-19 lockdown: what has changed and future prospects for restarting.

Ital J Pediatr 2020 Oct 2;46(1):142. Epub 2020 Oct 2.

Federazione Italiana delle Associazioni e Società Scientifiche dell'Area Pediatrica e Società Italiana di Emergenza Urgenza Pediatrica, Rome, Italy.

Background: The coronavirus disease 2019 (COVID-19) is currently rare in children and they seem to have a milder disease course and better prognosis than adults. However, SARS-Cov-2 pandemic has indirectly caused problems in pediatric medical assistance. In view of this we wanted to draw a picture of what happened during health emergency and analyze future prospects for restarting.

Methods: We involved the Italian pediatric scientific societies institutionally collected in the Italian Federation of Associations and Scientific Societies of the Pediatric Area (FIARPED); We sent a questionnaire to all scientific societies about the pediatric care activity during the COVID-19 emergency and future perspectives for the phase of post-containment.

Results: The analysis of the questionnaires showed significant decrease of:admission, outpatient visits and specialist consultancy activities during the COVID-19 emergency, primarily linked to the fear of infection. Instead it was increased the serious degree of diseases admitted. Most of scientific societies maintained the relationship with chronic patients through some form of telemedicine, reporting a strong positive opinion about this modality. Finally showed the need to give life a new approach for hospitalizations and outpatient visits through a greater use of telemedicine, educational programs on families and a more decisive role of family pediatricians.

Conclusions: Our study highlighted many aspects that can be improved in pediatric care. We think that It will be necessary a new shared strategy to improve the management and continuity of care for pediatric patients, primarily developing a network of collaboration between families, family pediatrician and hospitals and by enhancing the use of new methods of telecommunications.
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http://dx.doi.org/10.1186/s13052-020-00907-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531060PMC
October 2020

Immunoglobulin deficiency associated with a MAP2K1-related mutation causing cardio-facio-cutaneous syndrome.

Immunol Lett 2020 11 28;227:79-80. Epub 2020 Aug 28.

Center for Rare Diseases and Birth Defects, Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Università Cattolica del Sacro Cuore, Rome, Italy.

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http://dx.doi.org/10.1016/j.imlet.2020.08.009DOI Listing
November 2020

Impact of Costello syndrome on growth patterns.

Am J Med Genet A 2020 11 26;182(11):2797-2799. Epub 2020 Aug 26.

Department of Woman and Child Health and Public Health, Center for Rare Diseases and Birth Defects, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

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http://dx.doi.org/10.1002/ajmg.a.61812DOI Listing
November 2020

Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum.

Am J Hum Genet 2020 09 27;107(3):499-513. Epub 2020 Jul 27.

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address:

Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477014PMC
September 2020

Embryopathy Following Maternal Biliopancreatic Diversion: Is Bariatric Surgery Really Safe?

Obes Surg 2021 Jan 28;31(1):445-450. Epub 2020 Jul 28.

Rare Disease and Birth Defects Unit, Department of Woman, Child Health and Public Health, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy.

Pregnancy after bariatric surgery is usually considered safe. Recently, a few studies reported that bariatric surgery represents a risk factor for birth defects. A case series of six patients, born from women who had undergone biliopancreatic diversion, is reported. The clinical pattern was characterized by psychomotor development delay (100%), microphthalmia (83%), growth retardation (66%), hearing loss (66%), and variable facial dysmorphism. Based on the clinical profile and symptoms reported by women during pregnancy, a causal association between maternal chronic post-surgical malabsorption, congenital anomalies, and neonatal outcome is proposed, with vitamin A deficiency representing a major causing factor. Educational follow-up support, continuous clinical monitoring, and appropriate nutritional assessment appear to be crucial to reduce the potential risk of congenital malformations and child disability.
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http://dx.doi.org/10.1007/s11695-020-04882-wDOI Listing
January 2021

Treatment of Dystonia Using Trihexyphenidyl in Costello Syndrome.

Brain Sci 2020 Jul 14;10(7). Epub 2020 Jul 14.

Rare Diseases and Birth Defects Unit, Fondazione Policlinico A. Gemelli, IRCCS, 00168 Rome, Italy.

Costello syndrome (CS), a rare syndrome with multisystemic involvement inherited as a dominant trait, is characterized by developmental delay, coarse facial appearance, cardiac defects including hypertrophic cardiomyopathy, skin abnormalities, brain complications, and a predisposition to certain malignancies. The musculoskeletal system is particularly affected in CS, with peculiar orthopedic anomalies that impact posture and gait. Dystonia has been recently documented to contribute to abnormal postures and musculoskeletal anomalies characterizing CS, suggesting the possible use of pharmacological treatments to treat these complications. We report the case of a child affected by CS displaying a particularly severe musculoskeletal involvement with dystonic posture especially in the arms and legs. The Movement Disorder-Childhood Rating Scale (MD-CRS) and a gait analysis were used to assess clinical patterns of hyperkinetic movement disorder and dystonia. The child was further treated with trihexyphenidyl for six months with a final dosage of 14 mg. MD-CRS and gait analysis assessments provided evidence for a significant improvement of posture and the related musculoskeletal problems with no side effects. Our preliminary study report provides first evidence that pharmacological anti-dystonia treatment significantly improves movement and posture disorders in patients with CS. Further studies enrolling larger cohorts of patients should be performed to validate these preliminary observations.
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http://dx.doi.org/10.3390/brainsci10070450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408094PMC
July 2020

Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann-Steiner and Rubinstein-Taybi syndromes.

Eur J Hum Genet 2021 Jan 8;29(1):88-98. Epub 2020 Jul 8.

Genetica Medica e Biologia Applicata, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy.

Lysine-specific methyltransferase 2A (KMT2A) is responsible for methylation of histone H3 (K4H3me) and contributes to chromatin remodeling, acting as "writer" of the epigenetic machinery. Mutations in KMT2A were first reported in Wiedemann-Steiner syndrome (WDSTS). More recently, KMT2A variants have been described in probands with a specific clinical diagnosis comprised in the so-called chromatinopathies. Such conditions, including WDSTS, are a group of overlapping disorders caused by mutations in genes coding for the epigenetic machinery. Among them, Rubinstein-Taybi syndrome (RSTS) is mainly caused by heterozygous pathogenic variants in CREBBP or EP300. In this work, we used next generation sequencing (either by custom-made panel or by whole exome) to identify alternative causative genes in individuals with a RSTS-like phenotype negative to CREBBP and EP300 mutational screening. In six patients we identified different novel unreported variants in KMT2A gene. The identified variants are de novo in at least four out of six tested individuals and all of them display some typical RSTS phenotypic features but also WDSTS specific signs. This study reinforces the concept that germline variants affecting the epigenetic machinery lead to a shared molecular effect (alteration of the chromatin state) determining superimposable clinical conditions.
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http://dx.doi.org/10.1038/s41431-020-0679-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852672PMC
January 2021

Cantú syndrome versus Zimmermann-Laband syndrome: Report of nine individuals with ABCC9 variants.

Eur J Med Genet 2020 Sep 2;63(9):103996. Epub 2020 Jul 2.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Cantú syndrome (CS) is a rare developmental disorder characterized by a coarse facial appearance, macrocephaly, hypertrichosis, skeletal and cardiovascular anomalies and caused by heterozygous gain-of-function variants in ABCC9 and KCNJ8, encoding subunits of heterooctameric ATP-sensitive potassium (K) channels. CS shows considerable clinical overlap with Zimmermann-Laband syndrome (ZLS), a rare condition with coarse facial features, hypertrichosis, gingival overgrowth, intellectual disability of variable degree, and hypoplasia or aplasia of terminal phalanges and/or nails. ZLS is caused by heterozygous gain-of-function variants in KCNH1 or KCNN3, and gain-of-function KCNK4 variants underlie the clinically similar FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth) syndrome; KCNH1, KCNN3 and KCNK4 encode potassium channels. Within our research project on ZLS, we performed targeted Sanger sequencing of ABCC9 in 15 individuals tested negative for a mutation in the ZLS-associated genes and found two individuals harboring a heterozygous pathogenic ABCC9 missense variant. Through a collaborative effort, we identified a total of nine individuals carrying a monoallelic ABCC9 variant: five sporadic patients and four members of two unrelated families. Among the six detected ABCC9 missense variants, four [p.(Pro252Leu), p.(Thr259Lys), p.(Ala1064Pro), and p.(Arg1197His)] were novel. Systematic assessment of the clinical features in the nine cases with an ABCC9 variant highlights the significant clinical overlap between ZLS and CS that includes early developmental delay, hypertrichosis, gingival overgrowth, joint laxity, and hypoplasia of terminal phalanges and nails. Gain of K channel activity possibly accounts for significant clinical similarities of CS, ZLS and FHEIG syndrome and defines a new subgroup of potassium channelopathies.
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http://dx.doi.org/10.1016/j.ejmg.2020.103996DOI Listing
September 2020

Biallelic TRNT1 variants in a child with B cell immunodeficiency, periodic fever and developmental delay without sideroblastic anemia (SIFD variant).

Immunol Lett 2020 09 24;225:64-65. Epub 2020 Jun 24.

Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Università Cattolica del Sacro Cuore, Rome, Italy.

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http://dx.doi.org/10.1016/j.imlet.2020.06.012DOI Listing
September 2020

The dark side of COVID-19: The need of integrated medicine for children with special care needs.

Am J Med Genet A 2020 08 24;182(8):1988-1989. Epub 2020 Jun 24.

Department of Woman and Child Health and Public Health, Center for Rare Diseases and Birth Defects, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.

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http://dx.doi.org/10.1002/ajmg.a.61722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361344PMC
August 2020

A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome.

Eur J Hum Genet 2020 10 1;28(10):1422-1431. Epub 2020 Jun 1.

Children's Hospital of Philadelphia, Philadelphia, PA, USA.

There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.
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http://dx.doi.org/10.1038/s41431-020-0654-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608102PMC
October 2020

Nissen fundoplication in Cornelia de Lange syndrome spectrum: Who are the potential candidates?

Am J Med Genet A 2020 07 21;182(7):1697-1703. Epub 2020 May 21.

Department of Pediatrics, ASST-Lariana, "Sant'Anna" Hospital, Como, Italy.

Cornelia de Lange spectrum (CdLSp) is a rare genetic condition characterized by intellectual disability, facial dysmorphisms, major malformations, growth impairment, and development delay. Approximately 80% of CdLSp patients have gastroesophageal reflux disease (GERD) with a varied clinical presentation. The aim of this study is to define potential clinical/genetic risk factors based on the clinical phenotype description of CdLSp patients with severe GERD who underwent surgical treatment. We retrospectively collected data from 23 CdLSp patients, 13 females and 10 males. Mean age of the patients undergoing surgical treatment was of 4 years. 21/23 (91%) had a molecular characterization, of which 21/21 (100%) had a NIPBL gene mutation, while 2/23 (9%) did not have a genetical characterization, only a clinical diagnosis. Most of our patients presented a moderate-severe severity score (21/23, 91%) with limb malformations evidenced in 10/23 (44%) of our patients and a moderate-severe intellectual disability in 20/23 (87%). Therefore, CdLSp patients harboring NIPBL variants, upper limb malformations and severe psychomotor delay are more likely to suffer from severe GERD, not responsive to proton pump inhibitors treatment. These features should be considered as clinical markers for potentially severe GERD that might require surgical treatment.
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http://dx.doi.org/10.1002/ajmg.a.61625DOI Listing
July 2020

Novel Coronavirus Disease 2019 Infection in Children: The Dark Side of a Worldwide Outbreak.

Front Pediatr 2020 30;8:215. Epub 2020 Apr 30.

Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

In this pediatric perspectives article, we discuss current limits in the understanding of novel coronavirus infection. In our opinion, the burden of novel coronavirus infections is underestimated because not actively looked for. We discuss the basis of our observations and what this can generate, suggesting a different approach for the search of the virus in children.
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http://dx.doi.org/10.3389/fped.2020.00215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203211PMC
April 2020

Children's Healthcare During Corona Virus Disease 19 Pandemic: the Italian Experience.

Pediatr Infect Dis J 2020 07;39(7):e137-e140

From the Department of Woman and Child Health and Public Health.

The unexpected outbreak of Corona Virus Disease 19 had several consequences worldwide and on the Italian Health System. We report our experience in the reorganization of our Pediatric Department to prevent the risk of infection for both children and staff. We strongly believe that the need to face an unpredictable emergency situation should not affect the quality of the assistance to the non-Corona Virus Disease patients.
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http://dx.doi.org/10.1097/INF.0000000000002732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359905PMC
July 2020

How to Perform Pediatric Lung Ultrasound Examinations in the Time of COVID-19.

J Ultrasound Med 2020 Oct 22;39(10):2081-2082. Epub 2020 Apr 22.

Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.

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http://dx.doi.org/10.1002/jum.15306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264804PMC
October 2020

Bi-allelic Variants in the GPI Transamidase Subunit PIGK Cause a Neurodevelopmental Syndrome with Hypotonia, Cerebellar Atrophy, and Epilepsy.

Am J Hum Genet 2020 04 26;106(4):484-495. Epub 2020 Mar 26.

CHU-Sainte Justine Research Center, University of Montreal, Montreal, QC, Canada, H3T1C5; Department of Pediatrics, University of Montreal, Montreal, QC, Canada, H3T1C5. Electronic address:

Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs). In this report, we describe 12 individuals from nine unrelated families with 10 different bi-allelic PIGK variants. PIGK encodes a component of the GPI transamidase complex, which attaches the GPI anchor to proteins. Clinical features found in most individuals include global developmental delay and/or intellectual disability, hypotonia, cerebellar ataxia, cerebellar atrophy, and facial dysmorphisms. The majority of the individuals have epilepsy. Two individuals have slightly decreased levels of serum alkaline phosphatase, while eight do not. Flow cytometric analysis of blood and fibroblasts from affected individuals showed decreased cell surface presence of GPI-APs. The overexpression of wild-type (WT) PIGK in fibroblasts rescued the levels of cell surface GPI-APs. In a knockout cell line, transfection with WT PIGK also rescued the GPI-AP levels, but transfection with the two tested mutant variants did not. Our study not only expands the clinical and known genetic spectrum of IGDs, but it also expands the genetic differential diagnosis for cerebellar atrophy. Given the fact that cerebellar atrophy is seen in other IGDs, flow cytometry for GPI-APs should be considered in the work-ups of individuals presenting this feature.
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http://dx.doi.org/10.1016/j.ajhg.2020.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118585PMC
April 2020

Defining language disorders in children and adolescents with Noonan Syndrome.

Mol Genet Genomic Med 2020 04 14;8(4):e1069. Epub 2020 Feb 14.

Department of Neuroscience, Child and Adolescent Psychiatric Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Noonan Syndrome is a developmental disorder characterized by a distinctive phenotype including facial dysmorphism, webbed neck, short stature, heart defects, and variable cognitive deficits as major features. Over the years, neuropsychological and behavioral studies explored alteration of cognitive functioning and related domains, such as learning, memory, and attention. To our knowledge, however, data concerning the language profile in this disorder is scarce. The aim of the present study was to detect specific language functioning combining nonverbal intelligence quotient and language abilities and to pinpoint strengths and weaknesses in the language domains.

Methods: The language profile of 37 Italian participants with molecularly confirmed diagnosis of Noonan Syndrome was evaluated using specific tools to assess vocabulary and grammar comprehension and production, as well as phonological development.

Results: We observed that 78% of affected individuals exhibited language impairment. Within language domains, the strong area was lexical production and grammar production was the weak area. Almost half the participants manifested a similar trend of specific language impairment. Nonverbal intelligence quotient only correlated with grammar comprehension.

Conclusion: Our study expands present knowledge about the language profile in NS, and provides data that could enable more effective patient management and appropriate intervention.
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http://dx.doi.org/10.1002/mgg3.1069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196479PMC
April 2020

One case of anetoderma post-vitamin K injection in a newborn.

Int J Dermatol 2020 May 20;59(5):e168-e169. Epub 2020 Jan 20.

Institute of Dermatology, Catholic University and Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Rome, Italy.

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http://dx.doi.org/10.1111/ijd.14779DOI Listing
May 2020

Skeletal abnormalities are common features in Aymé-Gripp syndrome.

Clin Genet 2020 02 3;97(2):362-369. Epub 2019 Nov 3.

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Aymé-Gripp syndrome (AYGRPS) is a recognizable condition caused by a restricted spectrum of dominantly acting missense mutations affecting the transcription factor MAF. Major clinical features of AYGRPS include congenital cataracts, sensorineural hearing loss, intellectual disability, and a distinctive flat facial appearance. Skeletal abnormalities have also been observed in affected individuals, even though these features have not been assessed systematically. Expanding the series with four additional patients, here we provide a more accurate delineation of the molecular aspects and clinical phenotype, particularly focusing on the skeletal features characterizing this disorder. Apart from previously reported malar flattening and joint limitations, we document that carpal/tarsal and long bone defects, and hip dysplasia occur in affected subjects more frequently than formerly appreciated.
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http://dx.doi.org/10.1111/cge.13651DOI Listing
February 2020

Crisponi/cold-induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts.

Clin Genet 2020 01 16;97(1):209-221. Epub 2019 Sep 16.

Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy.

Crisponi/cold-induced sweating syndrome (CS/CISS) is an autosomal recessive disease characterized by hyperthermia, camptodactyly, feeding and respiratory difficulties often leading to sudden death in the neonatal period. The affected individuals who survived the first critical years of life, develop cold-induced sweating and scoliosis in early childhood. The disease is caused by variants in the CRLF1 or in the CLCF1 gene. Both proteins form a heterodimeric complex that acts on cells expressing the ciliary neurotrophic factor receptor (CNTFR). CS/CISS belongs to the family of "CNTFR-related disorders" showing a similar clinical phenotype. Recently, variants in other genes, including KLHL7, NALCN, MAGEL2 and SCN2A, previously linked to other diseases, have been associated with a CS/CISS-like phenotype. Therefore, retinitis pigmentosa and Bohring-Optiz syndrome-like (KLHL7), Congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome (NALCN), Chitayat-Hall/Schaaf-Yang syndrome (MAGEL2), and early infantile epileptic encephalopathy-11 syndrome (SCN2A) all share an overlapping phenotype with CS/CISS, especially in the neonatal period. This review aims to summarize the existing literature on CS/CISS, focusing on the current state of differential diagnosis, pathogenesis and treatment concepts in order to achieve an accurate and rapid diagnosis. This will improve patient management and enable specific treatments for the affected individuals.
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http://dx.doi.org/10.1111/cge.13639DOI Listing
January 2020