Angélica Moresco

Western University

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María Gabriela Obregón

Garrahan Hospital

Vajira H. W. Dissanayake

University of Colombo

Kelly L. Jones

Greenwood Genetic Center

Nirmala D. Sirisena

University of Colombo

Paul Kruszka

National Human Genome Research Institute

Yonit A. Addissie

National Human Genome Research Institute

Maximilian Muenke

National Institutes of Health

Meow‐Keong Thong

University of Malaya

Vorasuk Shotelersuk

Chulalongkorn University

C. S. Paththinige

Rajarata University of Sri Lanka

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National Institute of Health

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Garrahan Hospital

Istituti di Ricovero e Cura a Carattere Scientifico

National Institutes of Health

Inserm

Instituto de Salud Carlos III

Centre for Biomedical Network Research on Rare Diseases

National Human Genome Research Institute

Children's Hospital of Philadelphia

Pediatrics and Genetics

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Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina

Archivos Argentinos de Pediatria (2019)

Josefina Chinton Victoria Huckstadt Angélica Moresco Luis Pablo Gravina María Gabriela Obregón

Introduction.RASopathies are a set of syndromes with phenotypic overlapping features caused by gene mutations involved in the RAS/MAPK pathway.They are autosomal dominantly inherited and share common clinical characteristics, including short stature, craniofacial dysmorphisms, congenital heart disease, ectodermal manifestations, and a higher risk for cancer.A molecular diagnosis is a key factor.Objective.To identify PTPN11, SOS1, RAF1, BRAF, and HRAS mutations and compare the main clinical characteristics of patients with molecular confirmation.Population and methods.Children with a clinical diagnosis of RASopathy assessed between August 2013 and February 2017.Results.Mutations were identified in 71 % (87/122) of patients.The molecular test confirmed diagnosis in 73 % of patients with Noonan syndrome.The most prevalent mutation was c.922A>G (p.Asn308Asp) in the PTPN11 gene.A previously undescribed variant in RAF1 was detected: c.1467G>C (p.Leu489Phe).Cardiofaciocutaneous syndrome was confirmed in 67 % of cases with BRAF mutations.Costello syndrome and Noonan syndrome with multiple lentigines were confirmed in all cases.Conclusion.The confirmation of clinical diagnosis allowed for a more accurate differential diagnosis.The prevalence of PTPN11 (58 %), SOS1 (10 %), and RAF1 mutations (5 %) in children with Noonan syndrome, of PTPN11 mutations (100 %) in those with Noonan syndrome with multiple lentigines, of BRAF mutations (67 %) in those with cardiofaciocutaneous syndrome, and of HRAS mutations (100 %) in those with Costello syndrome was determined.

Noonan Syndrome

HRAS

Costello syndrome

PTPN11

10.5546/aap.2019.eng.330

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Citations (17)

Genotype–phenotype correlation of SMN locus genes in spinal muscular atrophy children from Argentina

European Journal of Paediatric Neurology (2016)

Sofía Medrano Soledad Monges Luis Pablo Gravina Laura Alías J. Mozzoni

SMN1

10.1016/j.ejpn.2016.07.017

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Citations (24)

Skeletal dysplasias in Latin America

American Journal of Medical Genetics Part C Seminars in Medical Genetics (2020)

Denise P. Cavalcanti Virginia Fano Cecília Mellado Maria Dora Jazmin Lacarrubba‐Flores Cynthia Silveira

Abstract Skeletal dysplasias (SD) are disturbances in growth due to defects intrinsic to the bone and/or cartilage, usually affecting multiple bones and having a progressive character. In this article, we review the state of clinical and research SD resources available in Latin America, including three specific countries (Brazil, Argentina, and Chile), that have established multidisciplinary clinics for the care of these patients. From the epidemiological point of view, the SD prevalence of 3.2 per 10,000 births from nine South American countries included in the ECLAMC network represents the most accurate estimate not just in Latin America, but worldwide. In Brazil, there are currently five groups focused on SD. The data from one of these groups including the website www.ocd.med.br , created to assist in the diagnosis of SD, are highlighted showing that telemedicine for this purpose represents a good strategy for the region. The experience of more than 30 years of the SD multidisciplinary clinic in an Argentinian Hospital is presented, evidencing a solid experience mainly in the follow‐up of the most frequent SD, especially those belonging the FGFR3 group and OI. In Chile, a group with 20 years of experience presents its work with geneticists and pediatricians, focusing on diagnostic purposes and clinical management. Altogether, although SD health‐care and research activities in Latin America are in their early stages, the experience in these three countries seems promising and stimulating for the region as a whole.

10.1002/ajmg.c.31861

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P345: Expanding the phenotype of an ultra-rare neurodevelopmental disorder associated with NACC1

Genetics in Medicine Open (2024)

Angélica Moresco Dorsa Kord Sunita Venkateswaran

NACC1 gene encodes Nucleus Accumbens Associated Protein 1 (NAC1), which is a ubiquitously expressed protein that contains a BTB/POZ domain and is primarily localized to cell nuclei, where it acts as a transcriptional regulator. It has been linked to multiple cellular processes, including cell cycle control and tumorigenesis, embryonic stem cell regulation, excitatory synaptic plasticity, as well as chromatin remodeling. It's role in the progression, survival, and recurrence of numerous carcinomas has been extensively studied over the last years. More recently a recurrent de novo variant (c.892C>T) in NACC1 has been associated with a neurodevelopmental disorder. NACC1-related disorder or Neurodevelopmental disorder with Epilepsy, Cataracts, Feeding difficulties, and delayed brain Myelination (NECFM) is a relatively newly identified, rare genetic condition associated with severe neurodevelopmental delays and/or intellectual disability, hypotonia, feeding difficulties resulting in failure to thrive, acquired microcephaly, and in some cases, bilateral cataracts, epilepsy including infantile spasms, incapacitating episodic irritability of unclear etiology, repetitive stereotypic motor behaviors and sleep disorder. Some reported cases showed cerebral atrophy and delayed myelination on cerebral imaging. Very few affected individuals (16) have been reported in the literature to date. All patients presented with a highly similar phenotype and the same de novo variant (c.892C>T) in NACC1. Recently functional studies demonstrated that this variant impairs glutamatergic neurotransmission in a dominant negative manner. Here, we describe a 21-month-old female, who presented at 7 months of age with failure to thrive, poor feeding, acquired microcephaly, developmental delay, bilateral congenital cataracts, subcutaneous hemangiomas, and congenital dysplastic nevus. She was born to a healthy mother with unremarkable pregnancy and birth. Despite normal birth parameters, microcephaly manifested by 4 months, with subsequent developmental regression in gross motor skills and significant delays in other domains of development. Trio whole exome sequencing revealed a heterozygous, de novo, pathogenic variant in NACC1(NM_052876.4):c.892C>T p.(Arg298Trp). Brain MRI at 8 months showed lobal volume loss, thin corpus callosum, T2 hyperintensities and thinning of periventricular white matter, delay in myelination status, and prominent Virchow Robin spaces. At age 1, she developed startle myoclonus, especially triggered by light stimulus, sleep myoclonus, as well as clinical episodes consistent with tonic seizures. She also experienced episodes of irritability and inconsolability with no identifiable triggers lasting 3-5 days. EEG did not show hypsarrhythmia, epileptiform activity or a photoparoxysmal response, however, did demonstrate background slowing and intermittent rhythmic slow wave activity. Few patients with NECFM have been described in the literature to date. Our case contributes to the understanding of the clinical spectrum associated with NACC1-related disorder and highlights the need for comprehensive genetic evaluations in patients with neurodevelopmental disorders. In addition to the irritability and stereotypies consistent with the recent reports, we have witnessed non-epileptic startle myoclonus in our patient, who also presented with dysplastic nevus and vascular malformations that have not been previously described. Long-term follow-up is needed to further delineate the significance of each of these findings and any potential risks or additional features. Recently, functional studies have shown to impair glutaminergic transmission therefore treatments targeting this pathway may help ameliorate both the seizures as well as the irritability and can lead to more effective therapeutic strategies.

Neurodevelopmental disorder

10.1016/j.gimo.2024.101239

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Clinical and auxological characteristics and quality of life of 50 children and adolescents with segmental overgrowth syndromes at a single center

Archivos Argentinos de Pediatria (2023)

María V Wolf Angélica Moresco Virginia Fano Silvia Caíno

Introduction. Segmental overgrowth syndromes are a group of rare diseases characterized by overgrowth in one or more parts of the body, mostly related to mosaic mutations in the AKT/PI3K/mTOR and RAS- MAPK signaling pathway. Our objective was to analyze the clinical and auxological characteristics and health-related quality of life (HRQoL) in this group of patients at a tertiary care hospital. Population and methods. Cross-sectional study of a follow-up cohort. Age, sex, sociodemographic data, anthropometric measurements of the affected and contralateral segments, complications, treatment, quality of life (PedsQL 4.0), and pain were analyzed. Central and dispersion measures were estimated. A univariate analysis between the quality of life and study variables was done. Results. A total of 50 patients were included; 29 were males. Median age: 9.95 (r: 1.44-17.81) years. The most common diagnosis was PIK3CA-related overgrowth spectrum (PROS) (37/50). The median number of affected segments was 2 (r: 1-7) per patient. Vascular malformations were observed in 40, and capillary malformations, in 20 patients. Pain was the most common complication (24/50). An asymmetry of the lower extremities of < 5 cm was observed in 31 patients. In most children, height was between the 50th and 97th percentiles. A lower HRQoL was observed among girls, patients with complex vascular malformations, and those with unmet basic needs (UBNs). Conclusions. PROS was the most common diagnosis. Pain was the most common complication. HRQoL was lower among girls, patients with combined vascular malformations, and those with UBNs.Introducción. Los síndromes de sobrecrecimiento corporal segmentario son un grupo de enfermedades poco frecuentes caracterizadas por exceso de crecimiento en una o más partes del cuerpo relacionadas, en su mayoría, con mutaciones en mosaico en la vía de señalización AKT/PI3K/mTOR y RAS-MAPK. Nuestro objetivo fue analizar las características clínicas y auxológicas, y la calidad de vida relacionada a salud (CVRS) en este grupo de pacientes en un hospital de tercer nivel de atención. Población y métodos. Estudio transversal de una cohorte en seguimiento. Se analizaron edad, sexo, datos sociodemográficos, mediciones antropométricas del segmento afectado y del contralateral, complicaciones, tratamiento, calidad de vida (PedsQL4.0) y dolor. Se calcularon medidas centrales y de dispersión. Se realizó análisis univariado entre calidad de vida y variables incluidas. Resultados. Se incluyeron 50 pacientes, 29 varones. Mediana de edad 9,95 (r 1,44-17,81) años. El diagnóstico más frecuente fue síndrome de sobrecrecimiento relacionado a PIK3CA (PROS) (37/50). Mediana de número de segmentos afectados 2 (r: 1-7) por niño. Cuarenta casos presentaron malformación vascular; 20, capilar. El dolor (24/50) fue la complicación más frecuente. Treinta y un pacientes mostraron asimetría de longitud de miembros inferiores, < 5 cm. La estatura se ubicó entre los centilos 50 y 97 en la mayoría de los niños. Menor CVRS se observó en mujeres, en pacientes con malformación vascular compleja y necesidades básicas insatisfechas (NBI). Conclusiones. PROS fue el diagnóstico más frecuente. El dolor fue una complicación frecuente. La CVRS fue menor en mujeres, pacientes con malformación vascular combinada y NBI.

Univariate analysis

10.5546/aap.2023-03017.eng

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Cover Image, Volume 176A, Number 5, May 2018

American Journal of Medical Genetics Part A (2018)

Paul Kruszka Antonio R. Porras Deise Helena de Souza Angélica Moresco Victoria Huckstadt

The cover image, by Paul Kruszka et al., is based on the Original Article Williams-Beuren Syndrome in Diverse Populations, DOI: 10.1002/ajmg.a.38672

10.1002/ajmg.a.38714

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The TREAT-NMD Duchenne Muscular Dystrophy Registries: Conception, Design, and Utilization by Industry and Academia

Human Mutation (2013)

Catherine L. Bladen Karen Rafferty Volker Straub Soledad Monges Angélica Moresco

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence <5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardized patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here, we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organizations, and industry.

Neuromuscular disease

10.1002/humu.22390

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Citations (100)

Mapping the differences in care for 5,000 Spinal Muscular Atrophy patients, a survey of 24 national registries in North America, Australasia and Europe

Journal of Neurology (2013)

Catherine L. Bladen Rachel Thompson J. Jackson Connie Garland Claire E. Wegel

SMN1

Neuromuscular disease

10.1007/s00415-013-7154-1

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Citations (95)

Williams–Beuren syndrome in diverse populations

American Journal of Medical Genetics Part A (2018)

Paul Kruszka Antonio R. Porras Deise Helena de Souza Angélica Moresco Victoria Huckstadt

Williams–Beuren syndrome (WBS) is a common microdeletion syndrome characterized by a 1.5Mb deletion in 7q11.23. The phenotype of WBS has been well described in populations of European descent with not as much attention given to other ethnicities. In this study, individuals with WBS from diverse populations were assessed clinically and by facial analysis technology. Clinical data and images from 137 individuals with WBS were found in 19 countries with an average age of 11 years and female gender of 45%. The most common clinical phenotype elements were periorbital fullness and intellectual disability which were present in greater than 90% of our cohort. Additionally, 75% or greater of all individuals with WBS had malar flattening, long philtrum, wide mouth, and small jaw. Using facial analysis technology, we compared 286 Asian, African, Caucasian, and Latin American individuals with WBS with 286 gender and age matched controls and found that the accuracy to discriminate between WBS and controls was 0.90 when the entire cohort was evaluated concurrently. The test accuracy of the facial recognition technology increased significantly when the cohort was analyzed by specific ethnic population ( P ‐value < 0.001 for all comparisons), with accuracies for Caucasian, African, Asian, and Latin American groups of 0.92, 0.96, 0.92, and 0.93, respectively. In summary, we present consistent clinical findings from global populations with WBS and demonstrate how facial analysis technology can support clinicians in making accurate WBS diagnoses.

10.1002/ajmg.a.38672

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Efecto de la altitud sobre el peso al nacer y eventos perinatales adversos en dos poblaciones argentinas

Revista de la Facultad de Ciencias Médicas de Córdoba (2013)

Carlos Grandi José Edgardo Dipierri Guillermo Luchtenberg Angélica Moresco Emma Alfaro

Introduction: Depending on the geographical altitude the purpose of this work was to analyze in two argentine populations the variation of birth weight (BW) and adverse perinatal outcomes, adjusting for maternal and obstetric factors.Material and Methods: Data from 4000 births in the provinces of Jujuy and 4000 in Buenos Aires (Sarda Maternity Hospital) (1996-2000) recruited and randomized from the Perinatal Information System was used. The data were grouped according to an altitudinal gradient composed by Sarda Maternity (20 masl) and the geographic regions of Jujuy province: Ramal (500 masl), Valle (1200 masl), Quebrada (2500 masl) and Puna (3500 masl). Outcome variables were BW > 3000 g, BW <2500 g, ponderal index (PI), prematurity, small for gestational age (SGA) and intrauterine growth restriction (FGR), while potentially confounding variables were: age, type of partner, education, overweight, obesity, smoking, hypertension, preeclampsia, urinary infection, growth restriction and cesarean section.Results: An increasing altitudinal gradient for adolescent mothers (<19years) and decreasing for the rest of the maternal obstetric variables was observed. The BW, BW>3000 g, BW<2500g and PI were negatively associated with altitude (p <0.001). Prematurity, SGA and FGR showed an opposite trend (p <0.001). Adjusted for confounding variables BW <3000 g, SGA, FGR<0.90 and PI <2.53 showed an increased risk with geographical altitude (p <0.05).Conclusions: Altitude was independently associated with BW restriction and adverse perinatal outcomes. Given the impact of BW reduction in the risk of chronic no communicable diseases this relationship in other populations, regardless of their location altitude, should be assess.

10.31053/1853.0605.v70.n2.20232

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Citations (12)