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Hamilton G, Stickler S, Ermakov M, Eggerstorfer MT, Nocera FP, Hohenegger M, Weigl L, Hochmair MJ, Kashofer K. Characterization of the BH1406 non-small cell lung cancer (NSCLC) cell line carrying an activating SOS1 mutation. Transl Lung Cancer Res 2024; 13:2987-2997. [PMID: 39670010 PMCID: PMC11632420 DOI: 10.21037/tlcr-24-570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 09/29/2024] [Indexed: 12/14/2024]
Abstract
Background Approximately 30% of the non-small cell lung cancer (NSCLC) patients which harbor no recognizable oncogenic driver mutation are not eligible for targeted therapy. Functional drug screening of tumor cells helps to identify susceptible drug targets not recognized by gene panels for targeted mutation analysis. The aim of this study is to characterize the BH1406 cell line carrying an activating SOS1 mutation and to check its sensitivity to cognate inhibitors. Methods The NSCLC cell line BH1406 was established from a pleural effusion and found to be sensitive to the SOS1 inhibitor BAY-293 in initial viability screenings. Since in a limited next-generation sequencing (NGS) lung cancer mutation panel no driver could be detected, the patient underwent chemotherapy with poor outcome. This cell line was further characterized by exome sequencing, SOS1 Western blotting, comparison of two-dimensional (2D) and three-dimensional (3D) chemosensitivity assays and phosphoprotein arrays. Results In whole-exome sequencing (WES) the SOS1 mutation P481delinsLFFL, positioned near the known P478L activating mutation was detected. Besides BAY-293, BH1406 cells proved to be sensitive to the SOS1 inhibitors MRTX0902 and BI-3406. The sensitivity of BH1406 cells to BI-3406 was increased under 3D conditions compared to 2D cultures. Western blot phosphoprotein arrays revealed reduced phosphorylation of CREB, GSK3, CHK-2 and STAT3 in BH1406 by BAY-293 treatment in 2D culture. In 3D conditions, cells switched from GSK3α to elevated ERK1/2 signaling, again blocked by the SOS1 inhibitor BAY-293. Similar results were obtained for the SOS1 inhibitors MRTX0902 and BI3406. Additionally, the PI3K inhibitor dactolisib, the GSK-3 inhibitor BI-5521 as well as the bromodomain protein-directed PROTAC ARV-771 inhibited the growth of BH1406 cells significantly and showed synergistic interaction with BAY-293. Furthermore, Western blots demonstrated reduced expression of SOS1 and MYC proteins in response to BAY-293 treatment. Conclusions The rare SOS1 P481delinsLFFL mutation in lung cancer may be targetable with corresponding inhibitors, alone or in combination with GSK3/PI3K/BET inhibitors. BH1406 cells represent a novel cellular model suitable for the molecular characterization of SOS1 druggability. Such rare oncogenic driver genes are not included in standard NGS panels and need to be detected by expanded assays like WES.
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Affiliation(s)
- Gerhard Hamilton
- Institute of Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Sandra Stickler
- Institute of Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Mikhail Ermakov
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria
| | | | - Francesca Paola Nocera
- Institute of Pharmacology, Medical University of Vienna, Vienna, Austria
- Department of Veterinary Medicine and Animal Production, University of Naples “Federico II”, Naples, Italy
| | - Martin Hohenegger
- Institute of Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Lukas Weigl
- Department of Special Anaesthesia and Pain Therapy, Medical University of Vienna, Vienna, Austria
| | | | - Karl Kashofer
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria
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Yamada M, Tanito K, Suzuki H, Nakato D, Miya F, Takenouchi T, Kosaki K. Café-au-lait Spots and Cleft Palate: Not a Chance Association. Cleft Palate Craniofac J 2024; 61:1932-1936. [PMID: 37448313 DOI: 10.1177/10556656231188205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/15/2023] Open
Abstract
The recognition of syndromic forms of cleft palate is important for condition-specific management. Here, we report a patient with cleft palate, congenital heart disease, intellectual disability, and café-au-lait spots who had a deletion of chromosome 15q14. The identification of the precise breakpoints using a Nanopore-based long-read sequencer showed that the deletion spanned MEIS2 and SPRED1 loci. Cleft palate and café-au-lait spots can be ascribed to MEIS2 and SPRED1, respectively. Patients with cleft palate and café-au-lait spots should be encouraged to undergo a detailed genomic evaluation, including screening for a 15q14 deletion, to enable appropriate anticipatory medico-surgical management and genetic counseling.
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Affiliation(s)
- Mamiko Yamada
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | | | - Hisato Suzuki
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Daisuke Nakato
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Fuyuki Miya
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Toshiki Takenouchi
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
| | - Kenjiro Kosaki
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
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Kapusta L, Beer G, Rothschild E, Baruch G, Barkay G, Marom D, Grinshpun-Cohen Y, Raskind C, Constantini S, Toledano-Alhadef H. Cardiac screening in pediatric patients with neurofibromatosis type 1: similarities with Noonan syndrome? Int J Cardiovasc Imaging 2024; 40:1475-1482. [PMID: 38739321 PMCID: PMC11258153 DOI: 10.1007/s10554-024-03125-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 04/28/2024] [Indexed: 05/14/2024]
Abstract
Both Neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are RASopathies. Characteristic cardiac phenotypes of NS, including specific electrocardiographic changes, pulmonary valve stenosis and hypertrophic cardiomyopathy have not been completely studied in NF1. PURPOSE The aims of this study were to assess: (1) similarities in the prevalence and types of ECG and conventional echocardiographic findings described in NS in asymptomatic patients with NF1, and (2) the presence of discrete myocardial dysfunction in NF1 patients using myocardial strain imaging. METHODS Fifty-eight patients with NF1 (ages 0-18 years), and thirty-one age-matched healthy controls underwent cardiac assessment including blood pressure measurements, a 12-lead ECG, and detailed echocardiography. Quantification of cardiac chamber size, mass and function were measured using conventional echocardiography. Myocardial strain parameters were assessed using 2-Dimensional (2D) Speckle tracking echocardiography. RESULTS Asymptomatic patients with NF1 had normal electrocardiograms, none with the typical ECG patterns described in NS. However, patients with NF1 showed significantly decreased calculated Z scores of the left ventricular internal diameter in diastole and systole, reduced left ventricular mass index and a higher incidence of cardiac abnormal findings, mainly of the mitral valve, in contrast to the frequently described types of cardiac abnormalities in NS. Peak and end systolic global circumferential strain were the only significantly reduced speckle tracking derived myocardial strain parameter. CONCLUSIONS Children with NF1 demonstrated more dissimilarities than similarities in the prevalence and types of ECG and conventional echocardiographic findings described in NS. The role of the abnormal myocardial strain parameter needs to be explored.
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Affiliation(s)
- Livia Kapusta
- Pediatric Cardiology Unit, Faculty of Medicine, Dana-Dwek children's hospital, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel
- Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Gil Beer
- Pediatric Cardiology Unit, Faculty of Medicine, Dana-Dwek children's hospital, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Ehud Rothschild
- Department of Internal medicine, Tel-Aviv Sourasky Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Guy Baruch
- Department of Internal medicine, Tel-Aviv Sourasky Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Gili Barkay
- Gilbert Israeli and International Neurofibromatosis Center and the Child Neurology Institute and Child Development Center, Faculty of Medicine, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv University, 6 Weizmann Street, Tel Aviv, 6423906, Israel
| | - Daphna Marom
- Genetic Institute, Faculty of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Yulia Grinshpun-Cohen
- Gilbert Israeli and International Neurofibromatosis Center and the Child Neurology Institute and Child Development Center, Faculty of Medicine, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv University, 6 Weizmann Street, Tel Aviv, 6423906, Israel
- Genetic Institute, Faculty of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Craig Raskind
- Department of Neonatology, Faculty of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Shlomi Constantini
- Gilbert Israeli and International Neurofibromatosis Center and the Child Neurology Institute and Child Development Center, Faculty of Medicine, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv University, 6 Weizmann Street, Tel Aviv, 6423906, Israel
- Department of Pediatric Neurosurgery, The Pediatric Brain Institute, Faculty of Medicine, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Hagit Toledano-Alhadef
- Gilbert Israeli and International Neurofibromatosis Center and the Child Neurology Institute and Child Development Center, Faculty of Medicine, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv University, 6 Weizmann Street, Tel Aviv, 6423906, Israel.
- Child Neurology Institute and Child development Center, Faculty of Medicine, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
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Huang P, Huang J, Huang Y, Yang M, Kong R, Sun H, Han J, Guo H, Wang S. Optimization and evaluation of facial recognition models for Williams-Beuren syndrome. Eur J Pediatr 2024:10.1007/s00431-024-05646-9. [PMID: 38871980 DOI: 10.1007/s00431-024-05646-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 05/24/2024] [Accepted: 06/04/2024] [Indexed: 06/15/2024]
Abstract
Williams-Beuren syndrome (WBS) is a rare genetic disorder characterized by special facial gestalt, delayed development, and supravalvular aortic stenosis or/and stenosis of the branches of the pulmonary artery. We aim to develop and optimize accurate models of facial recognition to assist in the diagnosis of WBS, and to evaluate their effectiveness by using both five-fold cross-validation and an external test set. We used a total of 954 images from 135 patients with WBS, 124 patients suffering from other genetic disorders, and 183 healthy children. The training set comprised 852 images of 104 WBS cases, 91 cases of other genetic disorders, and 145 healthy children from September 2017 to December 2021 at the Guangdong Provincial People's Hospital. We constructed six binary classification models of facial recognition for WBS by using EfficientNet-b3, ResNet-50, VGG-16, VGG-16BN, VGG-19, and VGG-19BN. Transfer learning was used to pre-train the models, and each model was modified with a variable cosine learning rate. Each model was first evaluated by using five-fold cross-validation and then assessed on the external test set. The latter contained 102 images of 31 children suffering from WBS, 33 children with other genetic disorders, and 38 healthy children. To compare the capabilities of these models of recognition with those of human experts in terms of identifying cases of WBS, we recruited two pediatricians, a pediatric cardiologist, and a pediatric geneticist to identify the WBS patients based solely on their facial images. We constructed six models of facial recognition for diagnosing WBS using EfficientNet-b3, ResNet-50, VGG-16, VGG-16BN, VGG-19, and VGG-19BN. The model based on VGG-19BN achieved the best performance in terms of five-fold cross-validation, with an accuracy of 93.74% ± 3.18%, precision of 94.93% ± 4.53%, specificity of 96.10% ± 4.30%, and F1 score of 91.65% ± 4.28%, while the VGG-16BN model achieved the highest recall value of 91.63% ± 5.96%. The VGG-19BN model also achieved the best performance on the external test set, with an accuracy of 95.10%, precision of 100%, recall of 83.87%, specificity of 93.42%, and F1 score of 91.23%. The best performance by human experts on the external test set yielded values of accuracy, precision, recall, specificity, and F1 scores of 77.45%, 60.53%, 77.42%, 83.10%, and 66.67%, respectively. The F1 score of each human expert was lower than those of the EfficientNet-b3 (84.21%), ResNet-50 (74.51%), VGG-16 (85.71%), VGG-16BN (85.71%), VGG-19 (83.02%), and VGG-19BN (91.23%) models. CONCLUSION The results showed that facial recognition technology can be used to accurately diagnose patients with WBS. Facial recognition models based on VGG-19BN can play a crucial role in its clinical diagnosis. Their performance can be improved by expanding the size of the training dataset, optimizing the CNN architectures applied, and modifying them with a variable cosine learning rate. WHAT IS KNOWN • The facial gestalt of WBS, often described as "elfin," includes a broad forehead, periorbital puffiness, a flat nasal bridge, full cheeks, and a small chin. • Recent studies have demonstrated the potential of deep convolutional neural networks for facial recognition as a diagnostic tool for WBS. WHAT IS NEW • This study develops six models of facial recognition, EfficientNet-b3, ResNet-50, VGG-16, VGG-16BN, VGG-19, and VGG-19BN, to improve WBS diagnosis. • The VGG-19BN model achieved the best performance, with an accuracy of 95.10% and specificity of 93.42%. The facial recognition model based on VGG-19BN can play a crucial role in the clinical diagnosis of WBS.
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Affiliation(s)
- Pingchuan Huang
- Department of Pediatric Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Jinze Huang
- Courant Institute of Mathematics Sciences, New York University, New York, NY, USA
| | - Yulu Huang
- Department of Pediatric Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Maohong Yang
- Department of Pediatric Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Ran Kong
- Department of Pediatric Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Haomiao Sun
- Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jin Han
- Prenatal Diagnosis Center, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong, China.
| | - Huiming Guo
- Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
- Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
| | - Shushui Wang
- Department of Pediatric Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
- Department of Pediatric Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.
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De Schepper J, Thomas M, Huysentruyt K, Becker M, Boros E, Casteels K, Chivu O, De Waele K, Dotremont H, Lysy PA, Massa G, Parent AS, Rochtus A, Gies I. Near Adult Height and Body Mass Index Changes in Growth Hormone Treated Short Children with Noonan Syndrome: The Belgian Experience. Horm Res Paediatr 2024; 98:193-205. [PMID: 38432193 DOI: 10.1159/000538034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 02/23/2024] [Indexed: 03/05/2024] Open
Abstract
INTRODUCTION A variable near adult height (NAH) outcome after growth hormone (GH) therapy in Noonan syndrome (NS) patients with short stature has been reported. The main objective of this study was to evaluate NAH and body mass index (BMI) evolution in a large Belgian cohort of NS patients treated for short stature. The secondary objectives were to investigate whether sex, genotype, the presence of a thoracic deformity, and/or a heart anomaly might affect NAH and to validate the recently developed NAH prediction model by Ranke et al. Methods: Clinical and auxological data of GH treated short NS patients born before 2001 were extracted from the national Belgrow registry. NAH was available in 54 (35 male) genotyped NS using a gene panel of 9 genes, showing pathogenic variants in PTPN11 in 32 and in SOS1 in 5 patients, while in 17 patients gene panel analysis was inconclusive (no-mutation group). RESULTS After a median (P10; P90) duration of 5.4 (2.2; 10.3) years of GH therapy with a median dose of 0.05 mg/kg/day NS patients reached a median NAH of -1.7 (-3.1; -0.8) SDS. Median total height gain was 1.1 (0.1; 2.3) SDS. Sex, genotype, and the presence of a thoracic or cardiac malformation did not correlate with NAH or total height gain. Linear regression modelling revealed that height SDS at start (β = 0.90, p < 0.001), mid-parental height SDS (β = 0.27; p = 0.005), birth weight SDS (β = 0.15; p = 0.051), age at start (β = 0.07; p = 0.032) were independently associated with NAH SDS. Median BMI SDS increased significantly (p < 0.001) from -1.0 (-2.5; 0.0) at start to -0.2 (-1.5; 0.9) at NAH. The observed NAH in a subgroup of 44 patients with more than 3 years of GH treatment was not statistically different from the predicted NAH by the Noonan NAH prediction model of Ranke. CONCLUSION Long-term GH therapy at a dose of 0.05 mg/kg/day in short NS patients is effective in improving adult height and BMI, irrespective of the genotype and presence or absence of cardiac and or thoracic anomalies.
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Affiliation(s)
- Jean De Schepper
- Division of Pediatric Endocrinology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
- Research Unit GRON, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Muriel Thomas
- The BElgian and Luxembourg Society for PEdiatric Endocrinology and Diabetology (BELSPEED), Brussels, Belgium
| | - Koen Huysentruyt
- Research Unit GRON, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
- Division of Pediatric Gastroenterology and Nutrition, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Marianne Becker
- Department of Pediatric Endocrinology and Diabetology, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg
| | - Emese Boros
- Pediatric Endocrinology Unit, Hôpital Universitaire de Bruxelles (HUB)- Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Université libre de Bruxelles (ULB), Brussels, Belgium
| | - Kristina Casteels
- Department of Pediatrics, Universitair Ziekenhuis Leuven, Leuven, Belgium
- Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Olimpia Chivu
- Department of Pediatrics, Clinique CHC MontLégia, Liège, Belgium
| | - Kathleen De Waele
- Department of Pediatrics, Universitair Ziekenhuis Gent, Gent, Belgium
| | - Hilde Dotremont
- Department of Pediatric Endocrinology and Diabetology, Universitair Ziekenhuis Antwerpen, Edegem, Belgium
| | - Philippe A Lysy
- Service of Specialized Pediatrics, Pediatric Endocrinology Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Guy Massa
- Department of Pediatrics, Jessa Ziekenhuis, Hasselt, Belgium
| | | | - Anne Rochtus
- Department of Pediatrics, Universitair Ziekenhuis Leuven, Leuven, Belgium
- Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Inge Gies
- Division of Pediatric Endocrinology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
- Research Unit GRON, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
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Marincak Vrankova Z, Krivanek J, Danek Z, Zelinka J, Brysova A, Izakovicova Holla L, Hartsfield JK, Borilova Linhartova P. Candidate genes for obstructive sleep apnea in non-syndromic children with craniofacial dysmorphisms - a narrative review. Front Pediatr 2023; 11:1117493. [PMID: 37441579 PMCID: PMC10334820 DOI: 10.3389/fped.2023.1117493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 06/06/2023] [Indexed: 07/15/2023] Open
Abstract
Pediatric obstructive sleep apnea (POSA) is a complex disease with multifactorial etiopathogenesis. The presence of craniofacial dysmorphisms influencing the patency of the upper airway is considered a risk factor for POSA development. The craniofacial features associated with sleep-related breathing disorders (SRBD) - craniosynostosis, retrognathia and micrognathia, midface and maxillary hypoplasia - have high heritability and, in a less severe form, could be also found in non-syndromic children suffering from POSA. As genetic factors play a role in both POSA and craniofacial dysmorphisms, we hypothesize that some genes associated with specific craniofacial features that are involved in the development of the orofacial area may be also considered candidate genes for POSA. The genetic background of POSA in children is less explored than in adults; so far, only one genome-wide association study for POSA has been conducted; however, children with craniofacial disorders were excluded from that study. In this narrative review, we discuss syndromes that are commonly associated with severe craniofacial dysmorphisms and a high prevalence of sleep-related breathing disorders (SRBD), including POSA. We also summarized information about their genetic background and based on this, proposed 30 candidate genes for POSA affecting craniofacial development that may play a role in children with syndromes, and identified seven of these genes that were previously associated with craniofacial features risky for POSA development in non-syndromic children. The evidence-based approach supports the proposition that variants of these candidate genes could lead to POSA phenotype even in these children, and, thus, should be considered in future research in the general pediatric population.
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Affiliation(s)
- Zuzana Marincak Vrankova
- Clinic of Stomatology, Institution Shared with St. Anne's University Hospital, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Clinic of Maxillofacial Surgery, Institution Shared with the University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic
| | - Jan Krivanek
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Zdenek Danek
- Clinic of Maxillofacial Surgery, Institution Shared with the University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic
| | - Jiri Zelinka
- Clinic of Maxillofacial Surgery, Institution Shared with the University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Alena Brysova
- Clinic of Stomatology, Institution Shared with St. Anne's University Hospital, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Lydie Izakovicova Holla
- Clinic of Stomatology, Institution Shared with St. Anne's University Hospital, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - James K. Hartsfield
- E. Preston Hicks Professor of Orthodontics and Oral Health Research, University of Kentucky Center for the Biologic Basis of Oral/Systemic Diseases, Hereditary Genetics/Genomics Core, Lexington, KE, United States
| | - Petra Borilova Linhartova
- Clinic of Stomatology, Institution Shared with St. Anne's University Hospital, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Clinic of Maxillofacial Surgery, Institution Shared with the University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, Brno, Czech Republic
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Yang W, Wang Y, Sirajuddin A, He J, Wu W, Sun X, Zhuang B, Li S, Xu J, Zhou D, Zhao S, Lu M. Multimodality Imaging in Noonan Syndrome: Case Series of Young Children. Radiol Cardiothorac Imaging 2023; 5:e220218. [PMID: 36860839 PMCID: PMC9969215 DOI: 10.1148/ryct.220218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 01/04/2023] [Accepted: 01/18/2023] [Indexed: 02/25/2023]
Abstract
Noonan syndrome (NS) is an autosomal dominant disorder characterized by distinctive facial anomalies, growth failure, and a wide spectrum of cardiac abnormalities. Here, the clinical presentation, multimodality imaging characteristics, and management in a case series of four patients with NS are presented. Multimodality imaging showed frequently biventricular hypertrophy accompanied by biventricular outflow tract obstruction and pulmonary stenosis, similar late gadolinium enhancement pattern, and elevation of native T1 and extracellular volume, which may serve as multimodality imaging features in NS to aid in patient diagnosis and treatment. Keywords: Pediatrics, Echocardiography, MR Imaging, Cardiac Supplemental material is available for this article. © RSNA, 2023.
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Harju S, Saari A, Sund R, Sankilampi U. Epidemiology of Disorders Associated with Short Stature in Childhood: A 20-Year Birth Cohort Study in Finland. Clin Epidemiol 2022; 14:1205-1214. [PMID: 36320440 PMCID: PMC9618248 DOI: 10.2147/clep.s372870] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 09/23/2022] [Indexed: 11/23/2022] Open
Abstract
Background Many primary and secondary disorders disturb growth and cause short stature (height below −2 SDS) in childhood. Growth monitoring programs aim at their early detection but are not evidence-based: epidemiology of childhood growth disorders is poorly characterized, and no consensus exists on priority target conditions. Herein, we describe population-based epidemiological data on several primary and secondary growth disorders associated with short stature in childhood. Materials and Methods This retrospective population-based 20-year birth cohort study examined 1 144 503 children (51% boys) born in Finland between 1998 and 2017, with 16.5 million care notifications including medical diagnoses. The first occurrences of key primary or secondary growth disorders were identified in multiple registers. Median ages at diagnosis (MAD), and age- and sex-specific cumulative incidences (CMI) from birth until 16 years of age were determined. Results Turner syndrome was the most common primary growth disorder (CMI 52 per 100 000 at 16 years, MAD 4.0 years). Most primary growth disorders were diagnosed before the age of 4 years, and thereafter, secondary growth disorders increased in number. MAD of growth hormone deficiency (GHD) was 8.7 (boys) and 7.2 years (girls). At 16 years, the CMI of GHD was higher in boys than in girls (127 versus 93 per 100 000, respectively), whereas the CMI of hypothyroidism was higher in girls (569 versus 306 per 100 000). Celiac disease was the most common secondary growth disorder and more common in girls than in boys (988 versus 546 per 100 000 at 16 years, respectively). Conclusion These population-based epidemiological data indicate that childhood growth monitoring should be age- and sex-specific. In the early childhood, the focus should be on primary growth disorders, and from preschool age also on secondary growth disorders. These results provide evidence for improving growth monitoring programs and diagnostic practices targeting on Turner syndrome, GHD, hypothyroidism, and celiac disease.
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Affiliation(s)
- Samuli Harju
- Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, Kuopio, Finland,Department of Paediatrics, Kuopio University Hospital, Kuopio, Finland,Correspondence: Samuli Harju, Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, PO Box 1627, Kuopio, 70211, Finland, Email
| | - Antti Saari
- Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, Kuopio, Finland,Department of Paediatrics, Kuopio University Hospital, Kuopio, Finland
| | - Reijo Sund
- Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, Kuopio, Finland
| | - Ulla Sankilampi
- Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, Kuopio, Finland,Department of Paediatrics, Kuopio University Hospital, Kuopio, Finland
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Dahlgren J, Noordam C. Growth, Endocrine Features, and Growth Hormone Treatment in Noonan Syndrome. J Clin Med 2022; 11:jcm11072034. [PMID: 35407641 PMCID: PMC8999676 DOI: 10.3390/jcm11072034] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 03/24/2022] [Accepted: 03/30/2022] [Indexed: 12/23/2022] Open
Abstract
Noonan syndrome is a heterogeneous congenital disorder. The main features are typical facial features, short stature and cardiac defects. The diagnosis is clinical: in 80% of patients with Noonan syndrome a genetic defect can be shown. Inheritance is predominantly autosomal dominant and seldom autosomal recessive. In 2001, PTPN11 was the first gene connected to Noonan syndrome, and until now, at least 20 other genes have been discovered. All genes code for proteins involved in the RAS-MAP-kinase pathway, and therefore, Noonan syndrome is one of the known RASopathies. Other RASopathies include neurofibromatosis and CFC syndrome. Short stature is one of the defining features of Noonan syndrome. The cause is not fully understood but is multifactorial. Other endocrinological features are confined to delayed puberty and hypogonadism in boys and males. To increase adult height, children with Noonan syndrome have been treated with human growth hormone since the 1990s. This seems to be beneficial in most of the children treated. In this narrative review, we describe the current knowledge on growth, endocrinological features and growth hormone treatment in patients with Noonan syndrome.
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Affiliation(s)
- Jovanna Dahlgren
- Department of Pediatrics, University of Gothenburg, 41685 Gothenburg, Sweden;
| | - Cees Noordam
- Centre for Paediatric Endocrinology Zurich (PEZZ), 8006 Zurich, Switzerland
- Department of Pediatrics, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands
- Correspondence: ; Tel.: +41-4-4364-3700
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Dalla-Torre R, Crenn V, Menu P, Isidor B, Guillot P, Le Goff B, Geffroy L, Dauty M, Fouasson-Chailloux A. Imatinib, a New Adjuvant Medical Treatment for Multifocal Villonodular Synovitis Associated to Noonan Syndrome: A Case Report and Literature Review. Front Med (Lausanne) 2022; 8:817873. [PMID: 35111788 PMCID: PMC8802824 DOI: 10.3389/fmed.2021.817873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 12/27/2021] [Indexed: 11/13/2022] Open
Abstract
Noonan syndrome (NS) is an autosomal dominant multisystem disorder caused by the dysregulation of the Rat Sarcoma/Mitogen-activated protein kinase (RAS/MAPK) pathway and characterized by short stature, heart defects, pectus excavatum, webbed neck, learning disabilities, cryptorchidism, and facial dysmorphia. Villonodular synovitis is a joint disorder most common in young adults characterized by an abnormal proliferation of the synovial membrane. Multifocal Villonodular synovitis is a rare disease whose recurrent nature can make its management particularly difficult. Currently, there is no systemic therapy recommended in diffuse and recurrent forms, especially because of the fear of long-term side effects in patients, who are usually young. Yet, tyrosine kinase inhibitors seem promising to reduce the effects of an aberrant colony stimulating factor-1 (CSF-1) production at the origin of the synovial nodule proliferation. We present here the case of a 21-year-old woman with NS associated to diffuse multifocal villonodular synovitis (DMVS). Our clinical case provides therapeutic experience in this very rare association. Indeed, in association with surgery, the patient improved considerably: she had complete daily life autonomy, knee joint amplitudes of 100° in flexion and 0° in extension and was able to walk for 10 min without any technical assistance. To our knowledge, this is the first case of a patient suffering from DMVS associated with a Noonan syndrome treated with Glivec® (oral administration at a dosage of 340 mg/m2 in children, until disease regression) on a long-term basis.
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Affiliation(s)
- Romain Dalla-Torre
- CHU Nantes, Service de Médecine Physique et de Réadaptation Locomotrice, University Hospital of Nantes, Nantes, France
- CHU Nantes, Service de Rhumatologie, University Hospital of Nantes, Nantes, France
| | - Vincent Crenn
- CHU de Nantes, Clinique Chirurgicale Orthopédique et Traumatologique, Hôtel-Dieu, Nantes, France
| | - Pierre Menu
- CHU Nantes, Service de Médecine Physique et de Réadaptation Locomotrice, University Hospital of Nantes, Nantes, France
- CHU Nantes, Service de Médecine du Sport, University Hospital of Nantes, Nantes, France
- INSERM UMR U1229/RMeS, Regenerative Medicine and Skeleton – Nantes University, Nantes, France
- IRMS, Institut Régional de Médecine du Sport, Hôpital Saint Jacques, Nantes, France
| | - Bertrand Isidor
- CHU Nantes, Service de Génétique Médicale, University Hospital of Nantes, Nantes, France
| | - Pascale Guillot
- CHU Nantes, Service de Rhumatologie, University Hospital of Nantes, Nantes, France
| | - Benoit Le Goff
- CHU Nantes, Service de Rhumatologie, University Hospital of Nantes, Nantes, France
| | - Loic Geffroy
- Chirurgie Orthopédique, Santé Atlantique, Saint Herblain, France
| | - Marc Dauty
- CHU Nantes, Service de Médecine Physique et de Réadaptation Locomotrice, University Hospital of Nantes, Nantes, France
- CHU de Nantes, Clinique Chirurgicale Orthopédique et Traumatologique, Hôtel-Dieu, Nantes, France
- CHU Nantes, Service de Médecine du Sport, University Hospital of Nantes, Nantes, France
- INSERM UMR U1229/RMeS, Regenerative Medicine and Skeleton – Nantes University, Nantes, France
| | - Alban Fouasson-Chailloux
- CHU Nantes, Service de Médecine Physique et de Réadaptation Locomotrice, University Hospital of Nantes, Nantes, France
- CHU de Nantes, Clinique Chirurgicale Orthopédique et Traumatologique, Hôtel-Dieu, Nantes, France
- CHU Nantes, Service de Médecine du Sport, University Hospital of Nantes, Nantes, France
- INSERM UMR U1229/RMeS, Regenerative Medicine and Skeleton – Nantes University, Nantes, France
- *Correspondence: Alban Fouasson-Chailloux
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11
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Albaghdadi M, Thibodeau ML, Lara-Corrales I. Updated Approach to Patients with Multiple Café au Lait Macules. Dermatol Clin 2021; 40:9-23. [PMID: 34799039 DOI: 10.1016/j.det.2021.08.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Café au lait macules (CALMs) are a normal and frequent finding in the general population, but multiple CALMs raise the possibility of an underlying neurocutaneous disease like neurofibromatosis type I. Certain features of CALMs like number, size, shape, and distribution are important in identifying children at higher risk of having a neurocutaneous disorder or another genetic disorder. Genetic testing can be especially helpful in establishing a diagnosis in atypical presentations, or when the child is young and other features of the disease aside from CALMs have not manifested.
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Affiliation(s)
| | - My Linh Thibodeau
- Division of Clinical and Metabolic Genetics, Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Irene Lara-Corrales
- Pediatric Dermatology, Division of Dermatology, Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario M5G1X8, Canada.
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12
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Fowlkes JL, Thrailkill KM, Bunn RC. RASopathies: The musculoskeletal consequences and their etiology and pathogenesis. Bone 2021; 152:116060. [PMID: 34144233 PMCID: PMC8316423 DOI: 10.1016/j.bone.2021.116060] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/07/2021] [Accepted: 06/10/2021] [Indexed: 01/07/2023]
Abstract
The RASopathies comprise an ever-growing number of clinical syndromes resulting from germline mutations in components of the RAS/MAPK signaling pathway. While multiple organs and tissues may be affected by these mutations, this review will focus on how these mutations specifically impact the musculoskeletal system. Herein, we review the genetics and musculoskeletal phenotypes of these syndromes in humans. We discuss how mutations in the RASopathy syndromes have been studied in translational mouse models. Finally, we discuss how signaling molecules within the RAS/MAPK pathway are involved in normal and abnormal bone biology in the context of osteoblasts, osteoclasts and chondrocytes.
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Affiliation(s)
- John L Fowlkes
- University of Kentucky Barnstable Brown Diabetes Center, Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America.
| | - Kathryn M Thrailkill
- University of Kentucky Barnstable Brown Diabetes Center, Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - R Clay Bunn
- University of Kentucky Barnstable Brown Diabetes Center, Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
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13
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Rodríguez F, Gaete X, Cassorla F. Etiology and Treatment of Growth Delay in Noonan Syndrome. Front Endocrinol (Lausanne) 2021; 12:691240. [PMID: 34149626 PMCID: PMC8212989 DOI: 10.3389/fendo.2021.691240] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 05/12/2021] [Indexed: 12/05/2022] Open
Abstract
Noonan syndrome is characterized by multiple phenotypic features, including growth retardation, which represents the main cause of consultation to the clinician. Longitudinal growth during childhood and adolescence depends on several factors, among them an intact somatotrophic axis, which is characterized by an adequate growth hormone (GH) secretion by the pituitary, subsequent binding to its receptor, proper function of the post-receptor signaling pathway for this hormone (JAK-STAT5b and RAS/MAPK), and ultimately by the production of its main effector, insulin like growth factor 1 (IGF-1). Several studies regarding the function of the somatotrophic axis in patients with Noonan syndrome and data from murine models, suggest that partial GH insensitivity at a post-receptor level, as well as possible derangements in the RAS/MAPK pathway, are the most likely causes for the growth failure in these patients. Treatment with recombinant human growth hormone (rhGH) has been used extensively to promote linear growth in these patients. Numerous treatment protocols have been employed so far, but the published studies are quite heterogeneous regarding patient selection, length of treatment, and dose of rhGH utilized, so the true benefit of GH therapy is somewhat difficult to establish. This review will discuss the possible etiologies for the growth delay, as well as the outcomes following rhGH treatment in patients with Noonan syndrome.
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Affiliation(s)
- Fernando Rodríguez
- Institute of Maternal and Child Research, University of Chile, Santiago, Chile
| | - Ximena Gaete
- Institute of Maternal and Child Research, University of Chile, Santiago, Chile
- Pediatrics Department, Hospital Clínico San Borja – Arriarán, Santiago, Chile
| | - Fernando Cassorla
- Institute of Maternal and Child Research, University of Chile, Santiago, Chile
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14
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Arrieta M, Ramos Gaspar R, Santos AL. Paleopathological diagnosis of a proportionate short stature on a female skeleton from the Coimbra collection: Turner syndrome versus other causes. INTERNATIONAL JOURNAL OF PALEOPATHOLOGY 2021; 33:234-244. [PMID: 34023583 DOI: 10.1016/j.ijpp.2021.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 05/04/2021] [Accepted: 05/04/2021] [Indexed: 06/12/2023]
Abstract
OBJECTIVE This paper discusses the possible etiologies for the proportionate short stature of a female individual and provides data to allow the diagnosis of future cases of Turner Syndrome (TS) in paleopathology. MATERIALS Skeleton of a 26-years-old maid, from the Coimbra Identified Skeletal Collection, who died of measles in 1920. METHODS Macroscopic examination, imaging techniques, and metric analysis. RESULTS Her estimated height is 138.91-144.3 cm, approximately three standard deviations below the average female stature for early 20th century Portugal. The crural, brachial, humero-femoral, and intermembral indexes show a proportionate body, uncommon in dwarfism. Small skull with prominent frontal, maxillary prognathism, enamel hypoplasia, cribra orbitalia, porotic hyperostosis, proliferative reaction in the petrous portion of the temporal, obliterated sagittal suture, oval foramen magnum, and small mandible with masculine features. The sternal ends of the ribs are wider and vertebrae present developmental defects (e.g. atlas with both left transverse foramina and posterior tubercle open, absence of the right transverse foramen in the axis, sacrum with six vertebrae). CONCLUSIONS The differential diagnosis point to a possible case of Turner Syndrome. SIGNIFICANCE This study describes the features of Turner Syndrome and provide detail metric analysis of this individual, which will be useful for future paleopathological diagnoses. LIMITATIONS The confirmation of the diagnosis will only be possible through genetic analysis. SUGGESTIONS FOR FURTHER RESEARCH Reanalysis of skeletal individuals with short stature to detect possible cases of Turner Syndrome.
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Affiliation(s)
- Mario Arrieta
- CONICET - Laboratorio de Biarqueología, Universidad Nacional de Río Cuarto, Ruta Nac. 36 - Km. 601, X5804BYA, Río Cuarto, Córdoba, Argentina.
| | - Rosa Ramos Gaspar
- Coimbra Hospital and Universitary Centre (CHUC), Portugal; Department of Life Sciences, Research Centre for Anthropology and Health (CIAS), University of Coimbra, Calçada Martim de Freitas, 3000-456, Coimbra, Portugal.
| | - Ana Luisa Santos
- Department of Life Sciences, Research Centre for Anthropology and Health (CIAS), University of Coimbra, Calçada Martim de Freitas, 3000-456, Coimbra, Portugal.
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15
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Porras AR, Summar M, Linguraru MG. Objective differential diagnosis of Noonan and Williams-Beuren syndromes in diverse populations using quantitative facial phenotyping. Mol Genet Genomic Med 2021; 9:e1636. [PMID: 33773094 PMCID: PMC8172204 DOI: 10.1002/mgg3.1636] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 02/10/2021] [Indexed: 01/07/2023] Open
Abstract
Introduction Patients with Noonan and Williams–Beuren syndrome present similar facial phenotypes modulated by their ethnic background. Although distinctive facial features have been reported, studies show a variable incidence of those characteristics in populations with diverse ancestry. Hence, a differential diagnosis based on reported facial features can be challenging. Although accurate diagnoses are possible with genetic testing, they are not available in developing and remote regions. Methods We used a facial analysis technology to identify the most discriminative facial metrics between 286 patients with Noonan and 161 with Williams‐Beuren syndrome with diverse ethnic background. We quantified the most discriminative metrics, and their ranges both globally and in different ethnic groups. We also created population‐based appearance images that are useful not only as clinical references but also for training purposes. Finally, we trained both global and ethnic‐specific machine learning models with previous metrics to distinguish between patients with Noonan and Williams–Beuren syndromes. Results We obtained a classification accuracy of 85.68% in the global population evaluated using cross‐validation, which improved to 90.38% when we adapted the facial metrics to the ethnicity of the patients (p = 0.024). Conclusion Our facial analysis provided for the first time quantitative reference facial metrics for the differential diagnosis Noonan and Williams–Beuren syndromes in diverse populations.
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Affiliation(s)
- Antonio R Porras
- Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, D.C., USA.,Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Marshal Summar
- Rare Disease Institute - Genetics and Metabolism, Children's National Hospital, Washington, D.C., USA
| | - Marius George Linguraru
- Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, D.C., USA.,School of Medicine and Health sciences, George Washington University, Washington, D.C., USA
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16
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Alfieri P, Cumbo F, Serra G, Trasolini M, Frattini C, Scibelli F, Licchelli S, Cirillo F, Caciolo C, Casini MP, D’Amico A, Tartaglia M, Digilio MC, Capolino R, Vicari S. Manic and Depressive Symptoms in Children Diagnosed with Noonan Syndrome. Brain Sci 2021; 11:brainsci11020233. [PMID: 33668418 PMCID: PMC7918671 DOI: 10.3390/brainsci11020233] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 02/01/2021] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
Noonan syndrome (NS) is a dominant clinically variable and genetically heterogeneous developmental disorder caused by germ-line mutations encoding components of the Ras–MAPK signaling pathway. A few studies have investigated psychopathological features occurring in individuals with NS, although they were poorly analyzed. The aim of the present work is to investigate the psychopathological features in children and adolescents with NS focusing on depressive and hypo-manic symptoms. Thirty-seven subjects with molecularly confirmed diagnosis were systematically evaluated through a psychopathological assessment. In addition, an evaluation of the cognitive level was performed. Our analyses showed a high recurrence of attention deficit and hyperactivity disorder symptoms, emotional dysregulation, irritability, and anxiety symptomatology. The mean cognitive level was on the average. The present study provides new relevant information on psychopathological features in individuals with NS. The implications for clinicians are discussed including the monitoring of mood disorders in a clinical evolution.
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Affiliation(s)
- Paolo Alfieri
- Child and Adolescent Psychiatry Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (F.C.); (G.S.); (M.T.); (C.F.); (F.S.); (S.L.); (F.C.); (C.C.); (M.P.C.); (S.V.)
- Correspondence: ; Tel.: +39-0668594721
| | - Francesca Cumbo
- Child and Adolescent Psychiatry Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (F.C.); (G.S.); (M.T.); (C.F.); (F.S.); (S.L.); (F.C.); (C.C.); (M.P.C.); (S.V.)
| | - Giulia Serra
- Child and Adolescent Psychiatry Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (F.C.); (G.S.); (M.T.); (C.F.); (F.S.); (S.L.); (F.C.); (C.C.); (M.P.C.); (S.V.)
| | - Monia Trasolini
- Child and Adolescent Psychiatry Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (F.C.); (G.S.); (M.T.); (C.F.); (F.S.); (S.L.); (F.C.); (C.C.); (M.P.C.); (S.V.)
| | - Camilla Frattini
- Child and Adolescent Psychiatry Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (F.C.); (G.S.); (M.T.); (C.F.); (F.S.); (S.L.); (F.C.); (C.C.); (M.P.C.); (S.V.)
| | - Francesco Scibelli
- Child and Adolescent Psychiatry Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (F.C.); (G.S.); (M.T.); (C.F.); (F.S.); (S.L.); (F.C.); (C.C.); (M.P.C.); (S.V.)
| | - Serena Licchelli
- Child and Adolescent Psychiatry Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (F.C.); (G.S.); (M.T.); (C.F.); (F.S.); (S.L.); (F.C.); (C.C.); (M.P.C.); (S.V.)
- Fondazione UILDM Lazio Onlus, 00167, Rome, Italy
| | - Flavia Cirillo
- Child and Adolescent Psychiatry Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (F.C.); (G.S.); (M.T.); (C.F.); (F.S.); (S.L.); (F.C.); (C.C.); (M.P.C.); (S.V.)
| | - Cristina Caciolo
- Child and Adolescent Psychiatry Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (F.C.); (G.S.); (M.T.); (C.F.); (F.S.); (S.L.); (F.C.); (C.C.); (M.P.C.); (S.V.)
| | - Maria Pia Casini
- Child and Adolescent Psychiatry Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (F.C.); (G.S.); (M.T.); (C.F.); (F.S.); (S.L.); (F.C.); (C.C.); (M.P.C.); (S.V.)
- Section of Child and Adolescent Neurology and Psychiatry, Department of Human Neuroscience, Sapienza University of Rome, 00161 Rome, Italy
| | - Adele D’Amico
- Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy;
| | - Marco Tartaglia
- Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (M.T.); (M.C.D.); (R.C.)
| | - Maria Cristina Digilio
- Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (M.T.); (M.C.D.); (R.C.)
| | - Rossella Capolino
- Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (M.T.); (M.C.D.); (R.C.)
| | - Stefano Vicari
- Child and Adolescent Psychiatry Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (F.C.); (G.S.); (M.T.); (C.F.); (F.S.); (S.L.); (F.C.); (C.C.); (M.P.C.); (S.V.)
- Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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Negahi A, Jahanshahi F, Boozari B, Sadeghipour A. The occurrence of giant mesenteric cyst and adrenal ganglioneuroma in a schizophrenic male patient presenting as pseudocyesis: A case report. Clin Case Rep 2021; 9:193-197. [PMID: 33489158 PMCID: PMC7813079 DOI: 10.1002/ccr3.3496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 07/29/2020] [Accepted: 10/20/2020] [Indexed: 11/09/2022] Open
Abstract
In psychological patients like our case, somatically expressed symptoms which can imply another psychological syndrome should be dealt with cautiously.
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Affiliation(s)
- Alireza Negahi
- General Surgery DepartmentRasoul Akram Hospital, Iran University of Medical SciencesTehranIran
| | - Fatemeh Jahanshahi
- Student Research CommitteeFaculty of MedicineIran University of Medical SciencesTehranIran
| | - Behnaz Boozari
- Pathology Department, Firoozgar HospitalIran University of Medical SciencesTehranIran
| | - Alireza Sadeghipour
- Pathology DepartmentRasoul Akram Hospital, Iran University of Medical SciencesTehranIran
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18
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Alhalabi MM, Alhalabi M. 48,XXYY syndrome presenting with long-term infertility and newly observed neck deformities: a case report. J Med Case Rep 2020; 14:58. [PMID: 32389125 PMCID: PMC7212598 DOI: 10.1186/s13256-020-02375-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 03/19/2020] [Indexed: 12/02/2022] Open
Abstract
Background Long-term infertility can be attributed to many factors, with the genetic factor being the most overlooked due to its many nonspecific morphological or endocrine signs. We present a rare case of a patient with progressive testicular failure associated with 48,XXYY syndrome. Case presentation A 39-year-old Arab man presented to our fertility clinic for fertility treatment. He was diagnosed with primary infertility, which had been present for 20 years at the time of presentation. Our patient had nonspecific morphological features of an abnormally wide neck with front slouching neck posture, clinodactyly of the third finger, and had moderate hypoandrogenemic features. A semen analysis revealed azoospermia. Genetic tests for azoospermia, including sex-determining region Y (SRY) detection and chromosome Y microdeletion, revealed no deletion present on the Y chromosome. Karyotyping was used and our patient was diagnosed with 48,XXYY syndrome. Conclusion Genetic testing (karyotyping and so on) played a key role in the diagnosis of our patient with long-term primary infertility secondary to 48,XXYY syndrome, and should play a vital role in all cases of long-term infertility, especially when presentation is accompanied by endocrine, skeletal, or morphological symptoms, signifying an underlying genetic factor.
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19
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Jensen B, James R, Hong Y, Omoyinmi E, Pilkington C, Sebire NJ, Howell KJ, Brogan PA, Eleftheriou D. A case of Myhre syndrome mimicking juvenile scleroderma. Pediatr Rheumatol Online J 2020; 18:72. [PMID: 32917212 PMCID: PMC7488857 DOI: 10.1186/s12969-020-00466-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 09/03/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Myhre syndrome is a genetic disorder caused by gain of function mutations in the SMAD Family Member 4 (SMAD4) gene, resulting in progressive, proliferative skin and organ fibrosis. Skin thickening and joint contractures are often the main presenting features of the disease and may be mistaken for juvenile scleroderma. CASE PRESENTATION We report a case of a 13 year-old female presenting with widespread skin thickening and joint contractures from infancy. She was diagnosed with diffuse cutaneous systemic sclerosis, and treatment with corticosteroids and subcutaneous methotrexate recommended. There was however disease progression prompting genetic testing. This identified a rare heterozygous pathogenic variant c.1499 T > C (p.Ile500Thr) in the SMAD4 gene, suggesting a diagnosis of Myhre syndrome. Securing a molecular diagnosis in this case allowed the cessation of immunosuppression, thus reducing the burden of unnecessary and potentially harmful treatment, and allowing genetic counselling. CONCLUSION Myhre Syndrome is a rare genetic mimic of scleroderma that should be considered alongside several other monogenic diseases presenting with pathological fibrosis from early in life. We highlight this case to provide an overview of these genetic mimics of scleroderma, and highlight the molecular pathways that can lead to pathological fibrosis. This may provide clues to the pathogenesis of sporadic juvenile scleroderma, and could suggest novel therapeutic targets.
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Affiliation(s)
- Barbara Jensen
- Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
| | - Rebecca James
- grid.240562.7Paediatric Rheumatology Department, Queensland Children’s Hospital, Brisbane, Australia
| | - Ying Hong
- grid.83440.3b0000000121901201Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH UK
| | - Ebun Omoyinmi
- grid.83440.3b0000000121901201Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH UK
| | - Clarissa Pilkington
- grid.424537.30000 0004 5902 9895Paediatric Rheumatology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Neil J. Sebire
- grid.424537.30000 0004 5902 9895Histopathology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Kevin J. Howell
- grid.426108.90000 0004 0417 012XMicrovascular Diagnostics, UCL Institute of Immunity and Transplantation, Royal Free Hospital, London, UK
| | - Paul A. Brogan
- grid.83440.3b0000000121901201Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH UK ,grid.424537.30000 0004 5902 9895Paediatric Rheumatology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Despina Eleftheriou
- grid.83440.3b0000000121901201Infection, Immunity and Inflammation Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH UK ,grid.424537.30000 0004 5902 9895Paediatric Rheumatology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK ,grid.83440.3b0000000121901201Centre for Adolescent Rheumatology Versus Arthritis at UCL, London, UK
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Noonan Syndrome in 12 -Year-Old Male: Case Report and Orthodontic Management of the Occlusion. BALKAN JOURNAL OF DENTAL MEDICINE 2020. [DOI: 10.2478/bjdm-2020-0020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Summary
Background/Aim: Noonan syndrome (NS) is an autosomal dominant disorder, caused by mutations on genes located on the long arm of chromosome 12. The condition has no sex or race predilection and its incidence is 1 per 1,000 – 2,500 live births. Individuals affected with Noonan syndrome have distinctive facial features, hypertelorism, short stature, congenital heart disease; mainly pulmonary stenosis and hypertrophic cardiomyopathy, chest deformities, variable learning disabilities and mental retardation. Orofacial findings in Noonan syndrome may be high-arched palate, micrognathia, dental malocclusion and articulation difficulties.
Case report: The present article reports on a male case of 12 years old, referred for treatment in the orthodontic office. Despite the difficulties of hyperactivity, the light mental delay and the gag reflex, the treatment was completed satisfactorily with fixed orthodontic appliances in 15 months. Both the patient and his parents were happy with the results. The patient is presently undergoing the retention period of this orthodontic treatment.
Conclusions: Despite the difficulties of treating a child with a genetic syndrome for his/her malocclusion, the reported case presented in this article proves that it is always worth trying for the benefit of the patient.
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Noonan syndrome: genetic and clinical update and treatment options. ANALES DE PEDIATRÍA (ENGLISH EDITION) 2020. [DOI: 10.1016/j.anpede.2020.04.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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22
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H S NS, S S, Patil R, Jadhav S, M C Y, Reddy B, Kharge J, Raghu TR, Shankar S, Raj S, N C, M N, Manjunath CN. Combined cardiac anomalies in Noonan syndrome: A case report. Int J Surg Case Rep 2020; 72:32-36. [PMID: 32506025 PMCID: PMC7276397 DOI: 10.1016/j.ijscr.2020.05.048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 05/20/2020] [Accepted: 05/20/2020] [Indexed: 12/02/2022] Open
Abstract
Noonan syndrome is the second most common syndromic cause of CHD. We present a rare case of Noonan syndrome having a combination of ASD, PS and HCM. Patient underwent balloon valvotomy for pulmonary stenosis. The patient is under regular follow-up and awaiting heart transplant. Introduction Noonan syndrome is the second most common syndromic cause of congenital heart disease. Most patients have an autosomal dominant inheritance, but some cases may be sporadic. Pulmonary stenosis is the most common cardiac manifestation in Noonan syndrome, associated with the atrial septal defect and hypertrophic cardiomyopathy. A combination of these three is present only in 5% of patients. Presentation of case We report a case of a 21-year-old female who presented to our hospital concomitant cardiac lesions associated with pulmonary stenosis, atrial septal defect, and hypertrophic cardiomyopathy. This combination of cardiac defects is an infrequent manifestation of Noonan syndrome. The patient presented with complaints of exertion syncope over the past two years. 2D-Echocardiography showed biventricular hypertrophy, dysplastic pulmonary valve, severe pulmonary stenosis, asymmetric septal hypertrophy and large atrial septal defect. The genetic analysis report showed autosomal dominant inheritance with Ras/MAPK (mitogen-activated protein kinase) Positive. Discussion Due to the wide spectrum of symptoms and presentations in Noonan cases, accurate clinical and genetic diagnosis, and comprehensive management of the disorder are strongly recommended. Conclusion We have described a case of rare combination of cardiovascular defects in Noonan Syndrome with a view to achieve better insight into the disease course and advantages of timely treatment and follow up. Our patient is currently in follow-up after treatment with percutaneous balloon pulmonary valvuloplasty, has improved symptoms, and is awaiting heart transplant.
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Affiliation(s)
- Natraj Setty H S
- Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India.
| | - Shankar S
- Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India
| | - Rahul Patil
- Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India
| | - Santosh Jadhav
- Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India
| | - Yeriswamy M C
- Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India
| | - Babu Reddy
- Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India
| | - Jayashree Kharge
- Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India
| | - T R Raghu
- Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India
| | - Sandeep Shankar
- Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India
| | - Sathwik Raj
- Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India
| | - Chethan N
- Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India
| | - Nithin M
- Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India
| | - C N Manjunath
- Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India
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Carcavilla A, Suárez-Ortega L, Rodríguez Sánchez A, Gonzalez-Casado I, Ramón-Krauel M, Labarta JI, Quinteiro Gonzalez S, Riaño Galán I, Ezquieta Zubicaray B, López-Siguero JP. [Noonan syndrome: genetic and clinical update and treatment options]. An Pediatr (Barc) 2020; 93:61.e1-61.e14. [PMID: 32493603 DOI: 10.1016/j.anpedi.2020.04.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/02/2020] [Accepted: 04/03/2020] [Indexed: 12/20/2022] Open
Abstract
Noonan syndrome (NS) is a relatively common genetic condition characterised by short stature, congenital heart defects, and distinctive facial features. NS and other clinically overlapping conditions such as NS with multiple lentigines (formerly called LEOPARD syndrome), cardiofaciocutaneous syndrome, or Costello syndrome, are caused by mutations in genes encoding proteins of the RAS-MAPKinases pathway. Because of this shared mechanism, these conditions have been collectively termed «RASopathies». Despite the recent advances in molecular genetics, nearly 20% of patients still lack a genetic cause, and diagnosis is still made mainly on clinical grounds. NS is a clinically and genetically heterogeneous condition, with variable expressivity and a changing phenotype with age, and affects multiple organs and systems. Therefore, it is essential that physicians involved in the care of these patients are familiarised with their manifestations and the management recommendations, including management of growth and development. Data on growth hormone treatment efficacy are sparse, and show a modest response in height gains, similar to that observed in Turner syndrome. The role of RAS/MAPK hyper-activation in the pathophysiology of this group of disorders offers a unique opportunity for the development of targeted approaches.
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Affiliation(s)
- Atilano Carcavilla
- Servicio de Endocrinología Pediátrica, Hospital Universitario La Paz, Madrid, España
| | - Larisa Suárez-Ortega
- Servicio de Endocrinología Pediátrica, Hospital Sant Joan de Déu, Esplugues del Llobregat, Barcelona, España
| | | | | | - Marta Ramón-Krauel
- Servicio de Endocrinología Pediátrica, Hospital Sant Joan de Déu, Esplugues del Llobregat, Barcelona, España
| | | | - Sofia Quinteiro Gonzalez
- Servicio de Endocrinología Pediátrica, Complejo Universitario Insular, Gran Canaria, Las Palmas de Gran Canaria, España
| | - Isolina Riaño Galán
- Servicio de Endocrinología Pediátrica, Hospital Central de Asturias, Oviedo/Uviéu, España
| | | | - Juan Pedro López-Siguero
- Servicio de Endocrinología Pediátrica, Hospital Regional Universitario de Málaga, Málaga, España.
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Briggs B, Savla D, Ramchandar N, Dimmock D, Le D, Thornburg CD. The Evaluation of Hematologic Screening and Perioperative Management in Patients with Noonan Syndrome: A Retrospective Chart Review. J Pediatr 2020; 220:154-158.e6. [PMID: 32111381 DOI: 10.1016/j.jpeds.2020.01.048] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 01/02/2020] [Accepted: 01/21/2020] [Indexed: 01/10/2023]
Abstract
OBJECTIVES To assess the potential impact of using screening recommendations for bleeding disorders in patients with Noonan syndrome on perioperative bleeding complications. STUDY DESIGN We performed a retrospective, single-site cohort study; patients were identified by query of the electronic medical record. All patients with a clinical diagnosis of Noonan syndrome over a 10-year period were included. Data on surgeries, hematologic evaluation, bleeding symptoms, and bleeding complications were extracted. Surgeries were graded as major or minor. RESULTS We identified 101 patients with Noonan syndrome, 70 of whom required surgery for a total of 164 procedures. Nine patients (9/70; 12.8%) had bleeding complications, occurring in those without comprehensive testing or perioperative intervention and undergoing major or dental surgery. Based on these findings, the risk of a bleeding complication for patients with Noonan syndrome who did not have comprehensive testing or perioperative intervention was 6.2% (95% CI 2.3%-10.1%), indicating the number needed to treat or screen would be 16 to prevent 1 bleeding complication (95% CI 9.9-43.9). The majority of patients had either no or incomplete evaluation (59 of 101; 58.4%). CONCLUSIONS With proper evaluation and management, the bleeding risk in patients with Noonan syndrome can be minimized. Efforts are needed to address the knowledge and implementation gap in this evaluation.
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Affiliation(s)
- Benjamin Briggs
- Department of Pediatrics, University of California San Diego, La Jolla, CA; Division of Hematology and Oncology, University of California San Diego, La Jolla, CA; Rady Children's Institute of Genomic Medicine, San Diego, CA.
| | - Dipal Savla
- Department of Pediatrics, University of California San Diego, La Jolla, CA
| | - Nanda Ramchandar
- Department of Pediatrics, University of California San Diego, La Jolla, CA; Rady Children's Institute of Genomic Medicine, San Diego, CA; Division of Infectious Disease, University of California San Diego, La Jolla, CA
| | - David Dimmock
- Rady Children's Institute of Genomic Medicine, San Diego, CA
| | - Dzung Le
- Department of Pathology, University of California San Diego, La Jolla, CA
| | - Courtney D Thornburg
- Department of Pediatrics, University of California San Diego, La Jolla, CA; Division of Hematology and Oncology, University of California San Diego, La Jolla, CA; Hemophilia and Thrombosis Treatment Center, Rady Children's Hospital San Diego, San Diego, CA
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25
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El Bouchikhi I, Bouguenouch L, Moufid FZ, Samri I, Abdouss F, Melhouf MA, Iraqui Houssaini M, Belhassan K, Atmani S, Ouldim K. Molecular and environmental characterization of Noonan syndrome in Morocco reveals a significant association with consanguinity and advanced parental age. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2020. [DOI: 10.1186/s43042-020-0047-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Abstract
Background
Noonan syndrome (NS) is one of the most common RASopathies, with an autosomal dominant inheritance. This disorder is caused by a range of genes belonging to the RAS-MAP kinase (rat sarcoma viral oncogene homolog/mitogen-activated protein kinases) pathway, with PTPN11 (protein-tyrosine phosphatase, non-receptor type 11) being the most involved genetic factor.
The aim of this study is to report PTPN11 mutations found in a cohort of Moroccans with Noonan syndrome, compare the mutation rate with various studies, and statistically assess involvement of prominent risk factors in manifestation of this disorder.
Thirty-one NS patients were screened for PTPN11 mutations using PCR-Sanger sequencing method. Pathogenic effect prediction, for detected variants, was carried out using PROVEAN, MutationTaster2, and HSF programs. Statistical tests were performed with R software. Chi-square and Fisher’s exact tests were used in percentage comparisons, while Student’s test was used in average comparisons.
Results
We detected five pathogenic mutations, one synonymous variant with a potential altering effect on splicing function, and three novel intronic duplications. PTPN11 mutation rate in our cohort is around 16.13%. Comparison of this rate with the corresponding rates in various populations shows notably significant differences across continents.
Conclusions
Besides genetic factors, the present study suggests involvement of additional environmental factors. Statistical assessment of clinical data confirms particularly the association of NS manifestation with consanguinity and advanced paternal age, and suggests an eventual implication of advanced maternal age as well.
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Sanri A, Gurkan H, Demir S. Cardiofaciocutaneous Syndrome Phenotype in a Case with de novo KRAS Pathogenic Variant. Mol Syndromol 2019; 10:344-347. [PMID: 32021610 DOI: 10.1159/000504374] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2019] [Indexed: 11/19/2022] Open
Abstract
Cardiofaciocutaneous (CFC) syndrome is one of the developmental disorders caused by a dysregulation of the Ras/mitogen-activated protein kinase (MAPK) pathway. RASopathies share overlapping clinical features, making the diagnosis challenging, especially in the newborn period. The majority of CFC syndrome cases arise by a mutation in the BRAF, MAP2K1, MAP2K2, or (rarely) KRAS genes. Germline KRAS mutations are identified in a minority of CFC and Noonan syndrome cases. Here, we describe a patient with a KRAS mutation presenting with a CFC syndrome phenotype. The female patient was referred for genetic testing because of congenital exophthalmos. Her facial appearance is distinctive with a coarse face, exophthalmos, ptosis, downslanting palpebral fissures, hypertelorism, deep philtrum, downturned corners of the mouth, and a short neck. She suffered from feeding difficulties, poor weight gain, and developmental delay. The sequencing of the genes involved in the MAPK pathway (PTPN11, SOS1, RAF1, KRAS, NRAS, MAP2K1, SHOC2, CBL, and SPRED1) identified a heterozygous de novo NM_004985.4:c.173C>T (p.Thr58Ile) in the KRAS gene. Germline KRAS mutations have been identified in approximately 2% of the reported NS cases and less than 5% of the reported CFC syndrome cases. Because CFC and Noonan syndrome share clinical overlapping features, the phenotype caused by KRAS mutations is often difficult to assign to one of the 2 entities. The mutation that we detected in our patient was previously reported in a patient with an Noonan syndrome phenotype. However, our patient predominantly exhibits CFC clinical features. In our case, coarse facial appearance and severe developmental delay help discriminate CFC from Noonan syndrome. Thus, patient follow-up, especially for delayed motor milestones suspected from RASopathies, is important for the discrimination of overlapping conditions as in the abovementioned syndromes.
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Affiliation(s)
- Aslihan Sanri
- Department of Pediatric Genetics, Samsun Training and Research Hospital, Samsun, Turkey
| | - Hakan Gurkan
- Department of Medical Genetics, Faculty of Medicine, Trakya University, Edirne, Turkey
| | - Selma Demir
- Department of Medical Genetics, Faculty of Medicine, Trakya University, Edirne, Turkey
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Stuurman KE, Joosten M, van der Burgt I, Elting M, Yntema HG, Meijers-Heijboer H, Rinne T. Prenatal ultrasound findings of rasopathies in a cohort of 424 fetuses: update on genetic testing in the NGS era. J Med Genet 2019; 56:654-661. [PMID: 31040167 DOI: 10.1136/jmedgenet-2018-105746] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 03/14/2019] [Accepted: 03/24/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND This study evaluates 6 years of prenatal rasopathy testing in the Netherlands, updates on previous data and gives recommendations for prenatal rasopathy testing. METHODS 424 fetal samples, sent in for prenatal rasopathy testing in 2011-2016, were collected. Cohort 1 included 231 samples that were sequenced for 1-5 rasopathy genes. Cohort 2 included 193 samples that were analysed with a 14-gene next generation sequencing (NGS) panel. For all mutation-positive samples in both cohorts, the referring physician provided detailed ultrasound findings and postnatal follow-up. For 168 mutation-negative samples in cohort 2, solely clinical information on the requisition form was collected. RESULTS In total, 40 (likely) pathogenic variants were detected (9.4%). All fetuses showed a variable degree of involvement of prenatal findings: increased nuchal translucency (NT)/cystic hygroma, distended jugular lymph sacs (JLS), hydrops fetalis, polyhydramnios, pleural effusion, ascites, cardiac defects and renal anomalies. An increased NT was the most common finding. Eight fetuses showed solely an increased NT/cystic hygroma, which were all larger than 5.5 mm. Ascites and renal anomalies appeared to be poor predictors of pathogenic outcome. CONCLUSION Fetuses with a rasopathy show in general multiple ultrasound findings. The larger the NT and the longer it persists, the more likely it is to find a pathogenic variant. Rasopathy testing is recommended when the fetus shows an isolated increased NT ≥5.0 mm or when NT of ≥3.5 mm and at least one of the following ultrasound anomalies is present: distended JLS, hydrops fetalis, polyhydramnios, pleural effusion, ascites, cardiac defects and renal anomalies.
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Affiliation(s)
- Kyra E Stuurman
- Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Marieke Joosten
- Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Ineke van der Burgt
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Mariet Elting
- Department of Clinical Genetics, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Helger G Yntema
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Hanne Meijers-Heijboer
- Department of Clinical Genetics, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Tuula Rinne
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
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28
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Croonen EA, Draaisma JMT, van der Burgt I, Roeleveld N, Noordam C. First-year growth in children with Noonan syndrome: Associated with feeding problems? Am J Med Genet A 2019; 176:951-958. [PMID: 29575624 DOI: 10.1002/ajmg.a.38649] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 01/04/2018] [Accepted: 01/29/2018] [Indexed: 11/06/2022]
Abstract
Children with Noonan syndrome show rapid decline of growth in the first year of life and feeding problems are present in over 50%. The aim of this study was to explore whether growth decelerates because of feeding problems or other Noonan syndrome-related factors. We performed a retrospective, longitudinal cohort study of clinically and genetically diagnosed subjects with Noonan syndrome (n = 143). Questionnaires about the phenotypic-genotypic profile and reported feeding problems were sent to eligible subjects. Data on first-year growth was obtained from growth charts. Ninety-one participants were excluded because of different criteria. A total of 52 subjects with Noonan syndrome were included. The largest decline in weight and length standard deviation score (SDS) occurred in the first 2.5 months after birth (-1.93 and -1.15, respectively), with feeding problems causing a decline of 0.57 SDS in the remaining months. At 1 year, children with feeding problems were on average 290 g lighter and 0.8 cm shorter than children without feeding problems. Weight gain was also negatively influenced by having a PTPN11 mutation (n = 39) and a higher gestational age, whereas children of parents with Noonan syndrome and with a higher birth weight gained more weight. Growth in length was reduced by having cardiac surgery and a higher gestational age, but positively influenced by birth length and maternal height. Growth in children with Noonan syndrome is impaired right after birth and only partially associated with feeding problems. In addition, several specific Noonan syndrome-related factors seem to influence growth in the first year.
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Affiliation(s)
- Ellen A Croonen
- Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jos M T Draaisma
- Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ineke van der Burgt
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Nel Roeleveld
- Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands.,Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Cees Noordam
- Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
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Multifocal Pigmented Villonodular Synovitis in the Noonan Syndrome. Case Rep Orthop 2018; 2018:7698052. [PMID: 30631623 PMCID: PMC6305014 DOI: 10.1155/2018/7698052] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 10/24/2018] [Accepted: 11/25/2018] [Indexed: 11/24/2022] Open
Abstract
Noonan-like/multiple giant cell lesion (NS/MGCL) is a rare condition overlapping with Noonan syndrome. Once thought to be a specific and separate entity, it is now suggested to be a variant of the Noonan syndrome spectrum. We report the case of an 8-year-old boy with a typical clinical picture of Noonan syndrome with a de novo germline mutation of PTPN11 (c.854 T>C). During his follow-up, the patient developed multifocal pigmented villonodular synovitis which first affected the left knee and shortly after both elbows.
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30
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Craniofacial and cutaneous findings in Noonan, Costello and LEOPARD syndromes. Postepy Dermatol Alergol 2018; 35:437-441. [PMID: 30429698 PMCID: PMC6232548 DOI: 10.5114/pdia.2017.70330] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 06/21/2018] [Indexed: 11/17/2022] Open
Abstract
Noonan, Costello and LEOPARD syndromes belong to a family of cardiofaciocutaneous disorders and share common genetic traits. As they are associated with a germline mutation in genes encoding proteins involved in RAS/MAPK, patients suffering from these syndromes are at a greater risk of cancer and abnormal myelopoiesis in infancy. Patients with cardio faciocutaneous syndromes share some clinically overlapping syndromes, therefore differential diagnosis can be problematic. In this paper we aim at demonstrating distinctive craniofacial and cutaneous manifestations of Noonan, Costello and LEOPARD syndromes which can be useful for clinicians who aim at treatment of children with rare diseases.
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31
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Bessis D, Morice-Picard F, Bourrat E, Abadie C, Aouinti S, Baumann C, Best M, Bursztejn AC, Capri Y, Chiaverini C, Coubes C, Giuliano F, Hadj-Rabia S, Jacquemont ML, Lacombe D, Lyonnet S, Mallet S, Mazereeuw-Hautier J, Miquel J, Molinari N, Parfait B, Pernet C, Philip N, Pinson L, Pouvreau N, Vial Y, Sarda P, Sigaudy S, Verloes A, Cavé H, Geneviève D. Dermatological manifestations in cardiofaciocutaneous syndrome: a prospective multicentric study of 45 mutation-positive patients. Br J Dermatol 2018; 180:172-180. [PMID: 30141192 DOI: 10.1111/bjd.17077] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/22/2018] [Indexed: 12/25/2022]
Abstract
BACKGROUND Data on dermatological manifestations of cardiofaciocutaneous syndrome (CFCS) remain heterogeneous and almost without expert dermatological classification. OBJECTIVES To describe the dermatological manifestations of CFCS; to compare them with the literature findings; to assess those discriminating CFCS from other RASopathies, including Noonan syndrome (NS) and Costello syndrome (CS); and to test for dermatological phenotype-genotype correlations. METHODS We performed a 4-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS Forty-five patients were enrolled. Hair abnormalities were ubiquitous, including scarcity or absence of eyebrows and wavy or curly hair in 73% and 69% of patients, respectively. Keratosis pilaris (KP), ulerythema ophryogenes (UO), palmoplantar hyperkeratosis (PPHK) and multiple melanocytic naevi (MMN; over 50 naevi) were noted in 82%, 44%, 27% and 29% of patients, respectively. Scarcity or absence of eyebrows, association of UO and PPHK, diffuse KP and MMN best differentiated CFCS from NS and CS. Oral acitretin may be highly beneficial for therapeutic management of PPHK, whereas treatment of UO by topical sirolimus 1% failed. No significant dermatological phenotype-genotype correlation was determined. CONCLUSIONS A thorough knowledge of CFCS skin manifestations would help in making a positive diagnosis and differentiating CFCS from CS and NS.
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Affiliation(s)
- D Bessis
- Department of Dermatology, Saint-Eloi Hospital, University of Montpellier, Montpellier, France.,INSERM U1058, Montpellier, France
| | - F Morice-Picard
- Department of Pediatric Dermatology, Pellegrin University Hospital of Bordeaux, Bordeaux, AP-HP, France
| | - E Bourrat
- Department of Pediatric Dermatology, Robert-Debré Hospital, AP-HP, Paris, France
| | - C Abadie
- Department of Clinical Genetics, Sud Hospital and University Hospital of Rennes, Rennes, France
| | - S Aouinti
- Department of Statistics, La Colombière Hospital and University of Montpellier, Montpellier, France
| | - C Baumann
- Department of Clinical Genetics, Robert-Debré Hospital, AP-HP and University of Paris-Diderot, Paris, France
| | - M Best
- Department of Dermatology, Saint-Eloi Hospital, University of Montpellier, Montpellier, France
| | - A-C Bursztejn
- Department of Dermatology, Brabois Hospital, University of Nancy, Nancy, France
| | - Y Capri
- Department of Clinical Genetics, Robert-Debré Hospital, AP-HP and University of Paris-Diderot, Paris, France
| | - C Chiaverini
- Department of Dermatology, L'Archet 2 Hospital and University of Nice, Nice, France
| | - C Coubes
- Department of Clinical Genetics, Arnaud de Villeneuve Hospital, University of Montpellier, Montpellier, France
| | - F Giuliano
- Department of Clinical Genetics, L'Archet 2 Hospital and University of Nice, Nice, France
| | - S Hadj-Rabia
- Department of Pediatric Dermatology, Necker-Enfants Malades Hospital, AP-HP, Paris, France
| | - M-L Jacquemont
- Department of Clinical Genetics, Femme-Mère-Enfant Hospital, University of South Reunion, Saint-Pierre, Réunion, France
| | - D Lacombe
- Department of Clinical Genetics, Pellegrin University Hospital of Bordeaux, Bordeaux, AP-HP, France
| | - S Lyonnet
- Department of Clinical Genetics, Necker-Enfants Malades Hospital, AP-HP, Paris, France
| | - S Mallet
- Department of Dermatology, La Timone Hospital, AP-HM and University of Marseille, Marseille, France
| | - J Mazereeuw-Hautier
- Department of Dermatology, Larrey Hospital, Reference Center for Rare Skin Diseases, University of Toulouse, Toulouse, France
| | - J Miquel
- Department of Pediatric Dermatology, Femme-Mère-Enfant Hospital, University of South Reunion, Saint-Pierre, Réunion, France.,Department of Dermatology, University of Rennes, Rennes, France
| | - N Molinari
- Department of Statistics, La Colombière Hospital and University of Montpellier, Montpellier, France
| | - B Parfait
- Department of Molecular Genetics and Biology, Cochin Hospital, AP-HP, University Paris V, Paris, France
| | - C Pernet
- Department of Dermatology, Saint-Eloi Hospital, University of Montpellier, Montpellier, France
| | - N Philip
- Department of Clinical Genetics, La Timone Hospital, AP-HM and University of Marseille, Marseille, France
| | - L Pinson
- Department of Clinical Genetics, Arnaud de Villeneuve Hospital, University of Montpellier, Montpellier, France
| | - N Pouvreau
- Department of Genetic Biochemistry, Robert-Debré Hospital, AP-HP and University of Paris-Diderot, Paris, France
| | - Y Vial
- Department of Genetic Biochemistry, Robert-Debré Hospital, AP-HP and University of Paris-Diderot, Paris, France
| | - P Sarda
- Department of Clinical Genetics, Arnaud de Villeneuve Hospital, University of Montpellier, Montpellier, France
| | - S Sigaudy
- Department of Clinical Genetics, La Timone Hospital, AP-HM and University of Marseille, Marseille, France
| | - A Verloes
- Department of Clinical Genetics, Robert-Debré Hospital, AP-HP and University of Paris-Diderot, Paris, France
| | - H Cavé
- Department of Genetic Biochemistry, Robert-Debré Hospital, AP-HP and University of Paris-Diderot, Paris, France
| | - D Geneviève
- Department of Clinical Genetics, Arnaud de Villeneuve Hospital, University of Montpellier, Montpellier, France.,INSERM U1183, Montpellier, France
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Genetic testing for lymphedema in RASopathies. EUROBIOTECH JOURNAL 2018. [DOI: 10.2478/ebtj-2018-0025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Abstract
Variants affecting the function of genes in the RAS–mitogen-activated protein kinase (MAPK) signal transduction pathway have been identified as responsible for a group of developmental syndromes known as RASopathies. Noonan (NS) and cardiofaciocutaneous syndromes (CFC) represent the most frequent and best characterized RASopathies. Many cases of RASopathies are associated with lymphatic malformations that finally may result in lymphedema. We developed the test protocol “Lymphedema in RASopathies” on the basis of the latest research findings and diagnostic protocols on lymphatic malformation in RASopathies. The genetic test is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.
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Perrino F, Licchelli S, Serra G, Piccini G, Caciolo C, Pasqualetti P, Cirillo F, Leoni C, Digilio MC, Zampino G, Tartaglia M, Alfieri P, Vicari S. Psychopathological features in Noonan syndrome. Eur J Paediatr Neurol 2018; 22:170-177. [PMID: 29037749 DOI: 10.1016/j.ejpn.2017.09.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 07/29/2017] [Accepted: 09/19/2017] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, skeletal and haematological/lymphatic defects, distinctive facies, cryptorchidism, and a wide spectrum of congenital heart defects. Recurrent features also include variable cognitive deficits and behavioural problems. Recent research has been focused on the assessment of prevalence, age of onset and characterization of psychiatric features in this disorder. Herein, we evaluated the prevalence of attention deficit and hyperactivity disorder (ADHD), anxiety and depressive symptoms and syndromes in a cohort of individuals with clinical and molecular diagnosis of NS. METHODS The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version (K-SADS PL) has been used for the assessment of psychiatric disorders according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Multidimensional Anxiety Scale for Children (MASC) and the Children's Depression Inventory (CDI) have been assessed for the evaluation of anxiety and depressive symptoms and syndromes, whereas Conners Teacher and Parent Rating Scales-long version (CRS-R) have been used to evaluate ADHD. RESULTS The study included 27 individuals (67% males) with an average age of 10.4 years (range 6-18 years) receiving molecular diagnosis of NS or a clinically related condition, evaluated and treated at the Neuropsychiatric Unit of Children's Hospital Bambino Gesù and at the Center for Rare Diseases of Fondazione Policlinico Universitario Agostino Gemelli, in Rome. Twenty individuals showed mutations in PTPN11, five in SOS1 and two in SHOC2. The mean IQ was 94 (Standard Deviation = 17, min = 56, max = 130). Seventy percent of the individuals (n = 19; 95% Confidence Interval = 52-85%) showed ADHD features, with six individuals reaching DSM-IV-TR criteria for ADHD disorder, and thirteen showing subsyndromal traits. Symptoms or syndrome of anxiety were present in 37% of the cohort (n = 10; 95% Confidence Interval = 19-56%), with two individuals showing anxiety disorder and eight cases exhibiting subsyndromal traits. CONCLUSION Our results show individuals with NS do present a very high risk to develop psychiatric disorders or symptoms during paediatric age. Based on these findings, preschool assessment of inattentive, hyperactivity/impulsivity and anxiety/depressive symptoms is recommended in order to plan a personalized treatment for psychological/psychiatric issues in affected individuals. Dedicated prospective studies are required to confirm the present data and better characterize the psychopathological profile in NS.
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Affiliation(s)
- Francesca Perrino
- Center for Rare Diseases, Department of Pediatrics, Polo Salute Donna e Bambino, Fondazione Policlinico Universitario A. Gemelli, Catholic University, Rome, Italy
| | - Serena Licchelli
- Department of Neuroscience, Unit of Child Neuropsychiatry, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Giulia Serra
- Department of Neuroscience, Unit of Child Neuropsychiatry, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; NESMOS Department, Sant'Andrea Hospital, Sapienza University of Rome, Italy; Department of Psychiatry, Harvard Medical School, Boston, MA, USA
| | - Giorgia Piccini
- Department of Neuroscience, Unit of Child Neuropsychiatry, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Cristina Caciolo
- Department of Neuroscience, Unit of Child Neuropsychiatry, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Patrizio Pasqualetti
- Service of Medical Statistics and Information Technology, Fatebenefratelli Foundation for Health Research and Education, Rome, Italy; Language and Communication Across Modalities Laboratory (LaCAM), Institute of Cognitive Sciences and Technologies (ISTC-CNR), Italy
| | - Flavia Cirillo
- Department of Neuroscience, Unit of Child Neuropsychiatry, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Chiara Leoni
- Center for Rare Diseases, Department of Pediatrics, Polo Salute Donna e Bambino, Fondazione Policlinico Universitario A. Gemelli, Catholic University, Rome, Italy
| | - Maria Cristina Digilio
- Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Giuseppe Zampino
- Center for Rare Diseases, Department of Pediatrics, Polo Salute Donna e Bambino, Fondazione Policlinico Universitario A. Gemelli, Catholic University, Rome, Italy
| | - Marco Tartaglia
- Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Paolo Alfieri
- Department of Neuroscience, Unit of Child Neuropsychiatry, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
| | - Stefano Vicari
- Department of Neuroscience, Unit of Child Neuropsychiatry, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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Wilbe M, Gudmundsson S, Johansson J, Ameur A, Stattin EL, Annerén G, Malmgren H, Frykholm C, Bondeson ML. A novel approach using long-read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders. Prenat Diagn 2017; 37:1146-1154. [PMID: 28921562 PMCID: PMC5725701 DOI: 10.1002/pd.5156] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 09/04/2017] [Accepted: 09/06/2017] [Indexed: 12/17/2022]
Abstract
Objective De novo mutations contribute significantly to severe early‐onset genetic disorders. Even if the mutation is apparently de novo, there is a recurrence risk due to parental germ line mosaicism, depending on in which gonadal generation the mutation occurred. Methods We demonstrate the power of using SMRT sequencing and ddPCR to determine parental origin and allele frequencies of de novo mutations in germ cells in two families whom had undergone assisted reproduction. Results In the first family, a TCOF1 variant c.3156C>T was identified in the proband with Treacher Collins syndrome. The variant affects splicing and was determined to be of paternal origin. It was present in <1% of the paternal germ cells, suggesting a very low recurrence risk. In the second family, the couple had undergone several unsuccessful pregnancies where a de novo mutation PTPN11 c.923A>C causing Noonan syndrome was identified. The variant was present in 40% of the paternal germ cells suggesting a high recurrence risk. Conclusions Our findings highlight a successful strategy to identify the parental origin of mutations and to investigate the recurrence risk in couples that have undergone assisted reproduction with an unknown donor or in couples with gonadal mosaicism that will undergo preimplantation genetic diagnosis. What's already known about this topic?
De novo mutations contribute significantly to severe early‐onset genetic disorders. what does this study add?
A novel successful strategy to identify the parental origin of de novo mutations and to investigate the recurrence risk by SMRT sequencing and ddPCR.
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Affiliation(s)
- Maria Wilbe
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Sanna Gudmundsson
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Josefin Johansson
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Adam Ameur
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Eva-Lena Stattin
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Göran Annerén
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Helena Malmgren
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Carina Frykholm
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Marie-Louise Bondeson
- Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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Khorgami MR, Moradian M, Omidi N, Aarabi Moghadam MY. Management of Cardiovascular Disorders in Patients with Noonan Syndrome: A Case Report. J Tehran Heart Cent 2017; 12:184-187. [PMID: 29576787 PMCID: PMC5849592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
The Noonan syndrome is a rare disorder, one of whose major complications is cardiovascular involvement. A wide spectrum of congenital heart diseases has been observed in this syndrome. The most common cardiac disorder is pulmonary valve stenosis, which has a progressive nature. Hypertrophic cardiomyopathy is less common, but its morbidity and mortality rates are high. We herein introduce a 12-year-old boy with the typical findings of the Noonan syndrome. His symptoms began from infancy, and there was a gradual exacerbation in his respiratory and cardiac manifestations with age. The cardiac involvement included right ventricular outflow tract and pulmonary valve stenosis, hypertrophic cardiomyopathy, and subaortic valve stenosis. Due to the progressive course of the disease, surgical repair was done. Although the patient had a difficult postoperative period, his general condition improved and he was discharged. At 3 months' follow-up, his symptoms showed improvement. Additionally, there was a reduction in the echocardiographic parameters of the outflow tract stenosis gradient as well as a significant improvement in the cardiac hemodynamic indices.
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Affiliation(s)
- Mohammad Rafie Khorgami
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Maryam Moradian
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.,Corresponding Author: Maryam Moradian, Assistant Professor of Pediatric Cardiology, Rajaie Cardiovascular, Medical and Research Center, Vali-Asr Street, Adjacent to Mellat Park, Tehran, Iran. 1996911151. Tel: +98 21 23922170. Fax: +98 21 22042026. E-mail: .
| | - Negar Omidi
- Primary Prevention Cardiovascular Research Center, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran.
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36
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Croonen EA, Essink M, van der Burgt I, Draaisma JM, Noordam C, Nijhuis-van der Sanden MWG. Motor performance in children with Noonan syndrome. Am J Med Genet A 2017. [PMID: 28627718 DOI: 10.1002/ajmg.a.38322] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Although problems with motor performance in daily life are frequently mentioned in Noonan syndrome, the motor performance profile has never been systematically investigated. The aim of this study was to examine whether a specific profile in motor performance in children with Noonan syndrome was seen using valid norm-referenced tests. The study assessed motor performance in 19 children with Noonan syndrome (12 females, mean age 9 years 4 months, range 6 years 1 month to 11 years and 11 months, SDS 1 year and 11 months). More than 60% of the parents of the children reported pain, decreased muscle strength, reduced endurance, and/or clumsiness in daily functioning. The mean standard scores on the Visual Motor Integration (VMI) test and Movement Assessment Battery for Children 2, Dutch version (MABC-2-NL) items differed significantly from the reference scores. Grip strength, muscle force, and 6 min Walking Test (6 MWT) walking distance were significantly lower, and the presence of generalized hypermobility was significantly higher. All MABC-2-NL scores (except manual dexterity) correlated significantly with almost all muscle strength tests, VMI total score, and VMI visual perception score. The 6 MWT was only significantly correlated to grip strength. This is the first study that confirms that motor performance, strength, and endurance are significantly impaired in children with Noonan syndrome. Decreased functional motor performance seems to be related to decreased visual perception and reduced muscle strength. Research on causal relationships and the effectiveness of interventions is needed. Physical and/or occupational therapy guidance should be considered to enhance participation in daily life.
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Affiliation(s)
- Ellen A Croonen
- Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marlou Essink
- Department of Rehabilitation, Pediatric Physical Therapy, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ineke van der Burgt
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jos M Draaisma
- Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Cees Noordam
- Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Maria W G Nijhuis-van der Sanden
- Department of Rehabilitation, Pediatric Physical Therapy, Radboud University Medical Center, Nijmegen, The Netherlands.,Radboud Institute for Health Sciences, IQ Healthcare, Radboud University Medical Center, Nijmegen, The Netherlands
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37
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Cochlear implantation and clinical features in patients with Noonan syndrome and Noonan syndrome with multiple lentigines caused by a mutation in PTPN11. Int J Pediatr Otorhinolaryngol 2017; 97:228-234. [PMID: 28483241 DOI: 10.1016/j.ijporl.2017.04.024] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 04/11/2017] [Accepted: 04/12/2017] [Indexed: 11/23/2022]
Abstract
Existing literature only reports a few patients with Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) who underwent cochlear implantation (CI). The present study describes four NS patients and one NSML patient with a PTPN11 mutation. They all had severe to profound hearing loss, and they received a CI. The age at which the CI surgery occurred ranged from 1 to 13 years old, and the audiological results in all five patients improved after the CI. Otological and audiological examinations in NS and NSML are important, and for those with severe hearing loss, the CI surgery improved the audiological outcome regardless of age.
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38
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Cardiel Ríos SA. Correction of a severe Class II malocclusion in a patient with Noonan syndrome. Am J Orthod Dentofacial Orthop 2017; 150:511-20. [PMID: 27585781 DOI: 10.1016/j.ajodo.2015.09.032] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Revised: 09/01/2015] [Accepted: 09/01/2015] [Indexed: 10/21/2022]
Abstract
Noonan syndrome is a developmental disorder characterized by a dysmorphic facial structure, short stature, and mild mental retardation, with associated cardiac defects and skeletal malformations. It may be sporadic or inherited as an autosomal dominant or recessive trait. The incidence of occurrence is 1 in 1000 to 2500 live births. The responsible gene is located on the long arm of chromosome 12. Diagnosis of the syndrome is made by both clinical inspection and karyotype. This is the case report of a 10-year-old Mexican boy who was referred for correction of orofacial and occlusal defects.
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Affiliation(s)
- Sergio A Cardiel Ríos
- Private practice, Morelia, Michoacán, Mexico; assistant professor, Department of Orthodontics, Hospital for Children "Federico Gómez", Mexico City, Mexico; assistant professor, Department of Orthodontics, Stomatoloski Fakultet, University of Belgrade, Belgrade, Serbia.
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39
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Ben-Shachar S, Dubov T, Toledano-Alhadef H, Mashiah J, Sprecher E, Constantini S, Leshno M, Messiaen LM. Predicting neurofibromatosis type 1 risk among children with isolated café-au-lait macules. J Am Acad Dermatol 2017; 76:1077-1083.e3. [PMID: 28318682 DOI: 10.1016/j.jaad.2017.02.027] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 02/08/2017] [Accepted: 02/09/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND Although isolated cafe-au-lait macules (CALMs) are a common skin finding, they are an early feature of neurofibromatosis type 1 (NF1). OBJECTIVE We sought to develop an algorithm determining the risk of children with CALMs to have constitutional NF1. METHODS We conducted a retrospective study of patients with isolated CALMs. Diagnosis of NF1 was based on detecting NF1 mutation in blood or fulfilling clinical criteria. RESULTS In all, 170 of 419 (41%) and 21 of 86 (24%) children with isolated CALMs who underwent molecular testing and clinical follow-up, respectively, were given a diagnosis of NF1. Presence of fewer than 6 CALMs at presentation or atypical CALMs was associated with not having NF1 (P < .001). An algorithm based on age, CALMs number, and presence of atypical macules predicted NF1 in both cohorts. According to the algorithm, children older than 29 months with at least 1 atypical CALM or less than 6 CALMs have a 0.9% (95% confidence interval 0%-2.6%) risk for constitutional NF1 whereas children younger than 29 months with 6 or more CALMs have a high risk (80.4%, 95% confidence interval 74.6%-86.2%). LIMITATIONS The study was designed to detect constitutional NF1 and not NF1 in mosaic form. CONCLUSIONS A simple algorithm enables categorization of children with isolated CALMs as being at low or high risk for having NF1.
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Affiliation(s)
- Shay Ben-Shachar
- Gilbert Israeli Neurofibromatosis Center, Tel-Aviv Medical Center, Tel-Aviv, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
| | - Tom Dubov
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Hagit Toledano-Alhadef
- Gilbert Israeli Neurofibromatosis Center, Tel-Aviv Medical Center, Tel-Aviv, Israel; Pediatric Neurology Unit and Child Development Center, Tel-Aviv Medical Center, Tel-Aviv, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Jacob Mashiah
- Pediatric Dermatology Unit, Tel-Aviv Medical Center, Tel-Aviv, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Eli Sprecher
- Pediatric Dermatology Unit, Tel-Aviv Medical Center, Tel-Aviv, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Shlomi Constantini
- Gilbert Israeli Neurofibromatosis Center, Tel-Aviv Medical Center, Tel-Aviv, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Moshe Leshno
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Ludwine M Messiaen
- Medical Genomics Laboratory, Department of Genetics, University of Alabama, Birmingham, Alabama
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Higgins EM, Bos JM, Mason-Suares H, Tester DJ, Ackerman JP, MacRae CA, Sol-Church K, Gripp KW, Urrutia R, Ackerman MJ. Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy. JCI Insight 2017; 2:e91225. [PMID: 28289718 DOI: 10.1172/jci.insight.91225] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Noonan syndrome (NS; MIM 163950) is an autosomal dominant disorder and a member of a family of developmental disorders termed "RASopathies," which are caused mainly by gain-of-function mutations in genes encoding RAS/MAPK signaling pathway proteins. Whole exome sequencing (WES) and trio-based genomic triangulation of a 15-year-old female with a clinical diagnosis of NS and concomitant cardiac hypertrophy and her unaffected parents identified a de novo variant in MRAS-encoded RAS-related protein 3 as the cause of her disease. Mutation analysis using in silico mutation prediction tools and molecular dynamics simulations predicted the identified variant, p.Gly23Val-MRAS, to be damaging to normal protein function and adversely affect effector interaction regions and the GTP-binding site. Subsequent ectopic expression experiments revealed a 40-fold increase in MRAS activation for p.Gly23Val-MRAS compared with WT-MRAS. Additional biochemical assays demonstrated enhanced activation of both RAS/MAPK pathway signaling and downstream gene expression in cells expressing p.Gly23Val-MRAS. Mutational analysis of MRAS in a cohort of 109 unrelated patients with phenotype-positive/genotype-negative NS and cardiac hypertrophy yielded another patient with a sporadic de novo MRAS variant (p.Thr68Ile, c.203C>T). Herein, we describe the discovery of mutations in MRAS in patients with NS and cardiac hypertrophy, establishing MRAS as the newest NS with cardiac hypertrophy-susceptibility gene.
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Affiliation(s)
| | - J Martijn Bos
- Department of Molecular Pharmacology and Experimental Therapeutics and Windland Smith Rice Sudden Death Genomics Laboratory.,Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Heather Mason-Suares
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts, USA.,Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - David J Tester
- Department of Molecular Pharmacology and Experimental Therapeutics and Windland Smith Rice Sudden Death Genomics Laboratory.,Department of Cardiovascular Diseases/Division of Heart Rhythm Services, Mayo Clinic, Rochester, Minnesota, USA
| | - Jaeger P Ackerman
- Department of Molecular Pharmacology and Experimental Therapeutics and Windland Smith Rice Sudden Death Genomics Laboratory
| | - Calum A MacRae
- Divisions of Cardiovascular Medicine and Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.,Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.,Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.,Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | | | - Karen W Gripp
- Center for Applied Clinical Genomics and.,Division of Medical Genetics, Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA
| | - Raul Urrutia
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine, Laboratory of Epigenetics and Chromatin Dynamics, Epigenomics Translational Program, Gastroenterology Research Unit, Mayo Clinic, Rochester, Minnesota, USA
| | - Michael J Ackerman
- Department of Molecular Pharmacology and Experimental Therapeutics and Windland Smith Rice Sudden Death Genomics Laboratory.,Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota, USA.,Department of Cardiovascular Diseases/Division of Heart Rhythm Services, Mayo Clinic, Rochester, Minnesota, USA
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41
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Papale A, d'Isa R, Menna E, Cerovic M, Solari N, Hardingham N, Cambiaghi M, Cursi M, Barbacid M, Leocani L, Fasano S, Matteoli M, Brambilla R. Severe Intellectual Disability and Enhanced Gamma-Aminobutyric Acidergic Synaptogenesis in a Novel Model of Rare RASopathies. Biol Psychiatry 2017; 81:179-192. [PMID: 27587266 DOI: 10.1016/j.biopsych.2016.06.016] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 05/16/2016] [Accepted: 06/14/2016] [Indexed: 11/16/2022]
Abstract
BACKGROUND Dysregulation of Ras-extracellular signal-related kinase (ERK) signaling gives rise to RASopathies, a class of neurodevelopmental syndromes associated with intellectual disability. Recently, much attention has been directed at models bearing mild forms of RASopathies whose behavioral impairments can be attenuated by inhibiting the Ras-ERK cascade in the adult. Little is known about the brain mechanisms in severe forms of these disorders. METHODS We performed an extensive characterization of a new brain-specific model of severe forms of RASopathies, the KRAS12V mutant mouse. RESULTS The KRAS12V mutation results in a severe form of intellectual disability, which parallels mental deficits found in patients bearing mutations in this gene. KRAS12V mice show a severe impairment of both short- and long-term memory in a number of behavioral tasks. At the cellular level, an upregulation of ERK signaling during early phases of postnatal development, but not in the adult state, results in a selective enhancement of synaptogenesis in gamma-aminobutyric acidergic interneurons. The enhancement of ERK activity in interneurons at this critical postnatal time leads to a permanent increase in the inhibitory tone throughout the brain, manifesting in reduced synaptic transmission and long-term plasticity in the hippocampus. In the adult, the behavioral and electrophysiological phenotypes in KRAS12V mice can be temporarily reverted by inhibiting gamma-aminobutyric acid signaling but not by a Ras-ERK blockade. Importantly, the synaptogenesis phenotype can be rescued by a treatment at the developmental stage with Ras-ERK inhibitors. CONCLUSIONS These data demonstrate a novel mechanism underlying inhibitory synaptogenesis and provide new insights in understanding mental dysfunctions associated to RASopathies.
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Affiliation(s)
- Alessandro Papale
- Neuroscience and Mental Health Research Institute, Division of Neuroscience, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Raffaele d'Isa
- Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milano
| | - Elisabetta Menna
- National Research Council (CNR), Neuroscience Institute, Milano; Humanitas Clinical and Research Center, Rozzano, Italy
| | - Milica Cerovic
- Neuroscience and Mental Health Research Institute, Division of Neuroscience, School of Biosciences, Cardiff University, Cardiff, United Kingdom; Department of Neuroscience, IRCCS Mario Negri Institute for Pharmacological Research, Milano
| | - Nicola Solari
- Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milano; Department of Neuroscience, IRCCS Mario Negri Institute for Pharmacological Research, Milano
| | - Neil Hardingham
- Neuroscience and Mental Health Research Institute, Division of Neuroscience, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Marco Cambiaghi
- Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milano
| | - Marco Cursi
- Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milano
| | - Mariano Barbacid
- Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Letizia Leocani
- Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milano
| | - Stefania Fasano
- Neuroscience and Mental Health Research Institute, Division of Neuroscience, School of Biosciences, Cardiff University, Cardiff, United Kingdom; Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milano
| | - Michela Matteoli
- National Research Council (CNR), Neuroscience Institute, Milano; Humanitas Clinical and Research Center, Rozzano, Italy
| | - Riccardo Brambilla
- Neuroscience and Mental Health Research Institute, Division of Neuroscience, School of Biosciences, Cardiff University, Cardiff, United Kingdom; Institute of Experimental Neurology, Division of Neuroscience, IRCCS-San Raffaele Scientific Institute, Milano.
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42
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Sheng Yang X, Ping Sun J, Yan B. Clinical Syndromes Associated with Cardiovascular Diseases: A Review. CARDIOVASCULAR INNOVATIONS AND APPLICATIONS 2017. [DOI: 10.15212/cvia.2016.0071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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43
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Yapijakis C, Pachis N, Voumvourakis C. Neurofibromatosis-Noonan Syndrome: A Possible Paradigm of the Combination of Genetic and Epigenetic Factors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 987:151-159. [PMID: 28971455 DOI: 10.1007/978-3-319-57379-3_14] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Neurofibromatosis-Noonan syndrome (NFNS) is a clinical entity possessing traits of autosomal dominant disorders neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). Germline mutations that disrupt the RAS/MAPK pathway are involved in the pathogenesis of both NS and NF1. In light of a studied Greek family, a new theory for etiological pathogenesis of NFNS is suggested. The NFNS phenotype may be the final result of a combination of a genetic factor (a mutation in the NF1 gene) and an environmental factor with the epigenetic effects of muscle hypotonia (such as hydantoin in the reported Greek family), causing hypoplasia of the face and micrognathia.
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Affiliation(s)
- Christos Yapijakis
- Department of Oral and Maxillofacial Surgery, School of Medicine, University of Athens, Attikon Hospital, Athens, Greece. .,"Cephalogenetics" Genetic Center, Athens, Greece. .,Department of Neurology, School of Medicine, University of Athens, Eginition Hospital, Athens, Greece.
| | - Nikos Pachis
- "Cephalogenetics" Genetic Center, Athens, Greece
| | - Costas Voumvourakis
- 2nd Department of Neurology, School of Medicine, University of Athens, Attikon Hospital, Athens, Greece
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44
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van Trier DC, Vos AM, Draaijer RW, van der Burgt I, Draaisma JM, Cruysberg JR. Ocular Manifestations of Noonan Syndrome. Ophthalmology 2016; 123:2137-46. [DOI: 10.1016/j.ophtha.2016.06.061] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Revised: 06/16/2016] [Accepted: 06/24/2016] [Indexed: 10/21/2022] Open
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45
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Zhang J, Li M, Yao Z. Molecular screening strategies for NF1-like syndromes with café-au-lait macules (Review). Mol Med Rep 2016; 14:4023-4029. [PMID: 27666661 PMCID: PMC5112360 DOI: 10.3892/mmr.2016.5760] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 04/26/2016] [Indexed: 12/28/2022] Open
Abstract
Multiple café-au-lait macules (CALM) are usually associated with neurofibromatosis type 1 (NF1), one of the most common hereditary disorders. However, a group of genetic disorders presenting with CALM have mutations that are involved in human skin pigmentation regulation signaling pathways, including KIT ligand/KIT proto‑oncogene receptor tyrosine kinase and Ras/mitogen‑activated protein kinase. These disorders, which include Legius syndrome, Noonan syndrome with multiple lentigines or LEOPARD syndrome, and familial progressive hyperpigmentation) are difficult to distinguish from NF1 at early stages, using skin appearance alone. Furthermore, certain syndromes are clinically overlapping and molecular testing is a vital diagnostic method. The present review aims to provide an overview of these 'NF1‑like' inherited diseases and recommend a cost‑effective strategy for making a clear diagnosis among these diseases with an ambiguous borderline.
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Affiliation(s)
- Jia Zhang
- Department of Dermatology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China
| | - Ming Li
- Department of Dermatology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China
| | - Zhirong Yao
- Department of Dermatology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China
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46
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El Bouchikhi I, Belhassan K, Moufid FZ, Iraqui Houssaini M, Bouguenouch L, Samri I, Atmani S, Ouldim K. Noonan syndrome-causing genes: Molecular update and an assessment of the mutation rate. Int J Pediatr Adolesc Med 2016; 3:133-142. [PMID: 30805484 PMCID: PMC6372459 DOI: 10.1016/j.ijpam.2016.06.003] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 06/14/2016] [Indexed: 12/16/2022]
Abstract
Noonan syndrome is a common autosomal dominant disorder characterized by short stature, congenital heart disease and facial dysmorphia with an incidence of 1/1000 to 2500 live births. Up to now, several genes have been proven to be involved in the disturbance of the transduction signal through the RAS-MAP Kinase pathway and the manifestation of Noonan syndrome. The first gene described was PTPN11, followed by SOS1, RAF1, KRAS, BRAF, NRAS, MAP2K1, and RIT1, and recently SOS2, LZTR1, and A2ML1, among others. Progressively, the physiopathology and molecular etiology of most signs of Noonan syndrome have been demonstrated, and inheritance patterns as well as genetic counseling have been established. In this review, we summarize the data concerning clinical features frequently observed in Noonan syndrome, and then, we describe the molecular etiology as well as the physiopathology of most Noonan syndrome-causing genes. In the second part of this review, we assess the mutational rate of Noonan syndrome-causing genes reported up to now in most screening studies. This review should give clinicians as well as geneticists a full view of the molecular aspects of Noonan syndrome and the authentic prevalence of the mutational events of its causing-genes. It will also facilitate laying the groundwork for future molecular diagnosis research, and the development of novel treatment strategies.
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Key Words
- CDC25, cell division cycle 25
- CHD, congenital heart defects
- CR, conserved region
- CRD, cysteine-rich domain
- GAP, GTPase activating protein
- GDP, guanosine-DiPhosphate
- GEF, guanine exchange factor
- GH, growth hormone
- GTP, guanosine-TriPhosphate
- HCM, hypertrophic cardiomyopathy
- IGF-1, insulin-like growth factor I
- MAP kinase signaling pathways
- Molecular etiology
- Mutation rate
- Noonan syndrome
- PTPN11
- RAS family
- RBD, RAS binding domain
- REM, RAS exchange motif
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Affiliation(s)
- Ihssane El Bouchikhi
- Medical Genetics and Oncogenetics Laboratory, HASSAN II University Hospital, BP 1835, Atlas, Fez 30000, Morocco.,Laboratory of Microbial Biotechnology, Faculty of Sciences and Techniques, University of Sidi Mohammed Ben Abdellah, B.P. 2202, Route d'Imouzzer, Fez 30000, Morocco
| | - Khadija Belhassan
- Medical Genetics and Oncogenetics Laboratory, HASSAN II University Hospital, BP 1835, Atlas, Fez 30000, Morocco
| | - Fatima Zohra Moufid
- Medical Genetics and Oncogenetics Laboratory, HASSAN II University Hospital, BP 1835, Atlas, Fez 30000, Morocco.,Laboratory of Microbial Biotechnology, Faculty of Sciences and Techniques, University of Sidi Mohammed Ben Abdellah, B.P. 2202, Route d'Imouzzer, Fez 30000, Morocco
| | - Mohammed Iraqui Houssaini
- Laboratory of Microbial Biotechnology, Faculty of Sciences and Techniques, University of Sidi Mohammed Ben Abdellah, B.P. 2202, Route d'Imouzzer, Fez 30000, Morocco
| | - Laila Bouguenouch
- Medical Genetics and Oncogenetics Laboratory, HASSAN II University Hospital, BP 1835, Atlas, Fez 30000, Morocco
| | - Imane Samri
- Medical Genetics and Oncogenetics Laboratory, HASSAN II University Hospital, BP 1835, Atlas, Fez 30000, Morocco
| | - Samir Atmani
- Medico-Surgical Unit of Cardio-pediatrics, Department of Pediatrics, HASSAN II University Hospital, BP 1835, Atlas, Fez 30000, Morocco
| | - Karim Ouldim
- Medical Genetics and Oncogenetics Laboratory, HASSAN II University Hospital, BP 1835, Atlas, Fez 30000, Morocco
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47
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Nistal M, Paniagua R, González-Peramato P, Reyes-Múgica M. Perspectives in Pediatric Pathology, Chapter 17. Other Hypergonadotropic Hypogonadisms. Pediatr Dev Pathol 2016; 19:278-90. [PMID: 26809023 DOI: 10.2350/16-01-1755-pb.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Affiliation(s)
- Manuel Nistal
- 1 Department of Pathology, Hospital La Paz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Ricardo Paniagua
- 2 Department of Cell Biology, Universidad de Alcala, Madrid, Spain
| | | | - Miguel Reyes-Múgica
- 3 Department of Pathology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA
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48
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Croonen EA, Harmsen M, Van der Burgt I, Draaisma JM, Noordam K, Essink M, Nijhuis-van der Sanden MWG. Perceived motor problems in daily life: Focus group interviews with people with Noonan syndrome and their relatives. Am J Med Genet A 2016; 170:2349-56. [PMID: 27338165 DOI: 10.1002/ajmg.a.37814] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Accepted: 06/13/2016] [Indexed: 12/27/2022]
Abstract
Studies from a patient perspective on motor performance problems in Noonan syndrome in daily life are lacking. The aims of this study were to provide insight into the motor performance problems that people with Noonan syndrome and/or their relatives experienced, the major consequences they suffered, the benefits of interventions they experienced, and the experiences with healthcare professionals they mentioned. We interviewed 10 adults with Noonan syndrome (two were joined by their parent), and 23 mothers (five of whom had Noonan syndrome), nine fathers (one of whom had Noonan syndrome) and one cousin who reported on 28 children with Noonan syndrome. People with Noonan syndrome reported particular problems related to pain, decreased muscle strength, fatigue, and clumsiness, which had an evident impact on functioning in daily life. Most participants believed that problems with motor performance improved with exercise, appropriate physiotherapy guidance, and other supportive interventions. Nevertheless, people with Noonan syndrome and/or their relatives did not feel heard and supported and experienced no understanding of their problems by healthcare professionals. This was the first study from a patient perspective that described the motor performance problems in people with Noonan syndrome, the major consequences in daily life, the positive experiences of interventions and the miscommunication with healthcare professionals. To achieve optimal support, healthcare professionals, as well as people with Noonan syndrome and/or their relatives themselves, should be aware of these frequently presented problems with motor performance. Research on these different aspects is needed to better understand and support people with Noonan syndrome.© 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Ellen A Croonen
- Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Mirjam Harmsen
- Radboud Institute for Health Sciences, IQ Healthcare, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ineke Van der Burgt
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jos M Draaisma
- Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Kees Noordam
- Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marlou Essink
- Department of Rehabilitation, Pediatric Physical Therapy, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Maria W G Nijhuis-van der Sanden
- Radboud Institute for Health Sciences, IQ Healthcare, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Rehabilitation, Pediatric Physical Therapy, Radboud University Medical Center, Nijmegen, The Netherlands
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49
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Jindal GA, Goyal Y, Burdine RD, Rauen KA, Shvartsman SY. RASopathies: unraveling mechanisms with animal models. Dis Model Mech 2016. [PMID: 26203125 PMCID: PMC4527292 DOI: 10.1242/dmm.020339] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
RASopathies are developmental disorders caused by germline mutations in the Ras-MAPK pathway, and are characterized by a broad spectrum of functional and morphological abnormalities. The high incidence of these disorders (∼1/1000 births) motivates the development of systematic approaches for their efficient diagnosis and potential treatment. Recent advances in genome sequencing have greatly facilitated the genotyping and discovery of mutations in affected individuals, but establishing the causal relationships between molecules and disease phenotypes is non-trivial and presents both technical and conceptual challenges. Here, we discuss how these challenges could be addressed using genetically modified model organisms that have been instrumental in delineating the Ras-MAPK pathway and its roles during development. Focusing on studies in mice, zebrafish and Drosophila, we provide an up-to-date review of animal models of RASopathies at the molecular and functional level. We also discuss how increasingly sophisticated techniques of genetic engineering can be used to rigorously connect changes in specific components of the Ras-MAPK pathway with observed functional and morphological phenotypes. Establishing these connections is essential for advancing our understanding of RASopathies and for devising rational strategies for their management and treatment. Summary: Developmental disorders caused by germline mutations in the Ras-MAPK pathway are called RASopathies. Studies with animal models, including mice, zebrafish and Drosophila, continue to enhance our understanding of these diseases.
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Affiliation(s)
- Granton A Jindal
- Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
| | - Yogesh Goyal
- Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
| | - Rebecca D Burdine
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Katherine A Rauen
- Department of Pediatrics, MIND Institute, Division of Genomic Medicine, University of California, Davis, Sacramento, CA 95817, USA
| | - Stanislav Y Shvartsman
- Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
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50
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Chaix MA, Andelfinger G, Khairy P. Genetic testing in congenital heart disease: A clinical approach. World J Cardiol 2016; 8:180-191. [PMID: 26981213 PMCID: PMC4766268 DOI: 10.4330/wjc.v8.i2.180] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Revised: 10/16/2015] [Accepted: 12/11/2015] [Indexed: 02/06/2023] Open
Abstract
Congenital heart disease (CHD) is the most common type of birth defect. Traditionally, a polygenic model defined by the interaction of multiple genes and environmental factors was hypothesized to account for different forms of CHD. It is now understood that the contribution of genetics to CHD extends beyond a single unified paradigm. For example, monogenic models and chromosomal abnormalities have been associated with various syndromic and non-syndromic forms of CHD. In such instances, genetic investigation and testing may potentially play an important role in clinical care. A family tree with a detailed phenotypic description serves as the initial screening tool to identify potentially inherited defects and to guide further genetic investigation. The selection of a genetic test is contingent upon the particular diagnostic hypothesis generated by clinical examination. Genetic investigation in CHD may carry the potential to improve prognosis by yielding valuable information with regards to personalized medical care, confidence in the clinical diagnosis, and/or targeted patient follow-up. Moreover, genetic assessment may serve as a tool to predict recurrence risk, define the pattern of inheritance within a family, and evaluate the need for further family screening. In some circumstances, prenatal or preimplantation genetic screening could identify fetuses or embryos at high risk for CHD. Although genetics may appear to constitute a highly specialized sector of cardiology, basic knowledge regarding inheritance patterns, recurrence risks, and available screening and diagnostic tools, including their strengths and limitations, could assist the treating physician in providing sound counsel.
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