Extensive Arterial Tortuosity and Severe Aortic Dilation in a Newborn With an EFEMP2 Mutation
2012; Lippincott Williams & Wilkins; Volume: 126; Issue: 23 Linguagem: Inglês
10.1161/circulationaha.112.119883
ISSN1524-4539
AutoresMaria Iascone, Maria Elena Sana, Laura Pezzoli, Paolo Bianchi, Daniela Marchetti, Giorgio Fasolini, Youcef Sadou, Anna Locatelli, Flavia Fabiani, Giovanna Mangili, Paolo Ferrazzi,
Tópico(s)Congenital heart defects research
ResumoHomeCirculationVol. 126, No. 23Extensive Arterial Tortuosity and Severe Aortic Dilation in a Newborn With an EFEMP2 Mutation Free AccessBrief ReportPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessBrief ReportPDF/EPUBExtensive Arterial Tortuosity and Severe Aortic Dilation in a Newborn With an EFEMP2 Mutation Maria Iascone, BSc, PhD, Maria Elena Sana, PhD, Laura Pezzoli, BSc, Paolo Bianchi, MD, Daniela Marchetti, BSc, PhD, Giorgio Fasolini, MD, Youcef Sadou, MD, Anna Locatelli, MD, Flavia Fabiani, MD, Giovanna Mangili, MD and Paolo Ferrazzi, MD Maria IasconeMaria Iascone From the USSD Laboratorio di Genetica Medica (M.I., M.E.S., L.P., D.M.); USC Patologia Neonatale (P.B., Y.S., G.M.); USC Radiologia (G.F.); USC Pediatria (A.L.); USC Oculistica (F.F.); and the Dipartimento Cardiovascolare (P.F.), Ospedali Riuniti di Bergamo, Bergamo, Italy. , Maria Elena SanaMaria Elena Sana From the USSD Laboratorio di Genetica Medica (M.I., M.E.S., L.P., D.M.); USC Patologia Neonatale (P.B., Y.S., G.M.); USC Radiologia (G.F.); USC Pediatria (A.L.); USC Oculistica (F.F.); and the Dipartimento Cardiovascolare (P.F.), Ospedali Riuniti di Bergamo, Bergamo, Italy. , Laura PezzoliLaura Pezzoli From the USSD Laboratorio di Genetica Medica (M.I., M.E.S., L.P., D.M.); USC Patologia Neonatale (P.B., Y.S., G.M.); USC Radiologia (G.F.); USC Pediatria (A.L.); USC Oculistica (F.F.); and the Dipartimento Cardiovascolare (P.F.), Ospedali Riuniti di Bergamo, Bergamo, Italy. , Paolo BianchiPaolo Bianchi From the USSD Laboratorio di Genetica Medica (M.I., M.E.S., L.P., D.M.); USC Patologia Neonatale (P.B., Y.S., G.M.); USC Radiologia (G.F.); USC Pediatria (A.L.); USC Oculistica (F.F.); and the Dipartimento Cardiovascolare (P.F.), Ospedali Riuniti di Bergamo, Bergamo, Italy. , Daniela MarchettiDaniela Marchetti From the USSD Laboratorio di Genetica Medica (M.I., M.E.S., L.P., D.M.); USC Patologia Neonatale (P.B., Y.S., G.M.); USC Radiologia (G.F.); USC Pediatria (A.L.); USC Oculistica (F.F.); and the Dipartimento Cardiovascolare (P.F.), Ospedali Riuniti di Bergamo, Bergamo, Italy. , Giorgio FasoliniGiorgio Fasolini From the USSD Laboratorio di Genetica Medica (M.I., M.E.S., L.P., D.M.); USC Patologia Neonatale (P.B., Y.S., G.M.); USC Radiologia (G.F.); USC Pediatria (A.L.); USC Oculistica (F.F.); and the Dipartimento Cardiovascolare (P.F.), Ospedali Riuniti di Bergamo, Bergamo, Italy. , Youcef SadouYoucef Sadou From the USSD Laboratorio di Genetica Medica (M.I., M.E.S., L.P., D.M.); USC Patologia Neonatale (P.B., Y.S., G.M.); USC Radiologia (G.F.); USC Pediatria (A.L.); USC Oculistica (F.F.); and the Dipartimento Cardiovascolare (P.F.), Ospedali Riuniti di Bergamo, Bergamo, Italy. , Anna LocatelliAnna Locatelli From the USSD Laboratorio di Genetica Medica (M.I., M.E.S., L.P., D.M.); USC Patologia Neonatale (P.B., Y.S., G.M.); USC Radiologia (G.F.); USC Pediatria (A.L.); USC Oculistica (F.F.); and the Dipartimento Cardiovascolare (P.F.), Ospedali Riuniti di Bergamo, Bergamo, Italy. , Flavia FabianiFlavia Fabiani From the USSD Laboratorio di Genetica Medica (M.I., M.E.S., L.P., D.M.); USC Patologia Neonatale (P.B., Y.S., G.M.); USC Radiologia (G.F.); USC Pediatria (A.L.); USC Oculistica (F.F.); and the Dipartimento Cardiovascolare (P.F.), Ospedali Riuniti di Bergamo, Bergamo, Italy. , Giovanna MangiliGiovanna Mangili From the USSD Laboratorio di Genetica Medica (M.I., M.E.S., L.P., D.M.); USC Patologia Neonatale (P.B., Y.S., G.M.); USC Radiologia (G.F.); USC Pediatria (A.L.); USC Oculistica (F.F.); and the Dipartimento Cardiovascolare (P.F.), Ospedali Riuniti di Bergamo, Bergamo, Italy. and Paolo FerrazziPaolo Ferrazzi From the USSD Laboratorio di Genetica Medica (M.I., M.E.S., L.P., D.M.); USC Patologia Neonatale (P.B., Y.S., G.M.); USC Radiologia (G.F.); USC Pediatria (A.L.); USC Oculistica (F.F.); and the Dipartimento Cardiovascolare (P.F.), Ospedali Riuniti di Bergamo, Bergamo, Italy. Originally published4 Dec 2012https://doi.org/10.1161/CIRCULATIONAHA.112.119883Circulation. 2012;126:2764–2768A female newborn was referred at birth to our hospital because of respiratory distress. Her family history was unremarkable except for the first-degree consanguinity of her parents. She had a mildly dysmorphic appearance, generalized hypotonia, and several musculoskeletal features such as joint laxity, arachnodactyly, pectus excavatum, flexion contracture of the wrists, and feet anomalies (Figure 1). Chest radiography showed a right pneumothorax, lungs with a ground glass appearance, elevation of the right hemidiaphragm, and scoliosis (Figure 2). ECG was normal for the age of patient except for a mild left ventricular hypertrophy (Figure 3). Transthoracic echocardiography revealed an aortic annulus of 7.4 mm with mild aortic insufficiency, a dilated aortic root (11 mm), and an ascending aortic aneurysm (11 mm) with a normal-sized aortic arch and descending aorta. The pulmonary trunk also was dilated (11 mm). Intracardiac morphology was normal. Ophthalmologic evaluation was normal.Download figureDownload PowerPointFigure 1. Pectus excavatum (A), flexion contracture of left wrist (B), and foot deformity (C).Download figureDownload PowerPointFigure 2. Radiographs showing a right pneumothorax, ground glass appearance of lungs, elevation of right hemidiaphragm, and abnormal curvature of the spine (A); arachnodactyly (B), and feet anomalies (C).Download figureDownload PowerPointFigure 3. ECG at age 20 days.At 6 months, further diagnostic assessment with computed tomography confirmed the ECG findings (Figure 4), showing extreme arterial tortuosity involving the aortic arch, supra-aortic trunks, pulmonary branches, and descending aorta (Figure 5) and extending from the cerebral vessels to the periphery (Figure 6). At that time, dilation of the aneurysm had progressed (ascending aorta 27 mm; aortic root 22 mm) despite treatment with β-blockers.Download figureDownload PowerPointFigure 4. Echocardiographic findings at 6 months. Sagittal (A), parasternal long axis (B), and short axis (C) projections showing dilation of the ascending aorta (Ao) and pulmonary trunk (PT). RPA indicates right pulmonary artery; RV, right ventricle; LV, left ventricle; and LA, left atrium.Download figureDownload PowerPointFigure 5. 3D reconstruction by computed tomography volume rendering of the heart and great vessels: anteroposterior (A), oblique (B), right-lateral (C), and posterior (D) views. There is a marked dilation of the ascending aorta and pulmonary trunk with extensive tortuosity of the supra-aortic trunks, pulmonary branches, and descending aorta. R indicates right; I, inferior; AR, antero-right; PL, postero-lateral; and L, left.Download figureDownload PowerPointFigure 6. 3D reconstruction by computed tomography volume rendering of the chest and abdomen showing a spinal deformity and tortuosity of the arterial tree (A) and dilation and tortuosity of the circle of Willis (B).Because these features overlap with several neonatal forms of well-described rare disorders such as Loeys-Dietz syndrome, Marfan syndrome, and arterial tortuosity syndrome,1 we performed whole-exome sequencing on the patient's and her parents' genomic DNA using Agilent SureSelect enrichment and Illumina 2×100 paired-end protocol. To analyze and filter the data, we used a specific pipeline based on current best practices,2,3 applying an autosomal recessive model. With this approach we detected a known homozygous mutation of p.Glu57Lys (hg19, chr11:65638826C>T NM-016938) in fibulin-4 (the EFEMP2 gene) in the proband; both parents were heterozygous carriers. This missense mutation previously was reported in autosomal recessive cutis laxa type 1B syndrome, and the phenotype of our patient was compatible with this diagnosis.4 This case highlights the value of whole-exome sequencing to reach a definitive diagnosis of rare genetic conditions characterized by high genetic heterogeneity and phenotypic overlap. In addition, this is the first extensive documentation of vascular abnormalities in a newborn with an EFEMP2 mutation.AcknowledgmentsThe authors sincerely thank Anna Rita Lincesso and Rosa Gallitelli for their valuable technical assistance.Sources of FundingL. Pezzoli was supported by Fondazione S. Martino-Creberg and M.E. Sana and L. Pezzoli were supported by a research grant of Regione Lombardia (D.R. 13465/22-12-2010).DisclosuresNone.FootnotesCorrespondence to Maria Iascone, BSc, PhD, Genetica Molecolare, USSD Laboratorio di Genetica Medica, Ospedali Riuniti, Largo Barozzi, 1, 24128 Bergamo, Italy. 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