Accepted Manuscript Metatropic dysplasia in third trimester of pregnancy and a novel causative variant in the TRPV4 gene Sara Bargiacchi, Matteo Della Monica, Roberto Biagiotti, Elena Andreucci, Serena Ciabattoni, Paolo Poggi, Marco Di Maurizio, Claudio Defilippi, Ettore Cariati, Sabrina Giglio, MD, PhD PII:
S1769-7212(16)30309-3
DOI:
10.1016/j.ejmg.2017.04.007
Reference:
EJMG 3282
To appear in:
European Journal of Medical Genetics
Received Date: 9 September 2016 Revised Date:
6 April 2017
Accepted Date: 10 April 2017
Please cite this article as: S. Bargiacchi, M. Della Monica, R. Biagiotti, E. Andreucci, S. Ciabattoni, P. Poggi, M. Di Maurizio, C. Defilippi, E. Cariati, S. Giglio, Metatropic dysplasia in third trimester of pregnancy and a novel causative variant in the TRPV4 gene, European Journal of Medical Genetics (2017), doi: 10.1016/j.ejmg.2017.04.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Metatropic dysplasia in third trimester of pregnancy and a novel causative variant in the
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TRPV4 gene
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Sara Bargiacchia, Matteo Della Monicaa, Roberto Biagiottib, Elena Andreuccia, Serena Ciabattonic,
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Paolo Poggib, Marco Di Mauriziod, Claudio Defilippid, Ettore Cariatib, Sabrina Giglioa,c.
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a. Medical Genetics Unit and b. Prenatal Diagnosis Unit and d. Department of Diagnostic Imaging,
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Meyer Children's University Hospital, viale Gaetano Pieraccini, 24 - 50139 Florence.
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c. Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences "Mario Serio", University of Florence, viale Gaetano Pieraccini, 6 - 50139 Florence;
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Corresponding author:
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Sabrina Giglio, MD, PhD
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Department of Clinical and Experimental Biomedical Sciences and Medical Genetics Unit, Meyer
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Children’s University Hospital, viale Pieraccini, 24 50139 Firenze Italy.
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Tel:+390555662216; Fax:+390555662849;
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E-mails:
[email protected];
[email protected]
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Conflicts of Interest
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The authors declare that they have no financial or other conflicts of interest in relation to this
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research and its publication.
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Abstract
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Prenatal diagnosis of skeletal dysplasias is particularly difficult for many reasons and differentiating
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these disorders in the prenatal period can be challenging because they are rare and many of the
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ultrasound findings are not necessarily pathognomonic for a specific disorder. The diagnosis is
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often made just after birth or exitus. The prenatal diagnosis of osteochondrodysplasias is based
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predominantly upon fetal ultrasound findings and it focuses substantially on the possible lethality of
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the disorder, without always being able to find a specific name for the disorder.
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Metatropic dysplasia is a rare osteochondrodysplasia due to mutations in the TRPV4 gene: TRPV4
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is a cation channel, non-selectively permeable to calcium, encoded by a gene on chromosome
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12q24.11; it is widely expressed and involved in many different physiological processes through
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responses to several different stimuli (physical, chemical, and hormonal) in ciliated epithelial cells.
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The exact incidence of this disorder is not known, however less than a hundred cases have been
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reported at present, with only two prenatal reports but without any reference to the molecular test.
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We describe the first report of molecular diagnosis of metatropic dysplasia carried out in prenatal
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diagnosis: the molecular testing of the TRPV4 (transient receptor potential cation channel,
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subfamily V, member 4, MIM *605427) gene in our case, in fact, detected a causative variant,
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confirming the diagnostic suspicion, which was made possible thanks also to the utilization of MRI
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and CT scan. In our case different imaging methods together with the close cooperation of a
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multidisciplinary team and test availability, allowed an accurate diagnosis.
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KEYWORDS: Metatropic dysplasia, fetal ultrasound, magnetic resonance imaging, prenatal
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osteochondrodysplasia, TRPV4 gene, genetic counseling 2
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Introduction
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Skeletal dysplasias are a large heterogeneous group of disorders consisting of abnormalities of bone
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or cartilage growth or their shape and structure. Over 430 different entities have been described,
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with very different clinical courses and prognoses. The overall birth prevalence of these disorders is
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estimated to be about 2.4-4.5 per 10,000 births [Bonafe et al, 2015]. Often, single gene disorders
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with autosomal dominant/recessive, X-linked modes of inheritance, imprinting errors, or
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chromosome abnormalities are the determining causes, but they can rarely be also due to extrinsic
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causes (e.g. maternal autoimmune diseases) [Chitayat et al, 2008]. A classification system was
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created to assign genetic bone disorders into major groups by their principal features (radiological,
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molecular etiology, inheritance, etc.) [Bonafe et al, 2015]. Despite the fact that fetal skeletal
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dysplasias are generally recognized on prenatal sonography, a precise prenatal diagnosis of a
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specific skeletal dysplasia can be challenging due to its rarity, the variety of the causative genes and
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the spectrum of mechanisms associated with their formation. The diagnosis, prenatally, is based
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predominantly upon fetal ultrasound (US) findings. Magnetic resonance imaging (MRI) can help in
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evaluating the cartilage components of the fetal skeleton, it is used as a complimentary method and
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it is considered harmless for the fetus. Computed tomography (CT), on the other hand, is not
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commonly used in prenatal imaging, but it can help to better define the features of the calcified
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bones; the main limitation of this technique is the potential effect of ionizing radiations on the fetus,
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but there are low-exposure techniques which result adequate for diagnosis and harmless for the
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fetus [American College of Obstetricians and Gynecologists’ Committee on Obstetric Practice,
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2016]. All these imaging methods, along with molecular analysis, may be used to support the
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probable diagnosis [Khalil et al, 2011].
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Metatropic Dysplasia is a very rare form of osteochondrodysplasia first described by Maroteaux et
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al. in 1966 [Maroteaux et al, 1966]. This severe skeletal disorder can be diagnosed in the neonatal
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change in the proportions of the affected children. The radiologic findings are characterized by
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short diaphyses, dumbbell appearance of the metaphyses, slender appearing fingers and toes, small
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iliac wings with narrow sacro-sciatic notches, delayed ossification of ischio/pubic bones and severe
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platyspondyly. Kyphoscoliosis is usually not present at birth and develops later. The severity of
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platyspondyly, kyphoscoliosis and odontoid hypoplasia has a prognostic impact, with subsequent
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risk for cardiorespiratory failure and cervical medullar compression [Genevieve et al, 2008].
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Dominant mutations in the gene encoding TRPV4 (transient receptor potential cation channel,
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subfamily V, member 4, MIM *605427), a calcium permeable ion channel, are associated with both skeletal
type
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arthropathy-brachydactyly,
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Parastremmatic dwarfism, SED Maroteaux type and Spondylometaphyseal dysplasia Kozlowski
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type) and neuromuscular (Charcot-Marie-Tooth disease type 2C, scapuloperoneal spinal muscular
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atrophy and congenital distal spinal muscular atrophy) disorders and a wide variability of clinical
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manifestations for each disorder have been described. TRPV4 is expressed broadly and has diverse
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physiologic roles: mechanosensation and nociception in the sensory nervous system [Alessandri-
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Haber et al, 2009], osmosensation and flow sensing in the kidney, stretch sensation in the bladder
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[Pochynyuk et al, 2013], skin barrier function [Kida et al, 2012], chondrogenesis, bone homeostasis
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[Masuyama et al, 2012], and regulation of adipose oxidative metabolism [Ye et al, 2012]. The exact
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pathophysiology of TRPV4 pathogenic variants that result in skeletal dysplasias is not well
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understood. Based on the lack of a comparable phenotype in the Trpv4 knockout mouse, it is
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presumed that the mechanism of disease in humans consists in a dominant gain of function,
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characterized by increased constitutive activity and elevated channel activation. This mechanism
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also fits with the vast majority of the known TRPV4 pathogenic variants being missense.
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The fact that mutations in the TRPV4 gene cause bone dysplasias is consistent with the channel
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being expressed in osteoblasts and osteoclasts at the earliest stages of chondrocyte differentiation
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Metatropic
dysplasia,
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ACCEPTED MANUSCRIPT and having an important role in cartilage, since it is expressed in the early stages of chondrocyte
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differentiation and modulates SOX9 expression in cell culture [Muramatsu et al, 2007].
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We report a prenatal case of severe metaphyseal enlargement and other phenotypic features which,
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at the first observation, had been misinterpreted as bowing of long bones on US images.
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The close cooperation of a multidisciplinary team made of gynecologists, geneticists and
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radiologists and the imaging methods (MRI and CT) together with the test availability, allowed us
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to reach an accurate diagnosis of metatropic dysplasia (MD), confirmed through the molecular
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analysis of the TRPV4 gene.
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Clinical report
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A 27-year-old woman was referred to our tertiary prenatal diagnosis center at 30+5 weeks of
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gestation, because of ‘ultrasound findings suggestive for skeletal dysplasia’ in a female fetus. This
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was the second spontaneous pregnancy of the couple. Nuchal translucency (NT) measurement at the
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first trimester screening was 1 mm. The second trimester US was reported unremarkable, but in the
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third trimester US showed “length of long bones below the 5° centile; slightly bent femurs;
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amniotic fluid above average”. After genetic counseling, the couple chose to undergo
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amniocentesis: array-CGH analysis (Agilent-4x180 K) and sequencing of the FGFR3 gene were
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performed, which both turned out to be negative. At 33+5 weeks of gestation the patient underwent
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a new US, which showed "arrest in the growth of the long bones with initial bowing, left
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hydronephrosis, and right inguinal hernia, augmented amniotic fluid". In order to better define the
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finding of inguinal hernia and have a comprehensive view of the cartilage, a fetal MRI was carried
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out at 34 weeks using a 1.5 Tesla magnet: the exam fully confirmed the US findings and showed a
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very large epiphyseal volume.
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FIG 1: Fetal MRI. Short dumbbell shaped femurs with very thin diaphysis (arrowheads) and very wide epiphyseal cartilages (arrows)
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A final fetal US at 35+5 weeks showed "severe micromelia (long bones