title: Fetal akinesia in metatropic dysplasia: The combined phenotype of chondrodysplasia and neuropathy?
abstract: Dominant mutations in the receptor calcium channel gene TRPV4 have been associated with a family of skeletal dysplasias (metatropic dysplasia, pseudo-Morquio type 2, spondylometaphyseal dysplasia, Kozlowski type, brachyolmia, and familial digital arthropathy) as well as with dominantly inherited neuropathies (hereditary motor and sensory neuropathy 2C, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy). While there is phenotypic overlap between the various members of each group, the two groups were considered to be totally separate with the former being strictly a structural skeletal condition and the latter group being confined to the peripheral nervous system. We report here on fetal akinesia as the presenting feature of severe metatropic dysplasia, suggesting that certain TRPV4 mutations can cause both a skeletal and a neuropathic phenotype. Three cases were detected on prenatal ultrasound because of absent movements in the second trimester. Case 4 presented with multiple joint contractures and absent limb movements at birth and was diagnosed with "fetal akinesia syndrome". Post-interruption and post-natal X-rays showed typical features of metatropic dysplasia in all four. Sequencing of the TRPV4 gene confirmed the presence of de novo heterozygous mutations predicting G78W (Case 1), T740I (Cases 2 and 3), and K276E (Case 4). Although some degree of restriction of movements is not uncommon in fetuses with skeletal dysplasia, akinesia as leading sign is unusual and suggests that certain TRPV4 mutations produce both chondrodysplasia and a peripheral neuropathy resulting in a severe "overlap" phenotype.
authors.affiliation: Service of Medical Genetics, University of Lausanne, Lausanne, Switzerland. Sheila.unger@chuv.ch
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Lausch
authors.forename: Franco
authors.initials: F
authors.lastname: Stanzial
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Irina
authors.initials: I
authors.lastname: Stefanova
authors.forename: Cristina Maria
authors.initials: CM
authors.lastname: Di Stefano
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.forename: Bernd
authors.initials: B
authors.lastname: Nilius
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
mesh_terms: D005260:Female; D005317:Fetal Growth Retardation / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D005333:Fetus / Q000002:abnormalities / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D017880:Limb Deformities, Congenital / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D008297:Male; D009134:Muscular Atrophy, Spinal / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D050916:TRPV Cation Channels / Q000235:genetics; D016216:Ultrasonography, Prenatal
chemical_list: D050916:TRPV Cation Channels; C416986:TRPV4 protein, human