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.

TRPV4 axonal neuropathy spectrum disorder

“…20 The three mutations identified in the fetuses and newborn with fetal akinesia and metatropic dysplasia were G78W in the N-terminal domain, K276E in finger loop 3 of the ARD and T740I in the C-terminal domain. 21 All three are novel as they have not been reported in any of the previously identified individuals with metatropic dysplasia. Finally Unger et al 21 refer to a manuscript in press by Cho et al detailing the finding of features of a neuropathy in a patient with SMDK and a mutation already documented in association with this phenotype (Cho et al mutation not revealed).…”

“…21 All three are novel as they have not been reported in any of the previously identified individuals with metatropic dysplasia. Finally Unger et al 21 refer to a manuscript in press by Cho et al detailing the finding of features of a neuropathy in a patient with SMDK and a mutation already documented in association with this phenotype (Cho et al mutation not revealed). 21 These observations together suggest that mutations at the four key residues in the ARD mentioned above cause a neurological disorder with probably secondary skeletal changes.…”

“…Unger et al 21 reported three fetuses and one newborn with a clear radiographic diagnosis of metatropic dysplasia but whose presenting features were reduced fetal movements and the finding of short long bones and a hypoplastic thorax on ultrasound scanning in the second trimester. Post mortem/post natal examination showed contractures in all four affecting hips, knees, elbows and fingers (arthrogryposis).…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Sometimes metatropic dysplasia is combined with lethal fetal akinesia. The nonlethal forms are characterized by short limbs, shortening of all long bones, enlargement of joints, severe kyphoscoliosis, severe platyspondyly, severe metaphyseal enlargement, and defects in ossification (Krakow et al, 2009;Camacho et al, 2010;Unger et al, 2011).…”

Combined Phenotypes of Spondylometaphyseal Dysplasia-Kozlowski Type and Charcot-Marie-Tooth Disease Type 2C Secondary to a TRPV4 Pathogenic Variant

“…al., 2010; Unger et al, 2011;Cho et al, 2012;Evangelista et al, 2015]. TRPV4 mutations are inherited in a dominant/heterozygous manner, and the clinical phenotype tends to be similar in families.…”