Further Evidence of a Continuum in the Clinical Spectrum of Dominant <b><i>PIEZO2</i></b>-Related Disorders and Implications in Cerebellar Anomalies

Abstract

<b><i>Introduction:</i></b> Pathogenic variants in the PIEZO family member 2 (<i>PIEZO2</i>) gene are known to cause Gordon syndrome (GS), Marden-Walker syndrome (MWS), and distal arthrogryposis type 5 (DA5). Out of these, MWS has a recognizable phenotype that can be discerned easily, but the distinction between GS and DA5 is less evident. Few children with pathogenic <i>PIEZO2</i> variants have been reported to show posterior fossa anomalies. <b><i>Methods and Results:</i></b> By candidate gene targeting guided by proper clinical evaluation and neuroimaging findings, a patient with classic MWS harboring a de novo novel variant (c.8237G&#x3e;A, p.W2746*) in the C-terminal region of PIEZO2 was identified. In addition, another girl with the typical clinical features of GS is also described carrying the most prevalent reported variant (c.8057G&#x3e;A, p.R2686H) in <i>PIEZO2</i>. The brain MRI of the 2 patients showed Dandy-Walker malformation (DWM). Diffusion tensor imaging visualized anteroposterior and downward aligned thin middle cerebellar peduncle. The association of DWM with arthrogryposis in the presence of <i>PIEZO2</i> variants remains quite interesting and provides more evidence that PIEZO2 plays a role in the development of hindbrain although the underlying mechanism remains unclear. Moreover, the 2 girls had distinct foot patterning in the form of shortening of the first and fifth toes. <b><i>Conclusion:</i></b> Phenotype analysis and a comprehensive review of the literature strongly support the previously published data and corroborate the evidence that heterozygous <i>PIEZO2-</i>related disorders represent a continuum with overlapping phenotypic features.