# The Broad Clinical Spectrum of Metatropic Dysplasia: A Case Series and Literature Review

## TL;DR

This paper describes three cases of metatropic dysplasia, a rare genetic bone disorder, highlighting the varied severity and co-occurring neurological symptoms.

## Contribution

The study adds new clinical insights into the variable manifestations of TRPV4-related disorders and their overlapping features.

## Key findings

- Three patients with metatropic dysplasia showed distinct severity profiles and extra-skeletal complications.
- TRPV4 variants p.Asn796del and p.Pro799Leu were identified, associated with both skeletal and neurological symptoms.
- The findings support a clinically heterogeneous spectrum of TRPV4-related disorders rather than separate conditions.

## Abstract

Metatropic dysplasia is an autosomal dominant skeletal disorder characterized by progressive kyphoscoliosis, severe platyspondyly, pronounced metaphyseal enlargement, and shortening of the long bones. This condition is caused by pathogenic variants in the TRPV4 (Transient Receptor Potential Vanilloid 4) gene, which encodes a non-selective calcium channel involved in bone homeostasis. Variants in TRPV4 have been associated with two major disease groups: skeletal dysplasias and neuropathies, with recent findings indicating an overlap in their clinical features. We report three patients with metatropic dysplasia, each presenting a distinct severity profile. All exhibited a bell-shaped thorax, significant platyspondyly, and shortened long bones with broad metaphyses. Notably, patients 1 and 3 had more complex clinical courses, including seizures and global developmental delay. Genetic analysis revealed two different TRPV4 variants: p.Asn796del (patient 1) and p.Pro799Leu (patients 2 and 3). These cases illustrate variability in extra-skeletal manifestations, complications, and prognosis. In our patients with TRPV4-related disorders, the co-occurrence of neurological symptoms and skeletal abnormalities suggests a clinically heterogeneous spectrum consistent with a single disease rather than distinct entities. A comprehensive, multidisciplinary approach is essential to optimize management and improve the quality of life for patients.