TRPV4-related disorders constitute a broad spectrum of clinical phenotypes including several genetic skeletal and neuromuscular disorders, in which clinical variability and somewhat overlapping features are present. These disorders have previously been considered to be clinically distinct phenotypes before their molecular basis was discovered. However, with the identification of TRPV4 variants in the etiology, they are referred as TRPV4-related disorders (TRPV4-pathies), and are now mainly grouped into skeletal dysplasias and neuromuscular disorders. The skeletal dysplasia group includes metatropic dysplasia, parastremmatic dysplasia, spondyloepiphyseal dysplasia Maroteaux type, spondylometaphyseal dysplasia Kozlowski type, autosomal dominant brachyolmia, and familial digital arthropathy-brachydactyly, whereas the neuromuscular group includes congenital distal spinal muscular atrophy (SMA), scapuloperoneal SMA and Charcot-Marie-Tooth neuropathy type 2C with common manifestations of peripheral neuropathy, joint contractures, and respiratory system involvement. Apart from familial digital arthropathy-brachydactyly, skeletal dysplasia associated with TRPV4 pathogenic variants share some clinical features such as short stature with short trunk, spinal and pelvic changes with varying degrees of long bone involvement. Of note, there is considerable phenotypic overlap within and between both groups. Herein, we report on the clinical and molecular spectrum of 11 patients from six different families diagnosed with TRPV4-related disorders. This study yet represents the largest cohort of patients with TRPV4 variants from a single center in Turkey.

Familial digital arthropathy-brachydactyly (FDAB) and Thiemann disease are non-inflammatory digital arthropathies with many phenotypic similarities. Thirty-three cases of Thiemann disease have been described so far (Mangat et al, Ann Rheum Dis 64:11-2, 2005; Ha et al, Thiemann's disease: a case Report, 2017) but no gene variants have been identified as causative to date. FDAB is reported in only a few patients and has been associated with three heterozygous missense variants in the Transient receptor potential vanilloid 4 (TRPV4) gene. We report a TRPV4 variant in a father and son referred with a diagnosis of Thiemann disease and compare the clinical and radiological features of Thiemann disease with Familial digital arthropathy-brachydactyly (FDAB). We hypothesize that these two entities may be one and the same. We describe a father and son referred with a diagnosis of Thiemann disease who were subsequently identified with a heterozygous variant (c.809G > T) in TRPV4. The identical genetic variant was previously reported to cause FDAB. A PUBMED® database search was conducted to retrieve articles related to Thiemann disease and FDAB. We were able to review the clinical and radiological findings of nineteen individuals affected by Thiemann disease and compare them with three families affected by FDAB. Thiemann disease initially affects the proximal interphalangeal joints and primarily the middle phalangeal bases. In FDAB, the distal phalangeal joints are first affected with the middle phalangeal heads being the primary site of changes. Radial deviation has only been described in FDAB. Our analysis determined that 5 of 20 individuals affected by Thiemann disease have clinical and radiological findings that also fit well with FDAB. FDAB and Thiemann disease are non-inflammatory digital arthropathies with phenotypic overlap. Although more extensive joint involvement, a distal hand joint preponderance and brachydactyly are expected in FDAB, there are striking clinical and radiological similarities between the two entities. Our analysis suggests that these two phenotypes may represent phenotypic variability of the same entity. Despite many attempts to identify other reported patients affected by Thiemann disease, we were not able to procure DNA from any of the cases to verify our findings. Genetic testing of an affected individual will be crucial in order to provide accurate reproductive genetic counselling about the autosomal dominant nature of this condition.