Thiemann disease and familial digital arthropathy - brachydactyly: two sides of the same coin?

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Arthritis; Hand; Osteoarthritis; Osteonecrosis; TRPV4.

Fig. 1

(a1, a2) patient (II). Multiple bony abnormalities present, particularly involving the heads of the middle phalanges characterized by irregularity, flattening, and radial angulation. Bilateral symmetric marked joint space loss of the 2nd-5th DIP and PIP joints, 1st IP joints, left 5th MCP and right 2nd MCP joints. Osteophyte formation in a similar distribution with a subchondral cyst in the left 3rd DIP. Shortening of the middle phalanges, worst at the second and fifth digit is seen. (b1, b2) patient (I). Short and broad middle phalanges bilaterally, worst at the 2nd and 5th fingers. Irregularity and sloping of the 2nd -5th middle phalangeal heads with resultant radial deviation. No secondary degenerative changes. (c) 19-year-old man reported by Jawad et al. with Thiemann disease. There is flattening and irregularity of the phalangeal epiphyses and broadening of the PIP and DIP joints. There are signs of secondary osteoarthritis including joint space loss and osteophyte formation. Mild shortening of 2nd-5th middle and distal phalanges. (d) 17-year-old boy reported by Nurdan Kotevoglu-Senerdem et al. with Thiemann disease. There is irregularity, fragmentation and flattening of the 2nd-4th PIP and DIP joints. (e) 25-year-old women reported by Seçkin et al. with Thiemann disease. Note irregularity and flattening of the epiphyses and flexion deformity of both fifth finger PIP joints. There is thickening at the base of all proximal phalanxes and all middle phalanxes were broad. There is narrowing at the third and fourth DIP and fifth PIP joints of both hands. (f) Thiemann disease case report of a 10-year-old female by Molloy et al. There are dense sclerotic distal phalangeal epiphyses (ivory epiphyses). There is broadening and irregularity of the 2-5th middle phalangeal bases with premature physeal fusion and relative shortening. Mild ulnar deviation of the right third PIP joint. Note: permissions were obtained from the copyright holder to reuse the images c,d,e and f

Fig. 2

Protein sequence and disease-causing mutations in TRPV4. PRD, protein rich domain. CaM, calmodulin. MAP7, microtubule-associated protein 7