Defining postoperative stability in children with radial polydactyly

There is little fundamental data on paediatric metacarpophalangeal joint instability in radial polydactyly following surgical reconstruction. We evaluated 27 thumbs in a healthy paediatric population (Group A: eight girls and 19 boys with a mean age of 9.7 years (range 2.7-14.2)) and 12 thumbs following Wassel-IV reconstruction (Group B: eight girls and four boys with a mean age at follow-up of 10.6 years (range 2.7-13.2)). Metacarpophalangeal joint radial deviation, ulnar deviation on stress testing, interphalangeal joint and metacarpophalangeal joint alignment on posterior-anterior radiographs were measured and scored according to parameters defining joint instability. The aim of our study was to provide fundamental data on thumb metacarpophalangeal joint mobility patterns and alignment for further postoperative evaluations in children. The average ulnar deviation and radial deviation on stress testing of the healthy (Group A) metacarpophalangeal joints was 25 degrees (10 degrees-45 degrees) and 30 degrees (10 degrees-55 degrees), respectively. In the operated (Group B) thumbs, the ulnar deviation and radial deviation was greater at 35 degrees (10 degrees-55 degrees) and 30 degrees (10 degrees-70 degrees). Ulnar deviation (UD) of the proximal phalanx at the metacarpophalangeal joint on posterior-anterior radiographs was a mean of 10 degrees (range -10 degrees-30 degrees) in Group B;this was significantly greater than in Group A at a mean of 5 degrees (range -5-20 degrees) (p = 0.029). The mean radial alignment of the interphalangeal joint (distal phalanx relative to the proximal phalanx) was significantly higher in Group B (15 degrees) than Group A (0 degrees) (p = 0.221). In the literature on radial polydactyly, cut off values defining metacarpophalangeal joint instability in children range from 5 degrees to 20 degrees. According to our results, high but physiological metacarpophalangeal joint mobility of the thumb needs to be taken into consideration when evaluating children following reconstruction. Ulnar or radial deviation greater than 30 degrees, in combination with the lack of a definite end point on metacarpophalangeal joint stress testing, may be regarded as unstable. Based on our study on healthy paediatric and reconstructed thumbs, comparison of joint stability with the healthy contralateral hand is recommended in order to define pathological instability

Molecular analysis of two novel missense mutations in the GDF5 proregion that reduce protein activity and are associated with brachydactyly type C

Growth and differentiation factor 5 (GDF5) plays a central role in bone and cartilage development by regulating the proliferation and differentiation of chondrogenic tissue. GDF5 is synthesized as a preproprotein. The biological function of the proregion comprising 354 residues is undefined. We identified two families with a heterozygosity for the novel missense mutations p.T201P or p.L263P located in the proregion of GDF5. The patients presented with dominant brachydactyly type C characterized by the shortening of skeletal elements in the distal extremities. Both mutations gave rise to decreased biological activity in in vitro analyses. The variants reduced the GDF5-induced activation of SMAD signaling by the GDF5 receptors BMPR1A and BMPR1B. Ectopic expression in micromass cultures yielded relatively low protein levels of the variants and showed diminished chondrogenic activity as compared to wild-type GDF5. Interestingly, stimulation of micromass cells with recombinant human proGDF5(T201P) and proGDF5(L263P) revealed their reduced chondrogenic potential compared to the wild-type protein. Limited proteolysis of the mutant recombinant proproteins resulted in a fragment pattern profoundly different from wild-type proGDF5. Modeling of a part of the GDF5 proregion into the known three-dimensional structure of TGFbeta1 latency-associated peptide revealed that the homologous positions of both mutations are conserved regions that may be important for the folding of the mature protein or the assembly of dimeric protein complexes. We hypothesize that the missense mutations p.T201P and p.L263P interfere with the protein structure and thereby reduce the amount of fully processed, biologically active GDF5, finally causing the clinical loss of function phenotype