P. Debeer

The fibulin-1 gene (FBLN1) is disrupted in a t(12;22) associated with a complex type of synpolydactyly.

Molecular analysis of the reciprocal chromosomal translocation t(12;22)(p11.2;q13.3) cosegregating with a complex type of synpolydactyly showed involvement of an alternatively spliced exon of the fibulin-1 gene (FBLN1 located in 22q13.3) and the C12orf2 (HoJ-1) gene on the short arm of chromosome 12. Investigation of the possible functional involvement of the fibulin-1 protein (FBLN1) in the observed phenotype showed that FBLN1 is expressed in the extracellular matrix (ECM) in association with the digits in the developing limb. Furthermore, fibroblasts derived from patients with the complex type of synpolydactyly displayed alterations in the level of FBLN1-D splice variant incorporated into the ECM and secreted into the conditioned culture medium. By contrast, the expression of the FBLN1-C splice variant was not perturbed in the patient fibroblasts. Based on these findings, we propose that the t(12;22) results in haploinsufficiency of the FBLN1-D variant, which could lead to the observed limb malformations.

PA26 is a candidate gene for heterotaxia in humans: identification of a novel PA26-related gene family in human and mouse

Heterotaxia is an aetiologically heterogeneous condition caused by an abnormal left-right axis formation, resulting in reversed left-right polarity of one or more organ systems. In a patient with heterotaxia and a de novo reciprocal translocation t(6;18)(q21;q21), we found that the PA26 gene was disrupted by the 6q21 breakpoint. Northern blot analysis showed decreased expression of the PA26 gene in an Epstein-Barr virus-transformed cell line of this patient. During early embryogenesis of Xenopus, the orthologue of PA26, XPA26 is exclusively expressed in the notochord, a midline structure. This further supports a possible role of PA26 in human situs determination. Mutation analysis of human PA26 gene in 40 unrelated individuals with unexplained heterotaxia failed to identify mutations, indicating that PA26 mutations are not a frequent cause of heterotaxia in humans. Analysis of the PA26 gene structure resulted in the identification of a novel PA26-related gene family, which we have named the sestrin family, and which comprises three closely related genes in human and in mouse.

Severe digital abnormalities in a patient heterozygous for both a novel missense mutation in HOXD13 and a polyalanine tract expansion in HOXA13

Hox genes encode a highly conserved family of transcription factors with fundamental roles in body patterning during embryogenesis.1 Studies in mouse and chick have shown that the 5‘ HoxD and HoxA genes are critical for vertebrate limb and urogenital tract development.2 In humans, mutations in HOXD13 and HOXA13 cause the rare dominantly inherited limb malformation syndromes synpolydactyly (SPD, MIM 186000) and hand-foot-genital syndrome (HFGS, MIM 140000), respectively. SPD is characterised by syndactyly between the third and fourth fingers and between the fourth and fifth toes, with variable digit duplication in the syndactylous web. Most cases result from expansions of a polyalanine tract in the N-terminal region of HOXD13 3–6 but frameshifting deletions have been identified in three families with an atypical foot phenotype.7,8 HFGS is characterised by short thumbs and halluces, hypospadias in males, Mullerian duct fusion defects in females, and urinary tract malformations in both sexes. Most cases result from nonsense mutations in HOXA13 , but two polyalanine tract expansions and one missense mutation have also been described.9–11 Here we report two Belgian families, one with the first missense mutation to be identified in HOXD13 and the other with only the third polyalanine tract expansion to be identified in HOXA13. Remarkably, intermarriage between the two families has resulted in a girl heterozygous for both mutations, the first human HOXD13 / HOXA13 double heterozygote to be reported. Her digital abnormalities are strikingly more severe than those in carriers of each individual mutation, suggesting that the two mutations act synergistically. ### The proband The proband (fig 1) was born with severe bilateral hand abnormalities (fig 2A-F). She had complete cutaneous syndactyly between the third and fourth fingers, duplication of the distal and proximal phalanges of the fourth fingers, and a rudimentary extra central metacarpal. In addition, both …

Responsiveness of the Dutch Version of the Dash as an Outcome Measure for Carpal Tunnel Syndrome

A cohort of 119 patients with carpal tunnel syndrome completed the questionnaire of the Dutch version of the DASH score pre-operatively and one year postoperatively. The mean DASH score decreased from 38.2 to 22.0. There was a significant correlation with the Boston carpal tunnel outcome score (r =0.78). With an effect size of 0.87 and a standardized mean response of 0.69, the Dutch version of the DASH is highly responsive for the evaluation of the outcome of surgery for carpal tunnel syndrome.

A novel NOG mutation Pro37Arg in a family with tarsal and carpal synostoses.

Noggin, an antagonist of members of the transforming growth factor-b family, plays an important role in joint morphogenesis. Mutations in the human Noggin gene, NOG, have been identified in sporadic and familial cases with disorders affecting joint formation. Proximal symphalangism (SYM1, OMIM 185800) is characterized by early onset progressive ankylosis of the proximal interphalangeal joints, carpal and tarsal bone fusions, and conductive hearing loss. In multiple synostosis syndrome (SYNS1, OMIM 186500) affected individuals share some clinical symptoms with SYM1 and have in addition brachydactyly, hypoplastic or absent middle phalanges, dislocation of the radial head, pectus carinatum, and a broad hemicylindrical nose. Individuals with tarsal/carpal coalition syndrome (TCC, OMIM 186570) have a

Physical mapping of the t(12;22) translocation breakpoints in a family with a complex type of 3/3′/4 synpolydactyly

We previously reported clinical and radiological findings in a Belgian family with a complex type of synpolydactyly associated with metacarpal and metatarsal synostoses, cosegregating with a balanced t(12;22). Recently, expansions of a polyalanine stretch within the first exon of the HOXD13 gene, which resides on chromosome 2q31, have been shown to cause synpolydactyly (SPD). Using exon amplification followed by direct sequencing, we were able to exclude the direct involvement of the HOXD13 gene in this family. As a first step toward the positional cloning of a candidate disease gene on chromosome 12 and/or 22 responsible for the type of complex synpolydactyly observed in this family, we report here the construction of a somatic cell hybrid retaining only the der(22) of the t(12;22)(p11.3;q13.3). STS content mapping and FISH experiments allowed us to position the chromosomal breakpoints between markers D12S1596 and D12S1034 on chromosome 12 and markers N73F4 and D22S158 on chromosome 22.

Fixation of a periprosthetic humeral fracture with CCG-cable system.

Abstract We report a case of periprosthetic fracture of the shoulder, treated operatively. A special plate/cable system (ECG) was used with an excellent outcome. This easy technique is recommended for such fractures.

Sporadic case of bilateral fusion of metacarpal 4 and 5

We describe a patient with a bilateral fusion of a hypoplastic 5th metacarpal with the 4th metacarpal. Family history was negative and no other abnormalities were noted. A17-year-oldmalewas seenat theGeneticClinicwith bilateral short, angulated 5th fingers (Fig. 1). Therewas no syndactyly. He had a normal function of both hands. Family history was normal and apart from the digital abnormality no other malformations were noticed. On X-ray, a hypoplastic 5th metacarpal fused with the fourth metacarpal was noticed. The outline of the hypoplastic 5th metacarpal can be distinguished in the 4th metacarpal (‘bone in bone’ appearance) (Fig. 2). Ultrasound of the kidneys was normal. Chromosome studies on a peripheral blood lymphocyte culture showed a 46,XY normal male karyotype after G-banding. Fusion ofmetacarpals 4 and 5 is not a frequent finding in non-syndromic hand malformations. Syndactyly type V (OMIM 186300), one of the rarest forms of nonsyndromic syndactyly, is characterized by fusion of metacarpals 4 and 5with angulation of digit 5. Different degrees of syndactyly, brachydactyly, split hand, and camptodactyly are also seen [Robinow et al., 1982]. Synostosis between metacarpals 4 and 5 has also been described as an X-linked recessive trait (OMIM 309630) [Orel, 1928; Holmes et al., 1972; Annerén and Amilon, 1994] but other reports suggest autosomal inheritance [Lerch, 1948; Habighorst and Albers, 1965]. A Y-like fusion of metacarpals 4 and 5 has also been observed in patients with a distal 13q deletion [Schinzel, 2001]. This report describes a sporadic case of an isolated synostosis betweenmetacarpals 4 and 5.Apart from this fusion no other handor foot abnormalities were noted. Since no other family members were affected, this case