Philippe Debeer

Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis

Osteopoikilosis, Buschke-Ollendorff syndrome (BOS) and melorheostosis are disorders characterized by increased bone density. The occurrence of one or more of these phenotypes in the same individual or family suggests that these entities might be allelic. We collected data from three families in which affected individuals had osteopoikilosis with or without manifestations of BOS or melorheostosis. A genome-wide linkage analysis in these families, followed by the identification of a microdeletion in an unrelated individual with these diseases, allowed us to map the gene that is mutated in osteopoikilosis. All the affected individuals that we investigated were heterozygous with respect to a loss-of-function mutation in LEMD3 (also called MAN1), which encodes an inner nuclear membrane protein. A somatic mutation in the second allele of LEMD3 could not be identified in fibroblasts from affected skin of an individual with BOS and an individual with melorheostosis. XMAN1, the Xenopus laevis ortholog, antagonizes BMP signaling during embryogenesis. In this study, LEMD3 interacted with BMP and activin-TGFβ receptor–activated Smads and antagonized both signaling pathways in human cells.

Haploinsufficiency of the HOXA gene cluster, in a patient with hand-foot-genital syndrome, velopharyngeal insufficiency, and persistent patent Ductus botalli

We acknowledge the participation of the proband and his parents. We thank Guy Van Camp for providing the YAC DNA, Reinhilde Toelen and Kristien Minner for excellent technical assistance, and Dr. F. Goodman and Dr. C. Hall (Institute of Child Health, London) for help in interpreting the x-rays and for stimulating discussions.

Variable phenotype in Greig cephalopolysyndactyly syndrome: clinical and radiological findings in 4 independent families and 3 sporadic cases with identified GLI3 mutations.

Greig cephalopolysyndactyly (GCPS) (OMIM 175700) is an autosomal dominant disorder characterized by a distinct combination of craniofacial, hand and foot malformations. In this report, clinical and radiological findings of 12 patients with GCPS derived from 4 independent families and 3 sporadic cases with documented GLI3 mutations are presented with particular emphasis on inter‐ and intrafamilial variability. In a particularly instructive family in which 9 members of 4 generations could be studied clinically and molecularly, a missense mutation (R625W) is transmitted and shows a partially penetrant pattern. In a branch of the family, the GCPS phenotype skips a generation via a normal female carrier without clinical signs providing evidence that GCPS does not always manifest full penetrance as generally supposed.

Erratum: Glenosphere Disengagement: A Potentially Serious Default in Reverse Shoulder Surgery

Implant failure is a serious complication in reverse shoulder arthroplasty. We determined the incidence of glenosphere disengagement in a cohort of 479 reverse shoulder prostheses (468 Delta III TM (DePuy International Ltd, Leeds, UK), 11 Aequalis TM (Tornier, Grenoble, France)). We also determined whether disengagement adversely affected clinical outcomes. The minimum followup was 12 months (mean, 28.6 months; range, 12-72 months). Disengagement of the glenosphere occur- red in 16 of 479 shoulders (3.2%). In 13 patients, the disengagement was partial (clear step-off between the baseplate and the glenosphere) and was not associated with a poor functional outcome with this short-term followup. In three patients, the disengagement led to a fracture of the central screw, leading to a complete disengagement of the glenosphere from the baseplate, necessitating revision in two; the third refused revision. Partial disengagement was seen in five of 11 Aequalis TM prostheses (45.4%) and eight of 468 Delta III TM prostheses (1.7%). The three total dis- engagements with central screw breakage all occurred in Delta III TM prostheses. We believe differences in the type of locking screws may explain the differences observed between the two types of reverse prostheses. Level of Evidence: Level III, retrospective study. See the Guidelines for Authors for a complete description of levels of evidence.

DNA Analysis of a Transplanted Cryopreserved Meniscal Allograft

SUMMARY Meniscal transplantation is frequently performed in young patients with a single meniscal-deficient compartment as a result of previous total meniscectomy. Indications, operative techniques, and preservation of meniscal allografts have been studied extensively. In this study we compared the DNA profile of a meniscal allograft with that of the human recipient 1 year after transplantation. Applying techniques routinely used in forensic analysis, we were able to show that the DNA profile of the meniscal allograft was 95% identical to that of the human recipient. These findings indicate that 1 year after transplantation the meniscal allograft is nearly completely repopulated by host cells.

Resection arthroplasty of the shoulder as a salvage procedure for deep shoulder infection: does the use of a cement spacer improve outcome?

HYPOTHESIS Resection arthroplasty can be performed for recalcitrant shoulder infection. It is unclear whether a spacer has any benefit. We hypothesized that spacers would increase infection control and improve clinical results. MATERIALS AND METHODS Twenty-one patients were evaluated retrospectively at a mean follow-up of 46.4 months: 11 patients did not receive a spacer (group A), and 10 patients did receive a spacer (group B). Patients were assessed clinically and with radiographs. Patients were scored using the Visual Analog Scale (VAS), Constant-Murley Score (CMS), Simple Shoulder Test, and Disabilities of Arm, Shoulder and Hand. RESULTS Infection was eradicated in 19 patients without additional surgery. Two patients had elevated C-reactive protein and erythrocyte sedimentation rate and were considered to have low-grade infections. Neither patient received a spacer and had not been revised. Infectious control was not significantly different between group A and group B (P = .48). Fourteen patients found the result good or acceptable. The VAS decreased from 6.5 to 2.6. The CMS increased significantly from 17.8 to 40.4. Active abduction averaged 78.1° and active flexion averaged 85.5°. External rotation was 21.0°. DISCUSSION No significant difference was shown between group A and group B. Preservation of the tuberosities was identified as a prognosticator for a good result. Unacceptable pain resulted in 5 patients with a spacer undergoing delayed reimplantation of a prosthesis. CONCLUSION Resection arthroplasty can be offered to patients with long-standing deep shoulder infection that was unresponsive to previous surgical treatment. Control of infection did not differ significantly between the groups. No improvement in outcome was demonstrated with the use of cement spacers.

Melorheostosis in a family with autosomal dominant osteopoikilosis: Report of a third family

We describe a three‐generation family with clinical and radiological findings of osteopoikilosis in five and melorheostosis in one individual. The co‐occurrence of both rare bone disorders suggests that both conditions might be related as suggested previously by Butkus et al. [1997: Am J Med Genet 72:43–46] and Nevin et al. [1999: Am J Med Genet 82:409–414]. The findings in this family strengthen the hypothesis that osteopoikilosis is an autosomal dominant condition and that an early postzygotic second hit mutation in the second allele results in melorheostosis.

Involvement of a palindromic chromosome 22-specific low-copy repeat in a constitutional t(X; 22)(q27;q11)

Segmental duplications or low‐copy repeats (LCRs) on chromosome 22q11 have been implicated in several chromosomal rearrangements. The presence of AT‐rich regions in these duplications may lead to the formation of hairpin structures, which facilitate chromosomal rearrangement. Here we report the involvement of such a low‐copy repeat in a t(X;22) associated with a neural tube defect. Molecular analysis of the chromosomal breakpoints revealed that the chromosome 22 breakpoint maps in the palindromic non‐AT‐rich NF1‐like region of low‐copy repeat B (LCR‐B). No palindromic region was encountered near the breakpoint on chromosome X. Our findings confirm that there is no single mechanism leading to translocations with chromosome 22q11 involvement. Because LCR‐B does not contain genes involved in neural tube development, we believe that the gene responsible for the observed phenotype is most likely localized on chromosome X.

2q31.1 microdeletion syndrome: redefining the associated clinical phenotype

Introduction The clinical phenotype of the chromosome 2q31 deletion syndrome consists of limb anomalies ranging from monodactylous ectrodactyly, brachydactyly and syndactyly to camptodactyly. Additional internal organ anomalies—for example, heart defects, ocular anomalies—may be present. Hemizygosity for HOXD13 and EVX2 genes was thought to cause the observed skeletal defects. Recently, based on the phenotype of patients with overlapping 2q31 interstitial deletions, a new SHFM5 locus was proposed, proximal to the HOXD cluster, between EVX2 and marker D2S294. DLX1 and DLX2 haploinsufficiency was suggested as the most plausible explanation for the observed SHFM-like limb anomalies in these cases. Methods and results Five unique, interstitial 2q31 deletion patients were selected to further characterise the 2q31 region and to establish a genotype/phenotype correlation map. The size of the deletions was delineated with a chromosome 2 specific tiling path bacterial artificial chromosome (BAC) array. The clinical and molecular data for this group of patients were compared to others in the literature. A common locus for the observed skeletal anomalies, including the HOXD genes and surrounding regulatory sequences, was delineated. These results correlate with recently published studies in animal models. In addition, a critical region for the facial gestalt of the 2q31.1 microdeletion syndrome was delineated. Conclusions These results reinforce the hypothesis that the variable skeletal phenotype in 2q31 deletion patients is a result of hemizygosity for the HOXD genes and that the 2q31.1 microdeletion syndrome is a well defined and clinically recognisable phenotype.

Limb skeletal malformations - what the HOX is going on?

Synpolydactyly (SPD) is a rare congenital limb disorder caused by mutations in the HOXD13 gene, a homeobox transcription factor crucial for autopod development. The hallmarks of SPD are the webbing between the third and the fourth finger and the fourth and the fifth toe, with a partial or complete digit duplication in the syndactylous web. Different classes of HOXD13 mutations are involved in the pathogenesis of synpolydactyly, but an unequivocal genotype-phenotype correlation cannot always be achieved due to the lack of structure-function data of HOXD13. Mutations in DNA binding or polyalanine tract domains of HOXD13 result in predictable clinical outcomes. However, mutations outside of these domains cause a broad variety of clinical features that complicate the differential diagnosis. In this review, we summarize the different classes of HOXD13 mutations causing synpolydactyly phenotypes with respect to their underlying pathogenic mechanism of action. In addition, we emphasize the importance of the chicken embryo as an animal model system for the study of (limb) development and potential genotype-phenotype correlations in SPD or other human malformation syndromes.