Ulnar-mammary syndrome is a rare pleiotropic disorder affecting limb, apocrine gland, tooth and genital development. We demonstrate that mutations in human TBX3, a member of the T-box gene family, cause ulnar-mammary syndrome in two families. Each mutation (a single nucleotide deletion and a splice-site mutation) is predicted to cause haploinsufficiency of TBX3, implying that critical levels of this transcription factor are required for morphogenesis of several organs. Limb abnormalities of ulnar-mammary syndrome involve posterior elements. Mutations in TBX5, a related and linked gene, cause anterior limb abnormalities in Holt-Oram syndrome. We suggest that during the evolution of TBX3 and TBX5 from a common ancestral gene, each has acquired specific yet complementary roles in patterning the mammalian upper limb.

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A multicenter study on fibrous dysplasia of bone (FD) was promoted by the European Pediatric Orthopaedic Society in 1999 in order to gain insight into the natural history of the disease and to evaluate current diagnostic and therapeutic approaches. We collected and reviewed clinical, radiographic, pathological, and molecular genetic data when possible, from a total of 64 cases diagnosed as either monostotic FD (MFD), polyostotic FD (PFD), or McCune-Albright syndrome (MAS), evaluated or treated in 11 participating centers. Results from the initial analysis of the series indicate five main points: (1) Significant diagnostic pitfalls affect the diagnosis of MFD and, to a lesser extent, PFD in orthopedic centers and allied radiology and pathology facilities, which may be circumvented by the adoption of stringent diagnostic criteria, and in some cases by the analysis of FD-associated GNAS1 mutations. (2) MFD carries a significant risk for fracture in the face of limited disease in the proximal femur, whereas its tendency to progress is restricted to a minority of cases, and long-term outcome is usually satisfactory, regardless of treatment, in non-progressive cases. (3) The profile of tibial disease, both in MFD and in PFD, is markedly different from that of femoral disease. (4) As expected, MAS patients have the most extensive disease and the most complicated course, regularly experience multiple fractures, and require adequate surgical treatment. It appears that conservative treatment of femoral fracture, or curettage and cancellous bone grafting, or fixation with screws and plates are not indicated for the treatment of femoral fractures in these patients and should all be discouraged. Internal fixation with intramedullary nails provides stabilization of extensively affected bones, and prevents further fractures and major deformities, and thus providing a better option both for acute and elective surgery in patients with extensive involvement of the femur or of other limb long bones. (5) Evaluation of patients with FD at orthopedic centers should include, but rarely does, a thorough evaluation of endocrine profile and phosphate metabolism, and proper pathological and radiographic assessment.

To investigate the mechanism underlying the GH-releasing effect of arginine (ARG), we studied the interactions of ARG (0.5 g/kg infused i.v. over 30 min) with GHRH (1 microgram/kg i.v.) and with pyridostigmine (PD, 60 mg orally) on GH secretion in 15 children and adolescents with familial short stature (5.1-15.4 years). In a group of eight subjects ARG induced a GH increase not statistically different to that observed after GHRH (peak, mean +/- SEM: 38.0 +/- 10.4 vs 64.0 +/- 14.4 mU/l). The combined administration of ARG and GHRH led to GH levels (101 +/- 15.2 mU/l) higher than those observed after GHRH (P less than 0.025) or ARG alone (P less than 0.001) and overlapping with those recorded after combined PD and GHRH administration (111 +/- 22.4 mU/l). In the other seven subjects, ARG and PD administration induced a similar GH response either when administered alone (25.2 +/- 13.6 and 27.8 +/- 4.0 mU/l, respectively) or in combination (33.8 +/- 5.4 mU/l). In conclusion, our results show that in children ARG administration potentiates GHRH- but not PD-induced GH increase. These findings agree with the hypothesis that the GH-releasing effect of both ARG and PD is mediated via the same mechanism, namely, by suppression of endogeneous somatostatin release. Combined administration of either ARG or PD with GHRH has a similar striking GH-releasing effect which is clearly higher than that of GHRH alone.