Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism.

Cherubism (MIM 118400) is an autosomal dominant inherited syndrome characterized by excessive bone degradation of the upper and lower jaws followed by development of fibrous tissue masses, which causes a characteristic facial swelling. Here we describe seven mutations in the SH3-binding protein SH3BP2 (MIM 602104) on chromosome 4p16.3 that cause cherubism.

Autosomal dominant craniometaphyseal dysplasia is caused by mutations in the transmembrane protein ANK.

Craniometaphyseal dysplasia (CMD) is a rare skeletal disorder characterized by progressive thickening and increased mineral density of craniofacial bones and abnormally developed metaphyses in long bones. Linkage studies mapped the locus for the autosomal dominant form of CMD to an approximately 5-cM interval on chromosome 5p, which is defined by recombinations between loci D5S810 and D5S1954. Mutational analysis of positional candidate genes was performed, and we describe herein three different mutations, in five different families and in isolated cases, in ANK, a multipass transmembrane protein involved in the transport of intracellular pyrophosphate into extracellular matrix. The mutations are two in-frame deletions and one in-frame insertion caused by a splicing defect. All mutations cluster within seven amino acids in one of the six possible cytosolic domains of ANK. These results suggest that the mutated protein has a dominant negative effect on the function of ANK, since reduced levels of pyrophosphate in bone matrix are known to increase mineralization.

Craniosynostosis in cherubism.

Cherubism is a rare autosomal dominant fibro-osseous disorder that affects almost exclusively maxilla and mandible. Extracranial skeletal involvement is rare. We report on three affected males in three generations. The youngest affected relative was examined at age 4 months. He also had craniosynostosis. His affected father and grandfather had cherubism and clubbing of the fingers. Cherubism was mapped to region 4p16. Because of the associated cranio-synostosis, we excluded the FGFR3 gene as a candidate gene for cherubism.

The gene for cherubism maps to chromosome 4p16.

Cherubism is an autosomal dominant disorder that may be related to tooth development and eruption. It is a disorder of age-related bone remodeling, mostly limited to the maxilla and the mandible, with loss of bone in the jaws and its replacement with large amounts of fibrous tissue. We have used a genomewide search with a three-generation family and have established linkage to chromosome 4p16. Three other families affected with cherubism were also genotyped and were mapped to the same locus. The combined LOD score is 4.21 at a recombination fraction of 0, and the locus spans an interval of approximately 22 cM.

Gradual bone distraction in craniosynostosis. Preliminary results in seven cases.

Seven patients with craniosynostosis (mean age 8 years, Apert syndrome, n = 4, Crouzon's disease, n = 3) underwent lengthening of the skull by gradual bone distraction. Three patients (group A) were treated by coronal craniectomy reaching the orbital fissure and gradual bone distraction. The other four (group B) underwent monobloc craniofacial disjunction and gradual bone distraction. The patients' progress was monitored clinically as well as by radiographs and photographs. The results showed that craniofacial disjunction followed by gradual bone distraction produced complete correction of exophthalmus and an improvement in the functional and aesthetic aspects of the middle third of the face without the need for bone grafts.

Lack of lymph node reaction to subcutaneously injected silicone gel: histological and computer aided morphometric study in rats.

The gel of silicone implants may bleed through the elastomeric envelope or may come into contact with the body because of rupture of the implant. We have studied the effects of free silicone gel injected into the subcutaneous space in rats and analysed the morphological features of the axillary and inguinal lymph nodes. Ninety six Wistar rats had 3 cm3 of silicone gel injected into their subcutaneous space and 96 Wistar rats (the control group) had distilled water injected into their subcutaneous space. The animals were killed on days 1,3,7,9,15, 30,60,90,120,180,270, and 365 after the injection. There was no detectable silicone and no damage to the lymph nodes on routine histopathological analysis. Small amounts of silicone that could migrate to lymph nodes could result in hyperplasia. To evaluate this possibility, a morphometric study based on a computer aided system compared the area of lymph node sections between treated and control animals, and showed no difference between treated and control groups. If silicone did migrate, it did not provoke morphological signs or hyperplasia in the lymph nodes.

Local reaction and migration of injected silicone gel: experimental study.

A study of the local and migratory effects of free silicone gel taken from a mammary prosthesis is reported. Thirty eight Wistar rats were injected in their subcutaneous space with 1 cm3 of silicone gel. The animals were sacrificed on day: 3, 7, 15, 30, 60, 180, 240, 360, 420, 450. The visceral organs (heart, kidneys, lungs, stomach, gonads, liver, pancreas, spleen, intestine), as well as the tissue adjacent to the region of injection, were histologically analyzed. There was no detectable silicone and no damage to the visceral organs based on routine histopathological analysis. The greatest fibrosis was observed at the extremities of the disk formed by the silicone in the subcutaneous space.

Capsular contracture and silicone gel: experimental study.

Wistar rats were used to study the effects, if any, of membrane thickness and implant volume of a silicone gel prosthesis on the development of fibrous capsule contraction. A total of 30 miniprosthesis with three different membrane thicknesses and two different volumes were implanted in the subcutaneous space of five animals. One hundred eighty days later the fibrous capsule was resected and histologically analyzed. Different grades of thickness were observed. The statistical analysis of the data indicates that the thickness of the prosthesis' membrane and the implant's volume did not impact significantly on the grade of fibrosis.