In its mild forms, the disorder causes children to develop chubby cheeks and upward-looking eyes like those of cherubs depicted in Baroque or Renaissance religious artwork.

The discovery, reported in the June 1 issue of Nature Genetics (Ueki et al.), is "very exciting" because it could lead to potential therapies or prenatal diagnosis for the disorder, said Bjorn Olsen, MD, PhD, chair of the HSDM-Forsyth department.

The discovery also provides important clues to the mechanisms underlying such bone degrading disorders as osteoporosis, according to Ernst Reichenberger, PhD, an instructor who, with Olsen, leads the research team.

The mutation affects primarily young children starting at about the age of three or four, when, normally, the primary teeth begin to fall out and secondary teeth erupt.

"At that time, there is much bone degradation and remodeling going on," Reichenberger says. In cherubism, he suggests, "there must be something wrong with the way certain bone cells receive information from other cells or extracellular matrix," which surrounds the cells. "Instead of doing their proper jobs," Reichenberger says, the cells that normally build or diminish bone "go crazy."

In its severe forms, cherubism can lead to excessive degradation of the jawbone. The bone tissue is then replaced by soft tissue masses which cause the swelling of the face and which can intrude into the eye socket and force the eyeballs to tilt upwards.

Cherubism patients also suffer from chronic inflammation of lymph nodes and from tooth malformation and loss. Many have difficulty chewing because of reduced jaw movement.

Cherubism normally recedes after puberty, and children with mild forms of cherubism generally appear normal as adults. Because no epidemiologic studies have yet been conducted, it is not known how many people, in addition to some 200 reported in the literature, have the disorder.

In April, HSDM-Forsyth department announced the discovery of a mutation that causes a different bone disorder, craniometaphyseal dysplasia, or CMD, which, in severe cases, leads to excessive craniofacial bone growth and a mask-like appearance.

While both discoveries are important to science's understanding of bone growth and degradation, the mutations causing the two disorders operate quite differently, according to Reichenberger.

The mutation causing CMD appears to affect a protein that regulates the transport of inorganic phosphate to the bones. The mutation leading to cherubism appears to affect a signaling mechanism that causes both bone degrading cells (osteoclasts) and bone building cells (osteoblasts) to function abnormally, he said.

The researchers' search for the gene and mutation for cherubism began in 1995 when a postdoctoral fellow, Valdenize Tiziani, brought blood from three Brazilian families to laboratories at the Forsyth Institute. The HSDM-Forsyth team used genomic screening and linkage analysis to compare segments of DNA from affected family members with segments from family members who are not affected.

The researchers knew from their previous work that the gene related to cherubism was located on chromosome 4p, in an area or "locus" that overlapped with the Huntington's disease gene region -- which had already been almost completely sequenced. This left only a small locus in which to search.

The Reichenberger team screened most of the 25 genes found in this locus, obtained DNA from additional affected families by contacting doctors in several countries, and compared the loci of affected and unaffected individuals.

In September 2000, Yasuyoshi Ueki MD, PhD, a postdoctoral fellow, discovered a mutation in the SH3BP2 gene, which codes for a protein (also called SH3BP2) that is involved in the signaling mechanism of certain cells.

Because cherubism involves both bone degradation and the growth of tumor-like tissue, the researchers hypothesize that the mutant protein functions differently in different kinds of cells.

For example, the mutant protein may activate osteoclasts, which degrade bone, and, in areas where the bone has been degraded, the protein may also activate osteoblasts or osteoblast precursors, which normally build bone. These atypical osteoblasts proliferate, fill in the cavities where bone has been degraded and continue to grow as a fibrous tissue mass, which causes the distorted facial expression of cherubistic children.

Discovery of the mutant gene for cherubism is "a major step" in understanding the signaling process in bone cells and could yield important clues about the development of secondary teeth, Olsen said.

By comparing the faulty signaling exhibited in cherubism with normal signaling, we will be able to pinpoint crucial mechanisms for bone remodeling, he explained. This knowledge, the researchers hope, will contribute to methods for treating or averting cherubism and could, one day, allow prenatal diagnosis.

Even more important, however, is that understanding the signaling mechanisms exhibited in cherubism could lead to deeper knowledge and treatment of bone diseases that affect large segments of the world's population. Among such diseases are osteoporosis -- in which bone becomes too thin -- and osteopetrosis, in which bone becomes too thick.

Because SH3BP2 appears to affect bone cells' responses to incoming signals, Reichenberger predicts that it will be found to have great impact on bone degradation and growth in general.

The Harvard-Forsyth Department of Oral Biology is a joint program of the Harvard Medical School and the Harvard School of Dental Medicine, and The Forsyth Institute, an independent oral research and education organization focused on oral and craniofacial science.

[Contact: Anita M. Harris]

06-Jun-2001