Cherubism – new hypotheses on pathogenesis and therapeutic consequences

Summary

Aims

The hereditary occurrence of cherubism indicates a probable genetic aetiology: a correlation with a mutation in the gene SH3BP2 has been demonstrated. A convincing concept of formal pathogenesis is not yet available. The study was aimed at advancing the understanding of the pathogenesis of cherubism by presenting a case study including genetic findings and an evaluation of the literature.

Results and conclusion

Because of its association with the development of the second and third molars, cherubism could be defined as a genetically determined alteration of tooth development. In this context, disturbed PTHrP – PTHrP receptor interaction induced by the mutation in SH3BP2 is discussed. The temporal and spatial determination of the clinical symptoms is explained by an interaction of SH3BP2-dependent signal transduction pathways with jaw morphogenesis (e.g. Hox-gene Msx-1). Because of the disease-induced lack of determination of the cap phase of the second and third molar, a spatial compartmentation, which is necessary for normal dental development, does not take place. This leads to dysregulation of mesenchymal bone building tissue areas, and to the development of giant cell granulomas with high osteoclastic activity.

Because of the genetic determination of cherubism and the associated dedifferentiation of the diseased tissue, a surgical removal should be exclusively restricted to specific indications. Therefore an attitude of wait and see is preferred.

Introduction

Cherubism – first described by Jones (1933) – received its name because of the angel-like appearance of the patients (chubby and upward directed look). The disease is attributed to an osteopathy also involving odontogenic dysplasia of the jaw bones, a form of fibrous dysplasia of bone and a giant cell granuloma (Burland, 1962; Hoppe et al., 1966). Occasionally, the disease is referred to as cherubism syndrome, since alterations in other bones may occur. It is generally accepted that it is a benign, in most cases hereditary, disease of bone, beginning at the age of 2 or 3 years, progressive in childhood, with a peak at the age of five, and showing spontaneous regression at the end of adolescence.

The diagnosis of cherubism is based on clinical, radiographic and histological findings. The clinical findings are:

• familial occurrence,

• characteristic alterations of the face, with pronounced bilateral involvement of the jaws in early childhood,

• high arched palate and missing second and third molars,

• a cyclical course,

• indolent lymph node swellings,

• spontaneous arrest or regression after adolescence,

• no involvement of the temporomandibular joint.

From a radiographic point of view, a multilocular, cystic, symmetrical expansion of the upper and lower jaws is seen. Computerized tomography shows honeycomb-like lesions of the mandibular cortical bone, with concomitant repair in the mandibular angle area. In the upper jaws, the tuberosity area is affected, with occlusion of the maxillary sinus and elevation of the orbital floor sometimes.

The histology is of limited diagnostic significance. Fibrous hyperplasia and a large number of multinucleated giant cells are noted. Pseudocystic structures are noted especially in the repair phase. The differential diagnosis of cherubism consists of fibrous dysplasia, giant cell granuloma, osteosarcoma, juvenile ossifying fibroma, fibrous osteoma, odontogenic cyst, hyperparathyroidism (Hoppe et al., 1966). Therefore, in addition to the typical histological features, the bilateral involvement of the jaws, as well as the typical course, and the familial occurrence of the disease are required for a diagnosis of cherubism (Haunfelder, 1967). Reports on cherubism without a familial occurrence (Sitzmann, 1973) or beginning at the age of 10 (Hoyer and Neukam, 1982; Opitz and Wittstock, 1990; Pulse et al., 2001) or immediately after birth (Mangion et al., 1999) should be viewed sceptically. By classification three degrees of severity are distinguished (Fordyce, 1978; Motamedi, 1998).

The familial occurrence of the disease has been and is still the subject of intense investigation. Talley (1952) and Andersen and McClendon (1962) showed that two-thirds of the families affected had two or three successive generations affected. In seven families, the diseased members affected one line of siblings only. The authors concluded an autosomal dominant inheritance with 100% penetrance in men and 60 – 80% in women.

Mangion et al. (1999) and Tiziani et al. (1999) showed that the gene region responsible for cherubism is located on chromosome 4p16.3. The clinically conspicuous disturbance in osteogenesis and a possible relation to tooth development, as well as the location of the gene in an interval between D4S127 and the telomere of 4p, led to the hypothesis that the genes FGFR3 and MSX1, located in this area, are causative for this disease. Finally, in a larger study, Ueki et al. (2001) found mutations in the gene for the SH3-binding protein SH3BP2, which is located within the critical area in 12 out of 15 families with cherubism. SH3BP2-dependent signal transduction seems to be involved especially in the regulation of elevated osteoclastic and osteoblastic activities during dentition.

Although the genetic cause of cherubism appears to have been identified, an accepted concept for its formal pathogenesis is not available yet. Therefore, it is the aim of this work to advance the understanding of the aetiology and pathogenesis of cherubism. A case study including molecular genetical findings as well as a synopsis of the literature will be presented.