Cherubism

Int. Y. oral Surg. 1972: 1:240-249 (Key words: cherl~bism; law diseases)

Cherubisrn NINA VON WOWERN

Departments of Oral Surgery and Oral Pathology, Royal Dental College, Copenhagen, and Department of Maxillo-Facial Sttrgery, University Hospital, Copenhagen, Denmark

ABSTRACT-- The nine known eases of cherubism in Denmark have been followed over a 7-year-period and were examined with regard to the clinical and radiographic appearance, the course and the tooth abnormalities of eherubism, and also to investigate whether the structure of the lesional tissue varied according to sex, age, family and severity of the disease. The most frequent location of cherubism seems to be a bilateral involvement of the anterior parts of the mandibular rami and molar regions, either with or without involvement of the maxillary tuberosifies, combined with aplasia of the second and third molars and malformation of the roots of the mandibular first molars but without pulpal changes. It seems that girls reach the stable period of the disease before boys, at 10 and 14 years of age, respectively. Before the age of 21 the gross and microscopic structure of the lesional tissue is always the same from patient to patient, as well as in the same patient at different ages, and corresponds to the structure of a giant cell granuloma, while in older patients the lesional tissue consists of fibrous tissue.

(Received/or publication 9 August, accepted 1 October 1972)

Cherubism is a hereditary bone disease which affects the jaws bilateraliy in children. The normal bone is partly replaced by a giant cell granuloma containing collagenous tissue; expansion of the affected jaw is a characteristic feature. According to the W H O classification, cherubism belongs to the group of non-neoplastic bone lesions (Pindborg, Kramer & Torloni 1971). In most reports cherubism is described in individuals or in single families (Caffey & Williams 1951, Waldron 1951, Talley 1952, Bruce, Brewer & Kennedy 1953, Branin 1954, Riley 1956, Hogan & Liebner 1957, Small & Young 1958, Thompson 1959, Deighan

1960, A b e y & Reece 1961, Kiehn, DesPrez & Harris 1961, Aiken 1962, Anderson & McClendon 1962, Marino, Meguira & Zavala 1964, Foissin & Ohanian 1965, Shuler & Silvermann 1965, Orth 1965, Topazinan & Costich 1965, Bradley 1967, Fleuchaus 1967, Haunfelder 1967, Ramon, Berman & Bubis 1967, Harris 1968, Cammisa 1970, Cornelius 1970, Khosla & K o r o b k i n 1970, Lawrence, Nogrady & Cloutier 1970). In cherubism the mandible is affected bilaterally (Jones 1965); in severe cases the entire mandible is included. In the maxilla, lesions m a y be found in the tuberosity areas, and in the severe cases greater parts of the

CHERUBISM maxilla are affected, with involvement of the infra-orbital rim and orbital floor and exposure of the inferior part of the sclerae (Jones 1933). The disease has a self-limiting course. The first changes are seen at the age of 15 months, but only radiographically; clinically the changes usually are present by the age of 5 years. The disease progresses through the ages of 8 to 12 years, then enters a stable period. After puberty a slow regression occurs, and between the ages of 20 and 30 years the fibrous tissue in the affected regions is replaced with sclerotic or normal bone (Burland 1962, Haunfelder 1971). A few reports deal especially with the microscopic structure of the pathologic tissue (Seward 1957, Goflin 196,7, Ramon et al. 1967, Waldron 1967, Hamner 1969). The purpose of this investigation has been to study (1) the clinical appearance and course of the disease, followed over a 7year-period, (2) tooth abnormalities in patients with cherubism, and (3) the gross and microscopic structure of the pathologic tissue and possible variation of these structures with regard to sex, age, family and severity of the disease.

241

never been encountered in any earlier generation. Radiographic examination of the skeleton and determinations of serum calcium, serum phosphorus and alkaline phosphatase were made in all cases. Biopsies from the second molar region of the mandible were taken in all cases at the first visit and also one to three biopsies of four patients during the follow-up period. Fifteen biopsies from the jaws were available for examination and 14 of these were obtained by the author. The last biopsy was borrowed from the Department of Oral Surgery and the Department of Oral Pathology, Royal Dental College, Aarhus. Serial sections were made of all biopsies, and the ninth and tenth sections were stained with either hematoxylin-eosin or van Gieson stain. Twenty sections of each biopsy were examined according to the scheme in Table 1. Three circular areas of 4 turn diameter, representative in structure for each third of a section, were chosen for counting of capillaries and giant cells, and the same areas were examined in all sections of the biopsy. Four patients had extractions of teeth in the affected areas, and in one patient an enlarged submandibular lymph node was removed. RESULTS

Clinical and radiographic examinations All patients had radiographs of the entire skeleton. No patients had involvement of

M A T E R I A L A N D METHODS The material comprises all registered cases of cherubism in Denmark, nine children in all, comprising three boys and six girls from four different families with, respectively, one, two, two and four patients in each family. The age at the first consultation and the length of the follow-up period are seen in Fig. 1. One case (a five-year-old girl) had just recently been diagnosed. The remaining patients were seen frequently during the follow-up period, ranging from 5 to 12 years, average 7 years; clinical and radiographic examinations were performed at each visit (Fig. 1). The known cases of the disease in three of the families are seen in Fig. 2. In none of these families had the parents shown signs of the disease, according to history and to clinical examination. In the family of the five-year-old girl the disease apparently had

YRS

oF AGE ~ ' ÷ ' 6 ' fi ' I~' 75' 1'7' 1'9' 2'~ '2~ ' 2'5'

Fig. 1, Age of the nine patients at first visit and length of follow-up period. Dots indicate number of times each patient has been examined.

242

WOWERN

OGIRL

O []AFFECTED ~D ~PROBABLYAFFECTED

<{5~ "~g

(D N O[]N [I]O R R PM R M O AB LABLL Yo

©

A

B

C

D

U m {D g [ I ~ ~ {D U © " H

G

F

E

Fig. 2. The frequency of the disease in the three different families [n which the disease had occurred before.

other parts of the skeleton or abnormal values of serum calcium, phosphorus or alkaline phosphatase. All patients had the characteristic round cheruNe faces, but only two patients showed a tendency for the inferior part of the selerae to be exposed (Fig. 3). The submandibular lymph nodes were painless and slightly enlarged in seven of the nine patients. N o other abnormalities were f o u n d outside the jaws.

AFFECTIONS OF THE JAWS The distribution of the affected areas of the jaws is seen in Table 2. I n one case the entire m a n d i b l e and the maxillary tuberosities were affected with expansion and partial destruction of the buccal cortex (Fig. 4). The height a n d the width of the horizontal

Fig. 3. Affected ll-year-old boy (to the left) with 7-year-old affected sister, normal 38-yearold father and normal 12-year-old sister.

CHERUBISM Table t. The scheme for the microscopic examination. The standard area for counting of giant cells and capillaries was 4 mm in diameter 1. Number of collagen fibers 2. Number of stromal cells 3. Shape of the cells 4. Number of caprilaries 5. Amount of extravascular erythroeytes 6. Amount of hemosiderin pigment 7. Amount of extravascular blood plasma 8. Number of vessels with perivascular collagen deposition 9. Number of giant cells 10. Size of giant cells 11. Number of nuclei 12. Distribution of giant cells

few - many

Table 2. Location of lesions in the jaws Number of patients Lesions in the mandibIe

few - many ovoid stellate few (under 10) many (over 10) small - large

Lesions in the maxillary tuberosities With

All over in the mandible, except the condyles

Without

1

Bilaterally in the rami and the molar regions

small - large

5

4

9

small - large

none - few few (under 20) moderate (20-50) many (50-70) small - large few (under 5) many (over 5) evenly distributed; in clots

part and the base of the m a n d i b l e were m a r k e d l y increased. In the last eight patients a bilateral expansion of the buccal cortex was found in the affected areas, and radiographically the findings w e r e of the same nature as depicted in Fig. 5.

TOpTH

243

ABNORMALITIES

Fig. 6 shows the n u m b e r of missing or malf o r m e d teeth in the nine patients. All patients had aplasia of all third molars, and of the m a n d i b u l a r second molars. The patients with i n v o l v e m e n t of the maxilla either had aplasia or demonstrated m a l f o r m a t i o n s of the second molars. T h e first molars were present in all patients, but in the mandible the roots were m a l f o r m e d . T h e teeth in the non-affected areas w e r e normal. In the pa-

tient with extensive destruction, diastemas and displacement of several teeth w e r e found.

RESULTS

OF FOLLOW-UP

STUDY

Eight of nine patients were f o l l o w e d f o r m o r e than five years (Fig. 1). No p r o g r e s sion of the disease was f o u n d in the girls after the age of 10 years, while the disease in the boys progressed until the age of 14; thereafter no f u r t h e r progression was f o u n d clinically. A relative regression of the disease was seen in the girls after the 16th year, as m o r e normal contours of the face d e v e l o p e d , but radiographically new b o n e f o r m a t i o n was not observed. Regression of the disease was not seen in the boys in the f o l l o w - u p period (not exceeding 18 years of age). O n l y in the most severely affected patient (Figs. 7-9) did root resorption occur, but it caused loss of all teeth in the m a n d i b l e except the first molar, the second p r e m o l a r and the canine in the right side.

Gross and microscopic struc[ure of the pathologic tissue GROSS STRUCTURE A yellowish-brownish, granulated, rubberlike soft tissue was found in all cavities in

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WOWERN

Fig. 4. Postero-anterior radiograph and occlusaI view of the mandible of the boy from Fig. 3. Note radiolucent areas in entire mandible, except condyles.

CHERUBISM

245

Fig. 5. Orthopantomogram of the affected girl from Figs. 3 and 7 at the age of 14 years, typical for eight of the nine patients.

the patients below 21 years of age. In the 24-year-old patient a grayish fibrous tissue constituted the lesional tissue.

MICROSCOPIC STRUC'I~

The serial sections revealed the same structure of the pathologic tissue throughout each NUMBER OF PATIENTS

biopsy. All biopsies, except for the one from the 24-year-old girl, showed identical structures, independent of sex, age, family and the severity and duration of [he disease. The tissue consisted of numerous spindleshaped cells with distinct ovoid nuclei, but with indistinct cell membranes, a few stellate cells, a few delicate fine eollagenous fibers,

M A X I LLA

I

i

MANDIBULA J ~ MALFORMED TEETH I I J M I S S I N G TEETH

Fig. 6. Number of patients with missing or malformed molars in maxilla and mandible.

Fig. 7. Brother and sister, from Fig. 3, at the ages of 18 and 14 years, respectively.

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WOWERN

Fig. 8. Pestero-anterior radiograph of the 18-year-old boy from Figs. 3 and 7. Note loss of teeth, caused by resorption of the roots.

a n d m a n y thin-walled capillaries (Fig. 10). G i a n t cells were seen, either lying fi'ee and distributed evenly in the tissue or located in relation to a wall of capillaries (Fig. 10). T h e total n u m b e r of giant ceils in the examined areas from all biopsies varied from 50 to 70, and each giant cell contained more than five nuclei (Fig. 1.0). The number of capillaries and the amount of extravascular erythrocytes and plasma increased with increasing n u m b e r of giant cells, whereas the a m o u n t of collagen decreased. I n one biopsy a perivascular deposition of collagen a r o u n d a few vessels was observed, but only in areas without giant cells. T h e n u m b e r of extravascular erythrocytes varied from biopsy to biopsy, but deposition of hemosiderin was very sparse in all biopsies. In most of the biopsies an area with

bundles of collagen fibers was found. Bone formation was never seen. Areas af myxomatous tissue were found in one biopsy. The structure of the pulp in the examined teeth was normal.

Fig. 9. Intraoral appearance of mandible in the 18-year-old boy from Figs. 3 and 7.

CHERUBISM

247

Fig. 10. Area with numerous spindle-shaped cells and giant cells with many nuclei, in relation to thin-walled capillaries; the tissue is nearly without collagen fibers.

The submandibular lymph node was hyperplastic, but with normal structure. The biopsy :from the 24-year-old girl contained exclusively a fibrous collagenous connective tissue with only a few fibroblasts and vessels.

DISCUSSION T h e present investigation confirms that cherubism is a bone disease which affects only the jaws, as all nine patients otherwise had completely normal skeletal structures. The severity of cherubism may vary from patient to patient (Seward 1962), from bilateral affections of the mandibular rami and molar region to a diffuse involvement of the entire mandible and maxilla. The

most frequently described location of the disease in families with several affected members is bilateral involvement in the anterior part of the mandibular rami and the molar regions (Branin 1954, Small 1958, Deighan 1960, Burland 1962, Orth 1965, Shuler & Silvermann 1965, Haunfelder 1967). The present findings (Fig. 6) apparently reflect the most frequent location of cherubism. In seven of the nine cases the submandibular lymph nodes were enlarged, but a physiologic hyperplasia of the lymph nodes is often found in children (Sicher 1952). Further, the histologic examination of the lymph node removed from one of the patients revealed only a slight hyperplasia. Therefore, enlargement of the lymph nodes as part of cherubism (Hogan & L i e b n e r

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WOWERN

1957, Aiken 1962) is probably not related to the disease, but is an expected finding in this age-group. Dental abnormalities vary according to involvement of the tooth-bearing segments of the jaws. The most common finding has been described as the absence of the mandibular second and third molar (Burland 1962). In the present nine cases, aplasia of the mandibular second and third molars and the maxillary third molar were found. In seven of the nine cases the roots of the first molars in the mandible were malformed and aplasia or malformation of the second molars in the maxilla was found in the eases with lesions in the tuberosity areas of the maxilla. In normal areas of the jaws the teeth were also normal. Only in the patient where the entire mandible was affected did the disease cause resorption and loss of teeth. Therefore, aplasia of the mandibular second and third molars and the maxillary third molar, aplasia or malformation of the maxillary second molars and malformation of the roots of the first mandibular molar comprise the characteristic dental pathology in cherubism. Resorption and Iater loss of teeth occurs only in severe cases. The pulp in the examined teeth was normal, revealing that cherubism does not cause pulpal changes in teeth from affected areas of the jaws. Further, this investigation confirmed the characteristic natural course of the disease. The girls reached the stable period before the boys, at respectively, 10 and 14 years of age. In the 24-year-old patient the yellowish-brownish granulated, rubber-like pathologic tissue was replaced by a grayish fibrous tissue, as could be expected (Burland 1962, Orth 1965). The characteristic microscopic structure (McClendon & Anderson 1962, T h o m a 1962, Waldron 1965, Camissa 1970, Seward 1957) was found in all sections of the biopsies from the patients below the age of 21 years. As in the investigations by Waldron

(1965) comprising 20 biopsies from patients with cherubism, no pathognomonic structures were found which could separate it from the structure of the pathologic tissue of a giant cell granuloma. According to R a m o n et al. (1967) and Hamner (1969) a perivascular collagen deposition should be a common and pathognomonic observation in cherubism. I n the present material it was found in one biopsy only, and must be considered too inconstant to be of value in the differential diagnosis. The deposition of hemosiderin and the number of extravascular erythrocytes, being a sign of fresh bleeding, may vary (Seward 1957, R a m o n et al. 1967). I n all the examined biopsies the amount of hemosiderin was sparse, while the number of extravascular erythrocytes increased with the n u m ber of capillaries in the area. Neither Waldron (1967) nor H a m n e r (1969) mention any variation in the microscopic structure of the pathologic tissue from different patients below 20 years of age. The present results substantiate their findings as all biopsies, except the one f r o m the 24-year-old girl, showed the same microscopic structure independent of age, sex, family and the severity of the disease. The composition of the biopsy f r o m the 24-year-old girl lends support to the assumption that the giant cell containing vascular tissue is replaced by a fibrous connective tissue after the 20th year of age in patients with cherubism (Burland 1962). When this tissue is replaced by bone is still unknown. A c k n o w l e d g m e n t - Supported by a grant from the Danish State Research Foundation.

REFERENCES ABEY, F. S. ,& REECE, C. H.: Cherubism. 1. oral Surg. 1951: 19: 63-69. AIrmEN, H. E.: Cherubism. J. Dis. Child. 1962:

103: 697-701.

CHERUBISM

ANDERSON, D. E. • MCCLENDON, J. L.: Hereditary fibrous dysplasia of the jaws. Oral Sllrg. 1962: 15: Suppl. 2: 5-16. BRADLEY, C. J.: Bilateral giant cell reparative granulomas with appearance of cherubism. J. oral Surg. 1967: 25: 555-558. BRANIN, D. E.: Bilateral giant cell tumors of the mandible in siblings. J. oral Surg. 1954: 12: 247-254. BRUCE, K. W., BREWER, A. & KENNEDY, R. L. J.: Familial intraosseous fibrous swellings of the jaws. Oral Surg. 1953: 6: 995-1001. BUmLA-~D,1. G.: Familial bilateraI osseous dysplasia of the jaws. Oral Surg. 1962: 15: Suppl. 2: 43-68. CAFFEY, J..& WILLIAMS, ]'. L.: Familial fibrous swellings of the jaws. Radiology 1951: -~6: 1-14. CAMM~SA, M.: I1 cherubimismo. Radiol. reed. (Torino) 1970: 56: 329-341. CORNELIUS, E. A.: Cherubism-hereditary fibrous dysplasia of the jaws. Amer. J. RoentgenoI. 1969: 106: 136-143. DEIGHAN,W. 1.: Cherubism. J. Maine reed. Ass. 1960: 51: 442-445. FLEUCI-IAUS, P. T.: Cherubism treated by curretage and autogenous bone ohips. J. oral Surg. 1957: 25: 348-355. FolSSlN, B. & O~hNL~, D.: A prospos de deux observations de cherubism. Ann. Oto.laryng. (Paris) 1965: 82: 467-472. GORLIN, R. J.: Comments. J. oral Surg. 1967: 25: 355. I-IAMNER, J. E.: The demonstration of perivascular collagen deposition in cherubism. Oral Sttrg. 1959: 27: 129-141. HARRIS, M.: Cherubism and the osteoclastoma. Oral Surg. 1968: 25: 613-619. HAUNFELDER, D.: Der "Cherubism'. Dtsch. Zahn-, Mund- u. Kieferheilk. 1967: 49: 5971. HOGAN, W. & LIEENER, E. J.: Familial fibrous swellings of the jaws. J. Pedlar. 1957: 51: 554--563. JONES, W. A.: Familial multilocular cystic disease of the jaws. Amer. 1. Cancer 1933: 17: 946-950. JONES, W. A.: Further observations regarding familial multilocular cystic disease of the jaws. Brit. J. Radiol. 1938: 11: 227-241. JONES, W. A., GERRI, ,,!'. ,& PRITCHARD, 1.: Cherubism. Oral Surg. 1952: 5: 292-305. JONES, W. A.: Cherubism. Oral Surg. 1965: 20: 648-653. KHOSLA, M. & KOROBKIN, M.: Cherubism. Amer. J. Dis. Child. 1970: 120: 458-461.

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KIEHN, C. L., DESPREZ, J. D. & HARRIS, A. I'i.: Cherubism. Amer. J. Surg. 1951: 102: 835838. LAWRENCE, O , NOGRADY, B. • CLOUTIER, A. M.: Cherubism. Amer. J. Roentgenol. 1970: 108: 468-472. MARINO, D. E., MEGUIRA, L. & ZAVALA, H.: Displasie fibrosa familial de los maxillares. Querubimismo. Pren. todd. argent. 1964: 51: 819-823. McCLENDON, J. L. & ANDERSON,D. E.: Cherubism. Oral Surg. 1952: 15: Suppl. 2: 17-42. ORT~, J. O. OP DEN: Cherubism. J. belge Radiol. 1955: 48: 499-518. PINDBORG~ J. 1., KRAMER, J'. R. H. & TORLONI, H.: Histological typing of odontogenic tumours, jaw cysts, and allied lesions. World Health Organisation, Geneva 1971, p. 19. RAMON, Y., BERMAN, W..~,z BUBIS, J. J.: Gingival fibromatosis combined with eherubism. Oral Surg. 1957: 24: 435-447. RmEY, F.: Familial fibrous swellings of the jaws. Radiology 1956: 67: 742-745. SEWARD, G. R.: Cherubism. Oral Surg. 1957: 10: 972-974. SAERES, R.: Familial fibrous dysplasia of jaws (cherubism). Pediatrics 1970: 25: 331-334. SHULER, R. I(. ,• SILVERMANN,F. N.: Dysplasia fibreuse familiale de machoires ou "eherubism'. Ann. Radiol. 1955: 8: 45-52. SICHER, H.: Oral anatomy. C. V. Mosby, St. Louis 1952, p. 337. SMALL, L. A. & YOUNG, M. C.: Familial osseous dysplasia of the jaws. J. oral Surg. 1958: 16: 35-45. TALLEY, D. B.: Familial fibrous dysplasia of the jaws. Oral Surg. 1952: 5: 1012-1019. THOMA, K. H.: Cherubism and other intraosseous giant-cell lesions. Oral Stlrg. 1962: 15: Suppl. 2: 1-4. THOMPSON, N.: Cherublsm. Brit. L plast. Surg. 1959: 12: 89-103. TOPAZIAN, R. G. & COSTICH, E. R.: Familial fibrous dysplasia of the jaws. J. oral Sttrg. 1955: 23: 559-655. WALDRON0C. A.: Familial incidence of bilateral giant cell tumors of the jaws. Oral Surg. 1951: 4: 198-207. WALDRON, C. A.: Comments. L oral Surg. 1965: 23: 566-568. Address: 4 Universitetsparken 2100 Copenhagen 0 Denmark