Med The adenomatous polyposis - jmg.bmj.com

5 Med Genet 1995;32:458-464

The dental phenotype in familial adenomatouspolyposis: diagnostic application of a weightedscoring system for changes on dental panoramicradiographs

Nalin Thakker, Rhodri Davies, Keith Homer, John Armstrong, Tara Clancy,Simon Guy, Rodney Harris, Philip Sloan, Gareth Evans

Department ofMedical Genetics,St Mary's Hospital,Hathersage Road,Manchester M13 OJH,UKN ThakkerR DaviesJ ArmstrongT ClancyS GuyR HarrisG Evans

Department of DentalMedicine and Surgery,University ofManchester,Manchester M15 6FH,UKN ThakkerK HomerP Sloan

Correspondence to:Dr Thakker.

Received 25 October 1994Revised version acceptedfor publication3 February 1995

AbstractA weighted scoring system (Dental Pan-oramic Radiograph Score) taking into con-sideration the nature, extent, and site ofosseous and dental changes on dental pan-oramic radiographs in familial adeno-matous polyposis is described. Theweighting takes into consideration the in-cidence of the anomaly in the generalpopulation. The reliability of the systemwas tested by application to 85 peopleknown to be affected by clinical or muta-tion analysis, 30 people lacking mutationin the adenomatous polyposis gene, and19 people shown to be at low risk (<1%) bylinkage analysis. Using the highest thresh-olds, a specificity of100% and sensitivity of- 68% was obtained. If all positive findingswere considered as significant, sensitivitywas increased to - 82% but the specificitywas reduced to -88%. Significant DPRSfindings were observed at a significantlyhigher frequency in patients aged over 20compared to the patients aged 20 and un-der. Overall, 68% ofthe affected subjectshad significant changes, and -18% hadnormal appearance on DPR, with the re-mainder having changes classified as min-imal or equivocal.

(J Med Genet 1995;32:458-464)

Familial adenomatous polyposis (FAP) is anautosomal dominant condition characterisedby the development of multiple adenomatouspolyps in the colon and rectum with high riskofsubsequent malignant transformation. In ad-dition, extracolonic changes occur in manyaffected subjects. These include epidermoidcysts, desmoid tumours, congenital hyper-trophy ofretinal pigment epithelium (CHRPE),osseous changes in the jaws and skeleton, anddental anomalies. FAP results from germlinemutations in the adenomatous polyposis coli(APC) gene on chromosome 5q21. l 2The adenomatous polyps usually develop in

the colon or rectum or both in adolescence orearly adulthood and malignant transformationusually occurs between the ages of 30 and 40.'Early identification of affected subjects andprophylactic surgical intervention is essentialin preventing the development of colorectalcarcinomas. Furthermore, presymptomatic

diagnosis is vital since two-thirds of those pre-senting with symptoms will have already de-veloped carcinoma and consequently will havea poorer prognosis.45

In families with a history of FAP, subjects atrisk may be diagnosed by using genetic markersclosely linked to the APC locus6 or by iden-tification of mutations in the APC gene.'27However, linked markers may not always beinformative or the pedigree structure may beunsuitable for linkage analysis. Furthermore,most mutations are unique within givenfamilies.'27 Current mutation screeningmethods are only able to identify the patho-logical mutation in 60 to 70% of the families.Alternative mutation analysis strategies in-volving in vitro transcriptional/translational as-says may prove to be more efficient.89 In theabsence of suitable rapid genetic tests for somefamilies, there is a dependence on clinicalscreening of subjects at risk for the iden-tification of those affected. This involves reg-ular colonoscopy. In addition, otherextracolonic features, such as CHRPE andchanges in the jaws, which may antedate theappearance of colonic polyps may prove usefulphenotypic markers. CHRPE is reported to bepresent in between 58 and 100% of cases'0-3and the presence or absence of CHRPE hasbeen used in optimal risk estimation in FAP. 10 12

Numerous studies have also identified jawchanges including osseous lesions, odontomes,supernumerary teeth, and an increased in-cidence of impacted teeth. 114-24 The use ofthese changes in a diagnostic test for FAP hasbeen limited because of the presence of similarchanges in unaffected people, lack of data onthe reliability of such a test, and lack offamiliarity of geneticists with features identifiedon dental panoramic radiographs. In this paperwe describe in detail the radiographic changesin FAP patients. In addition, we describe aweighted scoring system for these changes andreport its application and reliability in the diag-nosis of FAP.

Subjects and methodsFAP FAMILIESThe families were identified from the NorthWest Regional Polyposis Register, St Mary'sHospital, Manchester and included patientsreferred from the regional gastroenterology andsurgical units, and the University Dental Hos-

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The dental phenotype in familial adenomatous polyposis

Table 1 The number, age range, and sex ratio of subjects grouped according to FAPstatus

Group No Age range M:F

FAP affected A 85 10-77 44:41FAP unaffected (by mutation analysis) B 30 11-64 11:19FAP unaffected (by linkage analysis) C 19 12-63 11:8Clinically low risk D 19 25-62 8:11

Table 2 Dental panoramic radiograph scoring system. Weighted scores for number andsize (where appropriate) for each anomaly are shown. Derivation of the scoring systemand its application are detailed in "Subjects and methods"

Scoring cniteria

DPR anomaly No Score Size (cm) Score

Osteoma 0 0 <0 5 01 4 >0 5<2-0 32 7 >20<40 63-5 9 >40<60 86-8 11 >60 10(+1-3) (+2)

Dense bone island (DBI) 0 0 <0-5 01 2 >0 5<2-0 22 4 >20 43-5 66-8 8(+ 1-3) (+2)

Hazy sclerosis associated withroot(s) of single teeth 1 area 2 - _

>2 areas 4Hazy sclerosis associated withroot(s) of multiple teeth > 1 4 - -Hazy sclerosis not associated withroot(s) of teeth 1 2 <1-0 0

>2 4 >1-0 2Hazy sclerosis diffuse - 12 - -

Odontomes 0 01 72 9(+ 1) (+2)

Supernumerary teeth 0 0(unerupted or erupted) Mesiodens 3

1 62 9(+ 1) (+2)

Unerupted teeth 0 01 32 53 7(+ 1) (+2)

pital, Manchester. A total of 154 patients from37 unrelated families were studied. The agerange, sex ratio, and clinical status of patientswith respect to FAP are detailed in table 1.

Figure 1 Part of a dental panoramic radiograph showingleft mandible and maxilla. Well defined radiodense lesionstypical of endosteal osteomas are present (arrows), togetherwith an unerupted maxillary canine.

Briefly, the sample included 85 known affectedFAP patients (group A: patients who wereeither known to be affected at the time ofexamination or were subsequently identified asaffected clinically or by mutation analysis) and30 definitely unaffected people (group B: lack-ing the mutation present in the APC gene ofaffected members of their family). Two othergroups of "unaffected" people from FAP famil-ies were also included: 19 subjects determinedby linkage analysis with both intragenic andclosely linked flanking markers to be at lessthan 1% risk ofFAP (group C) and 19 subjectsdetermined by clinical examination to be atlow risk (group D). The latter is defined by theabsence of polyps and CHRPE at the age of25.

DENTAL PANORAMIC RADIOGRAPH SCORE (DPRS)All patients were subjected to clinical, oral,and radiographic examination with informedconsent and ethical approval. The radiographicexamination consisted of dental panoramicradiography (DPR). Additional appropriate in-traoral radiographs were done where indicatedto confirm DPR findings but were not used indata analysis. The radiographs were examinedblind and independently by three experiencedobservers including one consultant dental ra-diologist. The grading of radiographs, detailedbelow, was done retrospectively.The DPR scoring criteria are detailed in table

2. Various anomalies have been identified byus in a pilot study (unpublished data) and byothers in previous studies." 1424 These wereused to derive definitions of criteria for scoring.Well defined, round endosteal (fig 1) or ex-osteal (fig 2) radiodensities with regular mar-gins were scored as osteomas; well definedradiodensities but with irregularly shaped mar-gins were scored as dense bone islands (DBIs,fig 3), and an ill defined increase in bone density

Figure 2 Area of a dental panoramic radiographshowing exosteal osteomas (large arrows). Endostealosteomas are also present in the mandible (small arrows).

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Figure 3 Part of a dental panoramic radiograph showingirregular radiodense lesion typical of a dense bone island(arrow).

was scored as hazy sclerosis (fig 4). The sizeor the extent of the osseous lesions was alsonoted. In addition, for hazy sclerosis, as-

sociation with teeth was recorded. Other fea-tures used as diagnostic criteria were presence

or absence of odontomes (figs 4 and 5), super-

numerary teeth, and unerupted teeth (fig 5).Unerupted third molars were excluded fromanalysis.Four possible outcomes were considered;

these included (1) lack of any anomalies, (2)minimal change(s), (3) equivocal change(s),and (4) significant change(s). Each DPR an-

omaly was assigned a score. An overall DentalPanoramic Radiograph Score (DPRS) was de-termined by summation of the score for in-

Figure 4 Part of a dental panoramic radiograph showinghazy sclerosis affecting the body of the mandible. Anodontome is present (arrow).

Figure 5 Area of a dental panoramic radiograph from a

patient wearing complete dentures. An uneruptedmaxillary canine tooth is present (large arrow) in closeassociation with an odontome (small arrow).

dividual anomalies. The significance of thefindings was determined by assigning a specificrange of values of DPRS to each of the fouroutcomes (table 3).Where two features of any anomaly were

considered in the scores, for example, size andnumbers for osteomas and DBIs, all lesionswere individually assigned a size score togetherwith a single numbers score. This is illustratedby considering three osteomas of sizes 0-5 cm,1 cm, and 4-0 cm. The score for the numberof osteomas is 9 and the scores for the sizesare 0, 3, and 6, giving a final anomaly score of18.The score assigned to each anomaly reflected

its level of clinical significance if the anomalyoccurred in isolation. If an anomaly in isolationis considered clinically significant then a score

at or above the summated significance level(.7) is assigned to it, for example, presenceof two osteomas of whatever size. In contrast,for an anomaly not considered to be significantif present in isolation because, for example,it is seen in the general population relativelyfrequently, a relatively low score was given.Thus, in the absence of other features, theDPRS in this case would not exceed that re-

quired to achieve significance. This is il-lustrated by the scores assigned to the presenceof single unerupted teeth or a few DBIs of lessthan 05 cm. The weighting applied to eachscore is further considered below in the Dis-cussion.

Table 3 Significance of the dental panoramic radiographscores (DPRS). Calculation ofDPRS is detailed in"Subjects and methods"

Dental panoramic radiograph score Outcome

0-2 Normal3-4 Minimal change(s)5-6 Equivocal change(s).7 Significant change(s)

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Table 4 Frequency of anomalies in each group. The number ofpatients with theanomalies in each group is indicated and percentages are given in parentheses

GroupA Group B Group C Group DAnomaly (n = 85) (n = 30) (n = 19) (n = 19)

Osteomas 46 (54-1%) 0 (0%) 0 (0%) 3 (15-8%)Dense bone islands 36 (42 4%) 2 (6-7%) 1 (5 3%) 3 (15-8%)Hazy sclerosis 28 (32-9%) 1 (3-3%) 2 (10-5%) 2 (10-5%)Odontomes 8 (9-4%) 0 (0%) 0 (0%) 0 (0%)Supernumerary teeth 23 (27-1%) 0 (0%) 1 (5-3%) 0 (0%)Unerupted teeth 12 (14-1%) 0 (0%) 0 (0%) 0 (0%)

Table 5 Frequency of the possible DPR outcomes in each group. The number ofpatientswith the different DPR findings in each group is indicated and percentages are given inparentheses

Group A Group B Group C Group DDPR outcome (n = 85) (n = 30) (n = 19) (n = 19)

Normal 15 (17-7%) 27 (90 0%) 17 (89-4%) 13 (68-5%)Minimal change(s) 9 (10-6%) 3 (10-0%) 1 (5-3%) 2 (10-5%)Equivocal change(s) 3 (3 5%) 0 (0%) 1 (5-3%) 2 (10-5%)Significant change(s) 58 (68 2%) 0 (0%) 0 (0%) 2 (10-5%)

In addition to providing a value of diagnosticsignificance, the DPRS also provides a measure

of severity of the phenotype by including num-ber, size, or extent of changes in the individualscores beyond that necessary to establish out-come in a diagnostic test. This is illustrated bythe increasingly higher scores given to in-creasing number of osteomas seen on DPRseven though two or more osteomas or a singleosteoma greater than 0 5 cm would be sufficientfor diagnosis of FAP.

STATISTICAL ANALYSIS

Unless stated otherwise, the x2 test with Yates'scorrection was used where appropriate to testfor statistical significance with the acceptedsignificance level of p<0 05. Where expectedvalues in the x2 test fell below 5, Fisher's exactprobability test was used with the acceptedsignificance level of p<0 05. Bayesian cal-culations were used to derive probability ofcarrier status using DPRS outcomes as con-

ditional probability.

RELIABILITY OF TESTThe reliability of the test was determined byapplication of the DPRS to the known affected(group A) and unaffected groups (groups B andC). The clinically low risk group was excludedfrom analysis in view of the recently reportednon-penetrance and delayed onset of polyposis(see Discussion). Various parameters (speci-ficity, sensitivity, false positive rate, false neg-ative rate, positive predictive accuracy, negativepredictive accuracy, false alarm rate, and ef-ficiency) were determined.

ResultsThe percentage of patients in each of the fourgroups (A-D) showing changes on DPRs isshown in table 4. There were no statisticallysignificant differences (Fisher's exact prob-ability test) between the frequencies of an-

omalies observed in the two unaffected groups

(B and C); for the purpose of further statisticalanalysis the groups were combined. The

differences between the frequency of DPR an-omalies in the FAP affected group (group A)and the unaffected groups (groups B and C)were statistically significant. The commonestanomaly seen in the FAP affected group wasbony changes: 81% of patients showed osseouschanges including osteomas, DBI, or hazysclerosis (although not all the changes wereindividually significant by our criteria). Osseousanomalies were also the commonest changeseen in the unaffected groups (B and C) al-though they were present in only 8% of themembers of these groups combined. Of thepatients in group A, 12 showed a single sig-nificant change; eight patients had osteomas,three patients had DBIs, and one patient hadhazy sclerosis. Dental abnormalities (odon-tomes, supernumerary teeth, and impacted/unerupted teeth) were seen in 37% of the FAPpatients. In contrast only one person in groupB had a dental anomaly (maxillary super-

numerary tooth). Six of the 19 patients (32%)in group D (clinically low risk) had osseous

anomalies but none had dental anomalies.The number of people classified as having

significant changes, equivocal changes, min-imal changes, and normal radiographic ap-

pearance in each group are shown in table 5.The salient features are that in group A, 58of the 85 subjects showed significant changescompared to 0 out of 30 in group B and 0 outof 19 in group C. Three of 85 patients in groupA and one in 49 patients in groups B and Chad equivocal changes. When the significantfindings were counted as positive and all othercategories were classified as negative, there wasa statistically significant difference in the fre-quency of positive and negative test outcomesbetween the affected group (A) and the un-

affected groups (B and C).Using these counts in Bayesian calculation

with a prior probability of 50% ofbeing carrier,the probability of carrier status was ap-

proximately 17% with a negative DPRS find-ing, 54% with minimal or equivocal changes,and 100% (diagnostic) with significantchanges.

In the clinically low risk group of 19 people,two showed significant changes, two had equi-vocal changes, two had minimal changes, and13 had no changes. The reliability of the testwhen applied to the known affected group (A)and the known unaffected groups (B and C) isshown in table 6. When the significant findingswere counted as positive and all other categorieswere classified as negative, the test had speci-

Table 6 Reliability of DPRS as a diagnostic test usingdifferent DPRS outcomes. Two known unaffected groups(B and C) were considered together with the affected group(A)

DPRS (%)

Test parameter . 7 . 5 . 3

Specificity 100 95-9 87-8Sensitivity 68-2 71-8 82-4False positive rate 0 4 0 12-0False negative rate 31-8 28-2 17-7Positive predictive accuracy 100 96-8 92-1Negative predictive accuracy 64-5 66-2 74-1False alarm rate 0 3-2 7 9Efficiency 79-1 80-6 84-3

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Table 7 Age distribution of the affected FAP patients(group A) with significant changes on DPR (DPRS2 7)

Age range No ofpatients with DPRS . 7 (%) Total No

10-20 8 (42-1) 1921-30 10 (71-4) 1431-40 22 (76-9) 2641-50 8 (66-7) 1251-80 10 (71-4) 14

ficity and positive predictive accuracy of 100%coupled with a false positive rate and falsealarm rate of 0%. The sensitivity of the testwas 68-2% with a negative predictive accuracy

of 64-5% and a false negative rate of 31-8%.The efficiency of the test was approximately79%.The sensitivity of the test was only slightly

improved (from 68-2% to 71-8%) by con-

sidering the equivocal findings as positive (table6). However, if minimal changes were alsoconsidered as positive then sensitivity increasedto 82-4%. The specificity and the positive pre-dictive accuracy were reduced to 87-8% and92-1% respectively. The efficiency of the testincreased to 84-3% (table 6).

In group A, an increasing incidence of sig-nificant DPR anomalies (DPRS 7) with age

was observed up to the age of 30 (table 7).Forty two percent of patients aged 20 andunder had a DPRS .7 compared to 75%of the patients over 20. This difference was

statistically significant. However, the numberof patients at extremes of age was small.

DiscussionThe desirability of early identification ofpeoplewith FAP in the at risk group is apparentbecause screening for colonic polyps by colon-oscopy could be limited to these subjects thussaving those unaffected from unnecessary, un-

pleasant, and costly investigations. Althoughdental changes have been described previouslyin FAP, their use in the diagnosis of FAP hasbeen limited. This is chiefly because of thenon-specific nature of some of the changesand the consequent difficulty in attaching anysignificance to them in individual patients. Inorder to overcome this problem we have de-signed a weighted Dental Panoramic Ra-diograph Score (DPRS) which takes intoconsideration the nature, extent, and site ofthe changes seen on a dental panoramic ra-

diograph.In applying the weighting to each score, we

have taken into consideration our clinical ex-

perience and previous studies of radiographicanomalies in the general population and in FAPpatients. Small radiodensities, with or withoutregular margins and particularly in the man-

dibular molar and premolar regions, have beendescribed in between 0% and 10%25-31 of thegeneral population. These changes are oftenseen in relation to the roots of teeth whenpresent and presumably occur in response topulpal or periodontal pathoses. We have ob-served three types of osseous lesions in FAPpatients: osteomas, dense bone islands, andhazy sclerosis. Previous studies ofFAP patients

have grouped these as "osteomatous" lesionsor radio-opacities. We have chosen to considerthese lesions separately because in our ex-perience, small and often multiple radio-opa-cities with irregular margins (DBIs by ourdefinition) are often seen in unaffected patients.In contrast, solitary osteomas (circular radio-opaque lesions with regular margins) greaterthan 0 5 cm and multiple osteomas are not seenin such patients. This is confirmed by theabsence of osteomas in all the members andthe presence of DBIs in three of the 49 (- 6%)members of the unaffected groups (groups Band C) in the present study. These differencesare reflected in the weighting given to theseentities in the DPRS. Hazy sclerosis in FAPpatients has not been previously described. Asthis appearance may be seen as an inflammatorybone response to periodontal disease in un-affected subjects, an appropriate weighting wasgiven in DPRS to the site and extent of suchchanges. Overall, hazy sclerosis unrelated toteeth was given a higher score than that as-sociated with teeth.Supernumerary teeth, in particular those in

the maxillary midline (mesiodens), occur in thegeneral population with a frequency of up to1 %.32 In the absence of other changes, we havegiven a relatively low score value to the presenceof mesiodens and equivocal score value to thepresence of any other single supernumerarytooth. Unerupted teeth are relatively commonin the general population occurring with anoverall frequency of 17%.33 Unerupted thirdmolars are even more common (frequency of- 22%),33 so we have disregarded these in theDPRS. However, other unerupted teeth areincluded although a low score is given to thepresence of a single unerupted tooth.

In the present study, all radiographic an-omalies were significantly more frequent in theaffected group than in the unaffected group.The most frequent observation in the FAPpatients was the presence of osseous lesionsalthough we did not consider all of thesechanges to be individually significant in theDPRS. Our data are consistent with previousstudies which reported osseous changes in be-tween 76 and 93% and dental changes in 30%of FAP patients." 14-14The DPRS is a highly reliable diagnostic

index. With a DPRS .7, the specificity andpositive predictive rate was 100%, and a falsepositive rate of0% was obtained. However, thesensitivity is relatively low at 69% and this isnot improved significantly by consideration ofthe equivocal DPRS values as significant. Thislevel of sensitivity may appear surprising giventhe high prevalence of osseous changes in theaffected subjects; however, not all of these weredeemed to be significant in the scoring ofDPRS. Thirteen of the 85 (- 15%) FAPpatients had what we classified as insignificantosseous changes compared to five of the 49(- 10%) members of the unaffected groups (Band C). The sensitivity is considerably im-proved if all positive findings, that is, the min-imal and equivocal changes, are considered assignificant; however, the specificity and thepositive predictive accuracy are slightly re-

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duced. Overall, the efficiency of the test isslightly improved (from -79% to -84%).These data are remarkably similar to the pre-viously reported sensitivity and specificity of82% and 90% respectively for findings char-acteristic of FAP on DPRs.20 Giardiello et alloalso reported a similar level of sensitivity (84%)but a much lower specificity (50%). However,they considered the presence of one or morejaw lesions (any well circumscribed area ofradio-opacity or an odontome) as significant.This is clearly different from the thresholdsused in the present study. The presence of sixosteomas has been reported to be diagnosticfor FAP'7 but patients with such changes onlyrepresent a small percentage ofthe total sample.

In comparison, the other most commonlyused extracolonic phenotype marker, CHRPE,is reported to have sensitivity of between 58and 100% using various diagnostic thresholdcriteria. lo-" In unaffected populations, CHRPEis reported in up to 43% of people." A highlevel of specificity (between 94 and 100%) isalso reported applying diagnostic thresholdsbased on type, size, or number of CHRPElesions or presence of bilateral lesions."1-13 De-pending on the thresholds applied in the DPRS(as discussed above), comparable levels ofspecificity and sensitivity are obtained in thepresent study.

Application of DPRS to the clinically lowrisk group (group D) showed two subjects witha significant score. They were aged 58 and 52,were free of colonic polyps, and did not haveCHRPE. One had a single osteoma - 1 cmand the other had an osteoma (- 7 mm) and asmall dense bone island (- 5 mm) respectively.Previously reported incidence data indicate thatat risk people with no retinal features andnegative colonoscopy at the age of 34 yearsshould be considered to be free of FAP. Thissuggests that the two patients with the sig-nificant DPRS scores in the clinically low riskgroup represent false positives in our test. How-ever, we have recently described four familieswith non-penetrance and late onset of polyp-osis.34 Our studies indicate that at least 5%of affected subjects will be free of polyps onsigmoidoscopy at 30 years of age and some stillhave no polyps in their fifties. Thus the twosubjects may represent atypical FAP cases par-ticularly in view of the high specificity of thetest determined in this study. Mutation analysisis continuing and should establish which ofthese possibilities is correct.The higher frequency of significant DPRS

findings in the patients aged over 20 comparedto the patients aged 20 and under suggests thatthere may be an age dependent appearance ofthe jaw changes. This indicates that the test ismore likely to be informative in the older groupof patients.The usefulness of DPR in the diagnosis of

FAP is apparent from the data presented here.DPRS provides a highly specific method ofdetermining significance of findings on DPR.In addition, the incidence data should permituse of DPR findings together with oph-thalmoscopy findings and linkage analysis inBayesian calculations for optimal assessments

of risk where mutation analysis is not feasible.The DPRS is a highly reliable and reproducibleindex in our hands; however, we have examineda large series of patients to date and haveconsiderable experience in assessment of theradiographs. Further independent assessmentof DPRS by other groups is necessary in de-termining the usefulness or otherwise of thetest.

Part of this work was funded by a North West Regional HealthAuthority Medical Innovations Grant to GE, NT, PS, and RH.

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