Abstract
Desmoid tumours are rare neoplasms of fibroblastic origin which arise with disproportionate frequency in patients with familial adenomatous polyposis (FAP). They are thought to develop in about 10–25% of FAP patients and may be the leading cause of death amongst those who have undergone colectomy. Risk factors include trauma, having a distal germline APC mutation, having a family history of desmoids, and probably oestrogens. In very high-risk individuals there may be a case for delay of colectomy or chemoprophylaxis at the time of surgery. Desmoids are now known to be true neoplasms but with normal telomere length and telomerase activity. FAP-associated tumours seem to carry biallelic APC mutations, one of which lies in the distal part of the gene. Such loss of wild-type APC seems to occur relatively late in tumour development. It is likely that β-catenin plays an important role in tumourigenesis. FAP-associated desmoids tend to arise in the abdomen or abdominal wall. CT scanning gives the best information on tumour anatomy whilst T2-weighted MRI indicates likely behaviour. Treatment may simply consist of observation. Otherwise, usual first-line therapy is with sulindac with or without an anti-oestrogen. Cytotoxic chemotherapy is an option in unresectable tumours. Surgery is a reasonable first-line treatment in abdominal wall tumours but is risky for intra-abdominal tumours and may necessitate massive small bowel resection. Desmoids are the greatest remaining challenge in the management of FAP and further research into their aetiology needs to be combined with multicentre clinical trials of new treatments in order to improve management of the disease.
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JJ Reitamo TM Scheinin P Hayry (1986) ArticleTitleThe desmoid syndrome. New aspects in the cause, pathogenesis and treatment of the desmoid tumor Am J Surg 151 230–7 Occurrence Handle3946757 Occurrence Handle1:STN:280:DyaL287isl2kug%3D%3D Occurrence Handle10.1016/0002-9610(86)90076-0
AK Gurbuz FM Giardello GM Petersen et al. (1994) ArticleTitleDesmoid tumours in familial adenomatous polyposis Gut 35 377–81 Occurrence Handle8150351 Occurrence Handle1:STN:280:DyaK2c3gtVKltQ%3D%3D
AM Lofti RR Dozois H Gordon et al. (1989) ArticleTitleMesenteric fibromatosis complicating familial adenomatous polyposis: predisposing factors and results of treatment Int J Colorectal Dis 4 30–6 Occurrence Handle10.1007/BF01648547
L Bertario A Russo P Sala et al. (2001) ArticleTitleGenotype and phenotype factors as determinants of desmoid tumours in patients with familial adenomatous polyposis Int J Cancer 95 102–7 Occurrence Handle11241320 Occurrence Handle1:STN:280:DC%2BD3M3gslShuw%3D%3D Occurrence Handle10.1002/1097-0215(20010320)95:2<102::AID-IJC1018>3.0.CO;2-8
K Heinimann B Mullhaupt W Weber et al. (1998) ArticleTitlePhenotypic differences in familial adenomatous polyposis based on APC germline mutation status Gut 43 675–679 Occurrence Handle9824350 Occurrence Handle1:STN:280:DyaK1M%2FntFamtA%3D%3D Occurrence Handle10.1136/gut.43.5.675
W Friedl R Caspari M Sengteller et al. (2001) ArticleTitleCan APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families Gut 48 515–521 Occurrence Handle11247896 Occurrence Handle1:CAS:528:DC%2BD3MXislyhurg%3D Occurrence Handle10.1136/gut.48.4.515
KP Nugent AD Spigelman RKS Phillips (1993) ArticleTitleLife expectancy after colectomy and ileorectal anastomosis for familial adenomatous polyposis Dis Colon Rectum 36 1059–62 Occurrence Handle8223060 Occurrence Handle1:STN:280:DyaK2c%2FjvVCgsw%3D%3D Occurrence Handle10.1007/BF02047300
ML Arvanitis DG Jagelman VW Fazio et al. (1990) ArticleTitleMortality in patients with familial adenomatous polyposis Dis Colon Rectum 33 639–42 Occurrence Handle2165452 Occurrence Handle1:STN:280:DyaK3czivF2jsA%3D%3D Occurrence Handle10.1007/BF02150736
L Bertario S Presciuttini P Sala et al. (1994) ArticleTitleCauses of death and postsurgical survival in familial adenomatous polyposis: results from the Italian registry of familial polyposis writing committee Semin Surg Oncol 10 225–34 Occurrence Handle8085100 Occurrence Handle1:STN:280:DyaK2czmslejtQ%3D%3D
SK Clark RKS Phillips (1996) ArticleTitleDesmoids in familial adenomatous polyposis Br J Surg 83 1494–504 Occurrence Handle9014661 Occurrence Handle1:STN:280:DyaK2s7ms12ksA%3D%3D
HT Lynch R Fitzgibbons SuffixJr (1996) ArticleTitleSurgery, desmoid tumors, and familial adenomatous polyposis: case report and literature review Am J Gastroenterol 91 2598–601 Occurrence Handle8946994 Occurrence Handle1:STN:280:DyaK2s7gt1Omtg%3D%3D
SK Clark TG Smith DE Katz et al. (1998) ArticleTitleIdentification and progression of a desmoid precursor lesion in patients with familial adenomatous polyposis Br J Surg 85 970–3 Occurrence Handle9692575 Occurrence Handle1:STN:280:DyaK1czlsFejsQ%3D%3D Occurrence Handle10.1046/j.1365-2168.1998.00773.x
JJ Reitamo P Hayry E Nykyri et al. (1982) ArticleTitleThe desmoid tumor. I. Incidence, sex-, age- and anatomical distribution in the Finnish population Am J Clin Pathol 77 665–73 Occurrence Handle7091046 Occurrence Handle1:STN:280:DyaL383islGhtQ%3D%3D
P Hayry JJ Reitamo S Totterman et al. (1982) ArticleTitleThe desmoid tumor. II. Analysis of factors possibly contributing to the etiology and growth behavior Am J Clin Pathol 77 674–80 Occurrence Handle7091047 Occurrence Handle1:STN:280:DyaL383islGhug%3D%3D
S Klemmer L Pascoe J Decosse (1987) ArticleTitleOccurrence of desmoids in patients with familial adenomatous polyposis of the colon Am J Med Genet 28 385–92 Occurrence Handle2827474 Occurrence Handle1:STN:280:DyaL1c7gtlOitA%3D%3D Occurrence Handle10.1002/ajmg.1320280217
Sturt NJH, Gallagher MC, Bassett P et al., 2004 Evidence for genetic predisposition to desmoid tumours in familial adenomatous polyposis (FAP) independent of the APC germline mutation. Submitted for publication
WA McAdam JC Goligher (1970) ArticleTitleThe occurrence of desmoids in patients with familial polyposis coli Br J Surg 57 618–31 Occurrence Handle5451940 Occurrence Handle1:STN:280:DyaE3c3mslGrtg%3D%3D
CL Lim MJ Walker RR Mehta et al. (1986) ArticleTitleEstrogen and antiestrogen binding sites in desmoid tumors Eur J Cancer Clin Oncol 22 583–7 Occurrence Handle3770030 Occurrence Handle1:CAS:528:DyaL28Xkslarurk%3D Occurrence Handle10.1016/0277-5379(86)90047-7
F Tonelli R Valanzano ML Brandi (1994) ArticleTitlePharmacologic treatment of desmoid tumors in familial adenomatous polyposis: results of an in␣vitro study Surgery 115 473–9 Occurrence Handle8165538 Occurrence Handle1:STN:280:DyaK2c3hvVOqsg%3D%3D
Y Miyoshi H Ando H Nagase et al. (1992) ArticleTitleGerm-line mutations of the APC gene in 53 familial adenomatous polyposis patients Proc Natl Acad Sci USA 89 4452–6 Occurrence Handle1316610 Occurrence Handle1:CAS:528:DyaK38Xkt1Cjsrw%3D Occurrence Handle10.1073/pnas.89.10.4452
H Nagase et al. (1992) ArticleTitleCorrelation between the location of germline mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients Cancer Res 52 4055–7 Occurrence Handle1319838 Occurrence Handle1:CAS:528:DyaK38XkvVOktLs%3D
R Caspari S Olschwang W Friedl et al. (1995) ArticleTitleFamilial Adenomatous Polyposis: desmoid tumours and lack of opthalmic lesions (CHRPE) associated with APC mutations beyond codon 1444 Hum Mol Genet 4 337–40 Occurrence Handle7795585 Occurrence Handle1:CAS:528:DyaK2MXkvVeju7w%3D
DR Davies JG Armstrong N Thakker et al. (1995) ArticleTitleSevere Gardner syndrome in families with mutations restricted to a specific region of the APC gene Am J Hum Genet 57 1151–8 Occurrence Handle7485167 Occurrence Handle1:STN:280:DyaK28%2Fis1Wisw%3D%3D
RJ Scott NJ Froggatt RC Trembath et al. (1996) ArticleTitleFamilial infiltrative fibromatosis (desmoid tumours) (MIM135290) caused by a recurrent 3′ APC gene mutation Hum Mol Genet 5 1921–4 Occurrence Handle8968744 Occurrence Handle1:CAS:528:DyaK28XnsFKktL8%3D Occurrence Handle10.1093/hmg/5.12.1921
DM Eccles R Luijt Particlevan der C Breukel et al. (1996) ArticleTitleHereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene Am J Hum Genet 59 1193–201 Occurrence Handle8940264 Occurrence Handle1:CAS:528:DyaK2sXhtlSqtQ%3D%3D
J Couture A Mitri R Lagace et al. (2000) ArticleTitleA germline mutation at the extreme 3′ end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumour Clin Genet 57 205–12 Occurrence Handle10782927 Occurrence Handle1:STN:280:DC%2BD3c3ktlShsw%3D%3D Occurrence Handle10.1034/j.1399-0004.2000.570306.x
L Bertario A Russo P Sala et al. (2003) ArticleTitleMultiple approach to the exploration of genotype–phenotype correlations in familial adenomatous polyposis J Clin Oncol 21 1698–707 Occurrence Handle12721244 Occurrence Handle1:CAS:528:DC%2BD2cXpsVWqsbs%3D Occurrence Handle10.1200/JCO.2003.09.118
Z Dobbie M Spycher J-L Mary et al. (1996) ArticleTitleCorrelation between the development of extracolonic manifestations in FAP patients and mutations beyond codon 1403 in the APC gene J Med Genet 33 274–80 Occurrence Handle8730280 Occurrence Handle1:CAS:528:DyaK28XivFWktr4%3D Occurrence Handle10.1136/jmg.33.4.274
R Houlston M Crabtree R Phillips et al. (2000) ArticleTitleExplaining differences in the severity of familial adenomatous polyposis and the search for modifier genes Gut 48 1–5 Occurrence Handle10.1136/gut.48.1.1
C Soravia T Berk RS McLeod et al. (2000) ArticleTitleDesmoid disease in patients with familial adenomatous polyposis Dis Colon Rectum 43 363–9 Occurrence Handle10733118 Occurrence Handle1:STN:280:DC%2BD3c7psFamtA%3D%3D Occurrence Handle10.1007/BF02258303
R Fodde W Edelmann K Yang et al. (1994) ArticleTitleA targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors Proc Natl Acad Sci USA 91 8969–73 Occurrence Handle8090754 Occurrence Handle1:CAS:528:DyaK2cXmtVajtb0%3D Occurrence Handle10.1073/pnas.91.19.8969
R Smits W Houven Oordt Particlevan der van A Luz et al. (1998) ArticleTitleApc1638N: a mouse model for familial adenomatous polyposis-associated desmoid tumors and cutaneous cysts Gastroenterology 114 275–83 Occurrence Handle9453487 Occurrence Handle1:STN:280:DyaK1c7hsVagsA%3D%3D Occurrence Handle10.1016/S0016-5085(98)70478-0
R Smits A Kartheuser S Jagmohan-Changur et al. (1997) ArticleTitleLoss of Apc and the entire chromosome 18 but absence of mutations at the Ras and Tp53 genes in intestinal tumors from Apc1638N, a mouse model for Apc-driven carcinogenesis Carcinogenesis 18 321–7 Occurrence Handle9054624 Occurrence Handle1:CAS:528:DyaK2sXhs1yrtbY%3D Occurrence Handle10.1093/carcin/18.2.321
C Tolg R Poon R Fodde et al. (2003) ArticleTitleGenetic deletion of receptor for hyaluronan-mediated motility (Rhamm) attenuates the formation of aggressive fibromatosis (desmoid tumour) Oncogene 22 6873–82 Occurrence Handle14534534 Occurrence Handle1:CAS:528:DC%2BD3sXnvFSgsbc%3D Occurrence Handle10.1038/sj.onc.1206811
RB Luijt Particlevan der P Meera Khan HFA Vasen et al. (1996) ArticleTitleGermline mutations in the 3’ part of APC exon 15 do not result in truncated proteins and are associated with attenuated adenomatous polyposis coli Hum Genet 98 727–34 Occurrence Handle8931709 Occurrence Handle10.1007/s004390050293
C Soravia T Berk L Madlensky et al. (1998) ArticleTitleGenotype–phenotype correlations in attenuated adenomatous polyposis coli Am J Hum Genet 62 1290–301 Occurrence Handle9585611 Occurrence Handle1:CAS:528:DyaK1cXlslCiur8%3D Occurrence Handle10.1086/301883
SB Middleton K Pack RK Phillips (2000) ArticleTitleTelomere length in familial adenomatous polyposis-associated desmoids Dis Colon Rectum 43 1535–9 Occurrence Handle11089588 Occurrence Handle1:STN:280:DC%2BD3M%2Fkt1Gisg%3D%3D Occurrence Handle10.1007/BF02236734
M Li C Cordon-Cardo WL Gerald et al. (1996) ArticleTitleDesmoid fibromatosis is a clonal process Hum Pathol 27 939–43 Occurrence Handle8816889 Occurrence Handle1:STN:280:DyaK28vhtlOgtw%3D%3D Occurrence Handle10.1016/S0046-8177(96)90221-X
SB Middleton IM Frayling RK Phillips (2000) ArticleTitleDesmoids in familial adenomatous polyposis are monoclonal proliferations Br J Cancer 82 827–32 Occurrence Handle10732754 Occurrence Handle1:STN:280:DC%2BD3c7psVyqsA%3D%3D Occurrence Handle10.1054/bjoc.1999.1007
M Miyaki M Konishi R Kikuchi-Yanoshita et al. (1993) ArticleTitleCoexistence of somatic and germ-line mutations of APC gene in desmoid tumours from patients with familial adenomatous polyposis Cancer Res 53 5079–82 Occurrence Handle8221638 Occurrence Handle1:CAS:528:DyaK2cXivVCitQ%3D%3D
R Palmirotta MC Curia DL Esposito et al. (1995) ArticleTitleNovel mutations and inactivation of both alleles of the APC gene in desmoid tumours Hum Mol Genet 4 1979–81 Occurrence Handle8595425 Occurrence Handle1:CAS:528:DyaK2MXoslyrsrw%3D
H Lamlum M Ilyas A Rowan et al. (1999) ArticleTitleThe type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of germline mutation: a new facet to Knudson’s ‘two hit’ hypothesis Nat Med 5 1071–5 Occurrence Handle10470088 Occurrence Handle1:CAS:528:DyaK1MXlslKltrk%3D Occurrence Handle10.1038/12511
Clark SK. Studies in desmoid disease in familial adenomatous polyposis. MD thesis, University of Cambridge, 1998
Y Miyoshi K Iwao G Nawa et al. (1998) ArticleTitleFrequent mutations in the beta-catenin gene in desmoid tumours from patients without familial adenomatous polyposis Oncol Res 10 591–4 Occurrence Handle10367940 Occurrence Handle1:CAS:528:DyaK1MXjslyjsrk%3D
S Tejpar F Nollet C Li et al. (1999) ArticleTitlePredominance of beta-catenin mutations and beta-catenin dysregulation in sporadic aggressive fibromatosis Oncogene 18 6615–20 Occurrence Handle10597266 Occurrence Handle1:CAS:528:DyaK1MXnvFyhsLk%3D Occurrence Handle10.1038/sj.onc.1203041
E Montgomery MS Torbenson M Kaushal et al. (2002) ArticleTitleBeta-catenin immunohistochemistry separates mesenteric fibromatosis from gastrointestinal stromal tumor and sclerosing mesenteritis Am J Surg Pathol 26 1296–301 Occurrence Handle12360044 Occurrence Handle10.1097/00000478-200210000-00006
SS Cheon AYL Cheah S Turley et al. (2002) ArticleTitleb-Catenin stabilization dysregulates mesenchymal cell proliferation, motility, and invasiveness and causes aggressive fibromatosis and hyperplastic cutaneous wounds Proc Natl Acad Sci USA 99 6973–8 Occurrence Handle11983872 Occurrence Handle1:CAS:528:DC%2BD38XjvFCqsLY%3D Occurrence Handle10.1073/pnas.102657399
ML Larramendy M Virolainen E Tukiainen et al. (1998) ArticleTitleChromosome band 1q21 is recurrently gained in desmoid tumors Genes Chromosomes Cancer 23 183–6 Occurrence Handle9739022 Occurrence Handle1:CAS:528:DyaK1cXlvFyht7c%3D Occurrence Handle10.1002/(SICI)1098-2264(199810)23:2<183::AID-GCC12>3.0.CO;2-P
P Brandal F Micci B Bjerkehagen et al. (2003) ArticleTitleMolecular cytogenetic characterization of desmoid tumors Cancer Genet Cytogenet 146 1–7 Occurrence Handle14499689 Occurrence Handle1:CAS:528:DC%2BD3sXnt1Gnsbs%3D Occurrence Handle10.1016/S0165-4608(03)00122-5
JM Church (1995) ArticleTitleDesmoid tumours in patients with familial adenomatous polyposis Semin Colon Rectal Surg 6 29–32
SB Middleton SK Clark P Matravers et al. (2003) ArticleTitleStepwise progression of familial adenomatous polyposis-associated desmoid precursor lesions demonstrated by a novel CT scoring system Dis Colon Rectum 46 481–5 Occurrence Handle12682541 Occurrence Handle10.1007/s10350-004-6586-1
JC Healy RH Reznek SK Clark et al. (1997) ArticleTitleMR appearances of desmoid tumors in familial adenomatous polyposis AJR Am J Roentgenol 169 465–72 Occurrence Handle9242755 Occurrence Handle1:STN:280:DyaK2szos1Kltw%3D%3D
RKS Phillips MH Wallace PM Lynch et al. (2002) ArticleTitleA randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis Gut 50 857–60 Occurrence Handle12010890 Occurrence Handle1:CAS:528:DC%2BD38XkvVGktL8%3D Occurrence Handle10.1136/gut.50.6.857
WG Friend (1990) ArticleTitleSulindac suppression of colorectal polyps in Gardener’s syndrome Am Fam Physician 41 891–4 Occurrence Handle2305666 Occurrence Handle1:STN:280:DyaK3c7msVersg%3D%3D
R Poon R Smits C Li et al. (2001) ArticleTitleCyclooxygenase-two (COX-2) modulates proliferation in aggressive fibromatosis (desmoid tumor) Oncogene 20 451–60 Occurrence Handle11313976 Occurrence Handle1:CAS:528:DC%2BD3MXhsVKjtLo%3D Occurrence Handle10.1038/sj.onc.1204107
K Tsukada JM Church DG Jagelman et al. (1992) ArticleTitleNoncytotoxic drug therapy for intra-abdominal desmoid tumor in patients with familial adenomatous polyposis Dis Colon Rectum 35 29–33 Occurrence Handle1310270 Occurrence Handle1:STN:280:DyaK387ivVajsg%3D%3D Occurrence Handle10.1007/BF02053335
J Janinis M Patriki L Vini et al. (2003) ArticleTitleThe pharmacological treatment of aggressive fibromatosis: a systematic review Ann Oncol 14 181–90 Occurrence Handle12562642 Occurrence Handle1:STN:280:DC%2BD3s%2Flt12ksQ%3D%3D Occurrence Handle10.1093/annonc/mdg064
F Tonelli F Ficari R Valanzano et al. (2003) ArticleTitleTreatment of desmoids and mesenteric fibromatosis in familial adenomatous polyposis with raloxifene Tumori 89 391–6 Occurrence Handle14606641 Occurrence Handle1:CAS:528:DC%2BD3sXpsFerurs%3D
NM Lindor R Dozois H Nelson et al. (2003) ArticleTitleDesmoid tumors in familial adenomatous polyposis: a pilot project evaluating efficacy of treatment with pirfenidone Am J Gastroenterol 98 1868–74 Occurrence Handle12907346 Occurrence Handle1:CAS:528:DC%2BD3sXlvFGkurc%3D Occurrence Handle10.1111/j.1572-0241.2003.07479.x
J Mace J Sybil Biermann V Sondak et al. (2002) ArticleTitleResponse of extraabdominal desmoid tumors to therapy with imatinib mesylate Cancer 95 2373–9 Occurrence Handle12436445 Occurrence Handle1:CAS:528:DC%2BD38XpsFSitbk%3D Occurrence Handle10.1002/cncr.11029
K Seiter N Kemeny (1993) ArticleTitleSuccessful treatment of a desmoid tumour with doxorubicin Cancer 71 2242–4 Occurrence Handle8453544 Occurrence Handle1:STN:280:DyaK3s3gtFCgtg%3D%3D Occurrence Handle10.1002/1097-0142(19930401)71:7<2242::AID-CNCR2820710713>3.0.CO;2-0
S Risum S Bulow (2003) ArticleTitleDoxorubicin treatment of an intra-abdominal desmoid tumour in a patient with familial adenomatous polyposis Colorectal Dis 5 585–6 Occurrence Handle14617246 Occurrence Handle1:STN:280:DC%2BD3srjslWntA%3D%3D Occurrence Handle10.1046/j.1463-1318.2003.00534.x
A Weiss R Lackman (1989) ArticleTitleLow-dose chemotherapy of desmoid tumours Cancer 64 1192–4 Occurrence Handle2766217 Occurrence Handle1:STN:280:DyaL1MzlsVWltQ%3D%3D Occurrence Handle10.1002/1097-0142(19890915)64:6<1192::AID-CNCR2820640605>3.0.CO;2-J
A Azzarelli A Gronchi R Bertulli et al. (2001) ArticleTitleLow-dose chemotherapy with methotrexate and vinblastine for patients with advanced aggressive fibromatosis Cancer 92 1259–64 Occurrence Handle11571741 Occurrence Handle1:CAS:528:DC%2BD3MXnt12mu74%3D Occurrence Handle10.1002/1097-0142(20010901)92:5<1259::AID-CNCR1446>3.0.CO;2-Y
SK Clark KF Neale JC Landgrebe et al. (1999) ArticleTitleDesmoid tumours complicating familial adenomatous polyposis Br J Surg 86 1185–9 Occurrence Handle10504375 Occurrence Handle1:STN:280:DyaK1Mvjs1Kluw%3D%3D Occurrence Handle10.1046/j.1365-2168.1999.01222.x
AG Tzakis P Tryphonopoulos W Faria ParticleDe et al. (2003) ArticleTitlePartial abdominal evisceration, ex vivo resection, and intestinal autotransplantation for the treatment of pathologic lesions of the root of the mesentery J Am Coll Surg 197 770–6 Occurrence Handle14585412 Occurrence Handle10.1016/S1072-7515(03)00756-7
TW Clark (2003) ArticleTitlePercutaneous chemical ablation of desmoid tumors J Vasc Interv Radiol 14 629–34 Occurrence Handle12761317
RM Bright-Thomas A Agrawal R Hargest (2002) ArticleTitlePreclinical studies of gene transfer for the treatment of desmoid disease in familial adenomatous polyposis Br J Surg 89 1563–9 Occurrence Handle12445067 Occurrence Handle1:STN:280:DC%2BD38noslajuw%3D%3D Occurrence Handle10.1046/j.1365-2168.2002.02277.x
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Sturt, N.J.H., Clark, S.K. Current ideas in desmoid tumours. Familial Cancer 5, 275–285 (2006). https://doi.org/10.1007/s10689-005-5675-1
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DOI: https://doi.org/10.1007/s10689-005-5675-1