� 2006 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 140A:2245–2247 (2006)

Research Letter

Early-Onset Low-Grade Papillary Carcinoma of theBladder Associated With Apert Syndrome and a

Germline FGFR2 Mutation (Pro253Arg)

Andreas Andreou,1,2 Aude Lamy,3 Valerie Layet,4 Daniel Cailliez,5 Francoise Gobet,3

Christian Pfister,1 Michel Menard,2 and Thierry Frebourg6*1Department of Urology, Rouen University Hospital, Rouen, France

2Department of Pediatric Surgery, Le Havre Hospital, Le Havre, France3Department of Pathology, Rouen University Hospital, Rouen, France

4Department of Genetics, Le Havre Hospital, Le Havre, France5Department of Pathology, Le Havre Hospital, Le Havre, France

6Department of Genetics, Rouen University Hospital and Inserm U614, Faculty of Medicine, Rouen, France

Received 1 September 2005; Accepted 29 June 2006

How to cite this article: Andreou A, Lamy A, Layet V, Cailliez D, Gobet F, Pfister C, Menard M, Frebourg T. 2006.Early-onset low-grade papillary carcinoma of the bladder associated with Apert syndrome and a germline

FGFR2 mutation (Pro253Arg). Am J Med Genet Part A 140A:2245–2247.

To the Editor:

We have seen a 4-year-old girl with Apertsyndrome (Fig. 1) and an FGFR2 mutation(758C!G, resulting in Pro253Arg). She had severalepisodes of macroscopic hematuria. Ultrasoundscanning and an intravenous pyelogram demon-strated a large tumor of the bladder; cystoscopyshowed a 2 cm superficial lesion. Partial cystectomyand histopathological examination confirmed thediagnosis of a pTaG1 low-grade papillary urothelialcarcinoma (Fig. 2A). DNA sequencing from thetumor itself, not surprisingly, confirmed thepresenceof the same heterozygous mutation (Pro253Arg)(Fig. 2B).

Toour knowledge, this is thefirst documented caseof Apert syndrome with a papillary carcinoma of thebladder. Cohen [2000] reviewed other instances oftumors reported in Apert syndrome. Blank [1960]noted a thyroid adenoma in a postmortem case (hiscase 29). Cohen et al. [1987] reported a congenitalrhabdomyosarcoma of the hand, and in the seriesof Cohen and Kreiborg (n¼ 136 cases of Apertsyndrome, unpublished data, 1992), one patientdeveloped a fibrosarcoma of the arm during his fifthdecade. Cohen and Kreiborg [1993] also notedthyroid follicles within the thyroid cartilage underthe perichondrium.FGFR3 somatic mutations characterize the majority

of isolated pTaG1 superficial papillary bladdertumors [Cappellen et al., 1999; Billerey et al., 2001;

Kimura et al., 2001; van Rhijn et al., 2003; Bakkaret al., 2003]. These activating mutations are often thesame as those for thanatophoric dysplasia, type 1(742C!G, resulting in Arg248Cys; 746C!G, result-ing in Ser249Cys; and 1114G!T, resulting inGly372Cys). Even the single known mutation forthanatophoric dysplasia, type 2 (1954A!G, resultingin Lys652Glu) has been noted. In bladder tumors,FGFR3 mutations have been associated with afavorable clinical outcome, whereas TP53mutationshave been associated with an aggressive clinicaloutcome [Kimura et al., 2001; van Rhijn et al., 2003].FGFR3 mutations occur with lower frequency incervical cancer [Cappellen et al., 1999; Wu et al.,2000; Sibley et al., 2001], and have also beenreported with colorectal cancer [Jang et al., 2000,2001].

Needless to say, we detected no FGFR3mutation inthe bladder tumor, which developed in our 4-year-old girl with Apert syndrome. This case led ussubsequently to screen 14 isolated, superficial pTa orpT1 bladder tumors without detectable FGFR3mutations for the possible presence of somatic

*Correspondence to: Thierry Frebourg, Inserm U614, Faculty ofMedicine, 22 Boulevard Gambetta, 76183 Rouen, France.E-mail: Frebourg@chu-rouen.fr

DOI 10.1002/ajmg.a.31430

mutations in FGFR2, but we found none. In recentstudy of tumors by Hansen et al. [2005] none ofthe known documented FGFR2 mutations wereidentified in 58 tumor cell lines of various kinds orin 29 testicular germ cell tumors; only sequencevariations and allelic imbalance were found inFGFR2.

Nevertheless,FGFR2mutations have beennoted insome instances. For example, two mutations forgastric carcinoma have been identified. One of these(799T!C, resulting in Ser267Pro) is one of manypossible mutations for Crouzon syndrome andPfeiffer syndrome. Another is a splicing mutation(940-2A!G), which is one of many possible muta-tions for Pfeiffer syndrome [Jang et al., 2001].

Davies et al. [2005] screened the coding sequencesof 518 protein kinases for somatic mutations in 26primary lung cancers and 7 lung cancer cell lines.Most were silent, indicating that they were notimplicated in oncogenesis. However, some substitu-tions may contribute to oncogenesis. Among thesewere several somatic FGFR2 mutations in lungcancer, including one, which in the nonmosaic state,results in Pfeiffer syndrome (Trp290Cys).

Other FGF/FGFR alterations in neoplasia havebeen reviewed by Cohen [2003]. Spermatocyticseminomas, which are rare and thought to have alater developmental origin, should be documentedfor the possibility of activating FGFR2 mutations,although no such instances are known till date[Hansen et al., 2005].

ACKNOWLEDGMENTS

We are indebted to Michael Cohen for helpfuldiscussion and for a critical reading of the manu-script. We are also grateful to Andrew O. M. Wilkiefor suggestions.

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FIG. 1. Phenotype of the patient with Apert syndrome. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

FIG. 2. Bladder tumor. A: Histopathological examination showing a super-ficial papillary pTaG1 carcinoma (3.5�). B: Detection, by direct sequencing, ofa heterozygous FGFR2mutation, 758C!G, resulting inPro253Arg. [Color figurecan be viewed in the online issue, which is available at www.interscience.wiley.com.]

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BLADDER TUMOR, APERT SYNDROME, AND FGFR2 MUTATION 2247

American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a