Letter to the Editor

Nonpenetrance in FGFR3-Associated CoronalSynostosis Syndrome

To the Editor:

The Pro252Arg mutation in FGFR3 was first de-scribed in a collection of families with a variety of cra-niosynostosis syndrome phenotypes [Bellus et al.,1996; Muenke et al., 1997]. These include families thatsegregated findings suggestive of known syndromessuch as Pfeiffer, Jackson-Weiss, and Saethre-Chotzensyndromes, as well as the newly described Adelaide-type craniosynostosis [Ades et al., 1994], which wasmapped to 4p16, the FGFR3 locus [Hollway et al.,1995]. This collection of families included individualswho carried the mutation and who manifest only uni-or bilateral coronal craniosynostosis, or even macro-cephaly [Muenke et al., 1997]. Carpal-tarsal fusion andconed epiphyses, subclinical radiographic findings,were said to be the most consistent clinical marker fordetecting carriers [Muenke et al., 1997].

This subtle phenotypic presentation of the FGFR3mutation was further demonstrated in a series of re-cent papers. Gripp et al. [1998] tested 47 individualswith apparently isolated unilateral craniosynostosis orplagiocephaly for the FGFR3 mutation. Of the 37 pa-tients with unilateral coronal synostosis, four werefound to carry the mutation. Furthermore, in three ofthose four cases, an extremely mildly affected parentwas also found to carry the mutation. None of the pla-giocephaly patients was found to carry the mutation.Graham et al. [1998] suggested that carpal-tarsal fu-sion was the most specific finding for the FGFR3 mu-tation, being present in some individuals who did nothave craniosynostosis. Hollway et al. [1998] reportedon a family that segregated the FGFR3 mutation.While some affected individuals manifest craniosynos-tosis, others manifest only deafness. The authors pos-tulated that FGFR3 might be the DFN6 gene.

Here we report on a clinically and radiographicallynormal woman who carries the Pro250Arg mutation inFGFR3. This report demonstrates nonpenetrance ofthe FGFR3 mutation, and serves to emphasize theneed to test all first degree relatives of individuals

shown to carry the FGFR3 mutation, as even carefulclinical evaluation may miss some carriers.

CLINICAL REPORT

We were asked to evaluate A.F., a 3-month-old girlreferred for craniosynostosis. Head CT demonstratedfusion of the coronal sutures. This finding, togetherwith the normal-appearing hands and feet, promptedthe initial diagnosis of Crouzon syndrome. However,she lacked proptosis. Her father has a first cousin withCrouzon syndrome. While there were no findings ofCrouzon syndrome in the intervening relatives, A.F.’sfather was macrocephalic, with a head circumference of61 cm (>95th centile) and hyperteloric (interpupilarydistance >95th centile).

After we reviewed our medical records, we realizedthat the cousin with Crouzon syndrome was in fact apatient we had evaluated previously who was found tohave the Pro250Arg mutation in FGFR3. The mother ofthe cousin had been unavailable for molecular testingat that time. She had reported that no one else in thefamily was reported to have an abnormal skull shape,hand or foot anomalies, or hearing loss. We had theopportunity to examine her and found that she wasclinically normal (Fig. 1). She had normal hearing, andon physical exam she had a normal head circumference(54.5 cm, 50th centile), height in the normal range (165cm, 60th centile). She had a normal facial appearance,and normal hands and feet (both clinically and radio-graphically). Specifically, she did not have brachydac-tyly or radiographic evidence of carpal-tarsal fusion.Molecular testing confirmed that she had thePro250Arg mutation in FGFR3.

DISCUSSION

The finding of a clinically normal individual with thePro250Arg mutation further supports that FGFR3-related coronal synostosis syndrome demonstrates re-duced penetrance, with some individuals manifestingno clinical findings of the disorder. This is important torecognize, as the finding of reduced penetrance withthe FGFR3 mutation suggests that both parents of anapparently sporadic case should be tested regardless oftheir clinical status.

FGFR3-associated coronal synostosis syndrome isunique among clinical genetic syndromes in that it isthe first to be initially defined by a molecular finding,

*Correspondence to: Nathaniel H. Robin, M.D., Lakeside 1500,Cleveland, OH 44106-6506.

Received 9 June 1998; Accepted 21 July 1998

American Journal of Medical Genetics 80:296–297 (1998)

© 1998 Wiley-Liss, Inc.

the presence of the proline substitution for an arginineat amino acid 250 (Pro252Arg) [Bellus et al., 1996;Muenke et al., 1996]. Instead of evaluating patientswith a common clinical phenotype and searching for amolecular explanation, this syndrome became one ofthe first (but certainly not the last) in which clinicalgeneticists were provided with the ‘‘answer’’ and told tonow define the ‘‘question’’: What is the phenotype?Studies have shown that the phenotypic spectrum in-cludes Pfeiffer, Crouzon, and Jackson-Weiss syn-dromes, nonsyndromic coronal craniosynostosis, mac-rocephaly, and recently even isolated sensorineuralhearing loss [Hollway et al., 1998]. This report docu-ments that a normal phenotype should be added to thespectrum of clinical phenotypes seen with the FGFR3mutation.

REFERENCESAdes LC, Mulley JC, Senga IP, Morris LL, David DJ, Haan EA (1994):

Jackson-Weiss syndrome: Clinical and radiological findings in a largekindred and exclusion of the gene from 7p21 and 5qter. Am J MedGenet 51:121–130.

Bellus FA, Gaudenz K, Zackai EH, Clarke LA, Szabo J, Francomano CA,Muenke M (1996): Identical mutations in three different fibroblastgrowth factor receptor genes in autosomal dominant craniosynostosissyndromes. Nat Genet 14:174–176.

Graham JM, Braddock SR, Mortier GR, Lachman R, Van Dop C, Jabs EW(1998): Syndrome of coronal craniosynostosis with brachydactyly andcarpal tarsal coalition due to Pro250Arg mutation in FGFR3 gene. AmJ Med Genet 77:322–329.

Gripp K, McDonald-McGinn DM, Gaudenz K, Whitaker LA, Bartlett SP,Glat PM, Cassileth LB, Mayro R, Zackai EH, Muenke M (1998): Iden-tification of a genetic cause for isolated unilateral coronal synostosis: Aunique mutation in fibroblast growth factor receptor 3. J Pediatr 132:714–716.

Hollway GE, Phillips HA, Ades LC, Haan EA, Mulley JC (1995): Localiza-tion of craniosynostosis Adelaide type to 4p16. Hum Mol Genet 4:681–683.

Hollway GE, Suthers GK, Battese KM, Turner AM, David DJ, Mulley JC(1998): Deafness due to Pro250Arg mutation of FGFR3. Lancet 351:877–878.

Muenke M, Gripp KW, McDonald-McGinn DM, Gaudez K, Whitaker LA,Bartlett SA, Markowitz RI, Robin NH, Nwokoro N, Mulvihill JJ,Losken W, Mulliken JB, Guttmacher AE, Wilroy RS, Clarke LA, Holl-way G, Ades L, Haan E, Mulley JC, Cohen MM Jr, Bellus GA, Fran-comano CA, Moloney DM, Wall SA, Wilkie AOM, Zackai EH (1997): Aunique point mutation in the fibroblastgrowth factor receptor 3(FGFR3) gene defines a new syndrome. Am J Hum Genet 60:555–564.

Nathaniel H. Robin*Center for Human Genetics, Department

of GeneticsDepartment of Pediatrics

Jennifer A. ScottCenter for Human Genetics, Department

of Genetics

Alan R. CohenDepartment of Pediatric Neurosurgery

Jeffrey A. GoldsteinDepartment of Plastic SurgeryCase Western Reserve University School of

MedicineUniversity Hospitals of ClevelandCleveland, Ohio

Fig. 1. Front (A) and profile (B) of the phenotypically normal indi-vidual with the FGFR3 Pro250Arg mutation.

Letter to the Editor 297