Editorial Comment

Should Syndromes Be Defined Phenotypically orMolecularly? Resolution of the Dilemma

M. Michael Cohen, Jr. and Ruth E. MacLean*Department of Oral & Maxillofacial Sciences, Dalhousie University, Halifax, Nova Scotia, Canada

The molecular revolution has produced its own no-menclature. Some say that we should adopt molecularnomenclature to replace syndrome nomenclature; oth-ers maintain that we should keep syndrome nomencla-ture to keep learning hurdles to a minimum. Here, weadopt an integrated approach suggested by Biesecker[1998]. We think that molecular nomenclature shouldbe taken into account for three reasons. First, in someinstances the same mutation may cause two differentsyndromes. Second, different mutations may some-times cause the same syndrome. Third, there may bephenotypic/molecular correlations [Cohen and Mac-Lean, 1999].

There are many different mutations causing Crouzonsyndrome and Pfeiffer syndrome on fibroblast growthfactor receptor 2 (FGFR2). Some of these mutationsmay cause both Crouzon syndrome and Pfeiffer syn-drome, for example, Cys278Phe [Cohen, 1997, 1999].One way to integrate phenotypic and molecular diag-noses would be to indicate the phenotype when the mu-tation is the same:

Crouzon syndrome, FGFR2, Cys278PhePfeiffer syndrome, FGFR2, Cys278PheSecond, Pfeiffer syndrome may be caused by one mu-

tation on FGFR1 and by many mutations on FGFR2[Cohen, 1997, 1999]:

Pfeiffer syndrome, FGFR1, Pro252ArgPfeiffer syndrome, FGFR2, Thr341ProIf a syndrome is rare, then OMIM numbers could be

used as well. This does not apply to Crouzon andPfeiffer syndromes because they are not rare, butOMIM numbers are used to be consistent with thisexample:

Crouzon syndrome (123500), FGFR2, Cys278PhePfeiffer syndrome (101600), FGFR2, Cys278PheA third example shows how phenotypic/molecular

correlations apply to Apert syndrome, which has twocommon causative mutations in two adjacent aminoacids on FGFR2 [Slaney et al., 1996]:

Apert syndrome, FGFR2, Ser252Trp Higher fre-quency of cleft palate

Apert syndrome, FGFR2, Pro253Arg Higher fre-quency of severe syndactyly

The same mutation causing separately defined syn-dromes has created difficulties for genetic counseling.Three examples are given.

To date, about six FGFR2 mutations causing Crou-zon syndrome are identical to those that cause Pfeiffersyndrome. However, within families, Crouzon syn-drome and Pfeiffer syndrome generally breed true.Clinical overlap of the Jackson-Weiss type is very un-common. In a second example, completely differentphenotypes—one type of Creutzfeldt-Jakob disease andfamilial fatal insomnia—are caused by the same PRNPmutation (Asp178Asn) [Goldfarb et al., 1992].

In all three examples, the identical mutation cancause two different phenotypes. Because these pheno-types have a strong tendency to breed true suggeststhat as yet, unidentified modifying genes, developmen-tal factors, and/or environmental factors may be in-volved. Despite identical mutations and a few ex-amples of clinical overlap, after indicating the completerange of possible phenotypic overlap to the family, ifthe recurrence risk data indicate that in most cases aphenotype breeds true, genetic counseling should em-phasize variability of that specific phenotype (Fig. 1).

Finally, it is important to keep in mind that not allmolecularly defined syndromes have identified muta-tions in every patient. Usually a percentage of muta-tions in a given gene is identified in a given syndrome.In some disorders, the percentage is extremely high.For example, two very specific mutations in adjacentamino acids on FGFR2 account for 98% of all cases ofApert syndrome [Cohen, 1999; Wilkie et al., 1995].With other disorders such as Crouzon syndrome, thepercentage of mutations identified is considerably less.Several reasons may account for this lower percentage.

First, some mutations in the specific gene have yet tobe identified. Also, the number of mutations in a givensyndrome will have an effect on the percentage of mu-tations identified. With Apert syndrome, two very spe-cific mutations are known, but with Crouzon syndromeover 30 mutations on FGFR2 have been identified todate [Cohen, 1997, 1999]. Furthermore, Apert syn-

*Correspondence to: Ruth E. MacLean, B.A., Dalhousie Uni-versity, Halifax, Nova Scotia, Canada B3H 3J5.E-mail: remaclea@is.dal.ca

Received 26 May 1999; Accepted 28 May 1999

American Journal of Medical Genetics 86:203–204 (1999)

© 1999 Wiley-Liss, Inc.

drome is much more easily diagnosed than Crouzonsyndrome.

Second, genetic heterogeneity may occur with muta-tions in another gene or genes. For example, one mu-tation for Pfeiffer syndrome is found on FGFR1 and

many mutations for Pfeiffer syndrome occur on FGFR2[Cohen, 1997, 1999].

Third, clinical definition of a syndrome may vary de-pending on the experience of the clinician and onwhether a broad or a narrow definition is used. Anexample illustrates the problem. One large center iden-tifies mutations on FGFR2 in 90% of its Crouzon syn-drome patients; another large center identifies only60%. One possible interpretation is that the definitionused by the second center is too broad and includespatients with coronal synostosis and brachycephalywho do not actually have Crouzon syndrome.

REFERENCESBiesecker LG. 1998. Lumping and splitting: molecular biology in the ge-

netics clinic. Clin Genet 53:3–7.Cohen MM Jr. 1997. Transforming growth factors and fibroblast growth

factors and their receptors: role in sutural biology and craniosynostosis(editorial review). J Bone Miner Res 12:322–331.

Cohen MM Jr. 1999. Fibroblast growth factor receptor mutations. In: Co-hen MM Jr, MacLean RE, editors. Craniosynostosis: diagnosis, evalu-ation, and management, 2nd ed. New York: Oxford University Press.Chapter 7.

Cohen MM Jr, MacLean RE. in press. Anatomic, genetic, nosologic, diag-nostic, and psychosocial considerations. In: Cohen MM Jr, MacLeanRE, editors. Craniosynostosis: diagnosis, evaluation, and management,2nd ed. New York: Oxford University Press. Chapter 11.

Goldfarb LG, Peterson RB, Tabaton M, Brown P, LeBlanc AC, Montagna P,Cortelli P, Julien J, Vital C, Pendelbury WW, Haltia M, Wills PR,Hauw JJ, McKeever PE, Monari L, Schrank B, Swergold GD, Autilio-Gambetti L, Gajdusek DC, Lugaresi E, Gambetti P. 1992. Fatal famil-ial insomnia and familial Creutzfeldt-Jakob disease: disease phenotypedetermined by a DNA polymorphism. Science 258:806–808.

Slaney SF, Oldridge M, Hurst JA, Morris-Kay GM, Hall CM, Poole MD,Wilkie AOM. 1996. Differential effects of FGFR2 mutations on syndac-tyly and cleft palate in Apert syndrome. Am J Hum Genet 58:923–932.

Wilkie AOM, Slaney SF, Oldridge M, Poole MD, Ashworth GJ, Hockley AD,Hayward RD, David DJ, Pulleyn LJ, Rutland P, Malcolm S, WinterRM, Reardon W. 1995. Apert syndrome results from localized muta-tions of FGFR2 and is allelic with Crouzon syndrome. Nat Genet 9:165–172.

Fig. 1. Clinical delineation of two separate syndromes, X and Y. Thenmutations in the same gene are found to cause both syndromes. However,the mutations are completely separate in most cases, although an identicalmutation for both is found on occasion. This often results in overinterpre-tation of clinical overlap. However, the actual phenotypic overlap is notfound in most cases, each phenotype “breeding true.”

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