PRENATAL DIAGNOSISPrenat Diagn 2004; 24: 644–646.Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/pd.960

SHORT COMMUNICATION

Prenatal diagnosis of Pfeiffer syndrome type II

Bettina Blaumeiser1*, Philip Loquet2, Wim Wuyts1 and Markus M. Nothen1

1Department of Medical Genetics, University of Antwerp, Antwerp, Belgium2Department of Prenatal Diagnosis, St. Augustinus Hospital, Antwerp, Belgium

Pfeiffer syndrome is an autosomal dominant disorder characterized by coronal craniosynostosis, midfacehypoplasia, broad thumbs and great toes. On the basis of clinical findings, three subtypes have been delineated.The clinical variability of Pfeiffer syndrome as well as other causes of craniosynostosis can make a prenataldiagnosis based on sonography alone difficult. We describe a fetus in whom sonographic findings (including3D ultrasound) suggested a Pfeiffer syndrome type II and in which subsequent molecular analysis verified thediagnosis by identifying a de novo mutation in the FGFR2 gene. To the best of our knowledge, this is the firstreport of a prenatal molecular diagnosis of Pfeiffer syndrome in a patient without family history. Copyright 2004 John Wiley & Sons, Ltd.

KEY WORDS: Pfeiffer syndrome; prenatal diagnosis; ultrasound; craniosynostosis

INTRODUCTION

Pfeiffer syndrome is a rare autosomal dominant syn-drome that results from mutations in the human fibrob-last growth factor receptor (FGFR) genes, FGFR1 andFGFR2. The major clinical features are bilateral coro-nal craniosynostosis, midface hypoplasia, broad thumbsand great toes. The marked variability in the phenotypeprompted Cohen (1993) to divide Pfeiffer syndrome intothree clinical subgroups, namely, Types I, II and III.Type I is the classical phenotype with the features men-tioned above and, generally, the affected individuals pos-sess normal intelligence. Type II is the most severe formwith cloverleaf skull (Kleeblattschadel), severe ocularproptosis, CNS involvement, midface hypoplasia, anky-losis of the elbow and the typical broad great toes andthumbs. Usually, affected individuals do poorly and aresubject to early death. Type III resembles Type II withoutthe cloverleaf skull, but with a poor prognosis regard-ing neurological function and survival. Type II and IIIare usually sporadic. Although this clinical classifica-tion is not absolute, it is useful for determination of theprognosis.

Because of the heterogeneous phenotype and progno-sis, exact prenatal diagnosis and genetic counseling isdesirable. The differential diagnosis, however, is furthercomplicated by a variety of other causes of craniosyn-ostosis. Here, we report the first case of a prenatal diag-nosis of Pfeiffer syndrome type II that was suspectedby sonography and subsequently confirmed by mutationanalysis of the FGFR2 gene.

*Correspondence to: Dr Bettina Blaumeiser, Department of Med-ical Genetics, University of Antwerp, Universiteitsplein 1, 2610Antwerpen, Belgium. E-mail: bettina.blaumeiser@uia.ua.ac.be

CASE REPORT

A 30-year-old G2P1 was referred at 30 weeks’ gestationbecause of sonographic abnormalities. Using classic and3D sonography we could demonstrate a craniosynostosiswith cloverleaf skull, frontal bossing, severe ocular prop-tosis, protruding tongue, clubfeet, broad great toes andonly two umbilical vessels (Figure 1). Chordocentesisfor chromosome examination and DNA mutation anal-ysis of the FGFR1 and FGFR2 genes, respectively, aswell as a genetic counseling procedure were performed.Regarding surgical treatment options of the facial dys-morphisms and the skull deformity, the parents wereadvised by a craniofacial surgeon. The parents them-selves were healthy nonconsanguineous Caucasians, andthe pedigree revealed no relatives with congenital mal-formations. The paternal age, however, was increased,as the husband was 46 years old at the time of concep-tion. The cytogenetic diagnosis indicated a normal malekaryotype (46,XY). Mutation analysis of the FGFR1and FGFR2 genes demonstrated a 1019A>G (Y340C)mutation in exon 10 of the FGFR2 gene. This muta-tion could not be found in the parental DNA, indicatinga de novo mutation. To determine the parental originof the FGFR2 mutation, we sequenced exon 10 flank-ing sequences in the patient and parents’ DNA andsearched for potential informative polymorphisms. Twointronic polymorphisms, IVS9689ins/delTA in intron9 and IVS10+543 C>T in intron 10, were identifiedand allele specific PCR followed by sequence analysisrevealed that the 1019G>A mutation originated on thepaternal chromosome.

After being informed of the diagnosis of Pfeiffer syn-drome Type II and the most probably very poor progno-sis, the parents decided to terminate the pregnancy withthe permission of the ethical committee of the hospi-tal. Clinical examination of the premature stillborn fetusrevealed the typical external characteristics of Pfeiffer II

Copyright 2004 John Wiley & Sons, Ltd. Received: 22 March 2004Revised: 17 May 2004Accepted: 4 June 2004

PRENATAL DIAGNOSIS OF PFEIFFER SYNDROME TYPE II 645

(a) (b)

(c) (d)

Figure 1—Fetal sonography at 30 weeks’ gestation. (a) Craniosynostosis with cloverleaf skull; (b) protruding tongue; (c) clubfoot with broadgreat toe; (d) severe ocular proptosis

syndrome (Figure 2). An autopsy of the fetus confirmedthe features of craniosynostosis with cloverleaf skull,flattening of the midface with flat and broad nasal bridge,bilateral ocular proptosis, short neck, prominent thumbsand great toes and micropenis without further macro-scopic or microscopic abnormalities. Given the DNAresults the recurrence risk for the couple is low.

DISCUSSION

The differential diagnosis of prenatally detected cran-iosynostosis with cloverleaf skull anomaly is numer-ous. Among the most common are chromosome abnor-malities and genetic syndromes with craniosynostosisas a major feature (e.g. Apert, Antley-Bixler, Carpen-ter, Crouzon, Pfeiffer syndrome, thanatophoric dysplasiaetc.). Prenatal diagnosis can be made by ultrasound inalmost all cases (Delahaye et al., 2003). The cloverleafskull can be isolated (Van Der Ham et al., 1995), orultrasound can bring forward associated anomalies thatcan be helpful in the identification of the etiology. In

our case, 3D ultrasound was particularly useful in pro-viding images of the facial dysmorphisms characteristicof Pfeiffer syndrome (protruding eyes and tongue, mid-face hypoplasia), and it can also be used for evaluatingthe fetal sutures in cases of craniosynostosis (Benacerrafet al., 2000). In addition, an invasive prenatal proce-dure can be useful in confirming the clinical presump-tive diagnosis as it allows detailed and straightforwardmolecular analysis.

Mutations in the FGFR genes can be responsible forseveral craniosynostosis syndromes and other skeletalanomalies such as achondroplasia, hypochondroplasiaand thanatophoric dysplasia (Bellus et al., 1996; Hollo-way et al., 1997). So far, three FGFR genes involvedin skeletal dysplasia and craniosynostosis are known:FGFR1 on chromosome 8p, FGFR2 on chromosome10q, and FGFR3 on chromosome 4p. The geneticallyheterogeneous Pfeiffer syndrome can be caused by amutation in the FGFR1 gene, as well as by differ-ent mutations in the FGFR2 gene (Muenke and Schell,1995; Muenke et al., 1995). There is some correlationbetween the clinical subtypes I–III of Pfeiffer syndrome,

Copyright 2004 John Wiley & Sons, Ltd. Prenat Diagn 2004; 24: 644–646.

646 B. BLAUMEISER ET AL.

(a)

(b)

Figure 2—Stillborn fetus. (a) Cloverleaf skull, ocular proptosis, flatmidface, protruding tongue, prominent thumb; (b) clubfeet, broadgreat toe (parent consent form for publication of these photographshas been obtained)

other craniosynostosis syndromes and the different muta-tions, and a number of mutations in the FGFR2 genetend to be preferentially associated with a distinct pheno-type (Wilkie et al., 2002). Still, the prognosis, which is

very different in the three subtypes, must be determinedfrom the clinical picture. In our case, the molecular anal-ysis resulted in the identification of an FGFR2 Y340Cmutation. This mutation has previously been describedin Pfeiffer patients and results in the creation of anunpaired cysteine that may interfere with proper inter-molecular receptor dimerization (Cornejo–Roldan et al.,1999). Therefore, the 3D ultrasound-based clinical diag-nosis could be confirmed at the molecular level. Thepresent report shows that molecular genetics can pro-vide a valuable supplement in the differential diagnosisof prenatally detected cases of craniosynostosis nextto ultrasound examination. Furthermore, 3D ultrasoundprovided us, in this case, with images of the fetal facein a realistic fashion that was particularly helpful to theparents in the process of decision making.

REFERENCES

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Cornejo-Roldan LR, Roessler E, Meunke M. 1999. Analysis of themutational spectrum of the FGFR2 gene in Pfeiffer syndrome. HumGenet 104: 425–431.

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Muenke M, Schell U, Hehr A, et al. 1995. A common mutation in thefibroblast growth factor receptor-1 gene in Pfeiffer syndrome. NatGenet 8: 269–274.

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Copyright 2004 John Wiley & Sons, Ltd. Prenat Diagn 2004; 24: 644–646.