Search :     
2012-03-07-11 Case of the week #321 ©Luc De Catte   

Case of the week # 321
June, 21st   -  July, 5th , 2012

J. Van Keirsbilck, MD., Ph. Moerman, MD. PhD, K. Devriendt, MD.PhD, L. De Catte, MD. PhD
University Hospitals, KU Leuven, Leuven, Belgium

Case report:
A 36-year-old G2P1 patient was referred to our department for an ultrasound scan at 27 weeks. Her previous pregnancy ended in an extreme preterm delivery at 24 weeks, but the baby died in the early neonatal period. Further investigation did not reveal substantial cause of this extreme preterm birth. Her personal and family medical history was unremarkable. 
The indication for referral was an abnormally shaped fetal head. An amniocentesis was performed and showed a normal karyotype: 46,XY.

The answer of this case is Pfeiffer syndrome which was confirmed after birth.
The ultrasound performed at 27 weeks showed following findings:
  • Coronal and sagittal craniosynostosis leading to a turricephalic or “tower shaped” skull
  • Prominent forehead (frontal bossing)
  • Depressed nasal bridge
  • Exophthalmos and prominent open eyelids
  • Ocular hypertelorism
  • Low -set ears
  • Broad, deviated great toe
  • Single umbilical artery
A differential diagnosis was suggested: 
  • Pfeiffer syndrome
  • Carpenter syndrome
  • Apert syndrome
  • Crouzon syndrome. 
The typical craniosyntosis/cloverleaf skull, prominent proptosis and wide great toe suggested Pfeiffer syndrome.
The overall growth was appropriate for gestational age (75th percentile). There was normal development of upper and lower limbs. 
A fetal MRI was performed at 27 weeks.The images suggested craniosynostosis with the presence of brachycephaly, oxycephaly, cloverleaf skull, mild ventriculomegaly and prominent proptosis.
With the major abnormalities, the unfavorable prognosis was discussed with the patient. The couple opted for a termination of pregnancy at 28 weeks and 6 days. The postmortem examination confirmed our diagnosis. The autopsy showed a male fetus of 1330gr. There was a cloverleaf skull with preterm synostosis of the lambdoidal suture, sagittal suture and coronal suture. The frontal suture (metopic suture) stood widely open. Hypertelorism and proptosis was noticed with open eyelids, corneal clouding and ectropion. The concomitant altered dentinogenesis and varus position of the great toes (broader and longer) suggested Pfeiffers syndrome.
Fetal DNA analysis showed a T to C nucleotide substitution in exon IIIc of FGFR2 which is predicted to result in replacement of  the amino acid of Cysteine with Arginine at residue 342 (p.Cys342Arg). This variant has been previously reported in the literature, and is the most common single cause of Pfeiffer syndrome..

Pfeiffer syndrome is a rare autosomal dominant genetic disorder. It occurs in 0.1:10.000 births. Most commonly, it is associated with mutations in fibroblast growth factor receptor gen (FGFR)1 and FGFR2. Some mutations appear to result in a more severe phenotype with decreased prognosis for survival (a point mutation at the Ser351Cys locus of FGFR2).

The typical features of Pfeiffer syndrome include
  • variable degrees of craniosynostosis,
  • midface hypoplasia,
  • broad thumbs and great toes.
  • The presence of skeletal abnormalities (syndactyly and synostosis of the elbow), central nervous system (hydrocephalus) and gastrointestinal abnormalities (imperforate anus) are variable.
Pfeiffer syndrome is classified into three subtypes. The classification is helpful in predicting prognosis for mental development and survival.

Type 1 has the classic phenotype with symmetric bicoronal craniosynostosis, variable syndactyly, broad thumbs and wide great toes. Intelligence is normal or nearly normal, and most patients have a normal life-span.

Type 2 has a more phenotypic expression. Beside the coronal sutures, other sutures are frequently involved (metopic, sagittal and lambdoid) leading to the typical cloverleaf skull. Other characteristics are severe ocular proptosis, ankylosis of the elbows, broad thumbs and great toes, hydrocephalus and visceral anomalies. The prognosis is unfavorable and frequently leads to early death. 

Type 3 Pfeiffer syndrome is similar to type 2 in clinical features and outcome; however, the cloverleaf skull deformity is absent. The severe ocular proptosis is also present. Severe neurologic defects are common and patients typically die early.
Image 1, 2:  A turricephalic or “tower shaped” skull and frontal bossing

Image 3, 4: Single umbilical artery and ocular hypertelorism

Image 5-7: Exophthalmus and prominent open eyelidsBroad, deviated great toe. 

Video clip:

Postnatal images 5-6:

Back to case
Help Support :