Pfeiffer syndrome

Pfeiffer syndrome is inherited in an autosomal dominant manner. Many individuals with the severe forms (types 2 and 3) have a de novo pathogenic variant, whereas familial transmission is more commonly observed in type 1. Each child of an affected individual has a 50% risk of inheriting the pathogenic variant.

The diagnosis is suspected on the basis of characteristic clinical and radiological findings and can be confirmed by molecular genetic testing of FGFR1 or FGFR2. Cranial CT with three-dimensional reconstruction delineates suture involvement and guides surgical management.

Main differential diagnoses include:

• : Multisuture craniosynostosis with midface retrusion and proptosis but without broad medially deviated thumbs and great toes; significant phenotypic overlap with Pfeiffer and some pathogenic variants are shared; FGFR2.
• : Coronal craniosynostosis with variable hearing loss and mild hand and foot abnormalities, but typically without the broad, medially deviated thumbs and great toes characteristic of Pfeiffer syndrome; FGFR3 (p.Pro250Arg).
• : Craniosynostosis with symmetric, severe bilateral cutaneous and bony syndactyly of hands and feet, distinct from the broad medially deviated thumbs and great toes of Pfeiffer syndrome; FGFR2 (p.Ser252Trp, p.Pro253Arg).
• Jackson-Weiss syndrome: Craniosynostosis with characteristic broad great toes and tarsal/metatarsal fusion but typically normal thumbs, distinguishing from the broad thumbs of Pfeiffer; FGFR2.

• Identification of the underlying pathogenic variant confirms the molecular diagnosis, supports accurate classification of the craniosynostosis syndrome, and enables informed genetic counselling for the affected individual and their family.
• A confirmed molecular diagnosis can inform individualised surveillance and multidisciplinary clinical management, although it is not a prerequisite for targeted medical care; specific measures are determined by the treating physicians in consultation with the affected individual and their family.
• Identification of the familial pathogenic variant enables predictive testing of at-risk relatives, allowing targeted clinical evaluation and surveillance.

• Wenger T, Miller D, Evans K. FGFR Craniosynostosis Syndromes Overview. 2020 Apr 16. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301628. Available from:
• Katouni K, Nikolaou A, Mariolis T, Protogerou V, Chrysikos D, Theofilopoulou S, et al. Syndromic Craniosynostosis: A Comprehensive Review. Cureus. 2023;15(12):e50448. doi: 10.7759/cureus.50448. PMID: . PMCID: PMC10785997.