Pfeiffer syndrome

Sandra R Silva, MD Philippe Jeanty, MD, PhD

Updated 01/18/2006 by Juliana Leite, MD

Original text 05/27/1999 Philippe Jeanty, MD, PhD & Sandra R Silva, MD

Synonyms: Acrocephalosyndactyly type 5

Definition: The Pfeiffer syndrome is characterized by bilateral coronal craniosynostosis, midface hypoplasia and syndactyly of hands and feet, and enlarged thumbs congenital. It was originally described in eight persons from three generations by Pfeiffer in 1964. It is divided in three clinical subtypes, with diagnostic and prognostic implications:

● Type I. classical appearance with craniosynostosis, broad thumbs, syndactyly, and normal intelligence. This form is compatible with life. It has generally good outcome.● Type II. Cloverleaf skull, ocular proptosis, broad thumbs, variable visceral anomalies, elbow ankylosis, and severe compromise of the central nervous system (CNS). Usually results in early death.● Type III. Craniosynostosis, severe ocular proptosis without cloverleaf skull, elbow ankylosis, and variable visceral anomalies. Affected fetuses have severe neurologic compromise, with poor prognosis and early death.

Incidence: Unknown. Since the first description was done, around 30 cases have been reported.

Etiology: Type I: autosomal-dominant or fresh mutations. Types II and III: sporadic

Recurrence risk: Variable, depending on the etiology. When the transmission has an autosomal-dominant pattern, the recurrence risk is 50%. If caused by fresh mutations, the risk of recurrence is very low.

Diagnosis: Sonographic signs of Pfeiffer syndrome include craniofacial anomalies (brachycephaly, acrocephaly, craniosynostosis of the coronal suture, hypertelorism, small nose, and low nasal bridge) and hands and feet anomalies (partial syndactyly of second and third fingers and second, third, and fourth toes, broad thumb, and big toe).

Genetic anomalies: Pfeiffer syndrome is genetically heterogeneous. Some cases are linked to mutations at the fibroblastic growth factor receptor 1 (FGFR1) gene at chromosome 8p11.22–p12. Mutations at the FGFR2 gene, which map at chromosome 10q25–q26, were also reported. An exclusive paternal origin of a de novo mutation, associated with advanced paternal age, has been described in Pfeiffer syndrome.

Associated anomalies: Choanal atresia, tracheo and bronchomalacia, cloverleaf skull, fused vertebra, Arnold-Chiari malformation, hydrocephalus, and imperforate anus. After birth, seizures and mental retardation may develop.

Differential diagnosis: The main differential diagnosis includes the syndromes that are characterized by craniosynostosis (Apert, Carpenter, Crouzon, kleeblattschädel anomaly, and thanatophoric dysplasia).

Prognosis: The prognosis depends on the severity of associated anomalies, mainly on the severity of the CNS compromise. Type I has in general a good prognosis. Types II and III are not compatible with life, and death occurs early.

Management: Termination of pregnancy can be offered before viability. If continuation of the pregnancy is chosen, periodic sonographic evaluation of the anomalies (CNS anomalies in particular) is recommended.


Pfeiffer R. Dominant erbliche Akrocephalosyndactylie. Z. Kinderheilkd, 1964, 90: 301.

Jones KL. Pfeiffer syndrome in Smith’s recognizable patterns of human malformation. WB Saunders Company – Philadelphia – 1997, pp416-417.

Muenke M. et al. A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nat Genet, 1994, 8: 268.

Rutland Pe et al. Identical mutations in FGFR2 gene cause both Pfeiffer and Crouzon syndromes phenotypes.  Nat Genet, 1995, 9: 173.

Nazarro A, Monica MD, Lonardo F, Blasi AD, Baffico M, Baldi M, Nazarro G, Placido G, Scarano G. Prenatal ultrasound diagnosis of a case of Pfeifer syndrome without cloverleaf skull and review of the literature. Prenatal diag 2004;24:918-922

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