Pfeiffer syndrome (PS) is a frequent form of acrocephalosyndactyly (see this term), a group of rare genetic syndromes, and is characterized by variable degrees of bicoronal craniosynostosis, variable hand and foot malformations, and various other associated manifestations.
Annual incidence is 1/100,000. The disorder affects males and females equally.
Abnormal skull shape is usually detected in the neonatal period (possibly on prenatal ultrasound). Characteristic cranial features include a wide cranial vault, a flat occiput, broad forehead, a small nose with depressed nasal bridge, and orbital hypertelorism. The clinical picture depends on the extent of bicoronal craniosynostosis and the associated functional disorders (respiratory, otological, ocular, neurological). Three forms of PS have been described (Pfeiffer syndrome type 1, type 2, and type 3; see these terms). Type 1 is a less common, less severe form of PS and is characterized by moderate-to-severe midface hypoplasia, hand and foot abnormalities, but usually normal intellectual development. In contrast, types 2 and 3 are more frequent and are associated with more severe manifestations such as extreme proptosis and choanal stenosis or atresia, and complications (hydrocephalus and seizures) resulting in a poorer prognosis. Other complications include brain development disorders, exposure keratopathy, exorbitism, bilateral and symmetrical hearing loss, airway obstruction, and obstructive sleep apnea. Type 2 is distinguished form type 3 by the presence of kleeblattschädel, commonly referred to as trilobated or ''cloverleaf ''skull.
The majority of cases are caused by de novo mutations in the FGFR2 gene (10q25.3-q26), and very rarely in Type 1 cases, by mutations in the FGFR1 (8p11.23-p11.22) gene. Patients meeting criteria for a clinical diagnosis of Pfeiffer syndrome without a mutation in FGFR1 or FGFR2 are estimated to be as high as 21%. Spontaneous mutations have been associated with advanced paternal age. These genes are involved in cell signaling during embryonic development and mutations lead to premature closure of the cranial sutures.
The diagnosis is based on the presence of the characteristic clinical findings including craniosynostosis or cloverleaf skull, facial features, and variable hand and foot malformations. Radiological examinations may be required in some cases. Diagnosis can be confirmed by molecular genetic testing of the causative genes.
Differential diagnoses include other acrocephalosyndactyly syndromes (Apert and Saethre-Chotzen syndromes) and other syndromic forms of craniosynostosis, such as Crouzon, Cutis gyrata - acanthosis nigricans - craniosynostosis, Jackson-Weiss, Antley-Bixler, and Carpenter syndromes (see these terms).
Prenatal molecular genetic testing is possible. Results of genetic testing for low-risk pregnancies are of little prognostic value. Prenatal imaging may also be used for diagnosis if physical findings are apparent.
Genetic counseling should be provided to affected families. Inheritance from an affected parent in an autosomal dominant manner is reported in less severe cases of Pfeiffer syndrome (primarily type 1). De novo mutations are common in severe cases. PS shows complete penetrance.
Treatment is symptomatic and corrective, depending on the extent of disease manifestations. A multidisciplinary approach should be adopted to plan multiple-stage surgical interventions and other treatments with the aim of improving cosmetics, function and quality of life. The psychosocial aspects of the disease should also be addressed.
The success of timely treatment is the main prognostic factor. Favorable outcomes can be achieved but the prognosis remains poor in severe cases with a high risk of early demise due to respiratory and neurological complications.
Last update: October 2014
- Dr Austin HAMM
- Dr Nathaniel ROBIN