Pfeiffer syndrome update, clinical subtypes, and guidelines for differential diagnosis

Abstract

Seven Pfeiffer syndrome pedigrees (three 3 generation and four 2 generation) have been recorded to date in addition to at least a dozen sporadic cases. Autosomal dominant inheritance with complete penetrance is characteristic of the 7 familial instances. Variable expressivity has involved mostly the presence or absence of syndactyly and the degree of syndactyly when present. Classic Pfeiffer syndrome is designated type I. Type 2 consists of cloverleaf skull with Pfeiffer hands and feet together with ankylosis of the elbows. Such patients do poorly with an early death. All reported instances to date have been sporadic. Type 3 is similar to type 2 but without cloverleaf skull. Ocular proptosis is severe in degree and the anterior cranial base is markedly short. These patients also do poorly and tend to have an early death. To date all cases have occurred sporadically. Although these 3 clinical subtypes do not have status as separate entities, their diagnostic and prognostic implications are important. Type 1 is commonly associated with normal intelligence, generally good outcome, and can be found dominantly inherited in some families. Types 2 and 3 generally have severe neurological compromise, poor prognosis, early death, and sporadic occurrence. Recognition of type 3 is particularly important because extreme ocular proptosis in the absence of cloverleaf skull but with various visceral anomalies can result in failure to diagnose Pfeiffer syndrome and labeling the patient as an “unknown” or as a “newly recognized entity.” The major diagnostic clues in type 3, as well as in the other clinical subtypes, remain classic Pfeiffer hands and feet in association with craniosynostosis, regardless of craniofacial variability or the presence or absence of visceral anomalies. A ratio of hallucal width to second toe width is developed to provide guidelines for what constitutes a broad great toe in Pfeiffer syndrome. Cases that do not qualify as examples of Pfeiffer syndrome are then reviewed.