Pfeiffer syndrome is a rare genetic disorder affecting approximately 1 in 100,000 newborns. This condition is characterized by the premature fusion of certain skull bones (craniosynostosis). Individuals with Pfeiffer syndrome often present with distinctive facial features and abnormalities in their hands and feet. The syndrome stems from specific genetic mutations that disrupt normal development.
Genetic Mutations Responsible
Pfeiffer syndrome primarily arises from mutations in the FGFR1 and FGFR2 genes. These genes provide instructions for making fibroblast growth factor receptors, which are proteins involved in cell growth, division, and bone development. These receptors act like cellular antennae, receiving signals that guide cell maturation and tissue formation. Mutations in these genes alter the receptor’s function, leading to abnormal or prolonged signaling.
This altered signaling pathway promotes the premature fusion of bones, particularly in the skull. While both FGFR1 and FGFR2 mutations can cause Pfeiffer syndrome, FGFR2 mutations are more commonly observed and associated with more severe forms. Conversely, FGFR1 mutations are linked to milder forms.
Inheritance and Spontaneous Occurrence
Pfeiffer syndrome follows an autosomal dominant inheritance pattern. This means an individual needs to inherit only one copy of the altered gene from a parent to develop the condition. If a parent has Pfeiffer syndrome, there is a 50% chance their child will inherit the condition with each pregnancy.
Many cases of Pfeiffer syndrome, however, are not inherited but occur due to spontaneous mutations. These de novo mutations arise in individuals with no family history of the condition. Research indicates that advanced paternal age is a recognized risk factor for these spontaneous mutations.
Impact of Gene Mutations on Development
The altered fibroblast growth factor receptor signaling directly disrupts normal bone formation and growth. This disruption is particularly evident in the development of the skull, face, hands, and feet. The most prominent manifestation is craniosynostosis, where the fibrous seams between the skull bones fuse too early. This premature fusion can restrict the skull’s expansion, potentially increasing pressure on the growing brain.
The condition leads to a characteristic set of physical features. These often include midfacial hypoplasia (underdevelopment of the midface), resulting in a sunken appearance. Affected individuals may also have wide-set eyes, bulging eyes due to shallow eye sockets, and a high forehead. The hands and feet also show distinct abnormalities, such as broad and short thumbs and big toes, and sometimes partial webbing or fusion of the fingers and toes.
Variability in Presentation
Despite sharing the same genetic basis, the severity and specific features of Pfeiffer syndrome can vary considerably among affected individuals. This spectrum of presentation leads to the classification of Pfeiffer syndrome into three clinical types: Type 1, Type 2, and Type 3. Type 1 (classic Pfeiffer syndrome) is the mildest form, associated with normal intelligence and a typical lifespan.
In contrast, Type 2 and Type 3 are more severe forms of the syndrome. These types often involve neurological issues and can pose greater health challenges. Type 2 is recognized by a cloverleaf-shaped skull, which results from extensive bone fusion. This variability in presentation is often linked to the nature or location of the mutation within the FGFR genes.