Pfeiffer Syndrome

Cause and inheritance

Pfeiffer syndrome arises from a change in the FGFR1 or FGFR2 genes (fibroblast growth factor receptors). Most cases – including mild type 1 – are based on FGFR2 mutations. The FGFR1 mutation p.Pro252Arg is rarer and mostly associated with mild type 1; severe forms (types 2/3) are predominantly due to certain FGFR2 mutations.^[1] These genes control the growth and maturation of bone and tissue.

Inheritance is autosomal dominant. In many cases the change arises de novo, i.e. newly, without a parent being affected. If an affected person has children, there is a 50 % risk at each pregnancy of transmission. Pfeiffer syndrome occurs in an estimated 1 in 100,000 births. The expression within a family can be very variable.^[2]

Typical features

• Premature closure of cranial sutures (often coronal sutures, several sutures in types 2/3)
• High or tower-shaped skull, broad forehead
• Shallow eye sockets with protruding eyes (exophthalmos)
• Underdevelopment of the midface
• Broad, short thumbs and big toes, often tilted inward
• Partial fusions of fingers and toes (syndactyly), usually milder than in Apert syndrome
• Narrow upper airways, snoring or sleep apnoea
• Recurrent middle-ear problems or hearing loss
• In severe forms: hydrocephalus, Chiari malformation, raised intracranial pressure

Not every child has all features. Individual assessment is decisive.

Craniofacial procedures

The aim of craniofacial surgery is above all to protect the brain, eyes and breathing, not just to improve head shape.

1. Skull surgery in infancy

In case of restricted skull growth, early procedures create more room for the brain and lower intracranial pressure. Depending on the findings, posterior cranial vault expansion, distraction osteogenesis of the posterior skull or fronto-orbital advancement are considered. In severe forms with cloverleaf skull, early surgery is often necessary.

2. Midface advancement

In case of marked midface hypoplasia with breathing, eye or bite problems, a Le Fort III osteotomy or a monobloc advancement – usually with slow distraction – may become necessary. The timing depends on the functional urgency.

3. Hands and feet

The thumb and toe malpositions are often milder than in Apert syndrome. Hand-surgical correction can improve grip function; not every child needs an operation.

Eyes, hearing and development

Because of shallow eye sockets, the eyes may protrude – with a risk of corneal drying and injury. Regular ophthalmological checks are necessary. Middle-ear effusions and hearing loss are common, so regular hearing tests and, if needed, speech therapy are important. In type 1, development is usually normal; in types 2/3 it depends strongly on intracranial pressure and associated neurological findings.

Treatment in an interdisciplinary centre

Ideal is care by a specialised team with oral and maxillofacial / craniofacial surgery, neurosurgery, paediatrics, anaesthesia and intensive care, ophthalmology, ENT and sleep medicine, orthodontics, hand surgery, speech therapy, physiotherapy and occupational therapy, genetics as well as psychology.

When immediate medical help is needed

• Breathing pauses, bluish discolouration or severe respiratory distress
• Increasing drowsiness, vomiting, headaches or unusual irritability (sign of intracranial pressure)
• Rapid deterioration of the eyes or incomplete eyelid closure
• Fever or wound problems after operations

References

1. Bellus GA, Gaudenz K, Zackai EH, et al. (1996). Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes. Nat Genet, 14(2):174–6. DOI
2. Bessenyei B, Tihanyi M, Hartwig M, et al. (2014). Variable expressivity of Pfeiffer syndrome in a family with FGFR1 p.Pro252Arg mutation. Am J Med Genet A, 164A(12):3176–9. DOI
3. Renier D, Lajeunie E, Arnaud E, Marchac D (2000). Management of craniosynostoses. Childs Nerv Syst, 16(10–11):645–58. DOI