Pfeiffer Syndrome

Etiology

Pfeiffer syndrome exhibits autosomal dominant inheritance with complete penetrance and variable expressivity, particularly in the presentation of syndactyly.[3] The severity and combination of craniofacial and limb abnormalities can differ significantly even among affected individuals within the same family. Pfeiffer syndrome type 1 is associated with mutations in the FGFR1 and FGFR2 genes. Types 1 and 3 are linked exclusively to FGFR2 mutations, and most cases result from mutations in the FGFR2 gene located on chromosome 10q26.13. Mutations in the FGFR1 gene, located on chromosome 8p11.23, account for a small percentage of type 1 cases and are typically not associated with other Pfeiffer syndrome types.

The FGFR1 and FGFR2 genes encode fibroblast growth factor receptors 1 and 2, respectively. These receptors play a critical role in embryonic development, particularly in the differentiation of pluripotent stem cells into osteoblasts. Mutations can result in prolonged receptor signaling, leading to premature cranial suture fusion and abnormal development of the extremities.

There are 4 major FGFR2 mutations commonly associated with severe forms of Pfeiffer syndrome (p.W290C, p.Y340C, p.C342R, and p.S351C). In contrast, the FGFR1 mutation p.P252R is typically associated with a milder phenotype.[4] A well-characterized mutation in Pfeiffer syndrome is p.Pro252Arg, located in exon 5 of the FGFR1 gene.[5] One major risk factor for the development of Pfeiffer syndrome is advanced paternal age. The risk of transmission from an affected parent to offspring is 50% for each pregnancy, consistent with autosomal dominant inheritance. Both males and females are equally affected.

Epidemiology

Pfeiffer syndrome affects 1 in 100,000 newborns.[6] This condition is the second most common form of the acrocephalosyndactyly syndromes, with Apert syndrome being the most prevalent.[7]

Pathophysiology

A cloverleaf skull usually results from the premature closure of the coronal and lambdoid sutures. Bicoronal synostosis can lead to skull base hypoplasia and reduced intracranial volume, subsequently causing elevated intracranial pressure, which can present with symptoms such as headaches or visual disturbances. Characteristic facial features of Pfeiffer syndrome result from the premature fusion of the cranial bones. Abnormal craniofacial development leads to proptosis, wide-set eyes, a high forehead, an underdeveloped maxilla, and a beaked nose. Patients with Pfeiffer syndrome may experience upper airway obstruction related to midface hypoplasia and secondary nasal obstruction.

Maxillary hypoplasia reduces intraorbital volume, leading to proptosis, xerophthalmia, and exposure keratitis. Visual disturbances may arise from extraocular muscle imbalance secondary to proptosis or elevated intracranial pressure. Hearing loss in Pfeiffer syndrome can result from recurrent ear infections, middle ear hypoplasia, or auditory canal atresia. Additionally, maxillary hypoplasia contributes to narrowing of the nasopharynx, oropharynx, and larynx, which can cause snoring, nasal regurgitation, aspiration of food, and obstructive sleep apnea.

History and Physical

The physical examination in Pfeiffer syndrome typically reveals craniosynostosis, midface hypoplasia, broad thumbs and great toes, and soft tissue syndactyly. Additional features—such as proptosis, elbow ankylosis, and cloverleaf skull deformity—may be present in more severe forms of the condition. Physical features vary by subtype, making careful examination essential for accurate classification and management (see Table. Comparison of Pfeiffer Syndrome Types).

Pfeiffer syndrome type 1 is characterized by brachycephaly resulting from bicoronal synostosis, maxillary hypoplasia, hypertelorism, prognathism, and dental anomalies. Limb features include broad thumbs and great toes, variable brachydactyly-syndactyly, with normal intelligence typically preserved. Pfeiffer syndrome type 2 presents with more severe manifestations, including a cloverleaf skull (Kleeblattschädel type craniosynostosis), which is typically associated with hydrocephalus, maxillary hypoplasia resulting in proptosis, a “beak-shaped” nose, inferiorly positioned ears, and elbow joint ankylosis.[8] Hydrocephalus in these patients may result from venous hypertension, sleep apnea, cerebrospinal fluid obstruction due to acqueductal stenosis or basilar invagination, or from posterior fossa abnormalities. This form is usually associated with significant neurological and cognitive impairment, as well as visceral abnormalities.

The clinical features of Pfeiffer syndrome type 3 are similar to those of type 2, except for the presence of a cloverleaf skull deformity. Additional features may include a short anterior cranial fossa, natal teeth, pronounced proptosis, and various visceral abnormalities, such as hydronephrosis, pelvic kidneys, and hypoplastic gallbladder. Patients with type 3 may also exhibit cognitive and neurological impairments and are at risk of developing seizures postnatally.

Tracheal cartilaginous sleeve (TCS) is a congenital airway malformation observed in Pfeiffer syndrome, characterized by the absence of distinct tracheal rings. Instead, a continuous segment of cartilage extends from the subglottis to the carina. This anomaly is also seen in Apert and Crouzon syndromes. The presence of TCS can worsen the prognosis due to the associated respiratory complications.[9][10]

Although craniosynostosis is the primary neurological manifestation of Pfeiffer syndrome, other central nervous system anomalies are also commonly observed. These may include abnormal white matter development, megalencephaly, occipital encephalocele, agenesis of the corpus callosum, and Chiari 1 malformation.[11][12][13][14][15] Spinal abnormalities such as butterfly vertebrae, vertebral fusion, and sacrococcygeal extension may also be present.[16][17]

Additional anomalies that may be observed in Pfeiffer syndrome include cleft palate, choanal atresia, tracheomalacia, and imperforate anus. The primary ophthalmological findings associated with the syndrome are proptosis, strabismus, papilledema, and iris colobomas.[18]

Table. Comparison of Pfeiffer Syndrome Types

Evaluation

The diagnosis of Pfeiffer syndrome is primarily clinical, based on the presence of craniosynostosis and brachysyndactyly along with characteristic craniofacial and limb abnormalities. A provisional diagnosis may be made on clinical grounds; however, confirmation requires genetic testing. Molecular analysis should include mutation screening of FGFR1 (exon 7), FGFR2 (exons 8 and 10), and FGFR3 (exon 7).[6]

Sonographic features of Pfeiffer syndrome include craniofacial anomalies such as brachycephaly, acrocephaly, craniosynostosis, hypertelorism, a small nose, and a low nasal bridge. Limb abnormalities, including syndactyly, broad thumbs, and enlarged great toes, may also be detected.[19] Ultrasound has also been proposed as a potential screening tool for the early detection of TCS in patients with suspected Pfeiffer syndrome.[20][21][22][23]

Treatment / Management

The primary goals of surgical intervention in Pfeiffer syndrome are to decompress the brain by increasing intracranial volume, expand the infraorbital space to accommodate the globes, and enlarge the nasopharyngeal airway through advancement of the nasomaxillary-zygomatic complex.[24] These surgeries are typically performed in stages and require a multidisciplinary approach involving neurosurgery, craniofacial surgery, and otolaryngology to optimize both functional and aesthetic outcomes. (B3)

Multiple-stage surgeries constitute the standard treatment approach for patients with Pfeiffer syndrome. A suturectomy may be performed within the first year of life to "unlock" fused sutures, promoting continued brain growth and reducing intracranial pressure.[25] Cosmetic surgical corrections can also be undertaken for associated abnormalities. More commonly, extensive cranial vault reconstructions are necessary due to the involvement of multiple fused sutures. These include procedures such as LeFort osteotomies, monobloc osteotomies, fronto-orbital advancements, and posterior vault distraction osteogenesis.[26](B3)

Hydrocephalus in patients with Pfeiffer syndrome is typically managed with cerebrospinal fluid shunting. Results from a recent study demonstrated that individuals with Pfeiffer syndrome are more likely to require shunt placement and experience a higher rate of shunt revisions compared to those with other craniofacial syndromes[27]. Furthermore, patients with TCS often require tracheostomy, mainly to treat obstructive sleep apnea resulting from maxillary hypoplasia, choanal stenosis, and macroglossia. The rigidity of the trachea in these individuals complicates the proper sizing of tracheostomy tubes, posing additional challenges in airway management. In some cases, even after midfacial surgical correction, prolonged ventilatory support in the intensive care setting may be necessary.[28] Counseling the parents of children with TCS regarding the potential need for tracheostomy is essential, as it can significantly impact both long-term prognosis and quality of life. (B3)

Differential Diagnosis

The main differential diagnoses of Pfeiffer syndrome are other craniosynostosis syndromes. These include:

• Apert syndrome
• Crouzon syndrome
• Muenke syndrome
• Saethre-Chotzen syndrome
• Jackson-Weiss syndrome
• Antley-Bixler syndrome

Pfeiffer syndrome is closely related to Apert syndrome; however, they are genetically distinct conditions. Unlike Pfeiffer syndrome, Apert syndrome typically does not present with a cloverleaf skull or proptosis. Crouzon syndrome, another related craniosynostosis disorder, lacks the limb anomalies characteristic of Pfeiffer syndrome. Phenotypic overlap may occur with Muenke syndrome, which is caused by a specific FGFR3 mutation. Other differential diagnoses include Saethre-Chotzen syndrome and Jackson-Weiss syndrome, as both may present with broad toes, a feature also seen in Pfeiffer syndrome.[6]

Antley-Bixler syndrome is a rare craniosynostosis syndrome characterized by certain clinical features that may overlap with those of Pfeiffer syndrome type 2; it is an autosomal recessive condition associated with craniosynostosis (without the cloverleaf skull deformity), radiohumeral synostosis (rather than complete elbow ankylosis), femoral bowing, and a range of visceral anomalies. Notably, the visceral anomalies seen in Antley-Bixler syndrome are usually genital.[7]

Prognosis

Type 1 Pfeiffer syndrome has a relatively favorable prognosis in terms of intellectual development. In contrast, types 2 and 3 are associated with a significantly poorer prognosis due to severe neurodevelopmental complications, and childhood mortality is common in these cases.[7] A patient’s prognosis depends on the severity of the syndrome; however, craniofacial appearance usually improves with age. More recently, Robin et al examined the clinical course of 7 children with Pfeiffer syndrome type 3 and found that, despite severe manifestations, favorable outcomes were achieved with aggressive medical and surgical management.[29]

Complications

The primary complications associated with Pfeiffer syndrome include:

• Maldevelopment of the brain
• Cognitive delay
• Aspiration pneumonia
• Corneal ulcers and erosions due to proptosis
• Obstructive sleep apnea
• Seizures