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At a glance

Craniosynostosis with broad thumbs and halluces, midface hypoplasia, occasional syndactyly, and various other anomalies.

Synonym

Noack Syndrome (Acrocephalopolysyndactyly Type I)

Incidence

Approximately 1 in 100,000 live births. No gender preference has been reported.

Genetic inheritance

The mutations are either inherited in an autosomal dominant fashion or arise as sporadic cases (particularly PS Type II and III). The syndrome is caused by mutations in the fibroblast growth factor receptor 1 (FGFR-1) (on chromosome 8p11.2-p11) or FGFR-2 (on chromosome 10q26.13). Similar to Crouzon Syndrome, advanced paternal age is considered a risk factor.

Pathophysiology

The mutations in the FGFR-1 gene and sometimes the FGFR-2 gene result in premature maturation of fibroblast-derived cells and irregular bridging of the mesenchymal tissue that forms the bone. The cranium and distal extremities are primarily affected. During fetal development, premature ossification with increased subperiosteal bone formation in the calvarium is responsible for the craniosynostosis.

Diagnosis

Based on the clinical findings at birth or shortly thereafter (craniosynostosis with broad thumbs and great toes) and skull radiography showing premature coronal craniosynostosis.

Clinical aspects

Three subtypes of Pfeiffer Syndrome (PS) have been identified that differ with regards to clinical symptoms and prognosis, although significant overlap of symptoms and findings occurs:

  • Type 1: Classic and most common form of PS is designated Type 1 and characterized by craniosynostosis, midface hypoplasia, broad thumbs and halluces, brachydactyly, and variable syndactyly. The outcome is usually good.

  • Type 2: Consists of cloverleaf skull shape (Kleeblattschädel), severe ocular proptosis, severe central nervous system involvement (eg, hydrocephalus), elbow ankylosis and/or synostosis, broad thumbs and halluces, brachydactyly, and a variable degree of syndactyly. These patients often die at a very young age. All known cases to date have been sporadic.

  • Type 3: Similar to Type 2, but lacks the cloverleaf skull (Kleeblattschädel). Ocular proptosis is severe and the anterior cranial base is markedly shortened. Similar to Type 2, these patients often die at a very young age. To date, all cases have occurred sporadically.

Clinical findings

Typical facial features include mild craniosynostosis (usually affecting coronal and sagittal sutures) with acro- and/or brachycephaly, midface hypoplasia, maxillary hypoplasia, shallow orbits with proptosis, downslanting of the palpebral fissures, hypertelorism, ptosis, and strabismus. Hydrocephalus occurs in approximately 40% of patients with PS Type 1 and a significant correlation exists between elevated intracranial pressure (ICP) and the severity of upper airway obstruction. Other brain anomalies can include ventriculomegaly, ☞Arnold-Chari I malformation, and corpus callosum anomalies. Sporadically, odontoid hypoplasia and fused spinal vertebrae, typically at the cervical level, can occur. Visual impairment is common and most often due to optic neuropathy (from hydrocephalus with increased ICP), amblyopia and/or exposure keratopathy with corneal clouding. ...

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