Craniosynostosis Syndromes

Occasional Abnormalities

Short stature, intellectual disability, ocular hypertelorism, lacrimal duct stenosis, bifid uvula, cleft palate; teeth with broad, bulbous crowns, thin, narrow tapering roots, and diffuse pulp stones in the pulp chambers of all posterior teeth; microtia; short fourth metacarpals; hallux valgus; hallucal reduplication; cardiac anomaly; cryptorchidism; renal anomaly.

Natural History

Craniosynostosis is not an obligate feature. Although most patients are of normal intelligence, intellectual disability of a mild to moderate degree has been described that is typically associated with large gene deletions. Facial appearance tends to improve during childhood. Increased intracranial pressure has been seen in up to 21% of patients, even following primary surgical release of craniosynostosis. Annual monitoring for papilledema and language regression is recommended. Obstructive sleep apnea is documented in 5%. Conductive hearing loss related to middle ear disease is common, as is strabismus.

Occasional Abnormalities

Kleeblattschädel anomaly (cloverleaf skull); choanal atresia; ocular anterior chamber dysgenesis; exophthalmos; sensorineural hearing loss (malformed vestibule and/or cochlea); cartilaginous tracheal sleeve; laryngo-, tracheo-, and bronchomalacia; cleft palate; radiohumeral synostosis of elbow; symphalangism of index finger; brachydactyly; fused vertebrae; hydrocephalus; Chiari type I malformation; seizures; fifth-finger clinodactyly; arthrogryposis; intestinal malrotation; omphalocele; prune belly anomaly; imperforate anus; cryptorchidism; sacrococcygeal eversion resembling a human tail; tethered cord.

Natural History

Cohen delineated three clinical subtypes of Pfeiffer syndrome (PS) that are significant with respect to prognosis. Patients with type 1 have the “classic” phenotype, with craniosynostosis, broad thumbs, and great toes; variable degrees of syndactyly; and normal to near normal intelligence. Long-term outcome is excellent. Type 2 is associated with cloverleaf skull, severe ocular proptosis, severe central nervous system involvement, elbow ankylosis/synostosis, broad thumbs and great toes, and a variety of low-frequency visceral anomalies. Type 3 PS is similar to type 2 but lacks the cloverleaf skull. Although the vast majority of children with types 2 and 3 do very poorly, survival is possible, especially with aggressive medical and surgical treatment, particularly as it relates to the upper airway. Patients with types 2 and 3 PS have significant risk for exposure keratopathy, obstructive sleep apnea, and persistent increased intracranial pressure after release of craniosynostosis. Midface advancement, often at a young age, may be necessary to address airway concerns. Intellectual disability is common, but not invariable in PS types 2 and 3. Fluctuating hearing loss secondary to middle ear disease is common in all types.

Etiology

All three forms of Pfeiffer syndrome have an autosomal dominant mode of inheritance and type 1 is frequently familial. However, the vast majority of cases of types 2 and 3 reported to date have been sporadic events, likely the result of fresh gene mutation. Pfeiffer syndrome is genetically heterogeneous. Mutations in the fibroblast growth factor receptor 1 ( FGFR1 ) gene, which maps to chromosome 8p11.23, and in the fibroblast growth factor receptor 2 ( FGFR2 ) gene, which maps to chromosome 10q26.13, have been documented. Changes in the hands and feet tend to be less severe in children with FGFR1 mutations than in those with FGFR2 mutations. Of individuals with PS type 1, 5% have mutations in FGFR1. The remaining cases of type 1, as well as all cases of types 2 and 3, have mutations in FGFR2 . Three mutations in FGFR2 (p.Ser351Cys, p.Trp290Cys, and p.Cys342Arg) have been associated with severe phenotypes, although aggressive surgical management has improved outcome in three affected patients.

Comment

Prenatal diagnosis of types 2 and 3 Pfeiffer syndrome is increasingly reported. Affected fetuses present with polyhydramnios; abnormal skull shape, including clover-leaf skull; ventriculomegaly; proptosis and hypertelorism; frontal bossing; nasal malformation and commonly associated visceral malformations. The characteristic limb anomalies have also been recognized prenatally.

Occasional Abnormalities

Kleeblattschädel anomaly (cloverleaf skull); Chiari I malformation; corneal scarring; optic atrophy; short humerus, limitation of joint mobility, especially elbow, pre- and postaxial polydactyly; genu valga; gastrointestinal anomalies in 1.5%, including pyloric stenosis, esophageal atresia, intestinal malrotation, diaphragmatic hernia, and ectopic anus; respiratory anomalies in 1.5%, including pulmonary aplasia and anomalous tracheal cartilage sleeve; cardiac defects in 10%, including pulmonic stenosis, overriding aorta, ventricular septal defect, and endocardial fibroelastosis; genitourinary anomalies in 10%, including polycystic kidney, hydronephrosis, bicornuate uterus, vaginal atresia, and cryptorchidism; ovarian dysgerminoma.

Natural History

Early surgery for craniosynostosis does not necessarily prevent intellectual disability, although outcomes are better in those undergoing early decompression. Upper airway compromise, caused by a combination of reduction in size of the nasopharynx and reduction in patency of the choanae, and lower airway compromise caused by anomalies of the tracheal cartilage, may be responsible for early death. Exposure keratopathy may occur secondary to proptosis. Release of complex syndactyly to improve hand function is critical. Hearing loss secondary to chronic otitis media or congenital fixation of the stapedial footplate is common. Multiple surgeries are typically necessary to improve structure and function. Increased intracranial pressure, obstructive sleep apnea, refractive visual errors, and strabismus dictate ongoing surveillance. Long-term assessment of outcomes suggests many patients do well despite some residual limitations in function.

Etiology

This disorder has an autosomal dominant inheritance pattern. The vast majority of cases are sporadic new mutations associated with older paternal age. Mutations in the fibroblast growth factor receptor 2 gene ( FGFR2 ), which maps to chromosome 10q26.13, cause Apert syndrome. Two mutations account for 98% of cases. The p.Pro253Arg mutation (26% of cases) causes greater severity of syndactyly than the p.Ser252Trp mutation (76% of cases) in which cleft palate appears to be more common.

Comment

Apert syndrome is increasingly diagnosed prenatally. Prenatal findings include abnormal skull shape, including clover-leaf skull, hypertelorism, proptosis, agenesis of corpus callosum, and syndactyly of the hands and feet. Echogenic lungs and other associated visceral malformations have been visualized.

Different mutations in FGFR2 cause Crouzon syndrome as well as Pfeiffer syndrome.

Occasional Abnormalities

Intellectual disability; hydrocephalus; seizures; agenesis of corpus callosum; Chiari type I malformation; syringomyelia; keratoconus; glaucoma; iris coloboma; subluxation of globe; jugular foraminal stenosis; atresia of auditory meatus; cleft lip, with or without cleft palate; bifid uvula; tooth agenesis; pulmonary valve stenosis; tracheobronchomalacia; tracheal cartilaginous sleeve; subluxation of radial heads; sacrococcygeal eversion resembling a human tail; acanthosis nigricans involving eyelids, perioral, perialar, and neck skin predominantly.