Apert Syndrome

Excerpt

Clinical characteristics: Apert syndrome is characterized by the presence of multisuture craniosynostosis, midface retrusion, and syndactyly of the hands with fusion of the second through fourth nails. Almost all affected individuals have coronal craniosynostosis, and a majority also have involvement of the sagittal and lambdoid sutures. The midface in Apert syndrome is underdeveloped as well as retruded; a subset of affected individuals have cleft palate. The hand in Apert syndrome always includes fusion of the middle three digits; the thumb and fifth finger are sometimes also involved. Feeding issues, dental abnormalities, hearing loss, hyperhidrosis, and progressive synostosis of multiple bones (skull, hands, feet, carpus, tarsus, and cervical vertebrae) are also common. Multilevel airway obstruction may be present and can be due to narrowing of the nasal passages, tongue-based airway obstruction, and/or tracheal anomalies. Nonprogressive ventriculomegaly is present in a majority of individuals, with a small subset having true hydrocephalus. Most individuals with Apert syndrome have normal intelligence or mild intellectual disability; moderate-to-severe intellectual disability has been reported in some individuals. A minority of affected individuals have structural cardiac abnormalities, true gastrointestinal malformations, and anomalies of the genitourinary tract.

Diagnosis/testing: The diagnosis of Apert syndrome is established in a proband with classic clinical characteristics (multisuture craniosynostosis, midface retrusion, and syndactyly) and/or by the identification of a heterozygous pathogenic variant in FGFR2 by molecular genetic testing AND phenotypic features consistent with Apert syndrome.

Management: Treatment of manifestations: Management by a craniofacial team is ideal. In general, multisutural craniosynostosis should be surgically repaired in the first year of life; jaw surgery to advance the midface often occurs in childhood and adolescence. Cleft palate repair may be performed prior to the development of pressure consonants. Feeding therapy is often helpful. Pediatric dental care is recommended. Treatment of strabismus should be performed by an ophthalmologist with expertise in eye alignment in children with craniosynostosis. Hearing aids may be required for hearing loss. If airway obstruction is present, temporizing measures may be required. Treatment of sleep apnea by surgical intervention and/or supplemental oxygen via nasal cannula may be required. The type and timing of surgical repair for syndactyly depends on the presence of thumb syndactyly and extent of soft tissue deficiency. Early intervention services for speech abnormalities and developmental delay should be initiated. Standard treatment of congenital heart defects, malrotation, cryptorchidism in males, hydronephrosis, acne, and scoliosis should be instituted when appropriate.

Prevention of secondary complications: Timely surgical treatment of craniosynostosis may prevent increased intracranial pressure that can lead to papilledema and cognitive impairment; ocular lubricants to prevent exposure keratopathy and corneal scarring; anesthesia evaluation before any surgical intervention to prevent perioperative respiratory complications; spine precautions and consultation with a spine surgeon to prevent spinal cord injury and neurologic sequelae in those with cervical spine anomalies. Clinical feeding evaluation and/or video fluoroscopic swallow study is needed to determine if precautions are required to prevent aspiration pneumonia and subsequent chronic lung disease.

Surveillance: Measurement of head circumference and fontanelle size and assessment for increased intracranial pressure at each appointment in infancy and early childhood; assessment of developmental progress at each visit; evaluation by a craniofacial team regularly in infancy, childhood, and adolescence; dental care every six months; assessment for velopharyngeal insufficiency after emergence of language; assessment for speech disorders, ophthalmologic evaluation, and audiologic/otologic assessments at least annually; evaluation for the development of scoliosis annually in childhood and adolescence.

Agents/circumstances to avoid: Contact sports and activities that involve neck hyperflexion or extension for those with cervical spine anomalies; factors that potentiate hearing loss; use of CPAP/BiPAP for long-term treatment of sleep apnea.

Pregnancy management: For affected pregnant women: monitoring for signs and symptoms of worsening obstructive sleep apnea and anethesia evaluation prior to initiation of labor to identify any multilevel airway anomalies or vertebral anomalies that would result in additional risk with certain types of anesthesia; fiberoptic intubation could be required.

Genetic counseling: Apert syndrome is inherited in an autosomal dominant manner. However, most individuals with Apert syndrome have the disorder as the result of a de novo FGFR2 pathogenic variant. Advanced paternal age has been shown to be associated with de novo pathogenic variants for Apert syndrome. Affected individuals have a 50% chance of passing the pathogenic variant to each child. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in the family.