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.

Suggestive Findings

Apert syndrome should be suspected in individuals with the following clinical features.

Head

• Multisuture craniosynostosis, most commonly involving bilateral coronal sutures with variable involvement of the remaining cranial sutures
• Midface retrusion with a greater degree of vertical impaction than Crouzon syndrome (see FGFR-Related Craniosynostosis Syndromes)
• Prominent eyes with downslanting palpebral fissures
• Relative prognathism with malocclusion

Airway. Multilevel airway obstruction

Limbs/skeleton

• Syndactyly of the hands, including soft tissue and bone
  • The second, third, and fourth fingers are always included in the fusion, while the thumb and fifth digit may or may not be included.
  • Synonychia (fusion of ≥2 nails) of the second through fourth fingers is common. The appearance is sometimes referred to as a "mitten hand."
• Syndactyly of the feet, which may or may not include the great toe
• Tendency toward progressive bony fusion at multiple sites (e.g., progressive craniosynostosis, cervical vertebral fusions, bones of the hands and feet, carpus, and tarsus). Bony fusions (especially of the skull) may also occur after birth.

Establishing the Diagnosis

The diagnosis of Apert syndrome is established in a proband with:

• Classic clinical characteristics (multisuture craniosynostosis, midface retrusion, and syndactyly); OR
• Suggestive clinical features AND a heterozygous pathogenic variant in FGFR2 identified by molecular genetic testing (see Table 1).

When the phenotypic findings suggest the diagnosis of Apert syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

Note: All individuals with Apert syndrome have a heterozygous pathogenic variant in FGFR2, though clinicians may choose a targeted panel including common pathogenic variants that cause other forms of syndromic craniosynostosis if the diagnosis is unclear or if this approach is the most cost effective.

Single-gene testing. Sequence analysis of FGFR2 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. Typically, exon or whole-gene deletions/duplications are not detected.

• Perform sequence analysis first.
• If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.

A craniosynostosis multigene panel that includes FGFR2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Apert syndrome shows substantial overlap with the clinical characteristics seen in other FGFR2-associated craniosynostosis syndromes (e.g., craniosynostosis, midface retrusion, vertebral fusions). In most individuals, Apert syndrome can be readily distinguished from other syndromic craniosynostosis syndromes (e.g., Crouzon, Pfeiffer, Jackson-Weiss, Beare-Stevenson) at or before birth due to the presence of syndactyly. However, several other important distinguishing features have implications for surveillance and medical management (see Management).

Craniosynostosis is a near-universal finding in individuals with Apert syndrome, though some affected individuals with other typical manifestations (e.g., midface retrusion and syndactyly) without craniosynostosis have been reported. Most infants with Apert syndrome are born with fusion of one or more cranial sutures, though progressive craniosynostosis of other sutures can occur. As bony fusions are typically progressive in Apert syndrome, and most major cranial sutures do not typically fuse until adulthood, it is unknown whether the children reported with Apert syndrome without craniosynostosis at the time of diagnosis would go on to develop craniosynostosis later.

Depending on the involved sutures, most children with Apert syndrome have a large anterior fontanelle, which is displaced anteriorly onto the forehead [Cohen & Kreiborg 1996]. The most commonly involved sutures are the following:

• Coronal (near 100%), though many will have multisuture craniosynostosis or pan synostosis resulting in cloverleaf skull
• Sagittal (~85%)
• Lambdoid (81%)

Midface retrusion. Unlike Crouzon syndrome, in which the midface is normally formed but retruded, the midface in Apert syndrome is underdeveloped as well as retruded. There is a greater degree of vertical impaction leading to a shorter maxillary bone, with greater similarity to Pfeiffer syndrome than to Crouzon syndrome. The underdevelopment of the midface contributes to the development of shallow orbits and downslanting palpebral fissures. Underdeveloped maxillary structures result in malocclusion and the appearance of relative mandibular prognathism [Cohen & Kreiborg 1996].

Palatal abnormalities. Highly arched palate or cleft palate may occur. Cleft palate is frequently present in Apert syndrome (but rarely found in Crouzon syndrome) [Cohen & Kreiborg 1996].

Feeding issues. Feeding problems are common in children with Apert syndrome and have a number of causes. Palatal anomalies can cause difficulty with generating suction and therefore difficulty with intake of sufficient volume.

Narrowing of the choanae or nasal turbinates can cause respiratory distress, which can be mistaken for a primary feeding issue. In this case, the infant will often suck a few times and then unlatch to breathe through an open mouth. Infants who have a primary respiratory cause for their feeding issues generally have difficulty breathing through the nose and have other signs of upper-respiratory obstruction.

Children with Apert syndrome are at risk for gastrointestinal issues (see below) that can cause vomiting but do not typically affect the transfer of milk from the bottle or breast. Many children with Apert syndrome who have feeding difficulties require surgical intervention (e.g., repair of choanal atresia or stenosis, gastrostomy tube).

Clinical feeding evaluation and/or video fluoroscopic swallow study should be performed for all infants to identify aspiration (see Management). If there is aspiration, precautions should be taken (e.g., thickened feeds, limiting oral intake) to prevent aspiration pneumonia, pneumonitis, and chronic lung disease.

Dental abnormalities. Children with Apert syndrome often have dental anomalies that require management by orthodontics and/or oromaxillofacial surgery. Tooth agenesis (typically of maxillary canines) and enamel opacities occur in more than 40% of children with Apert syndrome. Ectopic eruption of maxillary first molars and lateral palatal swellings are also common. Other orthodontic differences include delayed dental eruption, missing teeth, dental crowding, and abnormal occlusal relationships. Abnormalities of primary and adult teeth can be present [Nurko & Quinones 2004, Dalben et al 2006].

Ocular abnormalities. The characteristic appearance of the eyes in Apert syndrome is prominent with downslanting palpebral fissures. The prominence of the eyes is typically due to a combination of bicoronal craniosynostosis and deficient development of the maxilla. Other primary ophthalmologic abnormalities include the following:

• Strabismus (60%)
• Refractive error (34%)
• Anisometropia (19%)

Secondary ophthalmologic findings that may develop over time include exposure keratopathy and corneal scarring (8%) and optic atrophy (8%). These secondary findings may be preventable with aggressive surveillance and treatment of incomplete lid closure and increased intracranial pressure [Khong et al 2006b].

Hearing loss/inner ear anomalies. Hearing loss is common (80%) and is typically conductive, caused by middle ear disease, ossicular abnormalities, and external auditory canal stenosis or atresia [Agochukwu et al 2014].

Abnormalities of the semicircular canals are found in 70% of affected individuals.

Multilevel airway obstruction. Individuals with Apert syndrome may have abnormalities at multiple sites [Cohen & Kreiborg 1992, Cohen & Kreiborg 1996, Wenger et al 2017].

• Narrowing of the nasal passages or choanae can lead to upper-airway obstruction, and may contribute to respiratory distress as well as feeding difficulties.
• Tongue-based airway obstruction may also occur.
  In children with cleft palate, repair of the cleft palate may unmask obstruction at the level of the pharynx and result in worsening of obstructive sleep apnea.
• Tracheal anomalies, including fused rings and tracheal cartilaginous sleeves, have been reported in a number of individuals.
  • Significant variability in severity is seen, ranging from mild respiratory symptoms requiring little intervention to severe obstruction requiring placement of tracheostomy.
  • Some children who require tracheostomy need a ventilator for delivery of positive airway pressure during sleep.

Syndactyly. The hand in Apert syndrome always includes fusion of the middle three digits; the thumb and fifth finger may also be involved. The fingernail for digits 2-4 is typically fused to form a single nail (synonychia). Syndactyly of the toes may involve the lateral three digits, digits 2-5, or all digits. In general, the upper limb is more severely affected than the lower limb. Synonychia has not been reported in the toes [Upton 1991, Cohen & Kreiborg 1995, Wilkie et al 1995].

Other limb anomalies that occur less frequently in individuals with Apert syndrome include the following [Maroteaux & Fonfria 1987, Sidhu & Deshmukh 1988, Gorlin 1989, Lefort et al 1992, Cohen & Kreiborg 1995, Mantilla-Capacho et al 2005]:

• Synostosis of the radius and humerus
• Preaxial and/or postaxial polydactyly of the hands and/or feet
• Broad distal phalanx of the thumb or broad distal hallux

Spinal fusions. Cervical vertebral fusions are found in 68% of individuals with Apert syndrome, most commonly involving C5-C6. Of those with fusions, approximately 50% have a single fusion and 50% have multiple fusions. The prevalence and location of vertebral fusions differs from Crouzon syndrome, in which only 25% have vertebral fusion, most commonly involving C2-C3. If spinal fusions or abnormalities of spinal fusion occur, scoliosis can result [Kreiborg et al 1992]. Other cervical spine anomalies include atlanto-axial subluxation (7%) and C1 spina bifida occulta (7%) [Breik et al 2016].

Progressive synostosis. Progressive fusion of several bones may occur, including bones of the skull, hands, feet, carpus, tarsus, and cervical vertebrae [Schauerte & St-Aubin 1966].

Restriction of movement involving the shoulder due to glenohumeral dysplasia can lead to functional impairment. This restriction tends to be progressive with decrease in forward flexion and abduction of the upper arm limiting the ability of the individual with Apert syndrome to perform "overhead" tasks [McHugh et al 2007, Murnaghan et al 2007].

Children with Apert syndrome may experience progressive deformities of the foot leading to pain and difficulty with gait. Over time the first metatarsal bone becomes relatively short with resultant shift in the weight-bearing function of the first metatarsal to the second metatarsal bone, and the great toes become increasingly short and angulated. Callus formation develops as weight is redistributed laterally leading to pain and limitation of daily activities. Affected individuals experience difficulty finding footwear that fits properly [Calis et al 2016].

Neurologic. Jugular foraminal stenosis is seen in 93% of affected individuals.

Approximately 60% of individuals with Apert syndrome have nonprogressive ventriculomegaly and 6%-13% have hydrocephalus.

• Stable ventriculomegaly does not necessarily require surgical intervention.
• Progressive ventriculomegaly can indicate hydrocephalus, which may require evaluation for endoscopic third ventriculostomy and/or ventriculoperitoneal shunt.

Structural brain malformations in Apert syndrome include the following [Cohen & Kreiborg 1990, Cinalli et al 1995, Renier et al 1996, Quintero-Rivera et al 2006, Tan & Mankad 2018]:

• Abnormalities of the corpus callosum (23%)
• Absent septum pellucidum (17%)
• Chiari I malformation and/or low-lying cerebellar tonsils (17%)
  Note: Only 2% of individuals with Apert syndrome were found to have chronic tonsillar herniation, which is present in 73% of those with Crouzon syndrome.
• Posterior fossa arachnoid cyst (7%)
• Limbic malformations

Neurodevelopment. Most individuals with Apert syndrome have normal intellect or mild intellectual disability, though some individuals have been reported with moderate-to-severe intellectual disability [Renier et al 1996, David et al 2016, Fernandes et al 2016]. Not surprisingly, children with Apert syndrome raised within the family have better cognitive outcomes than children who were institutionalized [Patton et al 1988, Cohen & Kreiborg 1990, Renier et al 1996]. The neurodevelopmental outcomes for children born with Apert syndrome today may be more promising than these earlier reports suggest, as surgical and medical management have become more advanced and children have improved access to early intervention programs.

Factors associated with a higher risk for intellectual disability include the following:

• Delay of first craniectomy until after one year of age
• Presence of structural brain malformations
  • Abnormalities of the septum pellicudum have been shown to be associated with lower IQ.
  • Data regarding the possible impact on IQ of an abnormal callosum and/or corpus callosum are conflicting.

Cardiovascular. Approximately 10% of individuals with Apert syndrome have structural cardiac abnormalities. The most common malformations include ventricular septal defect and overriding aorta; some children with complex congenital heart disease have been reported. Children with complex congenital heart disease are at greater risk for early death compared to children with structurally normal hearts [Cohen & Kreiborg 1993].

Gastrointestinal issues. Feeding difficulties can occur in Apert syndrome for a variety of reasons, and may require placement of a nasogastric or gastric tube.

One of 15 individuals with Apert syndrome had intestinal malrotation in one study, though it was unclear whether the remaining affected individuals had undergone formal radiologic evaluation for malrotation (upper GI); therefore, the true prevalence may be higher than reported [Hibberd et al 2016].

Distal esophageal stenosis has also been reported [Pelz et al 1994].

Other gastrointestinal malformations reported in Apert syndrome include the following:

• Pyloric stenosis
• Esophageal atresia
• Ectopic anus

Genitourinary. Anomalies of the genitourinary tract are identified in 9.6% of children with Apert syndrome, most commonly hydronephrosis or cryptorchidism. One child with Apert syndrome due to a germline FGFR2 pathogenic variant had a low-grade papillary urothelial carcinoma of the bladder, but no detected FGFR3 somatic variants (which can be associated with this type of cancer). As a single case was reported, it is unclear whether this is part of the phenotype of Apert syndrome [Cohen & Kreiborg 1993, Andreou et al 2006].

Skin changes. Hyperhidrosis is a consistent feature of Apert syndrome. Affected adults typically develop oily skin in adolescence and extensive acneiform lesions, including on the face, chest, back, and upper arms. Some affected individuals develop excessive skin wrinkling of the forehead [Cohen & Kreiborg 1995]. Nail dystrophy is also common [Bissacotti Steglich et al 2016].

Adults. A range of educational and employment ascertainment has been described. Adults with Apert syndrome appear to have more challenges with social development and relationships compared to unaffected controls and individuals with Crouzon syndrome [Tovetjärn et al 2012, David et al 2016, Lloyd et al 2016].

Genotype-Phenotype Correlations

Reports regarding genotype-phenotype correlations in Apert syndrome are variable. Some studies suggest no clear correlations [Park et al 1995].

• Pathogenic p.Pro253Arg variant
  • Some studies have suggested more significant hand and foot involvement in individuals with this pathogenic variant.
  • One study suggested better postsurgical craniofacial appearance in affected individuals with this variant, but the generalizability of this study is limited due to significant evolution of surgical techniques since the study was published [von Gernet et al 2000].
• Pathogenic p.Ser252Trp variant. Cleft palate has been reported to be more common in those with this variant.

No other features of Apert syndrome have been found to vary based on genotype [Slaney et al 1996, Lajeunie et al 1999].

Nomenclature

Apert syndrome may also be referred to as acrocephalysyndactyly type I.

Prevalence

The estimated birth prevalence of Apert syndrome ranges from 1: 80,000 to 1:160,000 live births [Cohen et al 1992, Tolarova et al 1997]. The frequency may be higher among children born to fathers with advanced paternal age, with the greatest number of variants in sperm from fathers older than age 60 years [Glaser et al 2003].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Apert syndrome, the evaluations summarized in Table 4 (if not performed already) are recommended.

Treatment of Manifestations