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 (or likely pathogenic) variant in FGFR2 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous FGFR2 variant of uncertain significance does not establish or rule out the diagnosis.

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 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 Gastrointestinal issues 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 caused by 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 already performed) are recommended.

Treatment of Manifestations

Prevention of Secondary Complications

Surveillance

A craniofacial team made up of the appropriate specialties allows for proper planning and coordination so that the affected individual may receive the best possible care [McCarthy et al 2012].

Ideally, the composition of the multidisciplinary team caring for a child with Apert syndrome should include the following specialists:

• Audiologist
• Dentist
• Dermatologist
• Feeding specialist
• Geneticist
• Neurodevelopmental and behavioral pediatrician
• Neurosurgeon
• Nurse
• Nutritionist
• Ophthalmologist
• Oral surgeon
• Orthodontist
• Orthopedist (hand and foot surgery)
• Otolaryngologist
• Pediatrician
• Plastic surgeon
• Psychologist
• Pulmonologist / sleep medicine
• Social worker
• Speech pathologist
• Spine surgeon

Agents/Circumstances to Avoid

Contact sports and activities that involve neck hyperflexion or extension should be avoided, unless the individual has had the cervical spine assessed and cleared.

Avoid factors that potentiate hearing loss (ototoxic medications, overly loud stimuli).

Use of CPAP/BiPAP for long-term treatment of sleep apnea should be avoided when possible because pressure on the midface will exacerbate midfacial retrusion.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

No published studies address management of pregnancy in women with Apert syndrome.

Affected pregnant women should be monitored carefully for signs and symptoms of worsening obstructive sleep apnea.

A pregnant woman with Apert syndrome should have a careful anesthesia evaluation prior to initiation of labor to determine whether multilevel airway anomalies or vertebral anomalies would result in additional risk with certain types of anesthesia.

• If an obstetric emergency necessitates use of general anesthesia, fiberoptic intubation could be required.
• If this need were identified prior to delivery, the delivery location and timing could be chosen to ensure that adequate personnel were present to perform fiberoptic intubation, if needed.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Apert syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed with Apert syndrome have an affected parent.
• Most individuals diagnosed with Apert syndrome have the disorder as the result of a de novo FGFR2 pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is unknown. Advanced paternal age has been shown clinically to be associated with de novo pathogenic variants for Apert syndrome [Moloney et al 1996, Yoon et al 2009]. It has been proposed that FGFR pathogenic variants are paradoxically enriched in the male germline because they confer a selective advantage to the spermatogonial cells in which they arise [Goriely et al 2003, Choi et al 2008, Bochukova et al 2009, Yoon et al 2009].
• Molecular genetic testing can be performed on the parents of a proband with an apparent de novo pathogenic variant; however; such testing is unlikely to provide additional information as the genetic status of the parents can be inferred based on their clinical status (Apert syndrome is 100% penetrant and therefore a heterozygous parent will be clinically affected).
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred de novo in the proband. Another possible explanation is germline mosaicism in a parent. Parental germline mosaicism has been reported in a family with affected sisters born to unaffected parents [Allanson 1986].

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected, the risk to sibs is 50%.
• If the parents are unaffected and/or the proband has a known FGFR2 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Allanson 1986].

Offspring of a proband. Each child of an individual with Apert syndrome has a 50% chance of inheriting the FGFR2 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the FGFR2 pathogenic variant, the parent's other family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the FGFR2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

FGFR2 belongs to a complex system of intracellular signaling consisting of multiple fibroblast growth factors (FGFs) and their receptors FGFRs. This signaling network functions in the control of cell proliferation, differentiation, migration, and death in many different contexts such as embryonic development, angiogenesis, immunity, and cancer. Diseases result from loss-of-function, gain-of-function, postzygotic mosaic, and/or somatic alterations in components of this network. For an excellent overview of this signaling network, along with effects of germline and somatic alterations in FGFs and FGFRs that result in human disease, see Katoh [2016] and references therein. Additionally Azoury et al [2017] focuses on FGFR-related craniosynostosis.

Gene structure. The transcript NM_000141.4 has 18 exons, with exon 1 being noncoding. The coding sequence, 648-3113 nt, encodes a signal peptide (648-710 nt) and the mature protein (711-3110 nt). This transcript may be referred to as transcript variant 1. Multiple alternatively spliced transcript variants encoding different isoforms are described. For a detailed summary of gene, transcripts, and protein isoforms, see Table A, Gene.

Pathogenic variants. Apert syndrome results from a gain of function of FGFR2, and as expected the range of pathogenic variants is limited. The recurrent and common variants p.Ser252Trp, p.Pro253Arg, and p.Ser252Phe cause the great majority of Apert syndrome (see Table 1, footnote 5). The corresponding nucleotide changes are in 5' end of exon 7. Novel variants are also known, including a splicing variant in intron 8 [Torres et al 2015] and gross deletions that alter the Ig-like domain structure (see Normal gene product). The latter include a 1.9-kb deletion that includes the extracellular IG-like domain IIIc (exon 8) and a 1.3-kb deletion (exon 9) that creates a chimeric IIIb/IIIc domain [Bochukova et al 2009, Fenwick et al 2011]. Three gross de novo insertions of Alu elements in or near exon 9, which encodes domain IIIc, are also described [Oldridge et al 1999, Bochukova et al 2009]. These novel variants are thought to result in exon skipping or other possible dysregulation that ultimately results in a gain of function.

Note that some literature describing pathogenic variants confuses the terminology of exon and domain. Alterations in exons 8 and 9, which encode IG-like domain IIIb and IIIc, respectively, may be referred to as alterations in exon IIIb and exon IIIc.

Normal gene product. Transcript NM_000141.4 encodes FGFR2 isoform 1 NP_000132.3 (also referred to as isoform BEK) of 821 amino acid residues.

A signal peptide, residues 1-21, is cleaved in post-translational processing to give the mature peptide, residues 22-821, which consists of an extracellular region composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment, and a cytoplasmic tyrosine kinase domain. Residues Ser252 and Pro253, the sites of recurrent pathogenic variants, are located in the linker between the second and third immunoglobulin-like domains.

Abnormal gene product. The gain-of-function FGFR2 variants are thought to reduce dissociation of ligand leading to enhanced signaling.

Cancer and Benign Tumors

Sporadic tumors occurring as single tumors in the absence of any other clinical findings of Apert syndrome frequently harbor somatic variants in FGFR2 that are not present in the germline. In these circumstances predisposition to these tumors is not heritable.

Somatic loss-of-function, gain-of-function, and gene fusions involving FGFR2 are reported in diverse cancers such melanoma, breast, gastric, endometrial, lung, and cholangiocarcinoma. For an excellent overview of FGF signaling network, along with effects of germline and somatic alterations in human disease, see Katoh [2016] and references therein.

Acknowledgments

The authors would like to acknowledge Dr Carrie Heike for her critical review of this GeneReview.

Revision History

• 30 May 2019 (ma) Review posted live
• 31 December 2017 (tw) Original submission

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