Apert syndrome is a rare autosomal dominant inherited craniosynostosis genetic condition that is apparent at birth through the premature fusion of coronal sutures resulting in the skull and facial deformities and syndactyly. It is due to gain-of-function missense mutations of fibroblast growth factor receptor (FGFR2)-2 on chromosome 10q.[rx]People with Apert syndrome can have distinctive malformations of the skull, face, hands, and feet. Apert syndrome is characterized by craniosynostosis, a condition in which the fibrous joints (sutures) between bones of the skull close prematurely. This can cause the top of the head to appear pointed and can affect facial bones. Certain fingers or toes may be fused or webbed. Affected children may also have an intellectual disability. The severity of symptoms varies between individuals. Apert syndrome almost always results from new genetic changes (mutations) that occur randomly. Rarely, it is inherited in an autosomal dominant pattern. People with Apert syndrome can undergo therapies that address specific symptoms. This could include a reconstructive skull, facial, hand, and foot surgeries.
Apert syndrome is a type of acrocephalosyndactyly (ACS known as acrocephalosyndactyly type 1 (ACS1). All forms of ACS are characterized by craniosynostosis and this affects the proper growth of the skull and head.
Causes
Apert syndrome is caused by a change (mutation) in the fibroblast growth factor receptor-2 (FGFR2) gene. This gene plays a critical role in skeletal development. Genes provide instructions for creating proteins that play distinct roles in our bodies. When a mutation of a gene occurs, the protein product may not work as it should. In Apert syndrome, mutations in FGFR2 result in these receptors not properly communicating with fibroblast growth factors. This affects the formation of normal sutures in the brain and can obstruct the development of many other structures in the body. This improper formation is what causes the malformations seen in Apert syndrome.
In almost all reported patients, the disorder has been caused by one of two specific mutations of the FGFR2 gene. (These mutations are designated “Ser252Trp” and “Pro253Arg.”) These mutations may cause slightly different presentations, including the severity of syndactyly. Different mutations in the FGFR2 gene may cause several other related disorders, including Pfeiffer syndrome, Crouzon syndrome, and Jackson-Weiss syndrome. (For further information on these disorders, please see the “Related Disorders” section of this report below.)
In up to 95% of patients, Apert syndrome results from a new mutation in the FGFR2 gene. These new mutations appear to occur randomly for unknown reasons (sporadically). It has been reported that sporadic cases may be associated with the increased age of the father.
Rarely, Apert syndrome is inherited in an autosomal dominant fashion. Dominant genetic disorders occur when only a single copy of a mutation is necessary to cause a particular disease. The risk of passing the mutation from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Mutations in a gene known as FGFR2 cause Apert syndrome. This gene provides instructions for making a protein called fibroblast growth factor receptor 2 (FGFR2). Among its multiple functions, the FGFR2 protein plays a key role in development before birth by signaling immature cells to become bone cells. A mutation in a specific part of the FGFR2 gene alters the protein, increasing its signaling. The abnormal signaling causes the cell to mature too quickly and promotes the premature fusion of bones in the skull, hands, and feet.
Symptoms
Apert syndrome is characterized by craniosynostosis, the premature closure of the fibrous joints (sutures) between certain bones in the skull. In individuals without craniosynostosis, sutures allow an infant’s head to grow and expand. Eventually, these bones fuse to form the skull. For people with craniosynostosis, the brain is still growing after these sutures prematurely close. The pressure of brain growth can cause various bones of the skull and face to change shape during development. Depending on which sutures prematurely close, the severity can vary. In most affected individuals, there is premature closure of the sutures between the bones forming the forehead and the upper sides of the skull. This tends to cause the head to appear pointed at the top (acrocephaly) from birth. In addition, the back portion of the skull may appear flattened, with a high and broad forehead. There can be a large, late-closing “soft spot” on the skull. Individuals may also have hydrocephalus, in which cerebrospinal fluid abnormally accumulates in the cavities of the brain. This can cause pressure on the brain.
The facial bones can be affected by craniosynostosis. This can lead to characteristic facial abnormalities. People with Apert syndrome may have widely spaced eyes (hypertelorism), bulging eyes, or down-slanting palpebral fissures. They may also have underdeveloped midfacial regions (maxillary hypoplasia) and palate abnormalities such as a cleft palate. The right and left sides of the face may not be symmetrical. People with Apert syndrome may have a flattened nose with a low bridge. Individuals may have delayed teeth growth, dental crowding, or an open bite. They can have moderate to severe acne. If the openings between the nose and throat are narrowed or blocked or the tracheal cartilage is malformed, this could interfere with breathing and swallowing. Individuals with these blockages can have upper respiratory tract infections, sleep apnea, and malnutrition.
Apert syndrome has several characteristic hand and foot malformations. Affected individuals can have short fingers and broad thumbs and great toes that deviate outward. They may also have partial to complete fusion (syndactyly) of certain fingers and toes. Many affected people have a complete fusion of the bones of the second to the fourth fingers, and one single, continuous nail (“mitten-like” syndactyly). However, other fusions can also happen. Finger joints tend to become stiff by about four years of age. In the feet, syndactyly also typically involves the second, third, and fourth toes. The toenails may be partially continuous or separate. Generally, upper limbs are more severely affected by Apert syndrome than the lower limbs.
Apert syndrome can affect other organ systems as well:
- Skeletal
- Decrease in the rate of growth leading to short stature, despite normal birth weight and birth length
- Fusion of vertebrae of the neck
- Fusion of the two arm bones
- Fusion of the wrist bones
- Neurologic
- Varying degrees of developmental delay
- Mild to moderate intellectual disability: IQ seems to depend on factors including the age of skull decompression surgery and the presence of additional brain anomalies
- Absence of corpus callosum, the fibrous tissue that joins the cerebral hemispheres of the brain
- Failure to form the membranes that typically separate cavities of the brain
- Enlarged brain cavity
- Malformations of the parts of the brain that deal with the autonomous nervous system (ANS). ANS controls automatic body functions like breathing or heart rate
- Ears
- Hearing loss
- Chronic ear infections.
- Heart (cardiac)
- Hole(s) in the ventricular wall
- The overriding aorta develops when the aorta is positioned directly over a hole in the ventricular wall, instead of over the left ventricle. As a result, the aorta can contain some blood from the right ventricle. This reduces the amount of oxygen transported.
- Abdomen
- Narrower opening between the lower part of the stomach and the upper part of the small intestine
- Blockage of esophagus
- Kidneys and Genitourinary
- Anus is out of position
- Blockage of the vagina
- Failure of testicles to fall
- Enlarged kidneys due to blockage
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Craniofacial. Head shape is determined by the sutures involved and the timing of premature fusion; the majority of individuals have some degree of turribrachycephaly. Midface retrusion is moderate to severe, with a greater degree of vertical impaction of the midface than most individuals with Crouzon syndrome [rx]. Additional common features include ocular anomalies (e.g., proptosis, strabismus, refractive error, anisometropia), cleft palate, dental anomalies (crowding, delayed eruption, crossbite, missing teeth), and hearing loss (80%) that is most often conductive.
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Respiratory. Multilevel airway obstruction is common, including choanal stenosis, tongue-based airway obstruction, and tracheal anomalies.
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Extremities. Findings include soft tissue and bony (“mitten glove”) syndactyly with or without polydactyly of fingers and toes often involving fusion of the second, third, and fourth digits with variable inclusion of the first and fifth digits; synonychia (a single nail for the second, third, and fourth digits) more commonly involving the upper extremities; synostosis of the radius and humerus in some individuals; and occasional rhizomelia [rx].
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Neurologic. Variable developmental delay and/or intellectual disability (50%) is possibly related to the timing of craniofacial surgery [rx]; ventriculomegaly is common, progressive hydrocephalus is less common (2%); structural brain malformations (e.g., Chiari I malformation, absent septum pellucidum, agenesis of the corpus callosum) have been reported.
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Integument. Hyperhidrosis, acneiform lesions, and nail dystrophy have been reported [rx].
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Other
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Fused cervical and/or thoracic vertebrae (68%), usually C5-C6
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Cardiac anomalies (10%) (e.g., ventricular septal defect, overriding aorta)
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Ovarian dysgerminoma (1 individual) [rx]. A single instance of low-grade papillary urothelial carcinoma was reported. It is unclear if these tumors are related to Apert syndrome.
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Diagnosis
A diagnosis of Apert syndrome is most often made at birth or during infancy. An individual is diagnosed through clinical evaluation and a variety of specialized tests. Physical features like facial anomalies or syndactyly would be identified. Skeletal abnormalities and congenital heart defects may be detected using imaging, like a computed tomography (CT) scan or an MRI. Hearing impairment may be detected during a newborn screening hearing test. Individuals may also have testing for mutations in the FGFR2 gene, which can provide a genetic diagnosis of Apert syndrome.
Apert syndrome should be suspected in individuals with the following clinical features.
Head
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Multistore craniosynostosis, most commonly involving bilateral coronal sutures with variable involvement of the remaining cranial sutures
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Midface retrusion with a greater degree of vertical impaction than Crouzon syndrome
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Prominent eyes with downslanting palpebral fissures
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Relative prognathism with malocclusion
Airway. Multilevel airway obstruction
Limbs/skeleton
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Syndactyly of the hands, including soft tissue and bone
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The second, third, and fourth fingers are always included in the fusion, while the thumb and fifth digit may or may not be included.
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Synonychia (fusion of ≥2 nails) of the second through fourth fingers is common. The appearance is sometimes referred to as a “mitten hand.”
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Syndactyly of the feet, which may or may not include the great toe
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The 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.
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.
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Perform sequence analysis first.
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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 is most likely to identify the genetic cause of the condition while limiting the 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.
In some instances, features of Apert syndrome may be detected before birth. This would be done through prenatal 2D or 3D ultrasound or magnetic resonance imaging (MRI). An ultrasound is a non-invasive procedure that can see an image of the fetus. This can detect differences in skull shape, facial anomalies, and syndactyly. Fetal MRI can provide greater detail of the fetal brain than ultrasound.
Treatment
The treatment of Apert syndrome varies based on which symptoms are seen in the individual. Such treatment may require care by a team of healthcare providers including pediatricians and surgeons. Specialists may include hearing specialists, neurosurgeons, physicians who specialize in disorders of the skeleton, joints, and muscles (orthopedists), and physicians who specialize in disorders of the ears, nose, and throat (otolaryngologists), and physicians who specialize in heart abnormalities (cardiologists).
Specific therapies for Apert syndrome are symptomatic and supportive. Craniosynostosis and hydrocephalus may result in abnormally increased pressure within the skull and on the brain. In such cases, early surgery (within 2 to 4 months after birth) may be advised to correct craniosynostosis. For those with hydrocephalus, surgery may also involve inserting a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain. The CSF would be drained into another part of the body where it can be absorbed.
Corrective and reconstructive surgery may be recommended to help correct craniofacial malformations. Surgery may also be able to help correct polydactyly and syndactyly, and other skeletal defects or physical abnormalities. For those with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may be necessary. For some individuals with hearing impairment, hearing aids may be beneficial.
Early intervention may be important to ensure that children with Apert syndrome reach their full potential. Special services like physical therapy, occupational therapy, and special education may be beneficial.
Genetic counseling is recommended for affected individuals and their families. A genetic counselor can explain the causes of Apert syndrome. They can also discuss the chances of having additional children with Apert syndrome. Psychosocial support for the entire family is essential as well.
References
