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Apert Syndrome
Introduction
Apert syndrome, also known as acrocephalosyndactyly type I, is a genetically inherited syndrome characterized by multisuture craniosynostosis, midface retrusion, and syndactyly. The syndrome was first described in 1906 by French physician Eugene Apert, who described 9 people with similar facial and extremity characteristics.[1]
The condition is caused by mutations in the FGFR2 gene, which encodes a protein that regulates cell and bone growth, crucial for normal skull, face, and limb formation. The genetic anomalies lead to abnormal bone development. Advanced paternal age is a significant risk factor for de novo mutations in Apert syndrome. Diagnosis is based on clinical features, supported by genetic testing for FGFR2 mutations. Treatment often involves surgical correction of craniosynostosis and syndactyly, alongside supportive therapies. With early intervention, affected individuals can have a near-normal life expectancy, though they may experience developmental and neurological challenges.
Etiology
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Etiology
Apert syndrome is inherited in an autosomal dominant fashion, though most cases result from de novo mutations. The condition is commonly caused by a gain-of-function missense mutation in exon IIIa of the FGFR2 gene on chromosome 10q, leading to amino acid substitutions Ser252Trp or Pro253Arg.[2][3]. Phenotypic differences may arise depending on the mutation. Patients with the Pro253Arg mutation often have more severe syndactyly, while the Ser252Trp mutation is associated with cleft palate.[4][5]
Epidemiology
Apert syndrome is a rare disease, estimated to occur in 1 in 65,000 to 200,000 births, depending on the study cited.[6] Male and female infants are equally affected. The incidence of the disease significantly increases with paternal age and is thought to provide a selective advantage within male spermatogonial cells.[7] The syndrome exhibits complete penetrance with variable expressivity, resulting in a spectrum of clinical presentations, from subtle findings to severe deformities, even within the same family. The condition has been reported to occur 2.9 times more frequently in the Asian population compared to Hispanics.[8]
Pathophysiology
Two-thirds of cases of Apert syndrome are due to a specific cytosine-to-guanine mutation at position 755 of the FGFR2 gene, resulting in a serine-to-tryptophan amino acid change on the paternally derived allele.[9] Several mouse models have been developed that provide insight into the underlying pathophysiology of these mutations. In mice, the FGFR2 receptor loses its specificity and can bind other fibroblast growth factors, suppressing apoptosis of osteoblasts, which leads to syndactyly and craniosynostosis. The exact underlying mechanism remains unclear but is likely linked to a specific fibroblast growth factor.[10][11]
History and Physical
The family history of patients suspected of having Apert syndrome is crucial to evaluation due to its autosomal dominant inheritance. While a lack of family history does not rule out the diagnosis because of the possibility of de novo mutations, a positive family history significantly increases its likelihood.
Patients with Apert syndrome typically present with craniosynostosis, midface hypoplasia, and symmetric syndactyly of the hands and feet (see Image. Cranioacial and Oral Findings in Apert Syndrome). The craniosynostosis is more severe compared to that seen in Crouzon syndrome, and the presence of syndactyly helps confirm the diagnosis. However, features such as hypertelorism (wide-set eyes), proptosis (bulging eyes), and down-slanting palpebral fissures are common in several craniosynostosis syndromes and cannot differentiate these conditions. Most patients also have a large anterior fontanelle displaced anteriorly. The midface is usually underdeveloped and retruded, leading to the underdevelopment of shallow orbits and down-slanting palpebral fissures.[12]
In addition to down-slanting palpebral fissures, patients with Apert syndrome are at risk for other ocular abnormalities, including strabismus, refractive errors, and anisometropia.[13][14] Hearing loss occurs in up to 80% of affected individuals, typically the conductive type, due to otitis media with effusion, ossicular abnormalities, and stenosis of the external auditory canal.[15][16][17]
Many patients with Apert syndrome experience multilevel airway obstruction due to narrow nasal passages, tongue-based airway obstruction, or tracheal anomalies.[18] Obstructive sleep apnea is also common, affecting roughly 30% of patients, and can persist despite midface advancement.[19][20]
Hand abnormalities are characterized by a short, radially deviated thumb, complex syndactyly of the middle 3 digits, syndactyly of the 4th webspace, and symphalangism or the congenital stiffness of the fingers due to failure of bone separation during fetal growth. Three specific subtypes of hand findings in Apert syndrome are identified based on hand shape: spade (side-to-side fusion with a flat palm), mitten (fusion of fingers resulting in a concave palm), and rosebud (tight fusion of all digits).[21] The fusion of the fingernails of the 2nd to 4th digits to form a single nail is referred to as "synonychia" (see Image. Hand Findings in Apert Syndrome).
Other craniofacial deformities in Apert syndrome include acrocephaly (cone-shaped calvarium), proptosis, prominent forehead, hypertelorism, down-slanting palpebral fissures, and a flattened nasal bridge. Oral findings include dental crowding, high-arched palate, narrow palate, and pseudo-clefts. Skeletal abnormalities may include cervical vertebrae fusions, often involving C5-C6, scoliosis, atlantoaxial subluxation, or C1 spina bifida occulta.[22]
Neurological involvement in Apert syndrome typically manifests as nonprogressive ventriculomegaly, corpus callosum abnormalities, jugular foramen stenosis, absent septum pellucidum, Chiari malformations, posterior fossa arachnoid cysts, and limbic defects.[23][24][25] While most patients with Apert syndrome have normal cognition or mild intellectual impairment, some have been reported to experience moderate-to-severe disability.[26][27]
Visceral anomalies associated with Apert syndrome include cardiovascular defects such as ventricular septal defects and overriding aortas, intestinal malrotation, distal esophagus stenosis, and pyloric stenosis. Genitourinary anomalies may include hydronephrosis or cryptorchidism.[28]
Evaluation
The evaluation of Apert syndrome in a patient with a known family history is primarily clinical, as the characteristic physical findings confirm the diagnosis. Additional testing is required in cases where the clinical presentation is unclear and no family history is present. Brain magnetic resonance imaging (MRI) and computed tomography (CT) help detect craniosynostosis or other skeletal abnormalities, including perisutural sclerosis, reduced serration, bony bridging, and the absence of sutures. The coronal sutures are most commonly affected, with variable involvement of the sagittal and lambdoid sutures. These imaging techniques also detect other abnormalities, such as increased intracranial pressure (ICP) and Chiari malformations.
ICP monitoring may be necessary due to the risk of intracranial hypertension, especially in syndromic craniosynostosis.[29][30] The ICP rises due to hydrocephalus, osseous changes in the skull base affecting venous outflow, and midface hypoplasia, leading to sleep apnea. Screening for intracranial hypertension begins with an ophthalmological assessment to check for papilledema. Optical coherence tomography is also effective for detecting ICP elevation.[31][32] ICP monitoring is indicated if these methods are inconclusive.[33][34] Polysomnography should be obtained to evaluate for sleep apnea in patients with suspected sleep-disordered breathing.[35][36]
Genetic and molecular testing can be pursued, as with other craniosynostosis syndromes where the diagnosis is unclear or features are atypical. The underlying mechanism of many craniosynostosis syndromes involves FGFR mutations and abnormal signaling. Prenatal genetic testing, MRI, and ultrasound can help confirm the diagnosis before birth.[37][38] Although amniocentesis and chorionic villus sampling are options, safer imaging techniques are likely to replace these higher-risk procedures, except in challenging cases.
As mentioned, history, physical examination, and imaging findings are used to confirm the specific craniosynostosis diagnosis. However, distinguishing between syndromes, including Pfeiffer, Apert, Saethre Chotzen, Carpenter, and Jackson Weiss, can be challenging due to significant overlap.
Treatment / Management
Like other craniosynostoses, management requires a team-based approach with multiple subspecialists, including pediatricians, neurosurgeons, plastic surgeons, craniofacial surgeons, ophthalmologists, and dentists. Surgery is necessary to prevent complications related to intracranial hypertension and protect the developing brain.
Several surgical approaches for craniosynostosis correction have been described in the literature, including fronto-orbital advancements, posterior vault distractions, and endoscopic strip craniectomies.[39][40][41][42][43][44][45] Surgeries for midface retrusion correction include Le Fort and monobloc distractions.[46][47][48][49][50] A detailed description of the surgical management of syndromic craniosynostosis can be found in the updated guidelines on the treatment and management of craniosynostosis.[51]
If hydrocephalus is present, treatment may involve placing a shunt or endoscopic 3rd ventriculostomy with or without choroid plexus coagulation.[52] When placing a ventriculoperitoneal shunt, the need for future open vault reconstructions must be considered. Placing a frontal shunt may expose the shunt hardware during vault reconstruction. A parieto-occipital shunt may be a better option. If concerns about future operations arise, an endoscopic 3rd ventriculostomy may be a reasonable first approach.
De Jong and colleagues published a treatment protocol for patients with syndromic craniosynostosis, recommending fundoscopy and polysomnography annually until 6 years of age, as well as hearing evaluations until 4 years of age. Pure tone audiometry is indicated if hearing evaluations are abnormal.
Differential Diagnosis
Apert syndrome shares overlapping features with several craniosynostosis syndromes. Consideration of these conditions, including the disorders below, is critical to avoid misdiagnosis and ensure targeted treatment.
- Achondroplasia
- Antley Bixler syndrome
- Beare Stevenson syndrome
- Crouzon syndrome
- Cutis gyrata
- Pfeiffer syndrome
- Thanatophoric dysplasia
- Muenke syndrome
- Jackson Weiss syndrome
- Saethre Chotzen syndrome
Timely and accurate diagnosis can significantly impact patient outcomes and guide the management of associated complications. Recognizing the differential diagnoses of Apert syndrome ensures that clinicians provide the most appropriate treatment plan.
Prognosis
As with many congenital conditions, early prenatal and perinatal diagnosis is crucial for counseling families regarding prognosis. Factors influencing mental development include the age at the first surgery, associated brain malformations, and family environment quality. One study found that 32% of patients had an intelligence quotient of at least 70, with over 50% having an intelligence quotient greater than 70 if surgery occurred before age 1 year.[53] Long-term follow-up studies indicate that patients often have positive psychosocial outcomes.[54][55]
Continued follow-up is vital to minimize complications related to craniosynostosis, such as strabismus, sleep apnea, and intracranial hypertension. These issues do not always fully resolve after surgery for individuals with cranial and facial defects. In a retrospective Australian study, 54% develop vision loss in at least 1 eye due to amblyopia after craniofacial surgery for Apert syndrome. Fortunately, optic atrophy was found in only 5% of cases, likely due to the widespread use of early craniofacial surgery for craniosynostosis syndromes.[56] Strabismus is also highly prevalent, developing in 2/3 of patients.[57] Severe-to-profound hearing loss is also more common in syndromic craniosynostoses than in nonsyndromic variants.[58] A team-based approach involving multiple subspecialists is essential for monitoring vision and life-threatening complications.
Complications
The main complications of Apert syndrome include increased ICP, which can lead to papilledema and cognitive impairment, as well as exposure keratopathy and corneal scarring. Respiratory issues, particularly due to sleep apnea, are common, and spinal cord injuries or neurologic deficits may occur in patients with cervical spine anomalies. Additionally, aspiration pneumonia and chronic lung disease are concerns that may develop. Managing these complications requires careful monitoring and an interprofessional approach to address the various health challenges associated with the syndrome.
Consultations
Given the complexity of Apert syndrome, patients require care from a variety of specialties to address the multifaceted challenges of the condition. Consultations must include the following:
- Neurosurgery
- Ophthalmology (pediatric, oculoplastic)
- Plastic surgery
- Maxillofacial surgery
- Otorhinolaryngology
- Audiology
- Dentistry
- Orthodontics
- Geneticist
An interprofessional approach is essential for providing comprehensive care to patients with Apert syndrome. Such collaboration improves patient outcomes and minimizes long-term complications.
Deterrence and Patient Education
Apert syndrome follows an autosomal dominant inheritance pattern, with advanced paternal age associated with de novo occurrences. The chance of passing the genetic trait to each child is 50%. If a pathogenic variant is present in the family, prenatal testing should be offered for pregnancies at increased risk.
Enhancing Healthcare Team Outcomes
Like other craniosynostoses, the management of Apert syndrome involves a team-based approach with multiple subspecialists, including pediatricians, neurosurgeons, plastic surgeons, craniofacial surgeons, ophthalmologists, and dentists. Surgical intervention is essential to prevent complete closure of the coronal suture and safeguard brain development. Collaboration among subspecialists is also essential to address complications such as strabismus, sleep apnea, and intracranial hypertension. An interprofessional team plays a critical role in monitoring for vision and life-threatening complications, making informed surgical decisions, and ensuring optimal long-term outcomes.
Media
(Click Image to Enlarge)
Craniofacial and Oral Findings in Apert Syndrome. The image depicts hypertelorism, vertical excess of the lower one-third of the face, a trapezoidal upper lip, and difficulty achieving forced lip closure. Intraoral changes are delayed dentition, crowding, Angle Class III malocclusion with dental compensation through lower incisor retrusion, and a circular open bite with a unilateral crossbite.
Filip, Public Domain, via Wikimedia Commons
(Click Image to Enlarge)
Hand Findings in Apert Syndrome. This image shows the characteristic fusion of the fingers (syndactyly) and nails (synonychia) commonly seen in individuals with Apert syndrome. These findings reflect the underlying genetic disruption in limb development associated with the condition.
Gzzz, Public Domain, via Wikimedia Commons
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