Apert Syndrome (acrocephalosyndactyly, type 1)

Apert [syndrome synonym: acrocephalosyndactyly, type 1, ACS1 or ACSI]

Apert syndrome (AS) is an uncommon autosomal dominant disease affecting about 1 in 65,000 individuals characterized by craniosynostosis, midface hypoplasia, and symmetric syndactyly of the hands and feet. The majority of cases are caused by de-novo activating mutations of the fibroblast growth factor receptor 2 (FGFR2) gene.

• What you should be alert for in the history

AS accounts for approximately 5% of cases of craniosynostosis and should be considered if a child presents with non-isolated craniosynostosis. Most children in the United States are detected prenatally or at birth, but children may present later with a history of headaches and vomiting secondary to increased intracranial pressure. Children may have a history of upper airway compromise evidenced by stridor and sleep apnea due to reduced nasopharyngeal and oropharyngeal space. Eye pain (due to corneal abrasions) and visual disturbances resulting from exorbitism may also be presenting symptoms.

Family history is usually non-contributory, as most cases of AS are caused by sporadic mutations in the male germline. The rate of FGFR2 mutations increases with age, hence children of fathers of advanced paternal age are at a greater risk of developing AS. Although AS is inherited in an autosomal dominant fashion, the rarity of familial cases is likely related to decreased reproductive potential in patients with AS.

• Characteristic findings on physical examination

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Calvarium: Premature fusion of multiple sutures is seen, with the coronal suture the most commonly involved suture. Premature coronal suture fusion results in decreased growth in the ventral-dorsal direction and compensatory growth in the medial-lateral and superior-inferior directions leading to acrocephaly and brachycephaly. During infancy, the skull has a widely gaping midline defect in the calvarium extending from the glabella to the posterior fontanelle. The midline defect leads to large, persistent anterior and posterior fontanelles until the patient is 3-4 years old, after which the defects close.

Facial features: Affected individuals have an asymmetric face with a prominent and wide forehead, ocular hypertelorism and proptosis, down-slanting palpebral fissures, a break in eyebrow continuity, low-set ears, depressed nasal bridge and a wide bulbous nose. (Figure 1)

Figure 1.

Oral and nasopharyngeal abnormalities: Underdevelopment of the maxillary bone leads to reduced nasopharyngeal dimensions. Cleft palate or bifid uvula occurs in 75% of children with AS. Other common dental findings include a high-arched palate, malocclusion, shovel-shaped incisors, and delayed or ectopic teeth eruptions.

Otologic: 80% of children with AS have conductive hearing loss which is caused most commonly by recurrent otitis media with effusion or middle ear anomalies.

Hand and foot: Upper extremities are generally more severely affected than lower extremities. Syndactyly of hands and feet most commonly presents with symmetric partial to complete fusion of the second, third and fourth digits with a single nailbed. In more severe cases, the fifth digit can be involved. The first digit is the least commonly involved. (Figure 2)

Figure 2.

Proximal appendicular skeleton: Limited glenohumeral or elbow mobility, short humerus, genua valga, femoral head, and neck alterations are less common findings.

Spine: C5/C6 vertebral fusion is seen in 50% of patients. Alternatively, C3/C4 fusion, C1 spina bifida occulta, atlanto-axial subluxation, pectus excavatum, scoliosis, lordosis, and flattening of the chest wall may also be seen.

Intelligence: Most patients with AS have mild mental retardation (mean IQ of 75), although some children may have normal intelligence.

Visceral: Cardiovascular anomalies occur in approximately 10% of patients, most commonly evidenced by a patent ductus arteriosus, atrial septal defect, and/or a ventricular septal defect. Genitourinary (GU) defects are found in 9.6% patients, with hydronephrosis, cryptorchidism, and clitoromegaly being the most common presentations. Respiratory anomalies occur in 1.5% patients, most commonly a solid cartilaginous trachea. Gastrointestinal (GI) anomalies occur in 1.5% of patients and may include esophageal atresia, pyloric stenosis, biliary atresia, or an imperforate anus.

Skin: Hyperhidrosis with transient elevations in temperature is a very common finding. Oily skin with severe pustular acneiform lesions on the face, trunk, and arms may be seen during adolescence and thereafter. Paronychial infections occur frequently and are found more commonly on the feet than on the hands. Hyperkeratosis of the plantar surfaces of the feet is a common finding. In addition, interrupted eyebrows, hypopigmentation, excessive skin wrinkling on the forehead, and skin dimples on the knuckles, shoulders, and elbows have been reported.

• Diagnostic studies

Molecular testing

Genetic testing for FGFR2 mutations has high sensitivity (>98%) and specificity (>99 %) for AS.

Prenatal testing

AS can be diagnosed via prenatal ultrasound (US) in the late second and third trimesters. Characteristic findings include a cloverleaf anomaly, acrobrachyocephalic skull shape, ventriculomegaly, or digit anomalies. An abnormal ultrasound should be followed by further imaging with an MRI and consideration of genetic testing of amniotic fluid. Unfortunately, in the United States, routine second-trimester ultrasound screening is generally performed between 18-20 weeks which precedes marked ultrasound abnormalities. As a result, AS is generally missed on routine prenatal US performed before 21 weeks. Most recently, PCR analysis of fetal DNA extracted from maternal serum has been used to diagnose AS in a non-invasive fashion. However, this technique may not be available at many centers.

Imaging

While the precise abnormalities observed in AS are variable, imaging plays a critical role in the workup and surgical planning of its cerebral and musculoskeletal manifestations. Common findings discovered on imaging include the following:

Skull (CT or plain film): coronal suture sclerosis, brachycephaly, shallow orbits, maxillary hypoplasia, and mandibular proptosis.

Brain (MRI): prominent convolutional markings (60-70%) and ventriculomegaly (40-50%). Other findings include a narrow foramen magnum, abnormal septum pellucidum, and agenesis of the corpus callosum.

Cervical spine (CT or plain film): C5/C6 (50%) or C3/C4 fusion (27%). Others findings might include C1 spina bifida occulta or atlanto-axial subluxation.

Proximal appendicular skeleton (CT or plain film): Aplasia or ankylosis of the shoulder, elbow and hip joints.

Distal appendicular skeleton (CT or plain film): Osseous syndactyly of the 2^nd-4^th digits, ankylosis of the interphalangeal joints, and fused carpal/tarsal or metacarpal/metatarsal bones.

• Differential diagnosis

The differential diagnosis of AS includes Crouzon syndrome, Pfeiffer syndrome, Saethre-Chotzen syndrome, Carpenter syndrome and Jackson-Weiss syndrome. All of these conditions are transmitted in an autosomal dominant fashion. The constellation of symptoms can be very helpful in differentiating these syndromes. Molecular analysis may be used to confirm the diagnosis.

Crouzon syndrome is caused by mutations in the third immunoglobulin-like domain of the FGFR2 gene and demonstrates variable expressivity and incomplete penetrance. It is characterized by craniosynostosis, brachycephaly, shallow orbits, and maxillary hypoplasia. However, unlike AS, there is no extremity syndactyly.

Pfeiffer syndrome presents similarly to AS, but with a milder phenotype. It is also characterized by craniosynostosis, midface deficiency, broad thumbs, broad great toes, brachydactyly with occasional syndactyly, and hearing loss. Ankylosis of phalanges is not present in Pfeiffer syndrome. Multiple mutations in FGFR1 and FGFR2 genes have been reported in Pfeiffer syndrome.

Saethre-Chotzen syndrome is caused by mutation in the TWIST gene located on 7p21, and is characterized by coronal synostosis, a low-set hairline, facial asymmetry, ptosis of eyelids, and variable brachydactyly with partial soft tissue syndactyly. The osseous fusions observed in AS are lacking in Saethre-Chotzen syndrome.

Jackson-Weiss syndrome is clinically similar to Pfeiffer syndrome, but lacks thumb abnormalities. Craniosynostosis, midface hypoplasia and foot anomalies are characteristic of this syndrome. Most cases involve mutations in FGFR2. However, a mutation in FGFR1 gene has been found in one patient presumed to have Jackson-Weiss syndrome.

The incidence of AS is 15.5 per million live births. Asians have the highest incidence at 22.3 per million live births, while Hispanics have the lowest incidence at 7.6 per million. Males and females are affected equally.

Most cases of AS are due to sporadic mutations which exhibit a paternal age effect, hence advanced paternal age confers an increased risk of having a child with AS. If the parents are unaffected but have a child with AS, the risk to future is offspring is minimal. AS is inherited in an autosomal dominant fashion, so if either parent has the disease, their offspring have a 50% risk of inheriting the mutation. Inherited cases of AS are rare, which is likely due to reduced genetic fitness and reproduction in affected individuals.

• Etiology

AS is caused by mutations in the gene encoding the fibroblast growth factor receptor 2 (FGFR2) protein located on chromosome 10q26.

• Pathophysiology

FGFR2 mutations occur almost exclusively in the male germline and increase in frequency in aged testes. The mutations occur randomly during mitosis of spermatogonial stem cells and confer a growth advantage to mutant cells. This selective advantage leads to a clonal expansion of mutant spermatogonia and spermatozoa which can then be transmitted to offspring. This phenomenon is called selfish spermatogonial selection.

FGFR2 is widely expressed in cartilage, osteoprogenitor cells, limb mesenchyme, skin, and the brain. The receptor is composed of three extracellular immunoglobulin-like domains, a transmembrane portion, and an intracellular tyrosine kinase which work together to transmit signals from the extracellular environment to downstream intracellular pathways. Two missense mutations, Serine252Trp and Pro253Arg, are responsible for almost all cases of AS and lead to alterations in the linker region between immunoglobulin-like loop II and loop III of FGFR2.

The S252W mutation is found in approximately 2/3 of cases of AS, while the P253R mutations accounts for approximately 1/3 of cases. There is phenotypic variability among these two mutations; patients with the S252W mutation present with more severe craniofacial anomalies, while patients with the P253R mutation have more severe syndactyly. Rarely, other mutations in the FGFR2 gene have been reported including S252F, M186T, E731K, and Alu-element insertion in or near exon 9.

In vivo and in vitro studies have demonstrated that FGFR2 mutations lead to increased activity of downstream signaling pathways including the ERK1/2, AKT, PKC, and p38 pathways. These pathways are critical regulators of cell proliferation, differentiation, and apoptosis. Enhanced cell signaling leads to increased differentiation of precursor cells into osteoblasts as well as increased osteoblast activity. The increased number and activity of osteogenic cells leads to increased subperiosteal bone matrix formation and premature calvarial ossification. The occipitofrontal circumference has been shown to be a good predictor of the intracranial volume and is a reliable method of determining which children are at greatest risk of impaired skull growth.

Premature coronal suture closure in the prenatal and early infancy periods leads to restricted growth perpendicular to the suture, resulting in brachycephaly (decreased anterior-posterior dimension). There is generally an associated midline defect from the glabellar to the posterior fontanelle which allows for brain growth and cranial expansion laterally. Altered positioning of the sphenoid bone and midface leads to decreased orbital volume and its related manifestations: ocular hypertelorism, proptosis, and down-slanting palpebral fissures. Maxillary hypoplasia causes severe narrowing of the nasopharyngeal and oropharyngeal space which may lead to severe sleep apnea.

In addition to its role in osteogenesis, the FGFR2 protein has been shown to play an important role in chondrocyte development and activity. Altered endochondral ossification via FGFR2 mutations likely contributes to the limb abnormalities observed in AS.

In the skin, the FGFR2 receptor undergoes alternative splicing to form the FGFR2b variant. This receptor is critical for cell proliferation via the downstream MAPK pathway, lipogenesis and sebaceous glandular tissue differentiation via the PI3K/AKT pathway, and regulating inflammation via the protein kinase C pathway. Hence, FGFR2 mutations lead to alterations in downstream effector pathways which increase sebum production and follicular keratinization, ultimately contributing to the development of the severe acneiform lesions associated with AS. Many of the common anti-acne agents have been shown to function partially by attenuating FGFR2 signaling. Anti-androgens suppress FGF-ligand expression, benzoyl peroxide induces FGFR2 degradation, tetracycline inhibits FGFR2b downstream matrix metalloproteinases, and retinoids inhibit FGFR2 pathways at multiple levels.

The etiology of the cognitive deficits commonly found in AS are likely multifactorial. The FGF receptor interacts with the L1 cell adhesion molecule (LCAM1) which is important in the development of cerebral white matter. Hence, the FGF receptor mutations found in AS may lead to primary white matter deficits. Additionally, uncorrected craniosynostosis may impair normal brain expansion. Increased intracranial pressure may also lead to neural destruction and impairment in brain development; early surgical correction has been shown to improve cognitive functioning. Finally, hearing and visual loss may impair normal neurocognitive development.

Although osseous anomalies constitute the most defining features of AS, involvement of other organ systems is important to recognize and treat to minimize patient morbidity and mortality.

Central nervous system lesions include the structural and intellectual anomalies mentioned previously. MRI is a useful tool to assess for anatomic lesions in the brain. Children may also benefit from audiology and IQ testing. Early intervention is critical to enhance the functional capabilities of patients.

Cardiovascular anomalies are present in 10% of patients, so an EKG and echocardiogram should be performed during initial evaluation. Patients with abnormalities should be followed by a cardiologist and referred to a cardiothoracic surgeon if congenital heart defects needing repair are found.

Respiratory anomalies are less common, but if present, pose a major risk for early morbidity and mortality. If sleep apnea is suspected, the patient should undergo polysomnography to confirm the diagnosis. Mechanical ventilation, tracheotomy, or surgical airway correction may be warranted.

GU lesions are also less common, but may present as hydronephrosis, cryptorchidism, and clitoromegaly. If GU abnormalities are suspected, a renal ultrasound should be performed. Patients with abnormalities should be referred to urology or gynecology as appropriate.

GI lesions including esophageal atresia, pyloric stenosis, biliary atresia, and imperforate or malpositioned anus, are most likely to present with the corresponding symptoms. As these conditions are rare and generally symptomatic, screening is generally unnecessary.

Severe pustular facial and truncal acne extending to arms and forearms is common. Most patients do not respond to first-line acne therapies and should be managed by dermatology.

Treatment of patients with AS requires a multidisciplinary approach and the collaboration of multiple specialists. While some of the syndromic manifestations may be managed medically, AS generally requires numerous surgeries which are performed in multiple phases throughout a patient’s life.

• Medical management

Acneiform skin lesions are generally resistant to first-line acne agents including topical agents and systemic antibiotics and should be treated with systemic isotretinoin. Given the severe side effects of isotretinoin (teratogenicity, hepatic dysfunction, dyslipidemia, visual changes, and pseudotumor cerebri), the risk/benefit ratio should be carefully weighed before initiating treatment. All patients should be followed up closely by a dermatologist. A prolonged course and repeated treatments may be necessary.

Mild corneal exposure may be managed with lubricants, eyelid taping, or adhesive cups. If severe, respiratory compromise may require oxygen therapy or mechanical ventilation. Sleep apnea may be treated with continuous positive airway pressure (CPAP). Newborns may require nasogastric or gastrostomy tube placement if respiratory difficulty impairs proper feeding.

Children with AS undergo significant psychosocial stress as they experience multiple surgeries, physical limitations, and the social stress of a disfigured appearance. Psychiatric evaluation and follow-up, child life services, occupational therapy, and physical therapy are often needed to maximize the emotional and physical health of the child. Families should be offered genetic counseling if there are questions about the risk of disease development in future offspring.

• Surgical management

Children with AS need careful airway management when undergoing general anesthesia as they have high rates of upper airway structural anomalies, increased secretions, and a hyper-reactive airway. Whenever possible, regional anesthesia should be utilized to reduce the amount of general anesthesia required. An emergency tracheostomy kit should be readily accessible whenever a patient with AS is sedated.

Removal of synostotic sutures should be performed in early infancy to accommodate brain growth, most of which occurs in the first year of life. Fronto-orbital advancement is usually performed when the patient is 6-12 months old. If performed too early, the bone may be too fragile; if performed too late, the bone may not be as malleable. Increased intracranial pressure may require a ventriculoperitoneal shunt to relieve papilledema and improve cognitive functioning. Additional cranial vault remodeling may be needed in early childhood to treat persistent increased cranial pressure or progressive deformities of craniofacial structures. Midface advancement and orthognathic surgery may be performed in later childhood or adolescence to improve airway, exorbitism, malocclusion, and dental esthetics. As the exact abnormalities seen in patients with AS are varied, surgical planning must be individualized.

Refractory obstructive sleep apnea may be managed surgically via tonsillectomy and adenoidectomy, midface advancement, or nasal airway dilation. If present, surgical management of elevated intracranial pressure or chiari malformation decompression improves central sleep apnea.

Surgical intervention of the hands and feet can be performed in two phases. The early phase involves two-stage syndactyly releases of all 10 fingers and toes. The first stage of early phase is typically performed at 9-12 months of age, and the second stage is generally performed 3 months later. The later phase is often performed between the ages of 9-12 years of age. The goal of the second phase is to correct fusion of the proximal and middle phalanges and angle the digits into a functional position.

What is the Evidence?

Katzen, JT, McCarthy, JG.. “Syndromes involving craniosynostosis and midface hypoplasia”. Otolaryngol Clin N Am.. vol. 33. 2000. pp. 1257-84. (This paper describes clinical features and genetics of different syndromes involving craniosynostosis.)

Kreibrog, S, Cohen, MM. “The oral manifestations of Apert syndrome”. J Craniofac Genet Dev Biol.. vol. 12. 1992. pp. 41-8.

Cohen, MM, Kreiborg, S.. “Skeletal abnormalities in Apert syndrome”. Am J Med Genet.. vol. 47. 1993. pp. 624-32.

Cohen, MM, Kreiborg, S.. “The central nervous system in the Apert syndrome”. Am J Med Genet.. vol. 35. 1990. pp. 36-45.

Cohen, MM, Kreiborg, S.. “Visceral anomalies in the Apert syndrome”. Am J Med Genet.. vol. 45. 1993. pp. 758-60.

Cohen, MM, Kreiborg, S.. “Cutaneous manifestations of Apert syndrome”. Am J Med Genet.. vol. 58. 1995. pp. 94-6. (The above five papers are the original papers that describe different aspects of clinical manifestations of Apert syndrome.)

Wilkie, AOM, Slaney, SF, Oldridge, M, Poole, MD. “Apert syndrome results from localized mutations of and is allelic with Crouzon syndrome”. Nature Genet.. vol. 9. 1995. pp. 165-72. (This is the first paper that demonstrated that FGFR2 mutations are responsible for the clinical constellation of AS.)

Melnic, BC, Schmitz, G, Zouboulis, CC.. “Anti-acne agents attenuate signal transduction in acne”. J Invest Dermatol.. vol. 129. 2009. pp. 1868-77. (This paper describes how many anti-acne agents function by decreasing FGFR2 signaling.)

Benjamin, LT, Trowers, AB, Schachner, LA.. “Successful acne management in Apert syndrome twins”. Pediatr Dermatol.. vol. 22. 2005. pp. 561-5. (This is a case report that demonstrates successful treatment of acne in Apert patients with isotretinoin.)

David, AL, Turnbull, C, Scott, R, Freeman, J. “Diagnosis of Apert syndrome in the second-trimester using 2D and 3D ultrasound”. Prenatal Diagn.. vol. 27. 2007. pp. 629-32.

Rubio, EI, Blask, A, Bulas, DI.. “Ultrasound and MR imaging findings in prenatal diagnosis of craniosynostosis syndromes”. Pediatr Radiol.. vol. 46. 2016. May. pp. 709-18.

Au, PK, Kwok, YK, Leung, KY, Tang, LY. “Detection of the S252W mutation in fibroblast growth factor receptor 2 () in fetal DNA from maternal plasma in a pregnancy affected by Apert syndrome”. Prenat Diagn.. vol. 31. 2011 Feb. pp. 218-20. (These papers discuss the prenatal diagnosis of AS.)

Agochukwu, NB, Solomon, BD, Muenke, M.. “Hearing loss in syndromic craniosynostoses: otologic manifestations and clinical findings”. Int J Pediatr Otorhinolaryngol. vol. 78. 2014 Dec. pp. 2037-47. (This paper discusses hearing loss in AS.)

Liu, C, Cui, Y, Luan, J, Zhou, X. “The molecular and cellular basis of Apert syndrome”. Intractable Rare Dis Res.. vol. 2. 2013 Nov. pp. 115-22. (This paper discusses the pathophysiology of how FGFR2 mutations lead to the cellular abnormalities found in AS.)

Xie, C, De, S, Selby, A.. “Management of the Airway in Apert Syndrome”. J Craniofac Surg.. vol. 27. 2016 Jan. pp. 137-41. (This paper discusses the surgical management of airway abnormalities in AS.)

Maliepaard, M, Mathijssen, IM, Oosterlaan, J, Okkerse, JM.. “Intellectual, behavioral, and emotional functioning in children with syndromic craniosynostosis”. Pediatrics. vol. 133. 2014 Jun. pp. e1608-15.

Fernandes, MB, Maximino, LP, Perosa, GB, Abramides, DV. “Apert and Crouzon syndromes-Cognitive development, brain abnormalities, and molecular aspects”. Am J Med Genet A.. vol. 170. 2016 Jun. pp. 1532-7. (These papers discuss the cognitive manifestations of patients with AS.)

Rijken, BF, den Ottelander, BK, van Veelen, ML, Lequin, MH. “The occipitofrontal circumference: reliable prediction of the intracranial volume in children with syndromic and complex craniosynostosis”. Neurosurg Focus.. vol. 38. 2015 May. pp. E9(This paper discusses the correlation between cranial circumference and intracranial volume.)

Breik, O, Mahindu, A, Moore, MH, Molloy, CJ. “Central nervous system and cervical spine abnormalities in Apert syndrome”. Childs Nerv Syst.. vol. 32. 2016 May. pp. 833-8. (This paper discusses the imaging findings of AS.)

Goriely, A, Wilkie, AO.. “Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease”. Am J Hum Genet.. vol. 90. 2012 Feb 10. pp. 175-200.

Maher, GJ, Goriely, A, Wilkie, AO.. “Cellular evidence for selfish spermatogonial selection in aged human testes”. Andrology. vol. 2. 2014 May. pp. 304-14. (These two papers discuss the evidence for and the mechanism of the paternal age effect in AS.)

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