Apert Syndrome: Symptoms, Types, Causes and Treatment

Apert syndrome is a rare but impactful condition that affects children from birth, altering the shape of the skull, face, hands, and feet. Caused by specific genetic mutations, it presents with a recognizable set of features but can vary widely in severity and associated complications. Understanding its symptoms, types, causes, and evolving treatment options is crucial not only for healthcare professionals but also for affected families navigating this complex diagnosis. This article provides a comprehensive, evidence-based overview of Apert syndrome based on current research.

Symptoms of Apert Syndrome

Apert syndrome manifests through a characteristic spectrum of physical and sometimes neurological features. While every individual is unique, certain hallmark symptoms are consistently observed and form the clinical basis for diagnosis. Early recognition of these signs is essential for timely intervention and optimal outcomes.

Symptom	Description	Frequency/Severity	Source(s)
Craniosynostosis	Premature fusion of skull bones	Universal, severe	1 5 6
Syndactyly	Fusion of fingers and toes	Universal, severe	1 4 6 12
Midfacial hypoplasia	Underdeveloped midface	Common, variable	1 6
CNS anomalies	Brain malformations, cognitive delay	Frequent, variable	3 5 13
Dental anomalies	Crowding, double teeth line	Common	1 6
Hearing loss	Conductive hearing loss	Sometimes observed	6
Ocular features	Proptosis, hypertelorism, strabismus	Common	1 6

Table 1: Key Symptoms

Overview of Physical and Neurological Features

Apert syndrome is instantly recognizable by the combination of craniosynostosis (premature fusion of skull sutures) and severe syndactyly (fusion) of the hands and feet. Children typically present with:

• Acrocephaly and Brachycephaly: The skull appears tall and shortened front-to-back due to early suture closure, often with a prominent forehead and flattened back of the head 1 6.
• Midfacial Hypoplasia: The midface (upper jaw and cheekbones) is underdeveloped, resulting in a sunken facial appearance, beaked nose, and sometimes a high-arched palate or cleft palate 1 6 8.
• Dental and Oral Anomalies: Crowded teeth, double rows of teeth, high-arched or cleft palate, and dental malocclusion are common 1 6.
• Hand and Foot Syndactyly: Complete fusion of fingers and toes, often with fused, thinned nails; the severity may vary but typically involves all digits 4 6 12.

Neurological and Sensory Symptoms

• CNS Malformations: MRI and other imaging may reveal brain anomalies such as hypoplasia of the corpus callosum, septum pellucidum, ventricular enlargement, and Chiari malformations. These may contribute to cognitive delays or intellectual disability in some cases 3 5 13.
• Hearing Loss: Conductive hearing loss is sometimes observed, likely due to craniofacial and middle ear anomalies 6.
• Ocular Abnormalities: Wide-set eyes (hypertelorism), proptosis (bulging eyes), and strabismus (misaligned eyes) are frequent, resulting from abnormal skull and orbital development 1 6.

Hand Function and Mobility

• Functional Impact: Despite surgical separation, hand function in Apert syndrome remains lower than in unaffected peers, though type of syndactyly does not significantly affect outcomes 4.
• Mobility Impairment: Complete syndactyly and restricted shoulder movement can limit daily activities and independence 6.

Psychological and Social Aspects

• Psychosocial Integration: With multidisciplinary care and reconstructive surgery, many individuals achieve good integration into mainstream education and community life, highlighting the importance of early and ongoing support 14.

Types of Apert Syndrome

While all cases share core features, Apert syndrome can be further classified based on patterns of cranial suture fusion and hand/foot involvement. This classification helps guide surgical planning and anticipate associated complications.

Type	Cranial Suture Pattern	Key Features	Source(s)
Class I	Bilateral coronal synostosis	Most common, normal cranial base	2 3
Class II	Pansynostosis	Flatter cranial base, more severe	2
Class III	Combination/perpendicular fusion	Kyphotic cranial base, mixed fusion	2
Hand Types	Type I, II, III (Upton)	Varying severity of syndactyly	3 4 12

Table 2: Types of Apert Syndrome

Cranial Synostosis-Based Classification

Researchers have identified three main cranial suture fusion patterns in Apert syndrome 2:

• Class I: Bilateral Coronal Synostosis

  • Most prevalent (55%)
  • Both coronal sutures fuse prematurely, leading to classic skull shape
  • Cranial base angulation typically remains normal

• Class II: Pansynostosis

  • All major vault sutures fuse
  • Results in a flatter cranial base and more restricted skull volume
  • May increase risk of intracranial hypertension and airway compromise

• Class III: Perpendicular Combination Synostosis

  • Involves mixed patterns, such as unilateral coronal with metopic or lambdoid suture fusion
  • Causes complex cranial base angulation and facial asymmetry

These subtypes can correlate with differences in airway compromise and surgical needs 2.

Hand and Foot Syndactyly Types

Hand involvement is classified into three types (Upton classification), influencing surgical strategy 3 4 12:

• Type I: Spade-like hand, all digits fused with single broad nail
• Type II: Thumb separated, index-to-little fingers fused
• Type III: Most severe, all fingers fused into a single mass

Studies show that, after surgical separation, hand function is generally similar across types, but remains below that of unaffected individuals 4.

CNS and Associated Variability

• Central Nervous System Anomalies: Approximately 29% of patients may develop Chiari malformations, and others may have anomalies of corpus callosum or septum pellucidum, with no clear link to cranial type or genotype 3 5 13.
• Other Features: Variation exists in the presence of cleft palate, hearing loss, and degree of intellectual disability 3 8.

Causes of Apert Syndrome

Apert syndrome is rooted in highly specific genetic mutations. Understanding these causes sheds light not only on the origins of the condition but also on why its features are so distinct and consistent.

Cause	Mechanism/Mutation	Impact on Development	Source(s)
FGFR2 mutations	S252W or P253R missense	Disrupts skull/limb growth	6 7 8 9 10 11
Autosomal dominant	Inherited or de novo	50% transmission risk	6 7
Loss of ligand specificity	FGFR2 activation by abnormal ligands	Ectopic signaling, severe phenotypes	10 11
Rare Alu insertions	Exon 9 FGFR2, splicing defect	Severe limb abnormalities	11

Table 3: Causes of Apert Syndrome

Genetic Basis

• FGFR2 Gene Mutations: Apert syndrome is almost universally caused by a mutation in the fibroblast growth factor receptor 2 (FGFR2) gene on chromosome 10 6 7 8 9.

  • Two adjacent amino acids—Ser252 and Pro253—are the sites of nearly all pathogenic mutations, resulting in S252W and P253R missense substitutions 7 8 9.
  • These mutations disrupt normal receptor function, leading to abnormal signaling during cranial and limb development.

• Inheritance Pattern: The condition follows an autosomal dominant inheritance pattern, meaning a single mutation can cause the syndrome. However, most cases arise from new (de novo) mutations rather than being inherited from a parent 6 7.

Molecular and Cellular Pathogenesis

• Loss of Ligand Specificity: Mutant FGFR2 receptors lose their normal ligand-binding specificity, allowing them to interact with inappropriate fibroblast growth factors and triggering abnormal bone growth 10.
• Ectopic Signaling: This leads to premature closure of skull sutures (craniosynostosis) and syndactyly due to altered bone and cartilage formation 9 10.
• Splicing Defects: In rare cases, Alu-element insertions in FGFR2 disrupt normal splicing, further altering receptor function and causing severe limb malformations 11.

Genotype-Phenotype Correlations

• S252W vs. P253R: While both mutations produce similar syndromes, the P253R mutation is associated with more severe syndactyly, while S252W more often involves cleft palate 8.
• Variable Expressivity: Despite genetic similarity, clinical severity can vary due to modifier genes, timing of mutation, and environmental factors 3 8.

Treatment of Apert Syndrome

Management of Apert syndrome is complex and requires a lifelong, multidisciplinary approach. Advances in surgical techniques and coordinated care have greatly improved both functional and psychosocial outcomes for affected individuals.

Treatment	Purpose/Approach	Timing/Outcomes	Source(s)
Cranial surgery	Relieve intracranial pressure, reshape skull	Infancy/early childhood	3 13 14 15
Facial surgery	Correct midface hypoplasia, improve airway	Childhood/adolescence	14 15
Hand/foot surgery	Digit separation, improve function	Early childhood, staged	12 15
Multidisciplinary	Combined specialists, psychosocial support	Ongoing	6 14

Table 4: Treatment Approaches

Surgical Management

Craniofacial Surgery

• Cranial Vault Expansion: Early surgery (such as fronto-orbital advancement or posterior vault distraction osteogenesis) is performed to prevent or treat raised intracranial pressure caused by restricted skull growth 13 15.

  • Posterior Vault Distraction Osteogenesis (PVDO): This newer technique often requires less blood transfusion and is associated with similar complication rates and hospital stays compared to traditional fronto-orbital advancement 15.
  • Timing: Early intervention is critical to minimize neurological complications and improve cognitive outcomes 3 13 15.

• Facial Reconstruction: Procedures like monobloc osteotomy, facial bipartition, and orthognathic surgery address midface hypoplasia, dental malocclusion, and airway issues, often staged throughout childhood and adolescence 14.

Hand and Foot Surgery

• Syndactyly Release: Digit separation is usually performed in a staged manner during early childhood to maximize functional use of the hands and feet 12 15.
  • Techniques have evolved to allow release of all digits in two operations, avoiding unnecessary amputations and improving outcomes 12.
  • Functional Osteotomies: Additional procedures may be done to optimize grasp and pinch, especially in older children 12.
  • Despite intervention, some functional impairment may persist compared to the general population 4.

Additional Procedures

• Airway and Hearing Management: Tracheostomy for severe airway obstruction and interventions for hearing loss may be necessary 6 14.
• Neurosurgical Interventions: Ventriculoperitoneal shunts may be placed for hydrocephalus or raised intracranial pressure, though increased surgical interventions can correlate with adverse developmental outcomes 3.

Multidisciplinary and Long-Term Care

• Team Approach: Care involves craniofacial surgeons, neurosurgeons, hand surgeons, ENT specialists, audiologists, speech therapists, orthodontists, geneticists, and psychologists 6 14.
• Psychosocial Support: Psychological counseling, educational support, and social integration are crucial for optimizing quality of life and mainstream participation 14.

Outcomes and Prognosis

• Developmental Impacts: Early, coordinated intervention reduces the risk of avoidable delays and improves long-term functional and psychosocial outcomes 3 14.
• Surgical Advances: Newer protocols and less invasive techniques continue to improve safety and reduce the number of required operations 12 15.
• Lifelong Follow-Up: Regular monitoring is essential for managing ongoing needs related to growth, development, and function 6 14.

Conclusion

Apert syndrome is a rare, complex disorder rooted in specific FGFR2 gene mutations. Early recognition and a coordinated, multidisciplinary approach can dramatically improve outcomes for affected children and their families.

Key points covered:

• Symptoms include craniosynostosis, syndactyly, midfacial hypoplasia, dental anomalies, CNS malformations, and sensory impairments.
• Types are classified based on cranial synostosis patterns and hand syndactyly severity, influencing management strategies.
• Causes are highly specific FGFR2 mutations leading to abnormal bone and soft tissue development through altered receptor signaling.
• Treatment requires early and ongoing surgical intervention, coordinated by a multidisciplinary team, with evolving techniques offering improved safety and function.

With advances in both medical understanding and surgical techniques, individuals with Apert syndrome can look forward to better health, function, and social integration than ever before.