Apert Syndrome

                                     Dr. KS Dhillon

Introduction

Apert syndrome is a genetically inherited syndrome that is characterized by craniosynostosis due to premature fusion of coronal sutures which results in syndactyly and skull and facial deformities. The syndrome was first described by French physician Eugene Apert in 1906. He described nine people with similar facial and extremity characteristics (1).

Etiology

The Apert syndrome is an autosomal dominant inherited craniosynostosis syndrome but most new cases are sporadic. It is due to mutations of fibroblast growth factor receptor (FGFR2)-2 on chromosome 10q (2).

Epidemiology

Apert syndrome is a very rare disease. It is estimated to occur in 1 in 65,000 to 200,000 births (3). Females and males are equally affected. The incidence of the disease increases with paternal age. It provides a selective advantage within the male spermatogonial cells (4). The syndrome has complete penetrance with variable expressivity. This results in patients being phenotypically unaffected to severe deformities within the same family.

Pathophysiology

About two-thirds of cases of Apert syndrome are due to a specific cytosine to guanine mutation at position 755 of the fibroblast growth factor receptor 2 (FGFR2) gene. It results in a serine to tryptophan amino acid change on the paternally derived allele (4,5). The disease incidence increases with the age of the father (4). There are only hypotheses as to why both the extremities and cranial sutures are affected. There is some data from a single mouse model. In mice, the FGFR2 receptor loses its specificity and can bind to other fibroblast growth factors. This can suppress apoptosis of osteoblasts resulting in craniosynostosis and syndactyly. The underlying mechanism remains unclear even in the mouse model. It is linked to a specific FGF (6).

History and Physical Examination

A family history is essential in patients suspected of having Apert syndrome due to its autosomal dominant inheritance. A lack of family history, however, does not rule out the diagnosis because of the possibility of de novo mutations. A positive family history, however, makes the diagnosis more likely.

Patients with Apert syndrome have midface hypoplasia, craniosynostosis, and symmetric syndactyly of the feet and hands. The craniosynostosis is more severe than that found in Crouzon syndrome. The additional finding of syndactyly helps confirm the diagnosis between multiple, similar syndromes in regards to their phenotype. However, features of proptosis (bulging eyes), hypertelorism (wide-set eyes), and down-slanting palpebral fissures are facial features found in several of the craniosynostoses that cannot be used to differentiate the syndromes but are usually helpful.

Examination of the hand shows a short, radially deviated thumb, complex syndactyly of the index, middle, and ring finger, syndactyly of the fourth webspace, and symphalangism which is congenital stiffness of the fingers due to failure of the bone to fully separate as typically happens during fetal growth. Based on the overall shape of the hand there are three specific subtypes of hand findings in Apert syndrome. These include spade where there is side-to-side fusion with a flat palm, mitten where there is fusion of fingers resulting in a concave palm, and rosebud where there is tight fusion of all digits. Craniofacial deformities in Apert syndrome and other craniosynostosis, include acrocephaly (cone-shaped calvarium), hypertelorism, down slanting palpebral fissures, proptosis, prominent forehead, and a flattened nasal bridge. Oral findings include a high-arched narrow palate, dental crowding, and pseudo-clefts. Internal organ anomalies and other skeletal anomalies, such as cervical fusion, can also be seen. It is also possible to see mild to moderate intellectual disability. 

Evaluation

In the setting of known family history, the evaluation for Apert syndrome is a clinical one. The characteristic physical examination findings confirm the diagnosis. Additional tests such as imaging techniques are useful in patients whose clinical presentation is unclear and there is no family history to support the diagnosis. Computed tomographic (CT) imaging and magnetic resonance imaging (MRI) of the brain are used to detect craniosynostosis and other skeletal abnormalities such as reduced serration, peri sutural sclerosis, and bony bridging and/or the absence of the suture altogether. These same imaging techniques can help detect complications related to the syndrome, such as increased intracranial pressure. 

In patients where the diagnosis is unclear or the syndrome has atypical features, genetic and molecular testing can be carried out. The underlying mechanism of multiple craniosynostosis syndromes is related to abnormal signaling and  FGFR mutations. Prenatal genetic testing, ultrasound, and MRI can be utilized to confirm the diagnosis before the child's birth (7). The use of amniocentesis and/or chorionic villus sampling can be performed. The combination of safer imaging techniques will render the higher-risk procedures obsolete except in the most difficult cases.

The history, physical examination, and imaging findings are used to confirm the specific craniosynostosis. It however can be difficult due to significant overlap amongst the syndromes such as Apert, Pfeiffer, Saether-Chotzen, Carpenter, and Jackson-Weiss syndromes.

Management

Management of craniosynostoses is a team-based approach requiring multiple subspecialists such as pediatricians, craniofacial surgeons, ophthalmologists, neurosurgeons, plastic surgeons, and dentists. There is a need for surgery to prevent complete coronal suture closure and protect brain development.

Earlier surgical decisions before the age of 1 provide better long-term outcomes (8). This however is based on anecdotal evidence and not randomized, controlled trials. There is also no standard of care for the treatment of syndactyly. Multiple revisions are usually needed as the child grows older.

Long-term follow-up is essential to reduce the risk of developing craniosynostosis-related complications, such as sleep apnea, strabismus, and elevated intracranial pressure. These issues are not completely resolved with surgical correction of the cranial and facial. In one retrospective study from Australia, 54% of patients had vision loss in at least one eye related to amblyopia that developed after craniofacial surgery for Apert syndrome. In this same study, the incidence of optic atrophy was low at 5%, presumably due to the widespread adoption of early craniofacial surgery for craniosynostosis syndromes (9). The incidence of strabismus is widespread as well, with two-thirds of patients developing it at some point (10). Severe to profound hearing loss is much more common in syndromic craniosynostoses than in nonsyndromic variants (11). A team-based approach with multiple subspecialists is necessary to monitor the development of vision and life-threatening complications related to Apert syndrome and to make difficult decisions regarding surgery.

In the laboratories chemical inhibitors of the FGFR signaling pathway restore normal FGFR signaling and rescue the associated skeletal defects.

Differential Diagnosis

The differential diagnoses of Apert syndrome include the following:

• Achondroplasia
• Conditions arising due to mutations of the fibroblast growth factor receptors
• Antley-Bixler syndrome
• Beare-Stevenson syndrome
• Crouzon syndrome
• Cutis gyrata
• Pfeiffer syndrome
• Thanatophoric dysplasia

Prognosis

The prognosis depends on what pathologies required surgical intervention and when the surgery was performed.

Complications

The main complications that are likely to occur in patients with Apert syndrome include the following:

• Exposure keratopathy and corneal scarring

• Respiratory complications

• Increased intracranial pressure that can cause cognitive impairment

and papilledema

• Spinal cord injury and neurologic deficits in patients with cervical spine anomalies

• Aspiration pneumonia and chronic lung disease

Conclusion

Apert syndrome has an autosomal dominant inheritance. Advanced paternal age is found to be associated with de novo occurrence of Apert syndrome. There is a 50% chance of the genetic trait being passed on to the children. If a pathologic variant person is present in the family it is necessary to do prenatal testing for pregnancies that are at increased risk. 

As with other craniosynostoses, management is a team-based approach that requires multiple subspecialists such as neurosurgeons, plastic surgeons, craniofacial surgeons, pediatricians, ophthalmologists, and dentists. Surgery is often necessary to prevent complete coronal suture closure and protect brain development.

Long-term follow-up is usually essential to reduce the risk of developing craniosynostosis-related complications, such as sleep apnea, strabismus, and elevated intracranial pressure. These issues, unfortunately, are not completely resolved with surgical correction of the facial and cranial defects. In one retrospective study from Australia, 54% of patients had vision loss in at least one eye related to amblyopia that developed after craniofacial surgery for Apert syndrome. In this same study, the incidence of optic atrophy was low at 5%, probably due to the widespread adoption of early craniofacial surgery for craniosynostosis syndromes (9). The incidence of strabismus is very common with two-thirds of patients developing it at some point (10). Severe to profound hearing loss is much more common in syndromic craniosynostoses as compared to nonsyndromic variants (11). Hence, a team-based approach with multiple subspecialists is necessary to monitor for the development of vision and life-threatening complications related to Apert syndrome and to make difficult decisions regarding the need for surgery. 

References

1. Kutkowska-Kaźmierczak A, Gos M, Obersztyn E. Craniosynostosis as a clinical and diagnostic problem: molecular pathology and genetic counseling. J Appl Genet. 2018 May;59(2):133-147.

2. Wilkie AO, Slaney SF, Oldridge M, Poole MD, Ashworth GJ, Hockley AD, Hayward RD, David DJ, Pulleyn LJ, Rutland P. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet. 1995 Feb;9(2):165-72.

3. Fearon JA. Treatment of the hands and feet in Apert syndrome: an evolution in management. Plast Reconstr Surg. 2003 Jul;112(1):1-12; discussion 13-9.

4. Goriely A, McVean GA, Röjmyr M, Ingemarsson B, Wilkie AO. Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line. Science. 2003 Aug 01;301(5633):643-6.

5. Moloney DM, Slaney SF, Oldridge M, Wall SA, Sahlin P, Stenman G, Wilkie AO. Exclusive paternal origin of new mutations in Apert syndrome. Nat Genet. 1996 May;13(1):48-53.

6. Hajihosseini MK, Duarte R, Pegrum J, Donjacour A, Lana-Elola E, Rice DP, Sharpe J, Dickson C. Evidence that Fgf10 contributes to the skeletal and visceral defects of an Apert syndrome mouse model. Dev Dyn. 2009 Feb;238(2):376-85.

7. Azoury SC, Reddy S, Shukla V, Deng CX. Fibroblast Growth Factor Receptor 2 (FGFR2) Mutation Related Syndromic Craniosynostosis. Int J Biol Sci. 2017;13(12):1479-1488.

8. Warren SM, Proctor MR, Bartlett SP, Blount JP, Buchman SR, Burnett W, Fearon JA, Keating R, Muraszko KM, Rogers GF, Rubin MS, McCarthy JG. Parameters of care for craniosynostosis: craniofacial and neurologic surgery perspectives. Plast Reconstr Surg. 2012 Mar;129(3):731-737.

9. Khong JJ, Anderson P, Gray TL, Hammerton M, Selva D, David D. Ophthalmic findings in Apert's syndrome after craniofacial surgery: twenty-nine years' experience. Ophthalmology. 2006 Feb;113(2):347-52.

10. Coats DK, Paysse EA, Stager DR. Surgical management of V-pattern strabismus and oblique dysfunction in craniofacial dysostosis. J AAPOS. 2000 Dec;4(6):338-42.

11. Goh LC, Azman A, Siti HBK, Khoo WV, Muthukumarasamy PA, Thong MK, Abu Bakar Z, Manuel AM. An audiological evaluation of syndromic and non-syndromic craniosynostosis in pre-school going children. Int J Pediatr Otorhinolaryngol. 2018 Jun;109:50-53.