What is Apert syndrome?

Risk Factors

Apert syndrome may be inherited from a parent who has the disorder, but it most frequently occurs as a sporadic (new) mutation. Because the trait is autosomal dominant, a parent with Apert syndrome has a 50 percent risk of transmitting the disease, as does the unaffected sibling of an affected individual. Research has established an association between advanced paternal age (greater than fifty years) and Apert syndrome. Prevalence is approximately 1 in 100,000 births, as reported by geneticists Nathaniel H. Robin, Marni J. Falk, and Chad R Haldeman-Englert in 2011.

Etiology and Genetics

The genetic mutation responsible for Apert syndrome affects a single gene on chromosome 10, band q26. It is known as fibroblast growth factor receptor 2 (FGFR2). All individuals have two copies of this gene, which consists of a sequence of approximately 120,000 DNA building blocks, or base pairs (120 kb). Apert syndrome results when one of these is replaced by an incorrect pair. According to Robin, Falk, and Haldeman-Englert, two different mutations are known to cause the disorder in 98 percent of cases. Both lead to abnormal development of the skull, face, and limbs. The presence of one mutation appears to increase the severity of face and skull abnormalities, while the other may lead to a more severe form of fusion of the hands and feet.

As an autosomal dominant trait, a single copy of the abnormal gene is all that is required for expression of the disease. The other copy of the gene is entirely normal. Despite the sometimes significant physical and mental impairment the disease can cause, familial cases are the most common means of transmission, with about 1 percent of cases arising from new mutations, as reported by the Oxford Molecular Genetics Laboratory in 2012.

Mutations in the FGFR2 gene lead to increased bone formation, particularly of the skull, during fetal life. This causes premature closure of the cranial sutures and abnormal growth of the skull and face. Development of the hands and feet are also affected. The result is the characteristic appearance of a flattened skull, sunken midface, and protruding eyes. Partial to complete fusion of the digits of the hands and feet (syndactyly) may also occur as a result of abnormal bone and soft tissue growth. Patients with one of the known mutations, Pro253Arg, have a more severe form of syndactyly and intellectual disability, while patients with the Ser252Trp mutation have a higher rate of cleft palate and visual impairment.

Symptoms

The major features of Apert syndrome are craniofacial malformation and syndactyly of fingers and toes. Proptosis (bulging eyes), a flattened head shape, and a small and concave middle third of the face result, Apert syndrome is distinguished from similar craniofacial conditions by coexisting syndactyly, often affecting both fingers and toes.

Additional associated symptoms include intellectual disability or developmental delay (variable), brain malformation, hearing loss and ear abnormalities, vision loss, heart defects, airway narrowing, hydrocephalus, sleep apnea, and severe acne. Affected infants are usually identified at birth because of the characteristic physical features.

Screening and Diagnosis

Since most cases arise from new mutations, prenatal screening for Apert syndrome is largely based on ultrasound imaging to identify typical cranial and limb malformations. If Apert syndrome is suspected, then pregnant patients should be referred to a specialized center for further evaluation and screening for related abnormalities. If the gene defect has been identified in an affected parent, then DNA testing, either sequence analysis or deletion/duplication analysis, is available by amniocentesis or chorionic villus sampling. Postnatal molecular analysis is available to confirm mutations in the FGFR2 gene.

Newborn diagnosis is confirmed by physical examination and skull x-ray to evaluate craniosynostosis (premature fusion of the cranial sutures). Other imaging studies can identify additional problems for future intervention. Hearing assessment, genetic counseling, and parent support is recommended.

Treatment and Therapy

Treatment begins immediately after birth. A multidisciplinary team is best equipped to address the wide variety of issues. Early surgery is often necessary to release the cranial sutures and allow normal brain growth. Several procedures are available to improve the structure and shape of the face. Fingers and toes may also require surgical separation. Other associated symptoms may be treated as required.

Prevention and Outcomes

There is currently no known strategy to prevent the sporadic occurrence of Apert syndrome. Prenatal diagnosis and counseling may allow parents and their health care team to prepare an early treatment plan.

Prognosis depends on the severity of symptoms and early surgical treatment. Advances in craniofacial management allow children with Apert syndrome to maximize social and intellectual functioning. Robin, Falk, and Haldeman-Englert reported that 50 percent will have intelligence and development close to the normal range.

Bibliography

"Apert Syndrome." Medline Plus. US National Library of Medicine, 4 Aug. 2011. Web. 18 July 2014.

Children’s Craniofacial Association. A Guide to Understanding Apert Syndrome. Dallas: Children’s Craniofacial Assn., 2008. Print.

"FGFR2." Genetics Home Reference. US National Library of Medicine, June 2013. Web. 18 July 2014.

Liptak, Gregory S., and Joseph M. Serletti. “Consultations with the Specialist: Pediatric Approach to Craniosynostosis.” Pediatrics in Review 19 (1998): 352–59. Print.

Robin, Nathaniel H. Genetics: Its Application to Speech, Hearing, and Craniofacial Disorders. San Diego: Plural, 2008. Print.

Robin, Nathaniel H., Marni J. Falk, and Chad R. Haldeman-Englert. "FGFR-Related Craniosynostosis Syndromes." GeneReviews. U of Washington, Seattle, 7 June 2011. Web. 18 July 2014.