Apert Syndrome


Apert syndrome is another genetically inherited syndrome characterized by craniosynostosis (premature fusion of coronal sutures) resulting skull and facial deformities and syndactyly. The syndrome was first described in 1906 by French physician Eugene Apert when he described nine people with similar facial and extremity characteristics.[1]


Apert syndrome is an autosomal dominant inherited craniosynostosis syndrome. It is due to gain-of-function missense mutations of fibroblast growth factor receptor (FGFR2)-2 on chromosome 10q.[2]


Apert syndrome is a rare disease and is estimated to occur in 1 in 65,000 to 200,000 births depending on the study cited.[3] Males and females are equally affected. The incidence of the disease significantly increases with paternal age and is felt to provide a selective advantage within the male spermatogonial cells.[4] The syndrome has complete penetrance but variable expressivity resulting in phenotypically unaffected to severe deformities within the same family.


Two-thirds of cases of Apert syndrome are due to a specific cysteine to guanine mutation at position 755 of the Fibroblast Growth Factor Receptor 2 (FGFR2) gene resulting in a serine to tryptophan amino acid change on the paternally derived allele.[4][5] The incidence of the disease increases with the age of the father.[4] Unfortunately, there are only hypotheses as to why both the extremities and cranial sutures are affected, and some data from a single mouse model. In mice, the FGFR2 receptor loses its specificity and can bind other fibroblast growth factors thereby suppressing apoptosis of osteoblasts resulting in syndactyly and craniosynostosis. The underlying mechanism is still not clear even in this mouse model, but it is linked to a specific FGF.[6]

History and Physical

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

Patients with Apert syndrome have craniosynostosis, midface hypoplasia, and symmetric syndactyly of the hands and feet. The craniosynostosis is more severe than that found in Crouzon syndrome, and the additional finding of syndactyly helps confirm the diagnosis between multiple, similar syndromes in regards to their phenotype. However, features of hypertelorism (wide-set eyes), proptosis (bulging 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 helpful.

In regards to the hand, a short, radially deviated thumb, complex syndactyly of the index, long, and ring finger, syndactyly of the fourth webspace, and symphalangism (congenital stiffness of the fingers due to failure of the bone to fully separate as typically happens during fetal growth) are characteristic findings of the hand. There are three specific subtypes of hand findings in Apert syndrome based on the overall shape of the hand. They are spade (side-to-side fusion with flat palm), mitten (fusion of fingers resulting in concave palm), and rosebud (tight fusion of all digits). There are other craniofacial deformities found in Apert syndrome and other craniosynostoses such as acrocephaly (cone-shaped calvarium), proptosis, prominent forehead, hypertelorism, down slanting palpebral fissures and a flattened nasal bridge. Oral findings included dental crowding, high-arched palate, narrow palate, and pseudo-clefts. Internal organs and other skeletal anomalies such as cervical fusions can be seen. Mild to moderate intellectual disability is also possible.


The evaluation for Apert syndrome in the setting of known family history is a clinical one as the characteristic physical examination findings confirm the diagnosis. In cases where the clinical presentation is not clear and no family history to support the diagnosis, additional tests such as advanced imaging techniques can help. Magnetic resonance imaging (MRI) and computed tomographic (CT) imaging of the brain are used to detect craniosynostosis or other skeletal abnormalities (perisutural sclerosis, reduced serration, and bony bridging and/or the absence of the suture altogether). These same imaging techniques can be helpful in detecting complications related to the syndrome such as increased intracranial pressure. 

Much like that discussed with Crouzon syndrome in which there is an unclear diagnosis, or the syndrome has atypical features, genetic and molecular testing can be pursued. Unfortunately, the underlying mechanism of multiple craniosynostosis syndromes is related to FGFR mutations and abnormal signaling. Prenatal genetic testing, MRI, and ultrasounds can be utilized to confirm the diagnosis before the birth of the child.[7] The use of amniocentesis and/or chorionic villus sampling can be performed, but the combination of safer imaging techniques will likely render the higher risk procedures obsolete except in the most difficult cases.

As described above, the history, physical, and imaging findings are used to confirm the specific craniosynostosis but can be difficult due to significant overlap amongst the syndromes (Pfeiffer, Apert, Saether-Chotzen, Carpenter, and Jackson-Weiss syndromes).

Differential Diagnosis

The differential diagnoses of Apert syndrome include:

  • Achondroplasia
  • Antley- Bixler syndrome
  • Beare- Stevenson syndrome
  • Conditions arising due to mutations of the Fibroblast Growth Factor Receptors
  • Crouzon syndrome
  • Cutis Gyrata
  • Pfeiffer syndrome
  • Thanatophoric dysplasia


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


The main complications likely to occur in patients with Apert syndrome include:

  • Increased intracranial pressure that can cause papilledema and cognitive impairment
  • Exposure keratopathy and corneal scarring
  • Respiratory complications
  • Spinal cord injury and neurologic deficits in patients with cervical spine anomalies
  • Aspiration pneumonia and further chronic lung disease


  • Ophthalmology (pediatric, oculoplastics)
  • Plastic surgery
  • Maxillofacial surgery
  • Neurosurgery
  • Otorhinolaryngology

Deterrence and Patient Education

Apert syndrome is having an autosomal dominant inheritance and advanced paternal age is found to be associated with the de novo occurrence of Apert syndrome. There is a 50% chance of the genetic trait being passed to each child. If a pathologic variant person is present in the family, prenatal testing for pregnancies at increased risk should be ideally performed.

Enhancing Healthcare Team Outcomes

Like other craniosynostoses, management is a team-based approach requiring multiple subspecialists such as pediatricians, neurosurgeons, plastic surgeons, craniofacial surgeons, ophthalmologists, and dentists. Surgery is required to prevent complete coronal suture closure and protect brain development.

Long-term follow up is essential to reduce the risk of developing complications related to craniosynostoses such as strabismus, sleep apnea, and elevated intracranial pressure. Unfortunately, these issues are not completely resolved with surgical correction of the facial and cranial defects as 54% of patients had vision loss in at least one eye-related to amblyopia that developed after craniofacial surgery for Apert syndrome in one retrospective study from Australia. Fortunately, 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.[10] The incidence of strabismus is extremely common as well with two-thirds of patients developing the entity at some point.[11] Severe to profound hearing loss is also much more common in syndromic craniosynostoses than nonsyndromic variants.[12] Thus, a team-based approach with multiple subspecialists involved to monitor for the development of vision and life-threatening complications related to Apert and to make difficult decisions and if and when to perform surgery.

(Click Image to Enlarge)
Patient with Apert syndrome, Extraorally: Hypertelorism, vertical excess of the lower third of the face, trapezoidal upper lip, forced lip closure possible, but difficult. Intraorally: Dentitio tarda, crowding, Angle Class III with dental compensation by retrusion of lower incisors, circular open bite with unilateral crossbite.
Patient with Apert syndrome, Extraorally: Hypertelorism, vertical excess of the lower third of the face, trapezoidal upper lip, forced lip closure possible, but difficult. Intraorally: Dentitio tarda, crowding, Angle Class III with dental compensation by retrusion of lower incisors, circular open bite with unilateral crossbite.
Contributed by Wikimedia Commons, Hohoff A, et al. (CC by 2.0) https://creativecommons.org/licenses/by/2.0/

(Click Image to Enlarge)
Pathology, Infant born with autosomal dominant disorder, Apert's Syndrome, Acrocephalosyndactyly, malformation of the cranium; face; hands; feet, Syndactyly
Pathology, Infant born with autosomal dominant disorder, Apert's Syndrome, Acrocephalosyndactyly, malformation of the cranium; face; hands; feet, Syndactyly
Contributed by Dr. James Hanson, The Centers for Disease Control and Prevention (CDC)
Article Details

Article Author

Christopher Conrady

Article Author

Bhupendra Patel

Article Editor:

Sandeep Sharma


8/10/2020 4:50:13 PM

PubMed Link:

Apert Syndrome



Kutkowska-Ka┼║mierczak A,Gos M,Obersztyn E, Craniosynostosis as a clinical and diagnostic problem: molecular pathology and genetic counseling. Journal of applied genetics. 2018 May     [PubMed PMID: 29392564]


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. Nature genetics. 1995 Feb     [PubMed PMID: 7719344]


Fearon JA, Treatment of the hands and feet in Apert syndrome: an evolution in management. Plastic and reconstructive surgery. 2003 Jul     [PubMed PMID: 12832871]


Goriely A,McVean GA,Röjmyr M,Ingemarsson B,Wilkie AO, Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line. Science (New York, N.Y.). 2003 Aug 1     [PubMed PMID: 12893942]


Moloney DM,Slaney SF,Oldridge M,Wall SA,Sahlin P,Stenman G,Wilkie AO, Exclusive paternal origin of new mutations in Apert syndrome. Nature genetics. 1996 May     [PubMed PMID: 8673103]


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. Developmental dynamics : an official publication of the American Association of Anatomists. 2009 Feb     [PubMed PMID: 18773495]


Azoury SC,Reddy S,Shukla V,Deng CX, Fibroblast Growth Factor Receptor 2 ({i}FGFR2{/i}) Mutation Related Syndromic Craniosynostosis. International journal of biological sciences. 2017     [PubMed PMID: 29230096]


Mathijssen IM, Guideline for Care of Patients With the Diagnoses of Craniosynostosis: Working Group on Craniosynostosis. The Journal of craniofacial surgery. 2015 Sep     [PubMed PMID: 26355968]


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. Plastic and reconstructive surgery. 2012 Mar     [PubMed PMID: 22373978]


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     [PubMed PMID: 16458095]


Coats DK,Paysse EA,Stager DR, Surgical management of V-pattern strabismus and oblique dysfunction in craniofacial dysostosis. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus. 2000 Dec     [PubMed PMID: 11124667]


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. International journal of pediatric otorhinolaryngology. 2018 Jun     [PubMed PMID: 29728184]