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Apert Syndrome

  • Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Maria Descartes, MD  more...
 
Updated: Apr 05, 2016
 

Background

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  • Apert syndrome is named for the French physician who described the syndrome acrocephalosyndactylia in 1906.
  • Apert syndrome is a rare autosomal dominant disorder characterized by craniosynostosis, craniofacial anomalies, and severe symmetrical syndactyly (cutaneous and bony fusion) of the hands and feet. See the images below.
    An infant with Apert syndrome is shown. Note the cAn infant with Apert syndrome is shown. Note the characteristic ocular hypertelorism, down-slanting palpebral fissures, proptotic eyes, horizontal groove above the supraorbital ridge, break of the eyebrows' continuity, depressed nasal bridge, and short, wide nose with bulbous tip.
    Note the mitten appearance of the hands with syndaNote the mitten appearance of the hands with syndactyly involving the second, third, fourth, and fifth fingers. This patient also has characteristic concave palms, hitchhiker posture (radial deviation) of the short broad thumbs, and contiguous nail beds (synonychia).
    Note the socklike appearance of the feet with syndNote the socklike appearance of the feet with syndactyly involving the second, third, fourth, and fifth toes. The patient also has contiguous nail beds (synonychia).
    In this profile photo, turribrachycephaly (high prIn this profile photo, turribrachycephaly (high prominent forehead), proptosis, a depressed nasal bridge, a short nose, and low-set ears are prominent.
    This radiograph demonstrates turribrachycephaly, sThis radiograph demonstrates turribrachycephaly, shallow orbits, ocular hypertelorism, and a hypoplastic maxilla.
    Note the osseous syndactyly involving the second, Note the osseous syndactyly involving the second, third, fourth, and fifth fingers; multiple synostosis involving the distal phalanges and proximal fourth and fifth metacarpals; symphalangism of the interphalangeal joints; shortening and radial deviation of the distal phalanx; and the delta-shaped deformity of proximal phalanx of the thumbs.
    Note the osseous syndactyly, fusion of the interphNote the osseous syndactyly, fusion of the interphalangeal joints, synostosis involving the proximal first and second metatarsals, and the partially duplicated and delta-shaped proximal phalanx of the great toes.
  • It is probably the most familiar and best-described type of acrocephalosyndactyly.
  • Reproductive fitness is low, and more than 98% of cases arise by new mutation.
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Pathophysiology

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  • During early infancy (< 3 mo), the coronal suture area is prematurely closed. A bony condensation line beginning at the cranial base and extending upward with a characteristic posterior convexity represents this occurrence. Anterior and posterior fontanelles are widely patent. The midline of the calvaria has a gaping defect, extending from the glabellar area to the posterior fontanelle via the metopic suture area, anterior fontanelle, and sagittal suture area. The skull with a gaping midline defect appears to permit adequate accommodation of the growing brain. The lambdoidal sutures appear normal in all cases.
  • During the first 2-4 years of life, the midline defect is obliterated by coalescence of the enlarging bony islands without evidence of any proper formation of sutures. An extreme short squama and orbital part of the frontal bone together with the posterior convexity of the coronal bone condensation line suggest that growth inhibition in the sphenofrontal and coronal suture area has its onset very early in fetal life.
  • Unique fibroblast growth factor receptor 2 (FGFR2) mutations lead to an increase in the number of precursor cells that enter the osteogenic pathway. Ultimately, this leads to increased subperiosteal bone matrix formation and premature calvaria ossification during fetal development. The order and rate of suture fusion determine the degree of deformity and disability. Once a suture becomes fused, growth perpendicular to that suture becomes restricted, and the fused bones act as a single bony structure. Compensatory growth occurs at the remaining open sutures to allow continued brain growth; however, complex, multiple sutural synostosis frequently extends to premature fusion of the sutures at the base of the skull, causing midfacial hypoplasia, shallow orbits, a foreshortened nasal dorsum, maxillary hypoplasia, and occasional upper airway obstruction.
  • The first genetic evidence that syndactyly in Apert syndrome is a keratinocyte growth factor receptor (KGFR)-mediated effect was provided by the observation of the correlation between KGFR expression in fibroblasts and severity of syndactyly. Patients with Ser252Trp and those with Pro253Arg have different phenotypic expression. The syndactyly is more severe with Pro253Arg mutation for both hands and feet, whereas cleft palate is significantly more common with Ser252Trp mutation.
  • Amblyopia and strabismus is more common in patients with the FGFR2 Ser252Trp mutation, and optic disc pallor is more frequent in patients with the FGFR2 Pro253Arg mutation.[1] Patients with FGR2 Ser252Trp mutations have a significantly greater prevalence of visual impairment compared with patients with the FGFR2 Pro253Arg mutation.[2, 3]
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Epidemiology

Frequency

United States

  • Prevalence is estimated at 1 in 65,000 (approximately 15.5 in 1,000,000) live births.[4, 5, 6]
  • Apert syndrome accounts for 4.5% of all cases of craniosynostosis.

Mortality/Morbidity

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  • Most patients experience some degree of upper airway obstruction during infancy. Upper airway compromise due to reduction in nasopharynx size and choanal patency as well as lower airway compromise due to anomalies of the tracheal cartilage may be responsible for early death.
  • Sleep apnea syndrome is common. Upper airway compromise, consisting of obstructive sleep apnea and cor pulmonale, may result from small nasopharyngeal and oropharyngeal dimension in the Apert craniofacial configuration.
  • Patients are at risk for complications resulting from elevated intracranial pressure despite surgical attempts to increase cranial capacity in infancy.

Race

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  • Asians have the highest prevalence (22.3 cases per million live births).
  • Hispanics have the lowest prevalence (7.6 cases per million live births).

Sex

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  • Apert syndrome has no sex predilection.

Age

See the list below:

  • Apert syndrome is detected in the newborn period due to craniosynostosis and associated findings of syndactyly in the hands and feet.
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Contributor Information and Disclosures
Author

Harold Chen, MD, MS, FAAP, FACMG Professor, Department of Pediatrics, Louisiana State University Medical Center

Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics

Disclosure: Nothing to disclose.

Coauthor(s)

Grace W Guo, MD Staff Radiologist, Department of Medical Imaging, Alfred I duPont Hospital for Children, Nemours Childrens Health System

Grace W Guo, MD is a member of the following medical societies: American College of Radiology, American Medical Association, Radiological Society of North America, Society for Pediatric Radiology

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

James Bowman, MD Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago

James Bowman, MD is a member of the following medical societies: Alpha Omega Alpha, American Society for Clinical Pathology, American Society of Human Genetics, Central Society for Clinical and Translational Research, College of American Pathologists

Disclosure: Nothing to disclose.

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An infant with Apert syndrome is shown. Note the characteristic ocular hypertelorism, down-slanting palpebral fissures, proptotic eyes, horizontal groove above the supraorbital ridge, break of the eyebrows' continuity, depressed nasal bridge, and short, wide nose with bulbous tip.
Note the mitten appearance of the hands with syndactyly involving the second, third, fourth, and fifth fingers. This patient also has characteristic concave palms, hitchhiker posture (radial deviation) of the short broad thumbs, and contiguous nail beds (synonychia).
Note the socklike appearance of the feet with syndactyly involving the second, third, fourth, and fifth toes. The patient also has contiguous nail beds (synonychia).
In this profile photo, turribrachycephaly (high prominent forehead), proptosis, a depressed nasal bridge, a short nose, and low-set ears are prominent.
This radiograph demonstrates turribrachycephaly, shallow orbits, ocular hypertelorism, and a hypoplastic maxilla.
Note the osseous syndactyly involving the second, third, fourth, and fifth fingers; multiple synostosis involving the distal phalanges and proximal fourth and fifth metacarpals; symphalangism of the interphalangeal joints; shortening and radial deviation of the distal phalanx; and the delta-shaped deformity of proximal phalanx of the thumbs.
Note the osseous syndactyly, fusion of the interphalangeal joints, synostosis involving the proximal first and second metatarsals, and the partially duplicated and delta-shaped proximal phalanx of the great toes.
A 9-month-old girl was seen because of syndactyly of the hands and feet as well as associated with craniofacial anomalies. The family and pregnancy histories were noncontributory. The child had broad thumbs with 2-5 digits with cutaneous syndactyly (only the right hand is shown here). The feet were characterized by brachydactyly and syndactyly of 2-5 toes. Genomic DNA analysis showed a heterozygous C-to-G mutation at nucleotide 755 of the fibroblast growth factor receptor 2 (FGFR2) gene (c.755C>G) that changes a codon for serine (TCG) to that for tryptophan (TGG) at amino acid position 252 (p.Ser252Trp). This mutation is diagnostic for Apert syndrome. Image courtesy of Grace W Guo, MD.
The right hand radiograph for the same patient in the previous image at age 15 months (left image) showed soft-tissue fusion between the second through fourth digits as well as fusion of the proximal soft tissues between the fourth and fifth digits. Hypoplastic, deformed phalanges were present with fusion of the proximal and middle phalanges of the second through fourth digits. Bony fusion was also seen at the bases of the fourth and fifth metacarpals along with fusion of the capitate and hamate. The thumb pointed laterally with a sharp angulation at the first metacarpophalangeal joint. A right hand radiograph from the child at age 1 month of age (right image) is provided for comparison. Similar abnormalities were also seen in the left hand (not shown). Image courtesy of Grace W Guo, MD.
Radiographs of both feet in the same child as in the previous images at age 1 month show foreshortening of the bilateral second metatarsals, the right third proximal phalanx and left fourth phalanx, and the distal phalanges of the left second, third, fourth, and fifth digits. Both great toes are bulbous and foreshortened, with deformed phalanges and partially duplicated metatarsals. Soft-tissue fusion was present in the second through fifth digits of both feet. Image courtesy of Grace W Guo, MD.
Magnetic resonance images of the brain obtained at in the same patient as in the previous slides at age 16 months of showed hypoplasia of the parieto-occipital white matter, with undulating bilateral lateral ventricle occipital horns (arrow; left image). Shallow orbits can be appreciated bilaterally with ocular hypertelorism (right image). Image courtesy of Grace W Guo, MD.
 
 
 
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