Apert Syndrome

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

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 c 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 synda 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 synd 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 pr 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, s This 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 interph 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.
  • 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. [1]
  • Amblyopia and strabismus are more common in patients with the FGFR2 Ser252Trp mutation, and optic disc pallor is more frequent in patients with the FGFR2 Pro253Arg mutation. [2] 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]
  • 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

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  • 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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