02 December 2007

Apert Syndrome

Article Last Updated: Nov 13, 2007

AUTHOR AND EDITOR INFORMATION

Author: Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, Pathology, Director of Perinatal Genetics and Genetic Laboratory Services, Louisiana State University Medical Center; Laboratory Director, Hema-Con Cancer Cytogenetics Laboratory, Gainesville, Florida

Harold Chen is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Human Genetics, and Teratology Society

Editors: James Bowman, MD, Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Hagop Youssoufian, MD, MSc, Vice President of Clinical Research, ImClone Systems Incorporated; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; Bruce Buehler, MD, Professor, Department of Pathology and Microbiology, Director, Hattie B Munroe Center for Human Genetics, Chairman, Department of Pediatrics, University of Nebraska Medical Center

INTRODUCTION

Background

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. 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.

Pathophysiology

During early infancy (<3>

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.

Frequency

United States

Prevalence is estimated at 1 in 65,000 (approximately 15.5 in 1,000,000) live births. Apert syndrome accounts for 4.5% of all cases of craniostenosis.

Mortality/Morbidity

  • 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

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

Sex

Apert syndrome has no sex predilection.

Age

Apert syndrome is detected in the newborn period due to craniosynostosis and associated findings of syndactyly in the hands and feet.

CLINICAL



History

  • Family history is usually not significant because most cases are sporadic. A paternal age effect increases in fathers older than 50 years.
  • Headache and vomiting are signs of acute increased intracranial pressure, especially in cases of multiple suture involvement.
  • Stridor and sleep apnea indicate problems with the upper airway, resulting from craniosynostosis of sutures of the base of the skull.
  • Visual disturbance can result from corneal injury due to exposed conjunctivitis and keratitis.
  • Many patients exhibit mental retardation, although patients with normal intelligence have been reported.

Physical

  • Skull and face

·

    • Craniostenosis is present. Coronal sutures most commonly are involved, resulting in acrocephaly, brachycephaly, turribrachycephaly, flat occiput, and high prominent forehead.
    • Large late-closing fontanels are observed.
    • A gaping midline defect is present.
    • A rare cloverleaf skull anomaly is present in approximately 4% of infants.
    • Common facial features during infancy include horizontal grooves above the supraorbital ridges that disappear with age, a break in the continuity of the eyebrows, and a trapezoid-shaped mouth at rest.
    • A flattened, often asymmetric face is observed.
    • Maxillary hypoplasia with retruded midface is present.
  • Ears, eyes, nose, and mouth

·

    • Patients have apparent low-set ears with occasional conductive hearing loss and congenital fixation of stapedial footplate.
    • Eyes exhibit down-slanting palpebral fissures, hypertelorism, shallow orbits, proptosis, exophthalmos, strabismus, amblyopia, optic atrophy, and, rarely, luxation of the eye globes, keratoconus, ectopic lentis, congenital glaucoma, lack of pigment in the fundi with occasional papilledema, and preventable visual loss or blindness.
    • The nose has a markedly depressed nasal bridge. It is short and wide with a bulbous tip, parrot-beaked appearance, and choanal stenosis or atresia.
    • The mouth area has a prominent mandible, down-turned corners, high arched palate, bifid uvula, and cleft palate.
    • Orthodontic problems include crowded upper teeth, malocclusion, delayed dentition, ectopic eruption, shovel-shaped incisors, supernumerary teeth, V-shaped maxillary dental arch, bulging alveolar ridges, dentitio tarda, some impaction, partial eruption, idiopathic root resorption, transposition or other aberrations in the position of the tooth germs, and severe crowding.
  • Extremities and digits

·

    • The upper limbs are more severely affected than lower limbs. Coalition of distal phalanges and synonychia found in the hands is never present in the feet. The glenohumeral joint and proximal humerus are more severely affected than the pelvic girdle and femur. The elbow is much less severely involved than the proximal portion of the upper limb.
    • Syndactyly involves the hands and feet with partial-to-complete fusion of the digits, often involving second, third, and fourth digits. These are often termed mitten hands and sock feet. In severe cases, all digits are fused, with the palm deeply concave and cup-shaped and the sole supinated.
    • Hitchhiker posture or radial deviation of short or broad thumbs results from abnormal proximal phalanx.
    • Brachydactyly occurs.
    • Nailbeds are contiguous (synonychia).
    • Some patients have subacromial dimples and elbow dimples during infancy.
    • Mobility at the glenohumeral joint is limited with progressive limitation in abduction, forward flexion, and external rotation with growth.
    • Limited elbow mobility is common with decreased elbow extension, flexion, pronation, and supination.
    • Short humeri are a constant finding beyond infancy.
    • Limited genu valga is present in many cases.
  • CNS

·

    • Intelligence varies from normal to mental deficiency, although a significant number of patients are mentally retarded. Malformations of the CNS may be responsible for most cases.
    • Common CNS malformations include megalencephaly, agenesis of the corpus callosum, malformed limbic structures, variable ventriculomegaly, encephalocele, gyral abnormalities, hypoplastic cerebral white matter, pyramidal tract abnormalities, and heterotopic gray matter. Progressive hydrocephalus is uncommon.
    • Papilledema and optic atrophy with loss of vision may be present in cases of subtle increased intracranial pressure.
  • Other skeletal and cartilaginous segmentation defects

·

    • Congenital cervical spinal fusion (68%), especially C5-C6
    • Aplasia or ankylosis of shoulder, elbow, and hip joints
    • Tracheal cartilage anomalies
    • Rhizomelia
  • Skin

·

    • Hyperhidrosis (common)
    • Synonychia
    • Brittle nails
    • Acneiform lesions (frequent after adolescence)
    • Interruption of the eyebrows
    • Hypopigmentation
    • Hyperkeratosis in the plantar surface
    • Paronychial infections (more common in feet than hands and in patients who are institutionalized patients)
    • Excessive skin wrinkling of forehead
    • Skin dimples at knuckles, shoulders, and elbows
  • Cardiovascular (10%)

·

·

    • Polycystic kidneys
    • Duplication of renal pelvis
    • Hydronephrosis
    • Stenosis of bladder neck
    • Bicornuate uterus
    • Vaginal atresia
    • Protuberant labia majora
    • Clitoromegaly
    • Cryptorchidism
  • Gastrointestinal (1.5%)

·

    • Pyloric stenosis
    • Esophageal atresia and tracheoesophageal fistula
    • Ectopic or imperforate anus
    • Partial biliary atresia with agenesis of gallbladder
  • Respiratory (1.5%)

·

    • Anomalous tracheal cartilage
    • Tracheoesophageal fistula
    • Pulmonary aplasia
    • Absent right middle lobe of lung
    • Absent interlobular lung fissures

Causes

  • More than 98% of cases with Apert syndrome are caused by specific missense substitution mutations, involving adjacent amino acids (ie, Ser252Trp, Ser252Phe, Pro253Arg) in the linker between the second and third extracellular immunoglobulin domains of FGFR2, which maps to chromosome bands 10q26. The remaining cases are due to Alu-element insertion mutations in or near exon 9 of FGFR2.
  • Most cases are sporadic, resulting from new mutations with a paternal age effect.
  • Most new mutations, estimated at 1 per 65,000 live births, imply that germline transversion rates at these 2 positions are currently the highest known in the human genome. The rarity of familial cases can be explained by reduced genetic fitness of individuals because of severe malformations and the presence of mental retardation in many cases.

DIFFERENTIALS

Other Problems to be Considered

  • Beare-Stevenson syndrome (OMIM 123790): Patients present with mental retardation and associated cutaneous disorders, including cutis gyrata and acanthosis nigricans. Patients with Beare-Stevenson syndrome may have FGFR2 mutations.
  • Carpenter syndrome (OMIM 201000): This condition is autosomal recessive. Patients present with a peculiar face, absence of osseous fusion of hand bones, and preaxial polydactyly of hands, feet, or both.
  • FGFR3-associated coronal synostosis syndrome: Patients present with variable clinical presentation overlapping with Pfeiffer, Jackson-Weiss, or Saethre-Chotzen syndrome phenotypes. Some individuals with a disease-causing mutation may have no clinical problems.
  • Jackson-Weiss syndrome (OMIM 123150): Patients present with enlarged or broad great toes with varus deviation and tarsal or metatarsal fusion, lack of thumb abnormalities, and craniofacial features, suggesting Pfeiffer syndrome. Patients may have FGFR2 mutations.
  • Pfeiffer syndrome (OMIM 101600): Patients present with hand and foot abnormalities characterized by broad thumbs and halluces with occasional cutaneous syndactyly. They also exhibit mild cranial deformities and lack of osseous fusion of the phalanges. Approximately 67% of patients with Pfeiffer syndrome have identifiable mutations in FGFR1 and FGFR2.
  • Saethre-Chotzen syndrome (OMIM 101400): Patients exhibit characteristic facies, relatively mild cranial deformity, and lack of osseous fusion of the hand bones. Approximately 75% of patients with Saethre-Chotzen syndrome have identifiable mutations in the TWIST gene.

WORKUP

Lab Studies

  • Molecular analysis

·

    • The molecular mechanism is exquisitely specific with a narrow mutational spectrum.
    • More than 98% of cases are caused by specific missense substitution mutations, involving adjacent amino acids (Ser252Trp, Ser252Phe, or Pro253Arg) in exon 7 of FGFR2.
    • The remaining cases are due to Alu-element insertion mutations in or near exon 9.

Imaging Studies

  • Skull radiography

·

    • Skull radiography can be performed to evaluate for craniostenosis, which usually involves coronal sutures and maxillary hypoplasia.
    • Abnormalities include sclerosis of suture line, bony bridging and beaking along the suture line, an indistinct suture line, turribrachycephaly, shallow orbits, and hypoplastic maxillae.
  • Spinal radiography

·

    • Spinal fusions, most commonly at the levels of C3-4 and C5-6, appear to be progressive and occur at the site of subtle congenital anomalies. They may not be apparent as congenital features.
    • Small-sized vertebral body and reduced intervertebral disc space are indicators of subsequent bony fusion.
  • Limb radiography: Radiographs of the limbs depict multiple epiphyseal dysplasia, short humeri, and glenoid dysplasia.
  • Hand radiography

·

    • Radiography of the hands can be performed to evaluate for cutaneous and osseous syndactyly.
    • The characteristic finding is complete syndactyly involving the second and fifth digits (mitten hands).
    • Multiple progressive synostosis involves distal phalanges, proximal fourth and fifth metacarpals, capitate, and hamate.
    • Symphalangism of interphalangeal joints is progressive.
    • Radiography of the distal phalanx reveals shortened and radial deviation.
    • Radiography of the proximal phalanx of the thumbs reveals delta-shaped deformity.
  • Foot radiography

·

    • Radiography of the feet can be performed to evaluate for cutaneous and osseous syndactyly. The characteristic finding is complete syndactyly involving the second and fifth digits (sock feet).
    • Fusion of tarsal bones, metatarsophalangeal and interphalangeal joints, and adjacent metatarsals
    • Delta-shaped proximal phalanx of the first toes
    • Occasional partial or complete duplication of the proximal phalanx of the great toes and first metatarsals
  • CT scanning

·

    • CT with comparative 3-dimensional reconstruction analysis of the calvaria and cranial bases has become the most useful radiological examination in identifying skull shape and presence or absence of involved sutures.
    • CT can precisely reveal the pathological anatomy and permit specific operative planning.
  • MRI

·

    • MRI reveals the anatomy of the soft-tissue structures and associated brain abnormalities (ie, nonprogressive ventriculomegaly; hydrocephalus; complete or partial absence of the septum pellucidum; absence of septal leaflets; and thinning, deficiency, or agenesis of the corpus callosum).
    • MRI can also reveal spatial arrangement of the bones.

Other Tests

  • Psychometric evaluation
  • Hearing assessment

TREATMENT

Medical Care

  • Consider early optimization of hearing with possible hearing aids.
  • Provide airway management.
  • Psychological counseling should include attachment and interaction with peers.
  • Genetic counseling should include discussion of the following:

·

    • Recurrence risk for an affected individual to have an affected offspring is 50%.
    • Recurrence risk for unaffected parents is negligible, except in the case of germinal mosaicism, in which the risk for future sibs depends on the proportion of germ cells bearing the mutant allele.
    • Advanced paternal age effect in new mutations has been shown clinically and demonstrated conclusively at the molecular level.

Surgical Care

  • Surgical care involves early release of the coronal suture and fronto-orbital advancement and reshaping to reduce dysmorphic and unwanted skull growth changes. Craniosynostosis requires multistaged operative procedures. A significant cosmetic improvement is possible. Initial surgery is often performed as early as age 3 months.
  • Facial cosmetic reconstruction for dysmorphisms is indicated.
  • A new technique of craniofacial disjunction, followed by gradual bone distraction (Ilizarov procedure), has been reported to produce complete correction of exophthalmos and improvement in the functional and aesthetic aspects of the middle third of the face without the need for bone graft in patients aged 6-11 years.
  • Surgical separation of digits (mitten-glove syndactyly) provides relatively little functional improvement.
  • Shunting procedure reduces intracranial pressure.
  • For orthodontic treatment, most patients require 2-jaw surgery (bilateral sagittal split osteotomy with mandibular setback and distraction in the maxilla). During the period of distraction, the orthodontist guides the maxilla into final position using bite planes and intermaxillary elastics.

Consultations

  • Neurosurgeon
  • Plastic surgeon
  • Oromaxillofacial surgeon
  • Craniofacial anesthesiologist
  • Radiologist
  • Otorhinolaryngologist
  • Orthodontist
  • Dentist
  • Orthopedist
  • Ophthalmologist
  • Clinical geneticist
  • Developmental pediatrician
  • Neurologist
  • Psychiatrist
  • Psychologist
  • Audiologist
  • Speech pathologist
  • Physical and occupational therapy specialist

Diet

No special diet is required.

Activity

No restriction of activity is required.

MEDICATION

Medication is not currently a component of care in patients with Apert syndrome. See Treatment.

FOLLOW-UP

Further Inpatient Care

  • Admit for surgical intervention.
  • Tracheostomy may be necessary for airway management.

Further Outpatient Care

  • Carefully monitor postoperative complications.

Transfer

  • Transfer may be indicated for further diagnostic evaluation and surgical intervention.

Complications

  • Potential eye or brain injury
  • Wound infections
  • Leakage of cerebrospinal fluid or meningocele formation
  • Increased intracranial pressure and hydrocephalus
  • Airway obstruction, respiratory insufficiency, and sleep apnea

Prognosis

  • Prognosis largely depends on the age at operation. Craniosynostosis can result in brain compression and mental retardation unless relieved by early craniectomy. Innovations in craniofacial surgery have enabled children with Apert syndrome to achieve their full potential by maximizing their opportunities for intellectual growth, physical competence, and social acceptance; however, early surgical treatment of craniosynostosis may not alter intellectual outcome.
  • Prognosis depends on associated brain malformations. Malformations of the corpus callosum and size of the ventricles appear to play no role in the final intelligence quotient (IQ) score, though malformations of septum pellucidum have a significant effect.
  • Quality of the family environment is another factor involved in intellectual achievement. Only 12.5% of children with Apert syndrome who are institutionalized reach a normal IQ score, compared with 39.3% of children from a healthy family background.

Patient Education

MISCELLANEOUS

Medical/Legal Pitfalls

  • Failure to perform early craniectomy
  • Failure to correct hand and foot deformities
  • Failure to provide adequate genetic counseling and offer prenatal diagnosis

Special Concerns

  • Prenatal diagnosis

·

    • When one of the parent is affected, the risk to offspring is 50%. Despite the striking physical features seen in newborns with Apert syndrome, de novo cases are not often prenatally diagnosed or are only identified in the third-trimester.
    • Prenatal ultrasonographic diagnosis can be made based on findings of acrocephaly, mittenlike hands, and proximally placed and radially deviated thumbs. CNS malformations such as mild ventriculomegaly and agenesis of corpus callosum may be visible in some fetuses with Apert syndrome before the pathognomonic skeletal changes are revealed. The abnormal cranial shape and orbital hypertelorism may be absent or very subtle in the second trimester of pregnancy, becoming obvious only in the third trimester. However, Apert syndrome can be accurately suspected in the second trimester by careful ultrasonographic examination of the fetus, including the extremities and skull shape using 3-dimensional ultrasonography.
    • If the molecular defect has been identified in the affected parent, prenatal molecular diagnosis can be achieved by direct DNA testing on fetal DNA obtained from amniocentesis or chronic villus sampling (CVS). In general, linkage analysis can be considered if a mutation has not been detected in the affected parent (although >98% of patients with Apert syndrome tested so far have FGFR2 mutations) and at least 2 affected relatives are available.

MULTIMEDIA

Media file 1: 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 continuity of eyebrows, depressed nasal bridge, and short wide nose with bulbous tip.

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Media type: Photo

Media file 2: 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 short broad thumbs, and contiguous nailbeds (synonychia).

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Media type: Photo

Media file 3: Note the sock appearance of the feet with syndactyly involving the second, third, fourth, and fifth toes. The patient also has contiguous nail beds (synonychia).

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Media type: Photo

Media file 4: In this profile, turribrachycephaly, high prominent forehead, proptosis, depressed nasal bridge, short nose, and low-set ears are prominent.

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Media type: Photo

Media file 5: This radiograph demonstrates turribrachycephaly, shallow orbits, ocular hypertelorism, and hypoplastic maxilla.

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Media type: Radiograph

Media file 6: Note osseous syndactyly involving the second, third, fourth, and fifth fingers; multiple synostosis involving distal phalanges and proximal fourth and fifth metacarpals; symphalangism of interphalangeal joints; shortening and radial deviation of distal phalanx; and delta-shaped deformity of proximal phalanx of the thumbs.

Click to see larger picture

Click to see detailView Full Size Image

Media type: Radiograph

Media file 7: Note osseous syndactyly, fusion of interphalangeal joints, synostosis involving proximal first and second metatarsals, and partially duplicated and delta-shaped proximal phalanx of the great toes.

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Click to see detailView Full Size Image

Media type: Radiograph

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Apert Syndrome excerpt

Article Last Updated: Nov 13, 2007

Reference Link:

http://www.emedicine.com/ped/topic122.htm

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