Apert Syndrome

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Harold ChenAtlas of Genetic Diagnosis and Counseling210.1007/978-1-4614-1037-9_14
© Springer Science+Business Media, LLC 2012

Apert Syndrome

Apert syndrome is named after 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 probably is the most familiar and best-described type of acrocephalosyndactyly. Prevalence is estimated at 1 in 65,000 (approximately 15.5 in 1,000,000) live births (Cohen and Kreiborg 1992, 1993a). Apert syndrome accounts for 4.5% of all cases of craniosynostosis.

Synonyms and Related Disorders

Acrocephalosyndactyly types 1 and 2; Apert-Crouzon disease; Vogt cephalodactyly

Genetics/Basic Defects

1.
Inheritance
a.
Autosomal dominant
 
b.
Sporadic in majority (>98%) of cases, resulting from new mutations with a paternal age effect
 
c.
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.
 
 
2.
Cause
a.
Caused by specific missense substitution mutations, involving adjacent amino acids (i.e., Ser252Trp or Pro253Arg) in the linker between the second and third extracellular immunoglobulins domains of FGFR2, which maps to chromosome bands 10q25–q26 (more than 98% of cases with Apert syndrome)
 
b.
Remaining cases are caused by Alu-element insertion mutations in or near exon 9 of FGFR2.
 
 
3.
Pathogenesis
a.
Unique fibroblast growth factor receptor 2 (FGFR2) mutations
i.
Leading to an increase in the number of precursor cells that enter the osteogenic pathway
 
ii.
Ultimately leading to increased subperiosteal bone matrix formation and premature calvaria ossification during fetal development
 
 
b.
Fusion of the cranial sutures
i.
The order and rate of suture fusion determine the degree of deformity and disability.
 
ii.
Once a suture becomes fused, growth perpendicular to that suture becomes restricted, and the fused bones act as a single bony structure.
 
iii.
Compensatory growth occurs at the remaining open sutures to allow continued brain growth.
 
iv.
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.
 
 
c.
Syndactyly of Apert syndrome
i.
A keratinocyte growth factor receptor (KGFR)-mediated effect, provided by the observation of the correlation between KGFR expression in fibroblasts and severity of syndactyly
 
ii.
Different phenotypic expression in patients with Ser252Trp and those with Pro253Arg. The syndactyly is more severe with Pro253Arg mutation for both hands and feet, whereas cleft palate is significantly more common with Ser252Try mutation.
 
 
d.
During early infancy (younger than 3 month of age)
i.
Premature closure of the coronal suture area, evident by a bony condensation line beginning at the cranial base and extending upward with a characteristic posterior convexity
 
ii.
Widely patent anterior and posterior fontanelles
 
iii.
Presence of a gaping defect of the midline of the calvaria, extending from the glabellar area to the posterior fontanelle via the metopic suture area, anterior fontanelle, and sagittal suture area. The skull with gaping midline defect appears to permit adequate accommodation of the growing brain.
 
iv.
Normal lambdoidal sutures in all cases
 
 
e.
During the first 2–4 years of life
i.
Obliteration of the midline defect by coalescence of the enlarging bony islands without evidence of any proper formation of sutures
 
ii.
Very early onset in fetal life of growth inhibition in the sphenofrontal and coronal suture area, suggested by an extremely short squama and orbital part of the frontal bone together with the posterior convexity of the coronal bone condensation line
 
 
 

Clinical Features

1.
History
a.
Headache and vomiting: signs of acute increase of intracranial pressure, especially in cases of multiple suture involvement
 
b.
Stridor and sleep apnea indicates upper airway problems, due to craniosynostosis of the base of the skull
 
c.
Visual disturbance due to exposure keratitis and conjunctivitis
 
d.
Mental retardation in many patients, though patients with normal intelligence have been reported
 
 
2.
Skull
a.
Craniosynostosis
 
b.
Coronal sutures most commonly involved, resulting in acrocephaly, brachycephaly, turribrachycephaly, flat occiput, and high prominent forehead
 
c.
Large late-closing fontanels
 
d.
Gaping midline defect
 
e.
Rare cloverleaf skull anomaly in approximately 4% of infants
 
 
3.
Facial features
a.
Horizontal grooves above the supraorbital ridges that disappear with age
 
b.
A break in the continuity of the eyebrows
 
c.
A trapezoid-shaped mouth at rest
 
d.
Flattened, often asymmetric face
 
e.
Maxillary hypoplasia with retruded midface
 
f.
Eyes
i.
Down-slanting palpebral fissures
 
iii.
Shallow orbits
 
iv.
Proptosis
 
v.
Exophthalmos
 
vi.
Lateral ptosis
 
vii.
Widened palpebral fissures
 
viii.
Tearing secondary to exposure keratitis
 
ix.
Prolonged corneal exposure resulting in corneal scars and opacification
 
x.
Partially open eye during sleep
 
xi.
 
xii.
Amblyopia
 
xiii.
Optic atrophy
 
xiv.
Keratoconus
 
xv.
Ectopic lentis
 
xvi.
Congenital glaucoma
 
xvii.
Lack of pigment in the fundi with occasional papilledema
 
xviii.
Rare luxation of the eye globes as an extreme complication of severe exorbitism, producing possible strangulation of the circulation of the globe and blindness
 
 
g.
Mouth
i.
A prominent mandible
 
ii.
Down-turned corners
 
iii.
High arched palate
 
iv.
Bifid uvula
 
v.
Cleft palate
 
vi.
Crowded upper teeth
 
vii.
Malocclusion
 
viii.
Delayed dentition
 
ix.
Ectopic eruption
 
x.
Shovel-shaped incisors
 
xi.
 
xii.
V-shaped maxillary dental arch
 
xiii.
Bulging alveolar ridges
 
 
h.
Ears
i.
Apparent low-set ears
 
ii.
Occasional conductive hearing loss
 
iii.
Congenital fixation of stapedial footplate
 
 
 
4.
Extremities and digits
a.
The upper limbs affected more severely than lower limbs
 
b.
Coalition of distal phalanges and synonychia of the hands (never present in the feet)
 
c.
The glenohumeral joint and proximal humerus affected more severely than the pelvic girdle and femur
 
d.
The elbow involved much less severely than the proximal portion of the upper limb
 
e.
Syndactyly of the hands and feet with partial-to-complete fusion of the digits, often involving second, third, and fourth digits. These often are termed mitten hands and socked feet. In severe cases, all digits are fused, with the palm deeply concave or cup-shaped and the sole supinated.
 
f.
Hitchhiker posture or radial deviation of short or broad thumbs resulting from abnormal proximal phalanx
 
g.
Brachydactyly
 
h.
Contiguous nailbeds (synonychia)
 
i.
Subacromial dimples and elbow dimples during infancy
 
j.
Limited mobility at the glenohumeral joint with progressive limitation in abduction, forward flexion, and external rotation
 
k.
Limited elbow mobility common with decreased elbow extension, flexion, pronation, and supination
 
l.
Short humeri, a constant finding beyond infancy
 
m.
Limited genu valga present in many cases
 
 
5.
Other skeletal and cartilaginous segmentation defects
a.
Congenital cervical spinal fusion (68%), especially C5–C6
 
b.
Aplasia or ankylosis of shoulder, elbow, and hip joints
 
c.
Tracheal cartilage anomalies
 
d.
Rhizomelia
 
 
6.
CNS
a.
Intelligence varying from normal to mental deficiency, though a significant number of patients are mentally retarded. Malformations of the CNS may be responsible for most cases.
 
b.
Common CNS malformations
ii.
Agenesis of the corpus callosum
 
iii.
Malformed limbic structures
 
iv.
Variable ventriculomegaly. Progressive hydrocephalus is uncommon.
 
vi.
Gyral abnormalities
 
vii.
Hypoplastic cerebral white matter
 
viii.
Pyramidal tract abnormalities
 
ix.
Heterotopic gray matter
 
x.
Papilledema and optic atrophy with loss of vision in cases with insidious intracranial pressure increase
 
 
 
7.
Cardiovascular (10%)
a.
Atrial septal defect
 
b.
Patent ductus arteriosus
 
c.
Ventricular septal defect
 
d.
Pulmonary stenosis
 
e.
Overriding aorta
 
f.
Coarctation of aorta
 
g.
Dextrocardia
 
i.
Endocardial fibroelastosis
 
 
8.
Genitourinary (9.6%)
a.
Polycystic kidneys
 
b.
Duplication of renal pelvis
 
c.
Hydronephrosis
 
d.
Stenosis of bladder neck
 
e.
Bicornuate uterus
 
f.
Vaginal atresia
 
g.
Protuberant labia majora
 
h.
Clitoromegaly
 
 
9.
Gastrointestinal (1.5%)
a.
Pyloric stenosis
 
b.
Esophageal atresia and tracheoesophageal fistula
 
c.
Ectopic or imperforate anus
 
d.
Partial biliary atresia with agenesis of gallbladder
 
 
10.
Respiratory (1.5%)
a.
Anomalous tracheal cartilage
 
b.
Tracheoesophageal fistula
 
c.
Pulmonary aplasia
 
d.
Absence of right middle lobe of the lung
 
e.
Absence of interlobular lung fissures
 
 
11.
Skin
a.
Hyperhidrosis (common)
 
b.
Acneiform lesions frequent after adolescence
 
c.
Interruption of the eyebrows
 
d.
Hypopigmentation
 
e.
Hyperkeratosis in the plantar surface
 
f.
Paronychial infections more commonly affected in feet than hands and observed more commonly in institutionalized patients
 
g.
Excessive skin wrinkling of forehead
 
h.
Skin dimples at knuckles, shoulders, and elbows
 
 
12.
At risk for complications resulting from elevated intracranial pressure despite surgical attempts to increase cranial capacity in infancy
 
13.
Early death
a.
Upper airway compromise
i.
Reduction in nasophrynx size
 
ii.
Choanal patency
 
iii.
Obstructive sleep apnea
 
iv.
Cor pulmonale
 
 
b.
Lower airway compromise due to anomalies of the tracheal cartilage
 
 
14.
Differential diagnosis
a.
Beare–Stevenson syndrome
i.
Mental retardation
 
ii.
Associated cutaneous disorders
a)
Cutis gyrata
 
b)
Acanthosis nigricans (hands and feet)
 
 
iii.
Caused by FGFR2 mutations
 
 
b.
Carpenter syndrome (see the chapter)
i.
An autosomal recessive disorder
 
ii.
A peculiar face
 
iii.
Preaxial polydactyly of hands, feet, or both
 
iv.
Absence of osseous fusion of hand bones
 
 
c.
FGFR3 -associated coronal synostosis syndrome
i.
Variable clinical presentation overlapping with Pfeiffer, Jackson–Weiss, or Saethre–Chotzen syndrome phenotypes
 
ii.
Some individuals with a disease-causing mutation may have no clinical problems
 
 
d.
Jackson–Weiss syndrome
i.
Caused by FGFR2 mutations
 
ii.
Enlarged or broad great toes with varus deviation
 
iii.
Tarsal or metatarsal fusion
 
iv.
Lack of thumb abnormalities
 
v.
Midface hypoplasia
 
 
e.
Pfeiffer syndrome
i.
Identifiable mutations in FGFR1 and FGFR2 (∼67% of patients)
 
ii.
Hand and foot abnormalities
a)
Broad thumbs and halluces
 
b)
Occasional cutaneous syndactyly
 
 
iii.
Lack of osseous fusion of the phalanges
 
iv.
Craniofacial features
a)
Turribrachycephaly
 
b)
Occasional clover-leaf skull
 
c)
Ocular hypertelorism
 
d)
Shallow orbits
 
e)
Sown-slanting palpebral fissures
 
f)
Proptosis
 
h)
Low nasal bridge
 
i)
Small nose
 
j)
Maxillary hypoplasia
 
k)
Mandibular prognathism
 
 
 
f.
Saethre–Chotzen syndrome (see the chapter)
i.
Characteristic facies
 
ii.
Relatively mild cranial deformity
 
iii.
Lack of osseous fusion of the hand bones
 
iv.
Identifiable mutations in the TWIST gene (∼75% of patients)
 
 
 

Diagnostic Investigations

1.
Psychometric evaluation
 
2.
Hearing assessment
 
3.
Imaging studies
a.
Skull radiography to evaluate craniostenosis, which usually involves coronal sutures and maxillary hypoplasia
i.
Sclerosis of suture line
 
ii.
Bony bridging and beaking along the suture line
 
iii.
An indistinct suture line
 
iv.
Turribrachycephaly
 
v.
Shallow orbits
 
vi.
Hypoplastic maxillae
 
 
b.
Spine radiography
i.
Spinal fusions, most commonly at the levels of C3-4 and C5-6, appearing to be progressive and occurring at the site of subtle congenital anomalies
 
ii.
Small-sized vertebral body and reduced intervertebral disc space: indicators of subsequent bony fusion
 
 
c.
Limb radiography
i.
Multiple epiphyseal dysplasia
 
ii.
Short humeri
 
iii.
Glenoid dysplasia
 
iv.
Cutaneous and osseous syndactyly
 
v.
Complete syndactyly involving the second and fifth digits (mitten hands)
 
vi.
Multiple progressive synostosis involves distal phalanges, proximal fourth and fifth metacarpals, capitate, and hamate.
 
vii.
Progressive symphalangism of interphalangeal joints
 
viii.
Shortened and radial deviation of distal phalanx
 
ix.
Delta-shaped deformity of proximal phalanx of the thumbs
 
x.
Complete syndactyly involving the second and fifth toes (socked feet)
 
xi.
Fusion of tarsal bones, metatarsophalangeal and interphalangeal joints, and adjacent metatarsals
 
xii.
Delta-shaped proximal phalanx of the first toes
 
xiii.
Occasional partial or complete duplication of the proximal phalanx of the great toes and first metatarsals
 
 
d.
Computed tomography
i.
CT scan with comparative 3-dimensional reconstruction analysis of the calvaria and cranial bases: the most useful radiological examination in identifying skull shape and presence or absence of involved sutures
 
ii.
Precise definition of the pathological anatomy, permitting specific operative planning
 
 
e.
Magnetic resonance imaging
i.
Demonstration of the anatomy of the soft-tissue structures and associated brain abnormalities
 
ii.
Visualization of the spatial arrangement of the bones
 
 
 
4.
Molecular analysis
a.
Exquisitely specific molecular mechanism with a narrow mutational spectrum
 
b.
More than 98% of cases: caused by specific missense substitution mutations, involving adjacent amino acids (Ser252Trp, Ser252Phe, or Pro253Arg) in exon 7 of FGFR2
 
c.
The remaining cases: due to Alu-element insertion mutations in or near exon 9
 
 

Genetic Counseling

1.
Recurrence risk
a.
Patient’s sib
i.
A negligible recurrence risk for patient’s sib when parents are not affected 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
 
ii.
50% risk, if a parent is also affected.
 
 
b.
Patient’s offspring: a 50% recurrence risk for an affected individual to have an affected offspring
 
c.
Advanced paternal age effect in new mutations has been shown clinically and demonstrated conclusively at the molecular level.
 
 
2.
Prenatal diagnosis
a.
Prenatal ultrasonography in low-risk pregnancies with finding of abnormal fetal skull shape
i.
Prenatal diagnosis of Apert syndrome suspected with findings of fetal “mitten hands” associated with abnormal skull shape and midfacial hypoplasia and confirmed by molecular diagnosis. Craniosynostosis is usually not detected until the third trimester.
 
ii.
Low yield for testing mutations in the FGFR2 gene
 
iii.
Mutation identification not helpful in determining the prognosis of a fetus, which is largely determined by the clinical diagnosis and not by the molecular diagnosis
 
 
b.
Prenatal MRI: a useful and sometimes indispensable, additional diagnostic tool (Weber et al. 2010)
 
c.
Fetoscopy to visualize fetal anomalies comparable to Apert syndrome in a pregnancy at risk: an invasive procedure not used currently
 
d.
Molecular genetic analysis
i.
An affected parent with identified mutation of FGFR2 gene: prenatal diagnosis available on fetal DNA obtained through amniocentesis or chorionic villus sampling
 
ii.
An affected parent without identified mutation of FGFR2 gene: linkage analysis available to an informative family with at least two affected family members based on an accurate clinical diagnosis and an accurate understanding of genetic relationships in the family
 
 
 
3.
Management
a.
Protection of the cornea
i.
Instill lubricating bland ointments in the eyes at bedtime to protect corneas from desiccation
 
ii.
Artificial teardrops during the day
 
iii.
Lateral or medial tarsorrhaphy in severe cases to narrow the palpebral fissure cosmetically and protect the corneas and the vision
 
 
b.
Upper airway obstruction during the neonatal period
i.
Remove excessive nasal secretions
 
ii.
Treat upper airway infection
 
iii.
Humidification with added oxygen
 
iv.
Judicious use of topic nasal decongestants
 
v.
Rarely requires orotracheal intubation
 
 
c.
Sleep apnea
i.
Polysomography (a sleep recording of multiple physiologic variables), currently the most reliable method for determining the presence of sleep apnea
 
ii.
Continuous positive pressure
 
iii.
Tracheostomy indicated in severely affected children
 
 
d.
Chronic middle ear effusion associated with bilateral conductive hearing deficit
i.
Antimicrobial therapy
 
ii.
Bilateral myringotomy and placement of ventilation tubes: the most effective treatment
 
 
e.
Craniofacial surgery
i.
Cranium
a)
Removes synostotic sutures
 
b)
Reshapes the calvaria
 
c)
Allows more normal cranial development to proceed with respect to shape, volume, and bone quality
 
d)
Relieves increased intracranial pressure
 
 
ii.
Orbits
a)
Correction of ocular proptosis: the primary objective of orbital surgery
 
b)
Reduction of increased interorbital distance (hypertelorism)
 
c)
Correction of increased interior malrotation
 
 
iii.
Nose
a)
Infants and child: nasal reconstruction focusing on correction of the excessively obtuse nasofrontal angle, flat nasal dorsum, and ptotic nasal tip
 
b)
Teenager and adult: reduction of the nasal tip bulk
 
 
iv.
Midface
a)
Normalization of midface appearance
 
b)
Expansion of the inferior orbit
 
c)
Volumetric expansion of the nasal and nasopharyngeal airways
 
d)
Establishment of a normal dentoskeletal relationship
 
 
v.
Mandible: mandibular osteotomies to improve dentoskeletal relations for masticatory and esthetic benefit
 
 
f.
Surgical reconstruction of syndactyly
 
g.
Psychological and social challenges confronted by individuals with Apert syndrome
i.
Emotional adjustment
 
ii.
Body image development
 
iii.
Impact of surgery and hospitalization on children with Apert syndrome
/static-content/images/672/chp%253A10.1007%252F978-1-4614-1037-9_14/MediaObjects/978-1-4614-1037-9_14_Fig10_HTML.jpg
Fig. 10
Radiograph of the right foot showing complete cutaneous syndactyly involving the second, third, fourth digits, and delta-shaped deformity of the proximal phalanx of the first toe
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Fig. 1
(ad) An infant with Apert syndrome showing characteristic facial appearance and typical mitten hands and socked feet
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Fig. 2
(ad) A 13-year-old girl with Apert syndrome showing characteristic facial appearance and postoperative status of the fingers and toes
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Fig. 3
(af) An adult with Apert syndrome showing typical craniofacial appearance, hearing loss (wearing hearing aids), and mitten hands. Radiographs showed cutaneous and osseous syndactyly, complete syndactyly involving the second through fifth digits (mitten hands), symphalangism of interphalangeal joints, delta-shaped proximal phalanx of the thumbs, complete syndactyly involving the second through fifth digits (socked feet), and partial duplication of the proximal phalanx of the great toes and first metatarsals
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Fig. 4
(ah) An adult with Apert syndrome showing typical craniofacial appearance with mitten hands and socked feet. Radiographs of hands and feet and skull showed cutaneous and osseous syndactyly, turribrachycephaly, shallow orbits, and hypoplastic maxilla
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Fig. 5
(ah) A daughter and a mother with Apert syndrome showing characteristic craniofacial features, mitten hands, and socked feet
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Fig. 6
(a, b) A 6-month-old male infant was evaluated for Apert syndrome which was diagnosed prenatally. The fetus was noted to have abnormal craniofacial features with mitten hands by ultrasonography. Molecular testing from cultured amniocytes indicated the presence of a C > G transversion at nucleotide 755 (c.755 C > G) of the fibroblast growth factor receptor 2 (FGFR2) gene. This change substitutes a tryptophan for a serine at amino acid 252 (p.S252W). The presence of this mutation is consistent with a clinical diagnosis of Apert syndrome. The infant showed severe acrocephaly, palpable coronal suture ridge, ocular hypertelorism with proptotic eyes, low-set ears, depressed nasal bridge, small soft palate cleft, hitchhiker like thumbs, mitten hands, and sock feet
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Fig. 7
Mitten-shaped hands with cutaneous syndactyly and synonychia
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Fig. 8
Radiograph of the right hand showing coalition of distal phalanges, symphalangism, cutaneous and osseous syndactyly, and delta-shaped deformity of the proximal phalanx of the thumb
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Fig. 9
Both feet showing socket-shaped feet, syndactyly of the feet with partial-to-complete fusion of the digits, involving second, third, and forth digits
 
 
 
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