Apert Syndrome Clinical Presentation

See the list below:

• Family history is usually not significant because most cases of Apert syndrome 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.

Skull and face

With craniosynostosis, coronal sutures most commonly are involved, resulting in acrocephaly, brachycephaly, turribrachycephaly, flat occiput, and high prominent forehead.

A case of Apert syndrome, confirmed by molecular genetic analysis, was observed in a newborn infant who did not have craniosynostosis at birth. Because this disturbance in osteogenesis may vary in timing and extent, the diagnosis of Apert syndrome should be considered even in the absence of this hallmark finding. ^[10]

Other characteristics include the following:

• 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 asymmetrical face is observed
• Maxillary hypoplasia with retruded midface is present

Ears, eyes, nose, and mouth

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 vision loss or blindness.

A study by Forte et al found that in both Crouzon and Apert syndrome, the bony orbit is shortened, orbital and orbital soft-tissue volumes are reduced, and the globe’s volume is increased. In the study, which included 10 children with Apert syndrome, nine children with Crouzon syndrome, and 12 controls, the length of the bony orbit was 12% and 17% shorter in the Apert and Crouzon syndrome patients, respectively; the bony orbital volume was 21% and 23% smaller, respectively; the globe’s volume was 15% and 36% larger, respectively; and the orbital soft-tissue volume was 19% and 29% less, respectively. ^[11]

Patients have apparent low-set ears, with occasional conductive hearing loss and congenital fixation of the stapedial footplate.

A retrospective study by Hogg et al documented inner ear anomalies, via CT scanning, in pediatric patients with Apert syndrome. The investigators found that in 12 out of 19 patients (63%), the lateral semicircular canal (SCC) was enlarged, while in 11 patients (58%), the bony window of the lateral SCC was absent. In 42% of the patients, both anomalies were present, giving the vestibular cavity a rectangular appearance. Of 11 patients for whom audiologic results were available, nine (82%) had conductive hearing loss. ^[12]

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, a high arched palate, a bifid uvula, and a 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. ^[13]

Extremities and digits

The upper limbs are more severely affected than lower limbs. Coalition of distal phalanges and synonychia found in the hands are 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.

Characteristics also include the following:

• Hitchhiker posture or radial deviation of short or broad thumbs results from abnormal proximal phalanx
• Brachydactyly occurs ^[14]
• 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

Central nervous system

Intelligence varies from normal to mental deficiency, although a significant number of patients have mental retardation. Malformations of the central nervous system (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. In a study of 94 patients with Apert syndrome, Breik et al found the main CNS abnormalities to also include prominent convolutional markings (67%), a crowded foramen magnum (36%), and a deficient septum pellucidum (13%). ^[15] 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

These include the following:

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

Skin

Cutaneous characteristics include the following:

• 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%)

Cardiovascular characterstics include the following:

• Atrial septal defect
• Patent ductus arteriosus
• Ventricular septal defect
• Pulmonary stenosis
• Overriding aorta
• Coarctation of aorta
• Dextrocardia
• Tetralogy of Fallot
• Endocardial fibroelastosis

Genitourinary

Genitourinary characteristics (9.6%) include the following:

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

Gastrointestinal

Gastrointestinal (GI) characteristics (1.5%) include the following:

• Pyloric stenosis
• Esophageal atresia and tracheoesophageal fistula
• Ectopic or imperforate anus
• Partial biliary atresia with agenesis of gallbladder

Respiratory

Respiratory characteristics (1.5%) include the following:

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

See the list below:

• 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. The incidence of FGFR2 mutations increases exponentially with paternal age, probably due to an increase in the frequency of these mutations and a selective advantage in the male germ line. ^{[16, 17]}

• 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.