Hypertelorism

Etiology

Experts believe hypertelorism is a result of an alteration in embryological facial development between the fourth and eighth week of fetal development. The frontonasal prominence is the embryological precursor of the forehead and nose. During normal development of the frontonasal prominence, lateral movement of the orbits followed by medial migration occurs. If an arrest occurs during the normal development of the frontonasal prominence, the primitive brain fills the space, preventing the normal medial migration of the orbits, causing an arrest in a lateral position.[4] 

A frank encephalocele and other masses in the frontonasal prominence can produce an obvious and extreme form of hypertelorism. Additional proposed mechanisms of hypertelorism include early ossification of the lesser wings of the sphenoid bone, preventing medial movement of the orbits, and causing fixation in the fetal position. In addition, craniosynostosis syndromes that result in premature closure of cranial sutures prevent normal orbital migration and development.[1] Children with Apert syndrome, one of the most common craniosynostosis syndromes, present with hypertelorism due to the prolapse of the cribriform plate of the ethmoid bone, causing a disturbance of the cranial base formation (see Image. Craniofacial and Oral Findings in Apert Syndrome).[4] Common genes involved in the pathogenesis of craniosynostosis include fibroblast growth factor receptor 1 (FGFR1), FGFR2, FGFR3, muscle segment homeobox (MSX2), ephrin-B1 (EFNB1), and transcription factor twist homologue 1 (TWIST1).[5]

Hypertelorism is not a syndrome in and of itself but rather a physical finding in many craniofacial syndromes. When evaluating a patient with hypertelorism, clinicians must consider the proposed embryological mechanisms. When the embryonic frontonasal prominence fails to develop normally, the patient will present with median facial clefting (also often referred to as frontonasal dysplasia). Alternatively, when dysplasia of bone development is the underlying contributive factor to hypertelorism, patients will present with craniosynostosis or cranial bone abnormalities. 

Syndromes associated with hypertelorism include the following:

• Craniosynostosis syndromes like Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Muenke syndrome, Jackson-Weiss syndrome, and Boston-type MSX2-related syndrome
• Bohring-Optiz syndrome
• Greig Cephalopolysyndactyly
• Noonan syndrome
• Joubert syndrome
• 4p deletion
• 9p duplication
• Tetrasomy 12p 
• Trisomy 18
• 22q11 syndrome
• Multiple pterygium syndrome
• Neurofibromatosis type 1
• Aarskog syndrome
• Cat-eye syndrome
• CHARGE association
• Larsen syndrome
• Loeys-Dietz syndrome
• Wolf-Hirshorn syndrome
• Morquio syndrome
• Opitz BBB syndrome
• Pena Shokeir syndrome
• Roberts syndrome
• Skeletal dysplasias
• Hurler Syndrome [6][7] 

Epidemiology

Frontonasal dysplasia or median facial clefting is rare, presenting in approximately 0.17% of all patients with clefting.[8] The incidence of clefting is approximately 1 per 700 births.[9] Craniosynostosis occurs in approximately 1 per 2000 live births, though not all patients with craniosynostosis syndromes have hypertelorism.[10] The overall estimated incidence of hypertelorism is rare, with some sources estimating the occurrence to be approximately 1 in 20,000 births.[11]

Pathophysiology

Hypertelorism occurs due to increased distance between the orbits, often resulting from developmental anomalies affecting craniofacial structures. The pathogenesis primarily involves aberrant neural crest cell migration and disrupted embryologic development of the cranial base.[12] The condition is frequently associated with midline defects, such as frontonasal dysplasia, craniosynostosis syndromes, and chromosomal abnormalities such as trisomy 18.

During normal development, the orbits form from neural crest-derived mesenchyme, contributing to facial morphogenesis. The failure of proper fusion of the frontonasal and maxillary processes or premature synostosis of cranial sutures leads to outward displacement of the orbits. Additionally, anomalies in the sphenoid and ethmoid bones contribute to the widened interorbital distance. Disruptions in signaling pathways, such as FGFR2 mutations in syndromic craniosynostosis, further support the genetic basis of hypertelorism.[6][13] 

History and Physical

Isolated hypertelorism is rare. Thus, clinicians must evaluate a patient with hypertelorism for additional physical findings. Clinicians typically observe hypertelorism at birth and, in some cases, even detect it prenatally as fetal ultrasound technology becomes more advanced.[7] Hypertelorism associated with medial clefting of the face or dysplasia of nasal capsule development is more likely to be associated with other congenital anomalies. Results from a study evaluating prenatally diagnosed hypertelorism revealed karyotypic aneuploidy as the most common finding occurring in 82% of fetuses. Study results reveal that all 11 fetuses have additional anomalies of the nervous system (n = 10), skeleton (n = 6), heart (n = 5), kidneys (n = 5), or abdomen (n = 3).[14]

Hypertelorism associated with craniofacial synostosis may be syndromic or nonsyndromic. Of the craniosynostosis syndromes, patients with Apert syndrome have a sunken appearance of the midface, beaked nose, crowding of the teeth, an underdeveloped maxilla, visual difficulties secondary to shallow eye sockets, mild to moderate intellectual disability, syndactyly or polydactyly, hyperhidrosis, and cleft palate.[15] Carpenter syndrome can present with a cloverleaf skull shape, low set ears, abnormal dentition, syndactyly or polydactyly, intellectual disability, umbilical hernia, obesity, congenital heart disease, hip and spine deformities, and genital abnormalities.[16] Patients with Crouzon syndrome can present with midface hypoplasia, a beaked nose, dental anomalies, hearing loss, and normal intelligence (see Image. Crouzon Syndrome in a Patient Exhibiting Craniofacial Deformities).[17]

Ultimately, the physical examination is variable, depending on the underlying etiology of hypertelorism. Thus, when clinicians discover hypertelorism, they must conduct a comprehensive physical examination to identify additional dysmorphic features or congenital abnormalities. Evaluation of a patient with hypertelorism, or pseudohypertelorism, is not complete without a comprehensive, head-to-toe physical examination for dysmorphology. Exam findings may offer clues to an underlying syndromic diagnosis. 

Physical examination may reveal the following findings: 

Craniofacial Examination

• Flat or prominent nasal bridge
• Small mandible
• Flat or prominent occiput
• Metopic ridge
• Low-set ears
• Large posterior fontanelle
• Malar hypoplasia
• Anteverted nose [18]

Ear Examination

• Preauricular tags or sinus
• Large or small ears
• Asymmetric size
• Posterior rotation
• Lack of usual fold of helix [18]

Oral Examination

• Bifid uvula
• High-arched palate
• Wide alveolar ridges
• Large tongue
• Thin upper lip
• Flat philtrum [18]

Ocular Examination

• Synophrys
• Epicanthal folds
• Hypo- and hypertelorism
• Ptosis
• Short palpebral fissures
• Upward slant to palpebral fissures
• Downward slant to palpebral fissures [18]

Integumentary Examination

• Low hairline
• Frontal upsweep/aberrant hair whorl
• Alopecia of the scalp
• Extra posterior cervical skin
• A large capillary hemangioma, other than on the posterior neck
• Café au lait spots
• Hypopigmented macules [18]

Chest Examination

• Short sternum
• Depressed sternum
• Wide-set or high-located nipples
• Shield chest [18]

Abdominal and Perineal Examination

• Deep sacral dimple
• Diastasis recti (>3 cm)
• Aplasia cutis congenital
• Umbilical hernia
• Inguinal hernia
• Small testes
• Hypospadias
• Small or hypoplastic genitals [18]

Foot Examination

• Syndactyly of toes
• Overlapping toes
• Wide gap ("sandal-gap") between toes
• Prominent heel
• Broad hallux
• Hallux valgus
• Hypoplastic nails [18]

Hand Examination

• Single palmar crease
• Other unusual crease patterns
• Clinodactyly
• Duplication of the nail
• Camptodactyly
• Partial cutaneous syndactyly
• Proximally placed thumb
• Broad thumb
• Duplication of thumbnail
• Small or dysplastic nails
• Overlapping fingers
• Long fingers
• Small or large hands
• Short metacarpals [18]

Evaluation

Evaluating a patient with hypertelorism involves taking specific facial measurements. While bony interorbital distances obtained through radiographs or computed tomography (CT) scans provide the most accurate data—especially for surgical planning—these methods are not practical for the initial clinical assessment.[19] Instead, clinicians obtain precise measurements using proper techniques and anatomical landmarks (see Image. Landmarks for Measuring Intercanthal Distance, Interpupillary Distance, and Outer Canthal Distance). To perform these measurements, the patient should sit comfortably facing the examiner, with both heads level and the patient looking straight ahead. (See Table. Mean Inner Canthal Distance by Age and Table. Outer Canthal Distance by Age.) A small transparent plastic ruler is placed across the nasal bridge to measure the ICD, OCD, and IPD. These values are then compared to normative data, with hypertelorism typically defined by measurements exceeding the 95th percentile. Standardized normative value tables, including abbreviated versions, are readily available online. The following tables include an abridged version adapted from the standard normative values.[20][21]

Table. Mean Inner Canthal Distance by Age

Table. Outer Canthal Distance by Age

In adults, clinicians use the Tessier classification to differentiate hypertelorism into 3 degrees based on the ICD. The Tessler classification system is as follows:

• First degree: The ICD is 30 to 34 mm
• Second degree: The ICD is 35 to 40 mm
• Third degree: The ICD is greater than 40 mm [22]

CT scan classification or Munro and Das classification classifies hypertelorism based on the orientation of the medial orbital walls on axial scan (see Image. Munro and Das Classification Based on Computed Tomography Appearance of Orbital Medial Walls).

• Type I: Parallel medial orbital walls
• Type II: Wedge-shaped walls posteriorly
• Type III: Oval widest dimension
• Type IV: Wedge-shaped anteriorly positioned ethmoid bone, posterior to the globe [23][24]

Clinicians determine additional necessary testing based on the associated examination findings. Depending on the underlying etiology or genetic syndrome contributing to the finding of hypertelorism, additional tests may include genetic testing, an echocardiogram to evaluate for congenital heart disease, a renal ultrasound to assess for structural congenital malformations, a skeletal survey, brain magnetic resonance imaging to evaluate underlying neuronal changes, or a mass, retinal examination, audiology testing, or sleep study.

Treatment / Management

Surgical correction of hypertelorism is primarily pursued for cosmetic reasons, though it can also address functional concerns in severe cases. The procedure is complex and typically requires both intracranial and extracranial approaches. Dr Paul Tessier pioneered this surgery, showing that surgeons could reposition the orbits without compromising vision. The primary goals are to medially reposition the orbits, correct any orbital dystopia, reconstruct the nasal bridge, and remove excess soft tissue to restore facial symmetry.

Surgeons usually operate when children are between 5 and 7 years of age. Operating before age 5 can interfere with the development of the maxillary arch and dental structures and present challenges due to underdeveloped bone strength. While surgical outcomes are more predictable in adults, early intervention is often preferred to address the psychosocial impacts of visible facial differences. Coexisting craniosynostosis should undergo correction within the first year of life. Orbital osteotomies are typically paired with soft tissue adjustments to create a more natural facial appearance.

The correction of hypertelorism requires a highly individualized, multidisciplinary approach. A collaborative team—often including craniofacial surgeons, neurosurgeons, and ophthalmologists—works together to plan and execute the procedure. Advances in imaging and 3- dimensional surgical planning have significantly improved precision and outcomes. Preoperative assessments guide the surgical plan, considering factors such as the degree of orbital displacement, associated craniofacial anomalies, orbital axis, and maxillary morphology.

Surgical Approaches

Box osteotomy

A box osteotomy involves a combined medial and lateral orbital osteotomy, followed by repositioning the orbits closer to the midline. This procedure lets the surgeon medially reposition the entire bony orbit by making precise bone cuts around the orbital rim, effectively narrowing the interorbital distance. Clinicians utilize this technique in patients with a normal maxillary arch and dental occlusion, normal orbital axis, and mild to moderate hypertelorism. The size and shape of the maxillary arch are crucial; if these are normal, clinicians prefer a box osteotomy as the focus is solely on repositioning the orbits.[25] 

Facial bipartition (Van der Meulen Technique) 

Clinicians use the facial bipartition or the Van der Meulen technique when hypertelorism is present along with narrowing of the maxillary arch as in Apert syndrome.[26][27] The procedure medializes and rotates the orbits, and lateralizes and expands the maxillary arch. The surgical approach involves making vertical osteotomies or bone cuts on either side of the facial midline, separating the midface into 2 distinct segments. Once separated, the facial halves are rotated inwards towards the midline, allowing for the narrowing of the orbital distance and correction of the width of the maxillary arch.[28] 

Monobloc advancement

Monobloc advancement involves repositioning and forward advancement of the entire front of the skull. This technique is useful for patients with severe craniofacial deformities. Osteotomies are made along the facial skeleton, detaching the midface from the skull. Then, clinicians move the entire facial structure to narrow the space between the eyes and correct other facial features. 

Additional procedures

Patients may require multiple other procedures and staged surgeries. Additional procedures include segmental orbital osteotomy, U-shaped osteotomy, rhinoplasty, canthopexy, dorsal nasal augmentation, and fronto-galeal flap.[1][29]

Differential Diagnosis

Pseudohypertelorism and telecanthus are important considerations in the differential diagnosis of hypertelorism, as both can create the appearance of widely spaced eyes without actual lateral displacement of the orbits. Pseudohypertelorism is a false impression of orbital widening, often due to facial features such as a flat nasal bridge, epicanthic folds, exotropia, narrow palpebral fissures, or widely spaced eyebrows. Telecanthus, on the other hand, is defined by an increased inner canthal distance with a normal outer canthal distance and no actual change in orbital positioning. Telecanthus is frequently associated with prominent epicanthic folds and is present in various genetic syndromes, including Down syndrome, Ehlers-Danlos syndrome, Klinefelter syndrome, Turner syndrome, fetal alcohol syndrome, Cri du Chat syndrome, and Waardenburg syndrome.[30]

Differentiating true hypertelorism from these mimicking conditions is essential for accurate diagnosis and appropriate management. Unlike true hypertelorism—which involves actual lateral displacement of the bony orbits—pseudohypertelorism and telecanthus do not require surgical correction of orbital positioning. Accurate clinical evaluation helps distinguish between these entities and guides further genetic, surgical, or supportive interventions.

Prognosis

Long-term outcomes depend on the underlying cause and the presence of other abnormalities. Patients with mild, isolated hypertelorism usually have a favorable prognosis, while those with syndromic hypertelorism may experience a range of developmental challenges and health complications related to associated congenital anomalies.

Complications

Because hypertelorism is associated with genetic syndromes, affected patients may experience developmental delays, intellectual disabilities, midline clefts, encephaloceles, and agenesis of the corpus callosum, among other anomalies. Their physical appearance may cause a negative self-image and difficulty integrating with peers. Patients who undergo surgical correction are at risk for bleeding, cerebrospinal fluid leak, infection, injury to the brain, blood vessels, and cranial nerves, ophthalmic injuries, dural tears, vision loss, blindness, and ptosis. In addition, affected patients can have a recurrence of hypertelorism.[29]