Goldenhar Syndrome

Key Points at a Glance

Key Points of This Disease

• Goldenhar syndrome is a congenital craniofacial syndrome caused by abnormal development of the first and second branchial arches.
• The three main features are epibulbar dermoid (limbal dermoid), accessory tragus, and preauricular fistula; 85% are unilateral and more common on the right side.
• Astigmatism (approximately 10 D) caused by limbal dermoid can lead to amblyopia, so early ophthalmologic intervention is important. ⁷⁾
• It is often accompanied by systemic complications such as vertebral anomalies, heart malformations, and corpus callosum abnormalities, requiring multidisciplinary management.
• Most cases are sporadic, but autosomal dominant familial cases have been reported, with a sibling recurrence rate of 2–3%.
• Treatment follows age-specific protocols, with staged surgical correction from the neonatal period through adulthood.

1. What is Goldenhar syndrome?

Goldenhar syndrome is a congenital craniofacial syndrome resulting from abnormal development of the first and second branchial arches. It is also known as facio-auriculo-vertebral (FAV) dysplasia, hemifacial microsomia, and oculoauriculovertebral (OAV) dysplasia.

Canton first reported it in 1861, and in 1952 Goldenhar described the triad of eye, ear, and mouth involvement. In 1963, Gorlin added vertebral anomalies and named it OAV dysplasia, and in 1978 Smith proposed the FAV sequence.

The prevalence is estimated at 1:3,500 to 1:7,000, with a male-to-female ratio of 3:2. ¹⁾ A population-based study in Western Australia estimated 15.8 per 100,000. ³⁾ 85% of cases are unilateral, with a right-sided predominance. ³⁾ Developmental delay and intellectual disability occur in 5–15% of patients. ¹⁾

Most cases are sporadic, but autosomal dominant familial cases have been reported, with a sibling recurrence rate of 2–3%. Involvement of the MSX homeobox gene has been suggested. ⁵⁾

Q How often does Goldenhar syndrome occur?

A

The prevalence is estimated at 1:3,500 to 1:7,000, classifying it as a rare disease. The male-to-female ratio is 3:2, and 85% of cases are unilateral. ¹⁾³⁾ Most cases are sporadic, but familial occurrence has also been reported.

Q Is Goldenhar syndrome hereditary?

A

Most cases are sporadic, but autosomal dominant familial cases have been reported, with a sibling recurrence rate of 2–3%. There are reports of families with siblings showing similar symptoms. ³⁾ No specific gene mutation has been identified; chromosomal tests such as array CGH are used as adjuncts.

2. Main symptoms and clinical findings

Subjective symptoms

• Decreased vision and astigmatism: Limbal dermoid distorts the cornea, causing high astigmatism (about 10D) and amblyopia. ⁷⁾
• Hearing loss: Conductive or sensorineural. Can be severe if due to malformation of the inner ear or auditory nerve ⁶⁾
• Trismus: Associated with hypoplasia of the mandible and temporomandibular joint

Clinical Findings

Ocular Findings

Epibulbar dermoid (limbal dermoid): A white, hemispherical, solid tumor commonly located on the inferotemporal side of the corneal limbus. Contains hair follicles, sebaceous glands, and sweat glands. Causes high astigmatism and amblyopia. ⁷⁾

Eyelid coloboma: Commonly occurs in the upper eyelid. Bilateral cases have also been reported. ¹⁾

Bilateral corneal anesthesia: Leads to neurotrophic keratitis and persistent corneal epithelial damage. ⁶⁾

Others: Iris and choroidal coloboma, strabismus, Duane retraction syndrome, epicanthus, lacrimal duct anomalies, glaucoma

Ear and Facial Findings

Accessory auricle and preauricular fistula: Skin tags or fistulas anterior to the auricle. One of the three main signs of GS.

Auricular malformation: Ranges from anotia to mild deformities. ⁵⁾

Sensorineural hearing loss: Severe cases with agenesis of cranial nerve VIII and internal auditory canal atresia have been reported. ⁶⁾

Facial asymmetry: Unilateral macrostomia and hypoplasia of the mandibular ramus and condyle. CBCT can show reduced ramus height and width. ³⁾

Skeletal and systemic complications: Vertebral anomalies (hemivertebra, butterfly vertebra, fused vertebra) are found in about 60% as cervical fusion. ⁵⁾ Kyphoscoliosis (case report with Cobb angle 42°) requiring posterior spinal fusion has been reported. ⁵⁾ In severe cases with cardiac anomalies (VSD, truncus arteriosus, PDA, tetralogy of Fallot), a child with SpO2 as low as 68% has been reported. ⁵⁾

Q How does limbal dermoid affect vision?

A

Limbal dermoids can distort the cornea and cause high astigmatism of about 10 diopters. Since astigmatism can lead to amblyopia, early surgical excision is recommended. ⁷⁾ A case has been reported in which astigmatism was reduced from 10 D to 6 D by combining dermoid excision with lamellar keratoplasty.

3. Causes and Risk Factors

Abnormal migration of neural crest cells or abnormal vascular supply during the blastogenesis stage of embryogenesis (days 30–45 of gestation) is considered the main mechanism of developmental disorders. ¹⁾ Abnormal migration of mesoderm or neural crest cells leads to developmental disorders of the first and second branchial arches, resulting in various morphological abnormalities of the eyes, ears, jaw, and vertebrae. ¹⁾

Environmental risk factors (all from the literature):

• Drug exposure: thalidomide, cocaine, retinoic acid, tamoxifen
• Maternal diabetes: suggested association with fetal developmental abnormalities ³⁾
• Multiple pregnancy and smoking exposure during pregnancy
• Chromosomal abnormalities: associated with del(5p), del(6q), del(22q), etc.
• Consanguineous marriage

Reports of familial cases with similar symptoms in siblings suggest a possible genetic link. ³⁾

Prevention and Daily Care

• Goldenhar syndrome is a congenital condition, and there is no established prevention method.
• Always consult your doctor about medication use, smoking, and alcohol consumption during pregnancy.
• Continue regular ophthalmology visits for the affected child. Early detection and treatment of amblyopia are crucial for visual prognosis.
• If hearing loss is present, consider early intervention with hearing aids and speech therapy.

4. Diagnosis and Examination Methods

Diagnosis is primarily clinical. The presence of at least two of the following items is required for diagnosis. ⁵⁾

• Unilateral micrognathia
• Epibulbar dermoid cyst
• Unilateral mandibular hypoplasia
• Vertebral anomalies

Imaging diagnosis: CBCT (cone-beam CT) allows detailed evaluation of mandibular hypoplasia. ³⁾ MRI is useful for assessing corpus callosum abnormalities and agenesis of cranial nerve VIII. ¹⁾⁶⁾ Prenatal ultrasound at 11–15 weeks of gestation may also be performed.

Genetic testing: No specific genetic test for GS has been established, but array CGH (chromosomal microarray analysis) may be considered.

Differential Diagnosis

Key points for differentiating from similar diseases are shown below.

Disease	Characteristic Findings	Differentiation from GS
Treacher Collins syndrome	Zygomatic and mandibular hypoplasia	Usually bilateral
Townes-Brocks syndrome	Accessory ear, hearing loss	Associated with thumb abnormalities, anal atresia, and renal anomalies
CHARGE syndrome	Semicircular canal abnormalities	Mainly cardiac malformations, esophageal atresia, and cranial nerve disorders
Pierre Robin sequence	Micrognathia, glossoptosis	Mainly cleft palate and airway obstruction

5. Standard treatment

A multidisciplinary approach (ophthalmology, plastic surgery, oral surgery, otolaryngology, cardiac surgery, orthopedics, speech therapy) is essential. Treatment follows a staged protocol according to the patient’s age and severity.

Newborn to 2 years

Assessment of breathing, feeding, and sleep: Check for airway obstruction, feeding difficulties, and sleep apnea.

Management of cardiac malformations: Life-threatening cardiac anomalies such as truncus arteriosus and PDA require early surgery. ⁵⁾

Ophthalmologic evaluation: Assess for limbal dermoid and risk of amblyopia, and plan early intervention.

2 to 8 years old

Mandibular hypoplasia: In severe cases, consider costochondral grafting or bone distraction at 2–4 years of age.

Correction of external ear deformity: Surgical correction of external ear deformity is performed at 6–8 years of age.

Limbal dermoid excision: Early excision prevents amblyopia and strabismus. Cases have been reported where dermoid excision combined with lamellar keratoplasty reduced astigmatism from 10D to 6D, with stability maintained for 2 years postoperatively. ⁷⁾

Teenagers and older: Surgical correction of jaw deformity is performed. The principle is to perform final facial reconstruction after skeletal growth is complete.

Details of Ophthalmic Management

• Reconstruction of eyelid coloboma: Composite grafting using hard palate mucosa for posterior lamella reconstruction is one option. ²⁾
• Tarsal sharing: Timing of surgery requires caution due to the risk of occlusion amblyopia.
• Management of neurotrophic keratitis: Use preservative-free artificial tears, and perform temporary tarsorrhaphy if necessary. Healing within 3 months has been reported. ⁶⁾

Hearing Management

Hearing aids are the first choice. In cases of severe inner ear or auditory nerve malformation, cochlear implants are indicated, but in cases of bilateral VIII nerve aplasia, brainstem implants should be considered. ⁶⁾

Precautions in Treatment

• Delayed excision of limbal dermoid leads to fixation of amblyopia. Regular refraction examinations and occlusion therapy should be performed concurrently.
• If eyelid coloboma is left untreated, corneal damage due to corneal exposure progresses, so early surgical evaluation is necessary.
• If spinal abnormalities are present, careful positioning during general anesthesia is required.

Q At what age should treatment be started?

A

According to age-specific protocols, treatment is performed stepwise from the neonatal period. In the neonatal period, respiratory and feeding management and management of cardiac malformations take priority. For limbal dermoid, early childhood excision is considered if there is a high risk of astigmatism or amblyopia. Correction of external ear deformities is typically performed at 6–8 years of age, and final correction of jaw deformities is generally done after the teenage years.

6. Pathophysiology and Detailed Mechanisms

The first pharyngeal arch gives rise to the mandible, malleus, incus, masticatory muscles, and the V2/V3 regions of the trigeminal nerve. The second pharyngeal arch gives rise to the body and lesser horn of the hyoid bone, stapes, facial muscles, and facial nerve. ¹⁾ Abnormal migration of mesoderm or neural crest cells derived from these pharyngeal arches leads to various morphological abnormalities of the eyes, ears, face, jaw, and spine. ¹⁾

Abnormal vascular supply hypothesis: A mechanism has also been proposed in which local hematomas in the developing ear and jaw region destroy differentiated tissues.

Mechanism of limbal dermoid formation: During optic cup formation, ectodermal tissue becomes trapped in the mesoderm, leading to the formation of a dermoid tumor containing skin appendages such as hair follicles, sebaceous glands, and sweat glands at the limbus.

Association with the corpus callosum: MRI studies suggest that thinning of the corpus callosum in Goldenhar syndrome is a secondary change (gliosis) due to demyelination and axonal loss, which may contribute to developmental delay and epilepsy. ¹⁾

Jayaprakasan et al. (2023) reported an atypical case of an 8-year-old girl presenting with bilateral eyelid coloboma, limbal dermoid, and auricular skin tags. ¹⁾ MRI revealed thinning of the posterior corpus callosum and gliosis in the centrum semiovale and posterior corona radiata. Clinically, she exhibited developmental delay and seizures, and the significance of corpus callosum abnormalities in Goldenhar syndrome is discussed.

Mechanism of bilateral cranial nerve involvement: Subtle bilateral abnormalities in the lateral wall of the cavernous sinus or the superior orbital fissure are thought to cause damage to the ophthalmic branch of the trigeminal nerve. ⁶⁾ Neurotrophic keratitis due to corneal anesthesia occurs via this mechanism. ⁶⁾

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7. Latest Research and Future Perspectives (Investigational Reports)

For patients: Please read this

The following content is currently at the research stage or under clinical trial and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Stem cell therapy: Attempts at “reprogramming” limbal dermoid through fetal tissue transplantation have been reported, and research is ongoing aiming to halt tumor regrowth.

Research on the association between corpus callosum abnormalities and Goldenhar syndrome: MRI studies have proposed a new interpretation of secondary corpus callosum thinning based on gliosis, and ongoing research is elucidating its impact on neurodevelopment. ¹⁾

Understanding systemic vascular anatomical variations: During surgery for gallstone pancreatitis in a 43-year-old GS patient, angiography revealed an anatomical variation where the common hepatic artery branched from the SMA (superior mesenteric artery). ⁴⁾ When performing surgery on GS patients, it is necessary to keep in mind the existence of various anatomical variations.

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8. References

1. Jayaprakasan SK, Waheed MD, Batool S, et al. Goldenhar Syndrome: An Atypical Presentation With Developmental and Speech Delay. Cureus. 2023;15(3):e36225.
2. Bagheri A, Feizi M, Tavakoli M. Tessier number 9 craniofacial cleft associated with Goldenhar syndrome and its surgical management: A report of a rare case. J Curr Ophthalmol. 2023;35:93-5.
3. Kunjumon SP, Mathew アカントアメーバ角膜炎, Suma MS, Iqbal MZ. Diagnostic imageology of Goldenhar syndrome: Report of a rare case. Contemp Clin Dent. 2023;14:313-6.
4. Borra R, Hamidullah A, Ren T, Bhaskara V. A Curious Case of Multimorbidity in a Patient With Goldenhar Syndrome Presenting With Vomiting. Cureus. 2024;16(10):e72662.
5. Varma AR, Meshram RJ, Varma AR, et al. Multicorrection Goldenhar syndrome (facio-auriculo-vertebral dysplasia): a rare follow-up case of 12-year-old female. Pan Afr Med J. 2021;39:96.
6. Pandey S, Sati A, Kumar P, Kaushik J. Bilateral cranial nerve involvement with facial asymmetry in a case of Goldenhar syndrome. Med J Armed Forces India. 2022;78:S296-S299.
7. Sharma B, Bajoria SK, Breh R, Rana F. Astigmatic reduction after dermoid excision in a child with Goldenhar syndrome. Med J Armed Forces India. 2023;79:109-112.