Goldenhar Syndrome – Symptoms and Treatment

Disease Definition and Causes

Goldenhar Syndrome is a rare congenital anomaly that alters the size and shape of facial structures. Typically, the changes are localized to one side of the face, causing asymmetry, but bilateral involvement can also occur.

This syndrome falls within the spectrum of congenital anomalies of the skull and facial structures, collectively termed “craniofacial microsomia.” This term refers to the reduction in size of any structure within the craniofacial region.

Synonyms for the syndrome: oculoauricular dysplasia, facio-auriculo-vertebral association, first and second branchial arch syndrome, otomandibular dysostosis, hemifacial microsomia, among others.
The approximate incidence rate of Goldenhar Syndrome is 1 case per 3500-25000 newborns. It occurs in males twice as often as in females.
The exact causes of the disease are still not fully understood. Most cases occur sporadically in families with no known medical history. However, 1-2% of patients with Goldenhar Syndrome have close relatives with a similar disorder, indicating the role of genetic factors in the development of this condition. Specifically, the involvement of the MYT1 gene, located on locus q13.33 of chromosome 20, is presumed.

Another possible factor in the development of Goldenhar Syndrome is chromosomal anomalies – loss or duplication of a chromosome segment. Typically, individuals with these disorders may have associated developmental defects such as heart, lung, kidney, limb, and central nervous system abnormalities.
Some researchers believe that disrupted blood flow or external damaging factors may contribute to the formation of the syndrome:

• Taking certain medications contraindicated during pregnancy;
• Harmful habits;
• Chemical and physical agents affecting the fetus during weeks 3-8 of intrauterine development.
  Additionally, the role of obstetric-gynecological factors such as previous abortions, diabetes, and obesity cannot be ruled out.
  The first descriptions of congenital anomalies of facial structures were found in ancient texts dating back to 2000 BCE. In Colombia and Mexico, ancient ceramic artifacts depicting various forms of hemifacial microsomia, including hereditary ones, have been found: one such artifact depicted a parent with a child in their arms, both having similar facial anomalies.

Symptoms of Goldenhar Syndrome

Goldenhar Syndrome is characterized by facial asymmetry (unilateral underdevelopment of the jaw) combined with anomalies of the ear shells, benign eye tumors, and spinal cord involvement (typically in the cervical spine). In most cases, these abnormalities are localized on the right side. However, up to 30% of people with Goldenhar Syndrome have bilateral anomalies of facial structures.

Facial anomalies associated with the syndrome include:

• Facial clefts and palate, anomalies of facial muscles, upper and lower jaws, cheekbones, and temporal bones.
• Ear shell anomalies: ranging from underdevelopment or complete absence of the ear shell to the formation of periauricular skin growths with normally formed ear shells.
• Eye anomalies (less common): unilateral or bilateral reduction of the eyeball (microphthalmia) to its absence (anophthalmia), epibulbar dermoid cysts of the eye (benign tumors), and retinopathies.

These facial anomalies may be accompanied by hearing impairment, improper tooth development and eruption, and other disorders that can affect the psycho-physical development of the child.

Pathogenesis of Goldenhar Syndrome

Facial structures begin to form in the early stages of pregnancy. By the second week of embryo development, the primary oral cavity forms at the embryonic head. By the end of the third week, it gradually deepens, reaching the foregut (endoderm), and, connecting with it, forms the beginning of the digestive tract. At the same time, on the sides of the embryo’s head, two indentations appear – the 1st and 2nd branchial arches, and a little later – the 3rd and 4th arches. Between them, branchial or pharyngeal arches are formed, consisting of several parts: pouch, arches, grooves, and membranes.

By the end of the first month of embryo development, the first branchial arch gives rise to five ectodermal prominences: frontal, two maxillary, and two mandibular. The unpaired frontal prominence in the third week divides into medial and lateral nasal prominences, from which, by the end of the 10th-11th week of intrauterine development, the forehead, eye sockets, nose, middle parts of the upper jaw, and upper lip are formed. The mandibular prominences form a single structure by the end of the fourth week, and the maxillary prominences by the sixth week of development. Also, by the sixth week, the tongue is formed from the paired lateral outgrowths of the mandibular arch. By the seventh week, the maxillary prominences unite with the frontal ones, resulting in the formation of the lips.

The formation of the ear shell involves the first and second branchial arches. The first arch forms the anterior third of the external ear – the tragus and the helix. Fusion of derivatives of both arches occurs very early: by the eighth week of development, the primary ear shell is already formed, however, the final relief of the ear is only completed by the end of the seventh month of embryo development.

Thus, the upper and lower jaws, chewing and facial musculature, external ear, and bony structures of the middle ear are formed from the first and second branchial arches from the third to the eighth week of embryo development. This period is “critical” for the occurrence of facial and jaw development defects. Disrupting normal development of craniofacial structures at this stage can result from combined effects of external factors, chromosomal, and genetic anomalies.

Classification and Stages of Development of Goldenhar Syndrome

The extent of defects in facial structures is assessed using the OMENS classification, which distinguishes five groups of anomalies:

• O – involvement of the eye socket;
• M – underdevelopment of the lower jaw;
• E – ear anomaly;
• N – involvement of the nerve;
• S – deficit of soft tissues.

The severity of these defects is determined by the classification created by scientists Pruzansky S. and Kaban L. B.:

• Grade 1 – reduction of the lower jaw and the glenoid fossa of the temporal bone while maintaining the anatomy of other structures;
• Grade 2a – deformation of the mandibular branch, condylar process, and glenoid fossa, accompanied by deficit of masticatory muscles, with the function of the temporomandibular joint preserved;
• Grade 2b – underdevelopment and deformation of the condyle and glenoid fossa, with the temporomandibular joint non-functional;
• Grade 3 – absence of the mandibular branch, condyle, and glenoid fossa with pronounced deficit of soft tissues on the affected side, the temporomandibular joint not formed.

Based on his long-term observations, dental surgeon G. V. Kruchinsky identified three variants of Goldenhar syndrome, each of which he subdivided into several types:

First and second pharyngeal arch syndrome:

• Unilateral ear type: symmetrical face with anomalies in the auricle.
• Unilateral maxillofacial and ear type (rarely bilateral): facial asymmetry due to underdevelopment of the jaws and other adjacent structures of mild to moderate severity.
• Unilateral craniofacial, joint, and ear type (rarely bilateral): pronounced facial asymmetry due to severe underdevelopment of the jaws and adjacent structures, absence of the joint process, head, or even the joint cavity, subcutaneous tissue atrophy, salivary glands, facial and masticatory muscles.

First pharyngeal arch syndrome:

• Unilateral mandibular type: moderate facial asymmetry due to moderate underdevelopment of the mandible with preservation of the auricle shape, narrowing of the auditory canal, or fistula.
• Unilateral or bilateral mandibular and ear type: moderate facial asymmetry due to moderate underdevelopment of the mandible with narrowing of the auditory canal and auricular anomaly (drooping, reduction, etc.).

According to the European Orphanet Rare Diseases Database, all clinical manifestations of Goldenhar syndrome can be divided into three groups:

Very common (80-99%):

• Facial asymmetry.
• Underdeveloped upper jaw.
• Hearing impairment.
• Ear anomalies (extra auricular horns).
• Flattening of facial cheeks.

Common (30-79%):

• Inner and middle ear anomalies.
• Vertebral anomalies.
• Auricular anomalies (often unilateral), up to underdevelopment.
• Atresia (closure) of the external auditory canal.
• Micrognathia.
• Breastfeeding disorders.
• Speech impairment.
• Cleft palate and/or lip (cleft lip).

Rare (5-29%):

• Agenesis of the corpus callosum (absence of pathways between the right and left hemispheres).
• Absence of one or both kidneys.
• Laryngeal anomalies.
• Rib anomalies.
• Underdevelopment or absence of eye, big toes.
• Cerebral cortex atrophy.
• Autism.
• Ventriculomegaly (enlargement of brain ventricles).
• Lung underdevelopment.
• Kidney malposition.
• Underdevelopment of part of the upper eyelid (coloboma).
• Laryngeal and tracheal anomalies.
• Macrostomia (non-closure of the mouth angle).
• Muscle hypotonia (weakness).
• Vision impairment.
• Short stature.
• Heart defects (Tetralogy of Fallot, ventricular septal defect).
• Scoliosis.
• Tracheoesophageal fistula.
• Intellectual disability.

Complications of Goldenhar syndrome:

In early age, asymmetry of the lower jaw leads to improper development and progressive deformation of the upper jaw and other facial skeletal structures. Over time, the child may find it difficult to chew and swallow. In cases of severe underdevelopment of the lower jaw, patients may experience persistent breathing problems, including sleep apnea (breathing pauses).

Overall, facial clefts and/or palatal defects, underdevelopment of the upper and lower jaw, facial muscles, zygomatic and/or temporal bones can cause problems with teeth, feeding difficulties, speech impairment, and changes in facial aesthetics.

Ear anomalies, in some cases, are accompanied by atresia (closure) of the auditory canal or its complete absence, leading to hearing impairment. This makes it difficult for the child to orient themselves in space since they cannot understand where a particular sound is coming from.

Eye anomalies, such as dermoid cysts and colobomas (underdevelopment of part of the upper eyelid), can lead to visual impairment, including partial or complete loss of vision.

Diagnosis of Goldenhar syndrome:

Diagnosing Goldenhar syndrome is usually straightforward. The diagnosis is based on assessing external features, clinical symptoms, and the results of additional tests such as CT scans, X-rays, cranial CT scans, echocardiography, and ultrasound. CT scans are typically performed to prepare the child for surgical treatment.

An essential part of fetal ultrasound screening at 18-20 weeks of gestation is evaluating facial structures. The examination method includes multidimensional assessment of the position and sizes of the orbits, structures of the eyeballs, proper formation of the jaws, nose, and philtrum, and the position and shape of the auricles. Fetal ultrasound examination of facial structures allows detection of underdevelopment of the lower jaw, cleft lip and/or palate, absence or underdevelopment of the eye and outer ear.

Genetic testing may be suggested to confirm the diagnosis, i.e., to rule out genetic conditions, including those involving similar facial anomalies associated with chromosomal and monogenic disorders. These conditions include progressive hemifacial atrophy, Nager syndrome, jaw and facial dysostosis, among others. However, no minimal diagnostic criteria have been established. Descriptions exist of individual cases diagnosed with this syndrome using testing before birth.

After birth, all children are assessed for hearing before they reach six months to prevent delays in psycholinguistic development. For this purpose, auditory evoked potentials are measured: recording the brain’s response to auditory stimuli. Often, hearing impairment is detected on the affected side in children with Goldenhar syndrome.

Treatment of Goldenhar syndrome

Treatment of Goldenhar syndrome involves multi-stage surgical interventions performed at different stages of craniofacial growth and development. The treatment is prolonged and depends on the localization and severity of the pathology. It aims to restore the shape and size of the jaws, outer ear, and other structures, as well as to restore hearing function, improve chewing, and enhance facial aesthetics.

The management of Goldenhar syndrome manifestations should begin as early as possible. Timely correction of jaw abnormalities by an orthodontist contributes to successful surgical treatment later on and maintains the balance of the facial skeleton.

Individually tailored endoprostheses or bone-cartilage autotransplants from ribs, which have a tendency to grow, are used to correct severe lower jaw defects. Silicone endoprostheses or autotransplants are also used to correct defects of the outer ear.

In cases of hearing impairment, hearing aids or alternative methods of hearing prosthetics are used. Regular sessions with a deaf educator and speech therapist are also necessary. All of these measures help prevent the child from falling behind in speech and overall development.

Feeding issues are addressed by using special bottles and nasogastric tubes, which are inserted into the stomach through the nose.

Growths located on the surface of the eyeballs may be removed in cases of vision impairment or if the tumor is large. For children under 7 years old, cyst removal surgery is performed under anesthesia. Congenital heart defects, kidney problems, and/or spinal anomalies are also corrected surgically.