Goldenhar Syndrome

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In 1952, Goldenhar described a pair of monozygotic twins discordant for hemifacial microsomia, mandibular hypoplasia, auricular malformations, and epibulbar dermoids. Gorlin et al.

later in 1963 coined the term “oculoauriculovertebral dyspla- sia” to describe patients with mandibular hypoplasia, microtia, epibulbar dermoids, and vertebral anomalies. Goldenhar syn- drome occurs in about 1 in 3500 live births.

GENETICS/BASIC DEFECTS

1. The term, “Oculoauriculovertebral dysplasia spectrum”, suggested to represent an etiologically diverse spectrum of congenital anomalies

a. Oculoauriculovertebral dysplasia (OAVS)

b. Facioauriculovertebral syndrome (Goldenhar-Gorlin syndrome)

c. Hemifacial microsomia (2nd most common facial anomaly, second only to cleft lip and palate)

d. Hemifacial microtia e. Otomandibular dysostosis

f. Original Goldenhar syndrome g. Goldenhar-Gorlin syndrome

h. Anomalies of the first and second branchial arches 2. Congenital anomalies

a. Usually unilateral b. Primarily right sided

c. More common in monozygous twins usually with one affected

3. Causes: unknown but likely heterogeneous a. Usually sporadic occurrence

b. Maternal teratogenic exposures i. Retinoic acid

ii. Thalidomide iii. Primidone

iv. Cocaine

c. Presumed vascular disruption d. Maternal diabetes

e. Discordant occurrence in monozygotic twins: aris- ing from a disturbance of blastogenesis leading to malformations

f. Autosomal dominant inheritance g. Autosomal recessive inheritance h. Associated chromosome abnormalities

i. Del(5p) ii. Monosomy 6q iii. Trisomy 7

iv. Dup(7q) v. Dup(8q)

vi. Trisomy 9 (mosaic) vii. Del(18q)

viii. Der(18) ix. R(21)

x. Del(22)(q13.31) xi. Dup(22)(q11.2q13.1)

xii. Trisomy 22 (mosaic) xiii. 47,XXY

xiv. 49,XXXXY

4. Pathogenesis: unknown but likely heterogeneous

a. Interference with vascular supply and focal hemor- rhage in the developing first and second branchial arch region

b. Impaired interaction of cranial neural crest cells with branchial arch mesenchyme

c. A disorder of blastogenesis

5. Hypothesis: candidate genes for OAVS, particularly in familial cases

a. Homeobox genes, especially of the MSX class i. Msx critical for the differentiation of first

branchial arch ectoderm-mesenchyme leading to various craniofacial structures

ii. Strongly expressed in cephalic neural crest cells prior to migration of the cells that contribute extensively to craniofacial development

b. Encompasses previous partial pathogenetic explana- tions for OAVS, including neurocristopahty and developmental field defects, and represents a unifying concept regarding the wide spectrum of involvement in OAVS

c. Mutations result in partial loss of function of these gene could explain incomplete penetrance and clini- cal variability occurring in individuals with different genetic backgrounds

CLINICAL FEATURES

1. Major clinical features a. Ocular manifestations

i. Epibulbar dermoids or lipodermoid ii. Unilateral microphthalmia

iii. Upper eyelid coloboma iv. Strabismus

v. Diminished visual acuity vi. Tilted optic disc

vii. Optic nerve hypoplasia viii. Tortuous retinal vessels

ix. Macular hypoplasia and heterotropia x. Microphthalmia

xi. Anophthalmia b. Ear anomalies

i. Microtia

ii. Preauricular tags and/or pits iii. Middle ear anomaly

iv. Inner ear defects v. Variable deafness c. Vertebral defects

i. Hemivertebrae

ii. Hypoplasia of vertebrae, usually cervical iii. Abnormal ribs

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Goldenhar Syndrome

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466 GOLDENHAR SYNDROME

d. Hemifacial microsomia i. Unilateral microtia

ii. Ipsilateral hypoplasia of malar, maxillary, and mandibular region, especially temporomandibular joint

iii. Ipsilateral macrostomia

iv. Ipsilateral hypoplasia of the facial musculature 2. Other associated features

a. Craniofacial features i. Cranial nerve palsy ii. Cleft lip/palate

iii. Malfunction of soft palate iv. Decreased parotid secretion

v. Anomalies in function or structure of the tongue vi. Low scalp hair line

vii. Brachial cleft remnants in anterior-lateral neck b. CNS anomalies

i. Hydrocephaly ii. Microcephaly iii. Plagiocephaly

iv. Frontal/occipital encephalocele v. Cranial bifidum

vi. Lipoma vii. Dermoid cyst

viii. Arnold-Chiari malformation ix. Lissencephaly

x. Holoprosencephaly/arhinencephaly xi. Arachnoid cyst

c. Congenital heart diseases (5–58% depending on ascertainment of cases)

i. Tetralogy of Fallot (with or without right aortic arch) and VSD (account for over half of the cases with congenital heart diseases)

ii. Pulmonary stenosis iii. Patent ductus arteriosus

iv. Coarctation of aorta

v. Total atrioventricular canal defect vi. ASD

vii. Transposition of great vessel

viii. Rare isolation of the left innominate artery infra- diaphragmatic total anomalous pulmonary venous connection

ix. Wolf-Parkinson-White syndrome d. Respiratory tract anomalies

i. Laryngeal anomaly

ii. Incomplete lobulation of the lung iii. Pulmonary hypoplasia to aplasia

iv. Sequestration

v. Focal tracheomalacia due to extrinsic vascular compression

vi. Obstructive sleep apnea e. Gastrointestinal anomalies

i. Esophageal atresia ii. Tracheo-esophageal fistula iii. Diaphragmatic hernia

iv. Imperforate anus f. Renal anomalies

i. Renal agenesis ii. Hydronephrosis iii. Ectopic kidney

iv. Double ureter v. Hydroureter

g. Prenatal growth deficiency h. Normal intelligence in most cases

DIAGNOSTIC INVESTIGATIONS

1. Radiography

a. Platybasia/occipitalization of atlas

b. Hypoplasia of the mandibular-maxillary bones c. Fused vertebrae, especially cervical

d. Segmentation anomaly of the vertebra e. Hemivertebrae

f. Klippel-Feil anomaly g. Rib anomalies

h. Aplasia of radius/thumb i. Spina bifida

2. Echocardiography: variable and nonspecific findings because cardiovascular abnormalities are complex in most cases

GENETIC COUNSELING

1. Recurrence risk

a. Patient’s sib: empiric recurrence risk of 2%

b. Patient’s offspring: unknown 2. Prenatal diagnosis by ultrasonography

a. Hemifacial microsomia

b. Microphthalmia or anophthalmia c. Cleft lip/palate

d. Unilateral facial cleft with macrostomia e. Unilateral ear hypoplasia

f. Unilateral preauricular tag g. Hemiatrophy of the nose

h. Hyposegmentation of the unilateral lung i. Single umbilical artery

j. Imperforate anus k. Polyhydramnios 3. Management

a. Surgical removal of epibulbar dermoids, if needed b. Cleft lip/palate repair

c. Combined surgical-orthodontic approach for dental occlusion

d. Traditional osteotomies, followed by acute orthopedic movement and osseous fixation for adult patients with maxillomandibular hypoplasia, facial asymmetry, con- genital micrognathia and hemifacial microsomia e. Alternative procedure: distraction osteogenesis

f. Assess cervical spine for instability before undergo- ing any general surgery. C1–C2 fusion or occipitocer- vical fusion may be needed

g. Anesthesia: anticipate airway obstruction and diffi- culty in tracheal incubation, resulting from a combi- nation of micrognathia, unilateral mandibular hypoplasia and vertebral anomalies including verte- bral fusion and odontoid elongation

REFERENCES

Andrews TM, Shott SR: Laryngeal manifestations of Goldenhar syndrome. Am J Otol 13:312–315, 1992.

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Baum JL, Feingold M: Ocular aspects of Goldenhar’s syndrome. Am J Ophthalmol 75:250–257, 1973.

Benacerraf BR, Frigoletto FD Jr: Prenatal Ultrasonographic recognition of Goldenhar’s syndrome. Am J Obstet Gynecol 159:950–952, 1988.

Bennum RD, Mulliken JB, Kaban LB, et al.: Microtia: a microform of hemifacial microsomia. Plast Reconstr Surg 76:859–863, 1985.

Boles DJ, Bodurtha J, Nance WE: Goldenhar complex in discordant monozygotic twins: a case report and review of the literature. Am J Med Genet 28:103–109, 1987.

Burck U: Genetic aspects of hemifacial microsomia. Hum Genet 64:291–296, 1983.

Cohen MM, Rollnick BR, Kaye CI: Oculoauriculovertebral spectrum: an updated critique. Cleft Palate J 26:276, 1989.

Converse JM, Coccaro PJ, Becker M, et al.: On hemifacial microsomia. The first and second branchial arch syndrome. Plast Reconstr Surg 51:268, 1973.

De Catte L, Laubach M, Legein J, et al.: Early prenatal diagnosis of oculoauriculovertebral dysplasia or the Goldenhar syndrome. Ultrasound Obstet Gynecol 8:422–424, 1996.

De Ravel TJ, Legius E, Brems H, et al.: Hemifacial microsomia in two patients further supporting chromosomal mosaicism as a causative factor. Clin Dysmorphol 10:263–267, 2001.

Ewart-Toland A, Yankowitz J, Winder A, et al.: Oculoauriculovertebral abnormalities in children of diabetic mothers. Am J Med Genet 90:303–309, 2000.

Forest-Potts L, Sadler TW: Disruption of Msx-1 and Msx-2 reveals roles for these genes in craniofacial, eye and axial development. Dev Dyn 209:70–84, 1997.

Friedman S, Caracal M: The high frequency of congenital heart disease in Oculoauriculovertebral dysplasia (Goldenhar syndrome) [letter]. J Pediatr 85:873–874, 1974.

Gastavson EE, Chen H: Goldenhar syndrome, anterior encephalocele, and aqueduct stenosis following fetal primidone exposure. Teratology 32:13–17, 1985.

Godel V et al.: Autosomal dominant Goldenhar syndrome. Birth Defects 18(6):621–628, 1982.

Goldenhar M: Associations malformatives de l’oeil et de l’oreille, en particuli- er le syndrome epibulbaire-appendices auriculaires dermoide fistula auris congenita et ses relations avec la dysostose mandibulo faciale. J Genet Hum 1:243–282, 1952.

Gorlin RJ, Jue KL, Jacobson L, et al.: Oculoauriculovertebral dysplasia. J Pediatr 63:991–999, 1963.

Gosain AK, McCarthy JG, Pinto RS: Cervicovertebral anomalies and basilar impression in Goldenhar syndrome. Plast Reconstr Surg 93:498–506, 1994.

Greenberg F, Herman GE, Stal S, et al.: Chromosomal abnormalities associated with Facioauriculovertebral spectrum. Am J Med Genet (Suppl 4):170, 1988.

Hathout EH, Elmendorf E, Bartley J: Hemifacial microsomia and abnormal chromosome 22. Am J Med Genet 76:71–73, 1998.

Healey D, Letts M, Jarvis JG: Cervical spine instability in children with Goldenhar’s syndrome. Can J Surg 45:341–344, 2002.

Kaymak C, Gulban Y, Ozcan AO, et al.: Anaesthetic approach in a case of Goldenhar’s syndrome. Eur J Anaesthesiol 19:832–838, 2002.

Kelberman D, et al. Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome. Hum Genet 109:638–645, 2001.

Kumar A, Friedman JM, Taylor GP, et al.: Pattern of cardiac malformation in oculoauriculovertebral spectrum. Am J Med Genet 46:423–426, 1993.

Kumar R, Blani B, Patwari AK, et al.: Goldenhar syndrome with rare associations. Indian J Pediatr 67:231–233, 2000.

Lessick M, Vasa R, Israel J: Severe manifestations of oculoauriculovertebral spectrum in a cocaine exposed infant. J Med Genet 28:803–804, 1991.

Lin HJ, Owens TR, Sinow RM, et al.: Anomalous inferior venae cavae with oculoauriculovertebral defect: Review of Goldenhar complex and malformations of left–right asymmetry. Am J Med Genet 75:88–94, 1998.

Madan R, Trikha A, Venkataraman RK, et al.: Goldenhar’s syndrome: an analy- sis of anaesthetic management. A retrospective study of seventeen cases.

Anaesthesia 45:49–52, 1990.

Mandelberg A, Ariel I, Mogle P, et al.: Tracheo-oesophageal anomalies in the Goldenhar anomalad. J Med Genet 22:149–150, 1985.

Mansour AM, Wang F, Henkind P, et al.: Ocular findings in the facioauriculovertebral sequence (Goldenhar-Gorlin syndrome). Am J Ophthalmol 100:555–559, 1985.

Margolis S, Aleksic S, Charles N, et al.: Retinal and optic nerve findings in Goldenhar-Gorlin syndrome. Ophthalmology 91:1327–1333, 1984.

McCarthy VP, Zimo DA, Lucas MA: Airway in the oculo-auriculo-vertebral spectrum: two cases and a review of the literature. Pediatr Pulmonol 32:250–256, 2001.

Monahan R, Seder K, Patel P, et al.: Etiology, diagnosis and treatment. J Am Dent Assoc 132:1402–1408, 2001.

Morrison PJ, Mulholland HC, Craig BG, et al.: Cardiovascular abnormalities in the oculo-auriculo-vertebral spectrum (Goldenhar syndrome). Am J Med Genet 44:425–428, 1992.

Nakajima H, Goto G, Tanaka N, et al.: Goldenhar syndrome associated with various cardiovascular malformations. Jpn Circ J 62:617–620, 1998.

Opitz JM: Blastogenesis and the “primary field” in human development. Birth Defects Original Article Series 29:3–37, 1993.

Phelps Prenat Diagn, Lloyd GAS, Poswillo DE: The ear deformities in craniofacial microsomia and oculo-auriculo-vertebral dysplasia. J Laryngol Otol 97:995–1005, 1983.

Pierpont MEM, Moller JH, Gorlin RJ: Congenital cardiac, pulmonary, and vascular malformations in oculoauriculovertebral dysplasia. Pediatr Cardiol 2:297–302, 1982.

Poswillo D: The pathogenesis of the first and second branchial arch syndrome.

Oral Surg 35:302–328, 1973.

Poswillo D: Otomandibular deformity: pathogenesis as a guide to reconstruc- tion. J Maxillofac Surg 2:64–72, 1974.

Rees DO, Collum LM, Bowen DI: Radiological aspects of oculo-auriculo-vertebral dysplasia. Br J Radiol 45:15–18, 1972.

Regenbogen L et al.: Further evidence for an autosomal dominant form of oculoauriculovertebral dysplasia. Clin Genet 21:161–167, 1982.

Robinow M, Reynolds JF, Fitzgerald J, et al.: hemifacial microsomia, ipsilateral facial palsy, and malformed auricle in two families: an autosomal dominant malformation. Am J Med Genet (Suppl 2):129–133, 1986.

Roesch C, Steinbicker V, Korb C, et al.: Goldenhar anomaly in one triplet derived from Intracytoplasmic sperm injection (ICSI). Am J Med Genet 101:82–83, 2001.

Rollnick BR, Kaye CI: Hemifacial microsomia and variants: pedigree data.

Am J Med Genet 15:233–235, 1983.

Rollnick BR, Kaye CI, Nagatoshi K, et al.: Oculoauriculovertebral dysplasia and variants: phenotypic characteristics of 294 patients. Am J Med Genet 26:361–375, 1987.

Schrander-Stumpel CT, Die-Smulders CE, Hennekam RC, et al.: Oculoauri- culovertebral spectrum and cerebral anomalies. J Med Genet 29:326–331, 1992.

Scholtz AW, Fish JH III, Kammen-Jolly K, et al.: Goldenhar’s syndrome: congenital hearing deficit of conductive or sensorineural origin? Temporal bone histopathologic study. Otology Neurotology 22:501–505, 2001.

Setzer ES, Ruiz-Castaneda N, Severn C, et al.: Etiologic heterogeneity in the oculoauriculovertebral syndrome. J Pediatr 98:88–90, 1981.

Stehling L: Goldenhar syndrome and airway management. Am J Dis Child 132:818, 1978.

Stoll C, Viville B, Treisser A, et al.: A family with dominant oculoauriculovertebral spectrum. Am J Med Genet 78:345–349, 1998.

Summitt RL: Familial Goldenhar syndrome. Birth Defects 5(2):106–109, 1969.

Sze RW, Paladin AM, Lee S, et al.: Hemifacial microsomia in pediatric patients: asymmetric abnormal development of the first and second branchial arches. Am J Roentgenol 178:1523–1530, 2002.

Sutphen R, Galan-Gomez E, Cortada X, et al.: Tracheoesophageal anomalies in oculoauriculovertebral (Goldenhar) spectrum. Clin Genet 48:66–71, 1995.

Tamas DE, Mahony BS, Bowie JD, et al.: Prenatal sonographic diagnosis of hemifacial microsomia (Goldenhar-Gorlin syndrome). J Ultrasound Med 5:461–463, 1986.

Taysi K, Marsh JL, Wise DM: Familial hemifacial microsomia: observations on three patients. Eur J Pediatr 20:47–53, 1983.

Thomas P: Goldenhar syndrome and hemifacial microsomia: observations on three patients. Europ J Pediatr 133:287–292, 1980.

Wilson GN: Cranial defects in the Goldenhar syndrome. Am J Med Genet 14:435–443, 1983.

Witters I, Schreurs J, Van Wing J, et al.: Prenatal diagnosis of facial clefting as part of the oculo-auriculo-vertebral spectrum. Prenat Diagn 21:62–64, 2001.

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Fig. 1. Two infants (A,B,C,D,E) with Goldenhar syndrome showing hemifacial microsomia, epibulbar dermoids, upper eyelid coloboma, clefting nose, macrostomia, and unilateral microtia with preauricular tag.

Fig. 2. An 8-month-old child with hemifacial microsomia showing facial asymmetry, unilateral microtia, and preauricular tags.

Fig. 3. An infant with primidone embryopathy presenting as Goldenhar syndrome showing hemifacial microsomia, facial palsy, upper eyelid coloboma, epibulbar dermoid, and hydrocephaly by MRI.