Oculo-Auriculo-Vertebral Spectrum

Disease Overview

Oculo-auriculo-vertebral spectrum (OAVS) refers to three rare disorders that many clinicians believe to be intimately related to one another and which represent the range of severity of the same disorder. These disorders are apparent at birth (congenital). As the name suggests, they involve malformations of the eyes, ears and spine.

Oculo-auriculo-vertebral disorder (OAVD) represents the mildest form of the disorder, while Goldenhar syndrome presents frequently as the most severe form. Hemifacial microstomia appears to be an intermediate form.

The disorder is characterized by a wide spectrum of symptoms and physical features that may vary greatly in range and severity from case to case. However, such abnormalities tend to involve the cheekbones, jaw, mouth, ears, eyes, and/or bones of the spinal column (vertebrae). Although, in most cases (about 60%), such malformations affect one side of the body (unilateral), approximately 10 to 33 percent of affected individuals have such malformations on both sides of the body (bilateral), with one side typically more affected than the other (asymmetry). In the majority of such cases, the right side is more severely affected than the left.

In most cases OAVS appears to occur randomly, with no apparent cause (sporadic). However, in some cases, family histories suggest autosomal dominant or recessive inheritance. In addition, some researchers suggest that the disorder may be caused by the interaction of many genes, possibly in combination with environmental factors (multifactorial inheritance).

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Synonyms

Facio-Auriculo-Vertebral Spectrum
FAV
First and Second Branchial Arch Syndrome
Goldenhar-Gorlin Syndrome
OAVS
OAV Spectrum
Oculo-Auriculo-Vertebral Dysplasia

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Subdivisions

Goldenhar Syndrome
Hemifacial Microsomia (HFM)
Oculo-Auriculo-Vertebral Disorder

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Signs & Symptoms

Oculo-auriculo-vertebral spectrum represents three rare disorders that are apparent at birth (congenital), and are characterized by a wide spectrum of symptoms and physical features that may vary greatly in range and severity from case to case. However, such abnormalities tend to involve the cheekbones, jaws, mouth, ears, eyes, and/or bones of the spinal column (vertebrae). In about 60 percent of the cases, such malformations involve one side of the body (unilateral). Yet, in approximately 10 to 33 percent of affected individuals, both sides of the body may be involved (bilateral), with one side usually more affected than the other (asymmetry). In many such cases, the right side is more severely affected than the left.

For unknown reasons, hemifacial microsomia (HFM) tends to affect only the right side of the face. IN HFM, both the jaw and the eye may be substantially smaller on the affected side. The cheek on the affected side may appear to be flatter due to under development of the cheekbones on that side. The external ear may be smaller (microtia) or even absent (anotia). There may also be hearing loss. Intelligence is not affected.

People with the Goldenhar variant of OAVS present with most if not all of the signs of HFM, but in 10 to 33 percent of the cases, the symptoms affect both sides of the face (bilateral). A cleft lip and/or cleft palate may be present but the presence of a cleft palate alone is more common. The muscles of the tongue and cheeks may cause severe difficulties with speech. Some tissue(s) of the eye may fail to close, presenting as a notch (coloboma) of varying size. In about one-third of cases, the patient presents with a cyst on the eye (dermoids cyst). Further, patients with Goldenhar syndrome can present with heart defects as well as kidney problems. People with Goldenhar syndrome may have underdeveloped kidneys on one side or even the lack of a kidney on the affected side. Two or more vertebrae may be fused or knitted together. Intelligence is not affected.

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Causes

In most cases, oculo-auriculo-vertebral spectrum occurs randomly, with no apparent cause (sporadic). However, in some cases, positive family histories have been identified that have suggested autosomal dominant, or, less frequently, autosomal recessive inheritance. In addition, many researchers suggest that OAVS may be caused by the interaction of many genes, possibly in combination with environmental factors (multifactorial inheritance).

For as yet unexplained reasons, it appears that women who have been exposed to certain medications (e.g., certain acne drugs with retinoic acid) or conditions (e.g., diabetes) during pregnancy have had children with abnormalities characteristic of OAVS. In addition, distinctive features associated with OAVS have also occurred in association with several chromosomal disorders. (For more information, see the Related Disorders section below.) The implications of such findings are not fully understood.

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Affected populations

OAVS affects males more frequently than females by an approximate 3:2 ratio. There is some disagreement in the medical literature concerning the disorder’s rate of occurrence. Reported estimates range from one in 3000 to 5000 live births up to one in 25,000-40,000 live births. Most of the physical characteristics associated with OAVS are apparent at birth (congenital), with the possible exception of facial asymmetry, which may not become apparent until approximately four years of age in many cases.

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Disorders with Similar Symptoms

Symptoms of the following disorders may be similar to those of oculo-auriculo-vertebral spectrum. Comparisons may be useful for a differential diagnosis:

Treacher Collins syndrome is an extremely rare genetic disorder characterized by distinctive abnormalities of the craniofacial area due to underdevelopment (hypoplasia) of certain portions of the skull (e.g., supraorbital rims and zygomatic arches) and lower jaw. Although the symptoms and physical characteristics associated with Treacher Collins syndrome may vary greatly in severity from case to case, craniofacial abnormalities tend to involve the cheekbones, jaws, mouth, ears, and/or eyes. Such craniofacial malformations may include underdeveloped (hypoplastic) or absent cheekbones; an incompletely developed, abnormally small lower jaw (mandibular hypoplasia and micrognathia); an unusually large mouth (macrostomia); malformations of the roof of the mouth (palate); and/or dental abnormalities such as misaligned teeth (malocclusion). Affected infants may also have underdeveloped (hypoplastic) and/or malformed (microtic) outer ears with blind ending or absent external ear canals (atresia), resulting in hearing impairment (conductive hearing loss). In addition, infants with the disorder may have downwardly slanting eyelid folds (palpebral fissues), partial or total absence of tissue (colobomas) from the outer third of the lower eyelids, and/or additional eye abnormalities. In approximately 40 percent of cases, Treacher Collins syndrome has autosomal dominant inheritance. However, in about 60 percent of cases, a positive family history is not found. Research suggests that such cases represent new genetic changes (mutations) that occur randomly, with no apparent cause (sporadic). (For more information on this disorder, choose “Treacher Collins” as your search term in the Rare Disease Database.)

CHARGE association, a rare disorder that results from several defects during early fetal development, is characterized by abnormalities affecting several organ systems of the body. CHARGE is an acronym representing (C)oloboma of the eye, particularly of the colored portion of the eye (iris), giving the iris an abnormal “keyhole” shape; (H)eart defects, including Tetralogy of Fallot, ventricular and/or atrial septal defects, and patent ductus arteriosus; (A)tresia of the choanae, a condition in which the passages, or choanae, connecting the back of the nose to the throat may be narrowed or blocked, preventing normal nasal breathing; (R)etardation of growth and development, as well as mental and psychomotor retardation in some cases; (G)enital and urinary anomalies; and (E)ar abnormalities such as malformation of the outer ears and bones of the middle ears, improper functioning of the eustachian tubes, obstruction of the ear canals, and/or hearing loss. Four of these characteristic findings must be present to confirm the diagnosis of CHARGE association. In addition to the classic features, individuals with CHARGE Association may also exhibit craniofacial abnormalities, renal and central nervous system malformations, and/or other abnormalities such as tracheoesophageal fistula and/or imperforate anus. The exact cause of CHARGE association is not known; however, most cases are thought to occur randomly, with no apparent cause (sporadic). (For more information on this disorder, choose “CHARGE” as your search term in the Rare Disease Database.)

VACTERL association, a rare disorder resulting from fetal development defects, is characterized by congenital abnormalities affecting several organ systems of the body. VACTERL is an acronym representing (V)ertebral abnormalities including hemivertebrae and malformation of the lower vertebrae (sacrum); (A)nal atresia, a condition in which there is absence of the anal opening; (C)ardiac defects, particularly ventricular septal defects; (T)racheo(E)sophageal fistula; (R)enal abnormalities including absence of the kidney and hydronephrosis; and improper development of one of the forearm bones (radial dysplasia) and other (L)imb defects. Symptoms may occur in various combinations and may be manifestations of several recognized disorders. Affected individuals may also exhibit additional abnormalities involving other systems of the body. In most cases, VACTERL association is thought to occur randomly, for no apparent reason (sporadic); however, researchers suggest that some cases may be inherited as an X-linked or autosomal recessive genetic trait. (For more information on this disorder, choose “VACTERL” as your search term in the Rare Disease Database.)

Townes-Brocks syndrome is a rare inherited disorder that is apparent at birth (congenital). Although symptoms and physical characteristics associated with the disorder may vary greatly in range and severity from case to case, abnormalities tend to involve the face, ears, arms and legs (limbs), gastrointestinal system, and kidneys. In individuals with the disorder, one side of the face may appear smaller than the other (hemifacial microsomia). Ear abnormalities may include malformation of the outer ears, excess tags of skin and/or indentations in front of the ears (preauricular tags and/or pits), and/or hearing impairment due to abnormalities of the internal ear (sensorineural hearing loss). Affected individuals may also have malformations of the thumbs, extra fingers (polydactyly), webbing between two or more fingers and/or toes (syndactyly), and/or other limb irregularities. In addition, individuals with Townes-Brocks syndrome may exhibit absence of the anal opening (imperforate anus); abnormal passages between the rectum and the genitals (rectovaginal or rectoperineal fistula); underdeveloped kidneys (renal hypoplasia); a condition in which urine flows backwards from the bladder into a ureter (vesicoureteral reflux); and/or other related abnormalities. In addition, in some cases, affected individuals may also have abnormalities of the heart and the reproductive organs. Townes-Brocks syndrome has autosomal dominant inheritance. (For more information on this disorder, choose “Townes Brocks” as your search term in the Rare Disease Database.)

Branchio-oto-renal (BOR) syndrome is a rare inherited disorder characterized by abnormalities primarily affecting the ears, neck and throat, and the kidneys. Affected individuals may exhibit excess tags of skin in front of the ears (preauricular tags), malformation of the middle and inner ear, malformed outer ears, and mild to severe conductive and/or sensorineural hearing loss. Additional abnormalities may include an abnormal passage from the throat to the outside surface of the neck (branchial fistula); an abnormal opening, cyst, or mass in the tonsil area; narrowing (stenosis) and/or absence (aplasia) of the tear ducts (lacrimal ducts); and/or craniofacial abnormalities including a long, narrow face, incomplete closure of the roof of the mouth (cleft palate), a deep overbite, and/or paralysis of certain muscles of the face. Individuals with BOR syndrome also often have mild to severe kidney (renal) abnormalities, including unusually shaped kidneys, duplication of the collecting system of the kidneys, and/or underdevelopment (hypoplasia) of the kidneys. branchio-oto-renal syndrome is inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “Branchio Oto Renal” as your search term in the Rare Disease Database.)

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Diagnosis

Rarely, oculo-auriculo-vertebral spectrum may be detected before birth (prenatally) by specialized tests such as ultrasound imaging. In fetal ultrasonography, reflected sound waves may be used to create an image of the developing fetus, revealing characteristic findings. In the case of OAVS, such findings depend on the presence or absence of bone in the lower jaw (mandible), severe abnormalities of the outer ears, cleft palate, and/or cleft lip.

OAVS may also be diagnosed and/or confirmed after birth (postnatally) by a thorough clinical evaluation, identification of characteristic physical findings, and advanced imaging techniques.

A variety of specialized tests may be conducted to confirm specific abnormalities potentially associated with oculo-auriculo-vertebral spectrum disorders. For example, computer-assisted tomography (CT) scanning may be an essential aid in the detection of middle ear abnormalities that may contribute to hearing loss. Advanced imaging techniques may also be helpful in detecting and/or confirming other potential abnormalities of the skull, spinal column, lungs, and/or kidneys. In some cases, additional specialized tests (e.g., echocardiograms, electrocardio-grams, cardiac catheterization, specialized x-ray studies, etc.) may be conducted to detect and/or confirm the presence of congenital heart defects that may be associated with the disorder.

Examination with an instrument (opthalmoscope) that visualizes the interior of the eye may also be conducted to detect, confirm, and/or characterize certain eye (ocular) abnormalities, such as microphthalmia or anophthalmia, epibulbar dermoids and lipodermoids, strabismus, etc.

Swallowing and feeding difficulties in newborns with OAVS may suggest abnormalities such as esophageal atresia and tracheoesophageal fistula. These abnormalities may be detected by means of a flexible, hollow tube used to inject fluid into or drain fluid from the body (catheter). If it cannot pass from the mouth to the stomach, congenital malformations may be present.

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Standard Therapies

Treatment

The treatment of OAVS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists who may need to work together to ensure a comprehensive, systematic approach to treatment. Such specialists may include pediatricians; physicians who diagnose and treat disorders of the ears, nose, and throat (otolaryngologists); eye specialists (ophthalmologists); neurologists; heart (cardiologists) and/or lung (cardiothoracic) surgeons; physicians who specialize in the diagnosis and treatment of disorders of the kidneys (nephrologists), urinary tract (urologists), and digestive tract (gastroenterologists); plastic surgeons; specialists who assess and treat hearing problems (audiologists); speech pathologists; and/or other health care professionals.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: [email protected]

For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

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Resources

(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., craniofacial abnormalities, ear abnormalities, hearing loss, visual impairment, skeletal malformations, cardiac disease, kidney abnormalities, esophageal atresia, tracheoesophageal fistula, mental retardation, etc.].)

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References

TEXTBOOKS

Schneider A. Goldenhar Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:716-17.

Gorlin RJ, Cohen MMJr, Hennekam RCM, eds. Syndromes of the Head and Neck. 4th ed. Oxford University Press, New York, NY; 2001:790-98.

Jones KL, ed. Smith’s Recognizable Patterns of Human Malformation. 5th ed. W. B. Saunders Co., Philadelphia, PA; 1997:642-45.

JOURNAL ARTICLES

Castori M, Brancati F, Rinaldi R, Adami L, Mingarelli R, Grammatico P, Dallapiccola B. Antenatal presentation of the oculo-auriculo-vertebral spectrum (OAVS). Am J Med Genet A. 2006;140:1573-79.

Fischer S, Ludecke HJ, Wieczorek D, Bohringer S, Gillesen-Kaesbach G, Horsthemke B. Histone acetylation dependent allelic expression imbalance of BAPX1 in patients with the oculo-auriculo-vertebral spectrum. Hum Mol Genet. 2006;15:581-87.

Tasse C, Bohringer S, Fischer S, Ludecke HJ, et al. Oculo-auriculo-vertebral spectrum (OAVS): clinical evaluation and severity scoring of 53 patients and proposal for a new classification. Eur J Med Genet. 2005;48:397-411.

Beck AE, Hudgins L, Hoyme HE. Autosomal dominant microtia and ocular coloboma: new syndrome or an extension of the Oculo-auriculo-vertebral spectrum? Am J Med Genet A. 2005;134:359-62.

Hirschfelder U, Piechot E, Schulte M, Leher A. Abnormalities of the TMJ and the musculature in the oculo-auriculo-vertebral spectrum (OAV). A CT study. J Orofac Orthop. 2004;65:204-16.

Miller TD, Metry D. Multiple accessory tragic as a clue to the diagnosis of the oculo-auriculo-vertebral (Goldenhar) syndrome. J Am Acad Dermatol. 2004;50(2 Suppl):S11-13.

FROM THE INTERNET

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Hemifacial Microsomia; HFM; Entry Number; 164210: Last Edit Date; 6/21/2005.

Oculo-auriculo-vertebral spectrum, Hemifacial microsomia, Goldenhar syndrome. UC Davis Children’s Hospital. 2006. 4pp.

www.ucdmc.ucdavis.edu/children/services/cleft/health/anomalies/oculo.html

Connor JM. Goldenhar Syndrome. Contact a Family. Medical Text Last Approved December 2004. 2pp.

www.cafamily.org.uk/cgi-bin/printable.pl

Tewfik TL, Alnoury KI. Manifestations of Craniofacial Syndromes. emedicine. Last Updated: August 7, 2006. 10pp.

www.emedicine.com/ent/topic319.htm

Goldenhar syndrome. FACES The National Craniofacial Association. Last Modified on: Thursday, March 18, 2004.

www.faces-cranio/Disord/Golden.htm

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