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Wildervanck Syndrome

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Copyright 1994, 1998, 2000, 2003, 2011

NORD is very grateful to Brendan Lee, MD, PhD, and Soledad Kleppe, MD, of the Department of Molecular and Human Genetics at Baylor College of Medicine, for assistance in the preparation of this report.

Synonyms of Wildervanck Syndrome

Disorder Subdivisions

General Discussion

Wildervanck syndrome, also known as cervicooculoacoustic syndrome, is a rare genetic disorder that primarily affects females. The disorder is characterized by a skeletal condition known as Klippel-Feil syndrome (KFS); abnormalities of certain eye (ocular) movements (i.e., Duane syndrome); and/or hearing impairment that is present at birth (congenital).

In individuals with KFS, there is abnormal union or fusion of two or more bones of the spinal column (vertebrae) within the neck (cervical vertebrae). Duane syndrome is characterized by limitation or absence of certain horizontal eye movements; retraction or "drawing back" of the eyeball into the eye cavity (orbit) upon attempting to look inward; and, in some cases, abnormal deviation of one eye in relation to the other (strabismus). In some affected individuals, additional physical abnormalities may also be present. In most cases, Wildervanck syndrome appears to occur randomly for unknown reasons (sporadically).

Symptoms

Wildervanck syndrome is typically characterized by three primary findings (triad). These include abnormal union or fusion of two or more bones of the spinal column (vertebrae) within the neck (Klippel-Feil syndrome); impairment or absence of certain eye (ocular) movements (Duane syndrome); and hearing impairment that is present at birth. However, according to some reports, this triad may be incomplete in some individuals with Wildervanck syndrome. In addition, in some cases, additional physical findings or mental retardation may be present.

Researchers have described three major subtypes of Klippel-Feil syndrome (KFS). According to this classification, KFS type I is characterized by extensive fusion of vertebrae of the neck (cervical vertebrae) and the upper back (i.e., upper thoracic vertebrae). In KFS type II, there is localized union or fusion at one or two cervical or thoracic vertebrae associated with incomplete development of one half of certain vertebrae (hemivertebrae) or other malformations of cervical vertebrae. KFS type III is characterized by fusion of vertebrae of the neck as well as vertebrae of the upper or lower back (i.e., lower thoracic or lumbar vertebrae).

Individuals with Wildervanck syndrome who are affected by KFS also tend to have an unusually short neck. In severe cases, the head may appear to be situated directly on the trunk. KFS may also be associated with limited movements of the head and neck and a low hairline at the back of the head (posterior hairline) that may extend to the shoulders. In addition, the face often appears dissimilar from one side to the other (facial asymmetry), and the neck may be abnormally twisted (torticollis), with the head rotated into an abnormal position. Some individuals with KFS may have a risk of developing neurological complications due to instability of cervical vertebrae and associated spinal cord injury that may occur spontaneously or following minor trauma. Such complications may include associated pain; unusual sensations (paresthesia), such as tingling or prickling; increased reflex reactions (hyperreflexia), weakness or paralysis of one side of the body (hemiplegia) or of the legs and the lower part of the body (paraplegia), or other findings. According to some researchers, evidence suggests that Wildervanck syndrome may be a clinical variant of KFS. (For further information on KFS, please see the "Related Disorders" section of this report below.)

In some instances, Wildervanck syndrome may also be characterized by additional skeletal abnormalities. These may include incomplete development of certain vertebrae, leaving a portion of the spinal cord exposed (spina bifida); abnormal curvature of the spine (scoliosis), rib defects; and/or a condition known as Sprengel's deformity. This condition is characterized by elevation and/or underdevelopment of the shoulder blade (scapula), limited movement of the arm on the affected side, and the development of a lump at the base of the neck due to elevation of the shoulder blade. There are some patients that only have an abnormal curvature of the spine (scoliosis).

As mentioned above, Wildervanck syndrome is also associated with Duane syndrome, a condition characterized by limitation or absence of certain horizontal eye movements and other eye (ocular) abnormalities. In those with Duane syndrome, there may be an impaired or absent ability to move the eyes outward (abduction), inward (adduction), or both. In addition, upon attempting to look inward, there may be abnormal narrowing of the eye slit (palpebral fissure narrowing) and retraction or "drawing back" of the eyeball into the eye cavity (orbit). Such abnormalities may affect one or both eyes (unilateral or bilateral). In some cases, affected individuals may also have abnormal inward or outward deviation of one eye in relation to the other (convergent or divergent strabismus).

In some individuals with Wildervanck syndrome, additional ocular abnormalities may be present. For example, some affected individuals may have pseudopapilledema, a condition in which swelling of the optic disc may be present from birth for unknown reasons. The optic disc, also known as the "blind spot," is the portion of the optic nerve that joins with the nerve-rich innermost region of the eye (retina). Additional ocular abnormalities may include incomplete or partial dislocation of the lenses of both eyes (bilateral subluxation), the formation of cysts on the eyeballs (epibulbar dermoids and lipodermoids) and drooping of the upper eyelids causing a narrowing of the palpebral aperture (blepharoptosis).

Wildervanck syndrome is also typically associated with hearing impairment at birth (congenital). Such hearing loss may result from impaired transmission of sound from the outer or middle ear to the inner ear (conductive hearing loss); failed transmission of sound impulses from the inner ear to the brain (sensorineural hearing loss); or both (mixed hearing loss). One or both ears may be affected (unilateral or bilateral hearing impairment). According to some reports, most affected individuals have sensorineural hearing loss due to structural abnormalities of the inner ear. For example, there may be abnormalities of the coiled bony passage (cochlea) that transforms sound vibrations into nerve impulses for transmission to the brain. Additional defects may include underdevelopment or malformation of regions involved with the sensation of position, movement, and balance (vestibular apparatus); absence of the nerve that conveys impulses for the sensation of sound and balance to the brain (vestibulocochlear nerve); and/or other abnormalities.

Some individuals with Wildervanck syndrome may also have additional abnormalities. For example, some may have malformations of the head and facial (craniofacial) area, such as an abnormally small head (microcephaly) or incomplete closure of the roof of the mouth (cleft palate). In addition, in some cases, Wildervanck syndrome may be associated with hydrocephalus, a condition in which there is obstructed flow or impaired absorption of the fluid surrounding the brain and spinal cord (cerebrospinal fluid [CSF]), resulting in increasing fluid pressure in the brain. Rarely, in some affected infants, there may be protrusion of the membranes surrounding the brain (meninges) through a defect in the back of the skull (occipital meningocele). Additional physical features may include abnormal outgrowths of skin (skin tags) or pits in front of the ears (preauricular tags and pits); kidney (renal) defects; the presence of lumps of solid matter (gallstones) within the gallbladder (cholelithiasis).

Some patients with structural malformations of the heart have been reported, (congenital heart [cardiac] defects). Cardiac defects may include an abnormal opening in the fibrous partition (septum) that separates the upper or lower chambers of the heart (atrial or ventricular septal defects) and little holes in the heart valves (aortic valve fenestration). Recently, some patients were reported with dilatation of the arteries from the heart (aneurism of the coronary artery) or rupture of the arteries of the spine (vertebral artery dissection). There are also some patients with associated vascular malformations such as only one artery of the heart (single coronary artery) or the persistence of a vena in the thorax that should disappear before birth (persistent left superior vena cava).
In addition, although intelligence is usually normal, intellectual disability has been reported in some affected individuals. Short stature has also been seen in some patients, and one individual was diagnosed with idiopathic growth hormone deficiency.

Causes

In most cases, Wildervanck syndrome appears to occur randomly for unknown reasons (sporadically). Because the disorder primarily affects females, some researchers suggest that Wildervanck syndrome may be transmitted as an X-linked dominant trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.

X-linked disorders are conditions that are coded on the X chromosome. Females have two X chromosomes, whereas males have one X chromosome and one Y chromosome. In females, certain disease traits on the X chromosome may in some cases be "masked" by the normal gene on the other X chromosome (X-chromosome inactivation). However, since males have only one X chromosome, if they inherit a gene for a disease present on the X, it is more likely to be fully expressed. According to researchers, in males who inherit a disease gene for an X-linked dominant disorder (hemizygotes), it is suspected that full expression of the disorder may be associated with a more severe course that may be incompatible with life even before birth.

According to other researchers, Wildervanck syndrome may result from the interaction of several different genes (polygenic inheritance), possibly in combination with certain environmental factors (multifactorial inheritance), with limitation to females.

Affected Populations

As mentioned above, Wildervanck syndrome primarily affects females. Since the disorder was originally described in 1952 (L.S. Wildervanck), almost 90 cases have been reported in the medical literature. According to some reports, approximately one percent of females with hearing impairment may be affected by Wildervanck syndrome.

Related Disorders

Symptoms of the following disorders may be similar to those of Wildervanck syndrome. Comparisons may be useful for a differential diagnosis:

Duane syndrome is an eye movement disorder present at birth characterized by horizontal eye movement limitation [a limited ability to move the eye inward toward the nose (adduction), outward toward the ear (abduction), or in both directions]. In addition, when the affected eye(s) moves inward toward the nose, the eyeball retracts (pulls in) and the eye opening (palpebral fissure) narrows. In some cases, when the eye attempts to look inward, it moves upward (upshoot) or downward (downshoot).

Duane syndrome falls under the larger heading of strabismus (misalignment of the eyes) under the subclassification of incomitant strabismus (misalignment of the eyes that varies with gaze directions) and subheading of what was previously termed extraocular fibrosis syndromes (conditions associated with fibrosis of the muscles that move the eyes), now termed Congenital Cranial Dysinnervation Disorders (CCDDs). The CCDDs are a group of congenital neuromuscular diseases resulting from developmental errors in innervation, the abnormalities involve one or more cranial nerves/nuclei with absence of normal innervation and/or secondary aberrant innervation. Duane syndrome has been subdivided clinically into three types: Type 1, Type 2, and Type 3. (For further information, choose "Duane" as your search term in the Rare Disease Database.)

Klippel-Feil syndrome (KFS) is a rare skeletal disorder primarily characterized by abnormal union or fusion of two or more bones of the spinal column (vertebrae) within the neck (cervical vertebrae). Some affected individuals may also have an abnormally short neck, restricted movement of the head and neck, and a low hairline at the back of the head (posterior hairline). The disorder is present at birth (congenital), but mild cases may go undiagnosed until later during life when symptoms worsen or first become apparent.

In some individuals, KFS can be associated with a variety of additional symptoms and physical abnormalities. These may include abnormal curvature of the spine (scoliosis) and/or vertebral instability, spina bifida occulta, raised scapula (Sprengel's deformity), absent rib(s) and other rib defects including cervical ribs, other skeletal abnormalities including skeletal malformations of the ear, nose, mouth and larynx including hearing impairment and cleft palate, malformations of the head and facial (craniofacial) area; anomalies of the urinary tract and/or kidney including absent or horse-shoe kidney; or structural abnormalities of the heart (congenital heart defects), mirror movements, webbing of the digits and digital hypoplasia. In addition, in some cases, neurological complications may result due to associated spinal cord injury.

KFS may occur as an isolated abnormality or in association with certain syndromes. In many individuals with KFS, the condition appears to occur randomly for unknown reasons (sporadically). In other cases, KFS may be inherited as an autosomal dominant or autosomal recessive trait. Researchers have determined that some cases of KFS are associated with mutations of the GDF6 gene on chromosome 8. (For further information, please choose "Klippel Feil" as your search term in the Rare Disease Database.)

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). (For further information on this disorder, choose "OAVS" as your search term in the Rare Disease Database.)

There are additional disorders that may be characterized by skeletal, ocular, auditory, or other abnormalities similar to those potentially associated with Wildervanck syndrome. (For more information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
Wildervanck syndrome may be detected at birth or during the first year of life based upon a thorough clinical evaluation, identification of characteristic physical findings, and specialized tests. Diagnostic studies may include advanced imaging techniques, such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. An MRI uses a magnetic field and radio waves to form detailed cross-sectional images of certain organs and tissues. Such techniques may help to detect and characterize abnormalities of the inner ear, union or fusion of certain bones of the spinal column (e.g., cervical vertebrae), possible impingement of vertebrae on the spinal cord, or other abnormalities potentially associated with the disorder. In addition, in some individuals with Wildervanck syndrome, exploratory surgery may be conducted to detect malformations of the middle ear (exploratory tympanotomy). Additional specialized tests may also be performed to confirm or characterize other abnormalities that may be associated with the disorder (e.g., certain ocular findings, congenital heart defects, renal abnormalities, etc.).

Treatment
The treatment of Wildervanck syndrome is directed toward the specific symptoms and physical findings that are present in each individual. Such therapies may require the coordinated efforts of a team of medical professionals who may need to systematically and comprehensively plan an affected child's treatment. These may include pediatricians; physicians who diagnose and treat disorders of the skeleton, muscles, joints, and related tissues (orthopedists); eye specialists (ophthalmologists); hearing specialists (e.g., otologists and audiologists); physicians who diagnose and treat heart abnormalities (cardiologists); surgeons; and/or other health care professionals.

Because some affected individuals with abnormal union or fusion of certain cervical vertebrae may have an increased risk of neurological complications, they should be regularly monitored by physicians. In addition, they should avoid activities that may lead to trauma or injury to cervical vertebrae.

In some individuals with Wildervanck syndrome, treatment measures may include surgical repair of certain abnormalities. For example, middle ear surgery may be recommended for some individuals with conductive hearing loss. Ocular surgery may help to improve or correct impairment of certain eye movements. In addition, for those with cervical spinal cord compression, surgery may be conducted to correct such compression or associated vertebral instability. Surgical measures may also be recommended for other skeletal, ocular, auditory, cardiac, or other abnormalities potentially associated with Wildervanck syndrome. The surgical procedures performed will depend upon the severity of the anatomical abnormalities, their associated symptoms, and other factors.

In addition, some affected individuals with hearing impairment may benefit from the use of specialized hearing aids. Other treatment for Wildervanck syndrome is symptomatic and supportive.

In some cases, early intervention may be important in ensuring that children with Wildervanck syndrome reach their potential. Special services that may be beneficial include special education, physical therapy, and/or other medical, social, and/or vocational services. Genetic counseling will also be of benefit for individuals with Wildervanck syndrome and their families.

Investigational Therapies

Research on birth defects and their causes is ongoing. The National Institutes of Health (NIH) sponsored the Human Genome Project which was aimed at mapping every gene in the human body and learning why they sometimes malfunction. It is hoped that this new knowledge will lead to prevention and treatment of genetic disorders in the future.

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: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Organizations related to Wildervanck Syndrome

References

TEXTBOOKS
Jones KL. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W.B. Saunders Company; 1997:254-255.

Gorlin RJ, et al., eds. Syndromes of the Head and Neck. 3rd ed. New York, NY: Oxford University Press; 1990:886-889.

Buyse ML. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications, Inc.; 1990:306-307, 653-654, 1015-1016

JOURNAL ARTICLES
Kumar A, Sahu A, Shetty S, Vijayalakshmi P. Wildervanck syndrome associated with cleft palate and short stature. Indian J Ophthalmol. 2010 Jul-Aug;58(4):323-5.

Dirik E, Yis U, Dirik MA, Cakmak├ži H, Men S. Vertebral artery dissection in a patient with Wildervanck syndrome. Pediatr Neurol. 2008 Sep;39(3):218-20.

Oe K, Mori K, Konno T, Yoneda T, Ueyama K, Yamagishi M. Ruptured aneurysm of the sinus of Valsalva with Wildervanck syndrome (cervico-oculo-acoustic syndrome), blepharoptosis and short stature: case report. Circ J. 2007 Sep;71(9):1485-7.

Tubbs RS, Oakes WJ, Blount JP. Isolated atlantal stenosis in a patient with idiopathic growth hormone deficiency, and Klippel-Feil and Duane's syndromes. Childs Nerv Syst. 2005 May;21(5):421-4. Epub 2004 May 7.

Balci S, Oguz KK, Firat MM, Boduroglu K. Cervical diastematomyelia in cervico-oculo-acoustic (Wildervanck) syndrome: MRI findings. Clin Dysmorphol. 2002 Apr;11(2):125-8.

Imaizumi K. [Wildervanck (cervico-oculo-acoustic) syndrome]. Ryoikibetsu Shokogun Shirizu. 2001;(33):361-2.

Smith SD, et al. Single gene influences on radiologically-detectable malformations of the inner ear. J Commun Disord. 1998;31:391-408.

Wang Y, et al. Wildervanck or cervico-oculo-acoustic syndrome. Lin Chuang Erh Pi Yen Hou Ko Tsa Chih. 1997;11:499-501.

Kumar A, et al. Wildervanck syndrome. Australas Radiol. 1996;40:160-161.

Johnson NA, et al. Wildervanck's syndrome presenting as hemiparesthesia. Mil Med. 1995;160:208-211.

Kose G, et al. Cholelithiasis in cervico-oculo-acoustic (Wildervanck's) syndrome. Acta Paediatr. 1993;82:890-891.

Gupte G, et al. Wildervanck syndrome (cervico-oculo-acoustic syndrome). J Postgrad Med. 1992;38:180-182.

Hughes PJ, et al. Wildervanck or cervico-oculo-acoustic syndrome and MRI findings. J Neurol Neurosurg Psychiatry. 1991;54:503-504.

Corsello G, et al. Cervico-oculo-acusticus (Wildervanck's) syndrome: a clinical variant of Klippel-Feil sequence? Klin Padiatr. 1990;202:176-179.

Report last updated: 2011/07/11 00:00:00 GMT+0