Oculocerebrocutaneous Syndrome

Disease Overview

Oculocerebrocutaneous (OCC) syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized primarily by eye (ocular), brain (e.g., cerebral) and skin (cutaneous) malformations. For example, many affected infants have semisolid or fluid-filled swellings (cysts) within the cavities of the skull (orbits) that accommodate the eyeballs and associated structures. In most patients, the eye on the affected side or sides is also abnormally small (microphthalmos). Brain abnormalities associated with OCC syndrome may include enlargement of the ventricular system, multiple fluid-filled spaces within and malformations of the outer region of the cerebral hemispheres (cerebral cortex), absence of the band of nerve fibers that joins the brain’s hemispheres (agenesis of the corpus callosum) and a typical malformation of mid- and hindbrain. Affected infants and children often have intellectual disability and episodes of uncontrolled electrical activity in the brain (seizures). In addition, OCC syndrome is characterized by underdevelopment or absence of skin in certain localized regions (focal dermal hypoplasia or aplasia), and most have protruding, flesh-colored or brownish outgrowths of skin (cutaneous tags) within certain facial areas, including around the eyelids, on the cheeks, or near the ears. In all individuals with OCC syndrome known so far, the disorder occurs sporadically (with no family history of similar disorders).

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Synonyms

Delleman-Oorthuys syndrome
Delleman syndrome
OCCS
OCC syndrome
orbital cyst with cerebral and focal dermal malformations

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Signs & Symptoms

OCC syndrome is characterized by distinctive eye (ocular), brain (e.g., cerebral) and skin (cutaneous) malformations. Most infants with the disorder have fluid-filled or semisolid swellings (cysts) within the cavities of the skull (orbits) that accommodate the eyeballs. The eye on the affected side or sides is characteristically small (microphthalmos). In some patients, the orbital cysts may contain benign (noncancerous), tumor-like nodules (hamartomas) consisting of ocular tissue. Affected infants may have additional ocular abnormalities, such as absence or defects (notches) of tissue (colobomas) of the upper eyelids, the lower eyelids, or the colored part of the eye(s) (irises) or abnormal persistence of the embryonic blood vessel (the hyaloid artery system) that supplies certain regions of the eyes (persistent fetal vasculature, the hyaloid artery usually disappears during the ninth month of fetal development.)

Infants with OCC syndrome may also have skeletal abnormalities. These may include underdevelopment (hypoplasia) of the orbits or other bones of the skull (e.g., zygomas); malformation of certain ribs or of the bones of the spinal column (vertebrae); and/or abnormal curvature of the spine (scoliosis).

OCC syndrome is also characterized by abnormalities of the brain. These malformations include the presence of malformations of the cerebral hemispheres (cerebral cortex), mainly polymicrogyria or periventricular heterotopia; abnormal, fluid-filled spaces in the outer region of the cerebral cortex; absence of the band of nerve fibers that joins the brain’s hemispheres (agenesis of the corpus callosum); and a very characteristic malformation of the mid- and hindbrain with a giant tectum and missing or hypoplastic vermis of the cerebellum. The ventricles (fluid filled cavities) in the brain may be enlarged and obstructive hydrocephalus may occur, a condition in which there is obstructed flow of the fluid surrounding the brain and spinal cord (cerebrospinal fluid [CSF]), resulting in increasing fluid pressure in the brain leading to rapid enlargement of the head and other symptoms. Many affected infants have intellectual disability, substantial delay in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor impairment), and episodes of uncontrolled electrical activity in the brain (seizures). In rare cases, infants with OCC syndrome may have protrusion of a portion of the brain and its surrounding membranes (meninges) through a defect in the back of the skull (occipital meningoencephalocele).

OCC syndrome also has distinctive skin (cutaneous) abnormalities. Most infants with the disorder have multiple localized areas in which the skin is underdeveloped (hypoplastic), absent (aplastic), or characterized by a “punched-out “appearance in some cases, involved areas appear as abnormal depressions in the skin. Although these lesions primarily affect the head, face, and trunk, they may occur anywhere on the body. Many affected infants also have protruding, brownish or flesh-colored outgrowths of skin (skin or cutaneous tags). Such cutaneous outgrowths usually appear around the eyes (periorbital). However, they may occur in other facial regions, such as the cheeks or near the ears, or, more rarely, in other bodily areas.

In some infants with OCC syndrome, the various cutaneous, ocular, orbital, or other malformations may involve one side of the body (unilateral). In those with unilateral involvement, the left side has been affected more often than the right. As a result, the face appears different on one side from the other (facial asymmetry). Less commonly, due to the presence of certain skeletal abnormalities, such as those mentioned above, one side of the body may appear different from the other (generalized body asymmetry).

Rarely, infants with OCC syndrome may have other signs, including undescended testes, incomplete closure of the roof of the mouth (cleft palate), clefts involving larger parts of the face or other physical features.

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Causes

In all reported individuals with OCC syndrome, there is no family history of the disorder. Therefore, geneticists suggest that OCC syndrome is caused by a genetic change (variant or mutation) that appears to be present in some of the cells of the body only (somatic mosaicism) and is thought to be the consequence of a randomly occurring, new event in one of the cells present at a very early embryonic stage.

A few affected individuals have had relatives with conditions distantly similar but probably unrelated to OCC syndrome. For example, the mother of one affected individual had defects of ocular tissue affecting both eyes (bilateral colobomas), and a cousin of another had an ocular cyst.

The exact cause of OCC is still unknown and difficult to determine.

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Affected populations

OCC syndrome has been reported more frequently in males than in females; however, the prevalence is unknown. Since the disorder was originally described in 1981 (JW Delleman & JWE Oorthuys), approximately 40 patients have been reported in the medical literature.

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Disorders with Similar Symptoms

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

Microphthalmia with linear skin defects syndrome is a rare genetic disorder that is caused by an alteration on the X chromosome (most often a missing piece in chromosome region Xp22.2 that includes the HCCS gene) which affects only females. The disorder is characterized by eye (ocular) defects, including abnormally small size of the eyes (microphthalmia); and clouding of the front, usually transparent surface of the eyes (corneal opacities). These ocular defects typically occur in association with underdevelopment or absence of skin in “streak-like” (linear) patterns, primarily affecting the head and neck region and healing into hyperpigmented areas with age. Some affected females may have additional abnormalities, including congenital heart defects, a small head (microcephaly), absence of the band of nerve fibers that joins the two hemispheres of the brain (agenesis of the septum pellucidum), seizures, or intellectual disability.

Focal dermal hypoplasia is also a rare genetic X-linked disorder caused by a change (mutation) in the PORCN gene. The condition is characterized by distinctive abnormalities of the skin, the fingers and toes, the eyes, and other bodily regions. Primary cutaneous abnormalities include underdevelopment of localized areas of skin (focal dermal hypoplasia) with protrusion of fat (herniation); red streaking of the skin; and multiple benign (noncancerous) tumors (papillomas) of the skin or mucous membranes (including the esophagus and the larynx). Most affected females also have ocular defects, such as small eyes (microphthalmia); absence or defects of ocular tissues (colobomas of the iris or the choroid); or abnormal malalignment of one eye in relation to the other (strabismus, usually turned in or esotropia). Limb malformations may include webbing or fusion (syndactyly) of certain fingers or toes; permanent flexion of one or more digits (camptodactyly); additional fingers or toes (polydactyly); or absence of certain digits (usually in the middle of the hand). Also present are skeletal abnormalities, such as an unusually small, rounded skull; malformations of bones in the spinal column (vertebrae); unusual streaks (striations) in the long bones or abnormal curvature of the spine. Many affected individuals also have abnormal eruption, irregular spacing, defective enamel, or absence of some teeth (hypodontia); an abnormal vertical notch in the upper lip (cleft lip); incomplete closure of the roof of the mouth (cleft palate); or other physical abnormalities. Most individuals with the disorder have intellectual disability. (For further information on this disorder, choose “focal dermal hypoplasia” as your search term in the Rare Disease Database.)

Encephalocraniocutaneous lipomatosis is a rare genetic disorder that is typically characterized by skin abnormalities, ocular defects and multiple benign fatty tumors (lipomas) in the brain or along the spinal cord. ECCL may involve one or both sides of the body (unilateral or bilateral). It can be associated with a normal development or mild to severe intellectual disability and may lead to episodes of uncontrolled electrical activity in the brain (seizures). Affected individuals have multiple subcutaneous lipomas and other benign tumor-like lesions (hamartomas), involving the surface of the eye (epibulbar dermoids), and may show protruding outgrowths of skin (skin tags) that may involve the eyelids, the nose, or other regions. They may also show areas localized loss of scalp hair (alopecia) possibly with underlying fatty tissue (so-called nevus psiloliparus), and areas of underdeveloped (hypoplastic) or absent (aplastic) scalp. Additional findings in the brain include fluid-filled spaces in the brain (porencephalic cysts), anomalies of the vessels and of the protective membranes surrounding the brain and spinal cord (i.e., leptomeninges). Affected individuals may have a large head (macrocephaly); congenital malformation of the aorta; cystic bone lesions that may be progressive. Sometimes, they develop jaw tumors and a particular brain tumor (low-grade gliomas). To date, all individuals with ECCL are the only individuals in their families with the disorder (isolated). In some patients, somatic mosaic mutations in the FGFR1 gene or the KRAS gene have been identified, meaning that the mutation (genetic change) is only present in part of the cells of the body (somatic mosaicism). This is the consequence of a randomly occurring, new event in one of the cells present at a very early embryonic stage.

Goldenhar syndrome, a term used synonymously with “oculo-auriculo-vertebral (OAV) spectrum,” is a rare genetic disorder apparent at birth (congenital). The disorder is characterized by a wide spectrum of signs and physical features that vary greatly in extent and severity from patient to patient. However, the abnormalities tend to involve the cheekbones, jaws, mouth, ears, eyes, and bones of the spinal column (vertebrae). Although the malformations usually affect one side of the body (unilateral), some affected individuals have such abnormalities on both sides (bilateral) in which one side is more affected than the other. Due to these malformations, the face usually appears smaller on one side (hemifacial microsomia). Craniofacial abnormalities include underdevelopment of the cheekbones (malar hypoplasia), bones of the upper and lower jaws, and bones forming a portion of the lower skull (temporal hypoplasia); incomplete development of certain muscles of the face; an abnormally wide mouth (macrostomia); incomplete closure of the roof of the mouth (cleft palate); an abnormal groove in the upper lip (cleft lip); and/or abnormalities of the teeth. Malformation (microtia) or absence (anotia) of the outer ears (auricles or pinnae) also occurs; narrow, blind ending, or absent external ear canals (atresia); abnormal outgrowths of skin and cartilage on or in front of the ears (preauricular tags); or abnormalities affecting the middle or inner ears, resulting in hearing impairment (either conductive or sensorineural hearing loss). Eye abnormalities may include the formation of solid benign tumors on the surface of the eyeball(s) (epibulbar dermoids and lipodermoids), partial absence of tissue (coloboma) from the upper eyelids, abnormally small eye(s) (microphthalmia), narrowing of the openings (palpebral fissures) between the upper and lower eyelids (blepharophimosis), or other ocular abnormalities. In some individuals, additional physical malformations and/or mild intellectual disability may occur. Goldenhar syndrome is usually an isolated event with no family history. A few reports imply a positive family history, suggesting autosomal dominant or autosomal recessive inheritance. In addition, some investigators have suggested that the disorder may be caused by the combined interaction of a few genes (oligogenic inheritance). (For further information on this disorder, choose “Goldenhar” as your search term in the Rare Disease Database.)

Aicardi syndrome is a rare disorder affecting females only. Individuals with Aicardi syndrome have underdeveloped or absent tissue connecting the left and the right halves of the brain (agenesis corpus callosum) in combination with a multitude of other brain lesions. These brain lesions overlap substantially with those seen in OCC syndrome although the typical mid-hindbrain malformation seen in OCC syndrome is unknown in Aicardi syndrome. Affected individuals show severe intellectual disability, infantile spasms and other types of seizures. Examination of the eyes typically shows holes in the retina (chorioretinal lacunae), but the eye anomalies known in OCC syndrome may be seen occasionally. Anomalies of the ribs, the spine, and the skin may be associated. Aicardi syndrome occurs sporadically. The underlying gene has not yet been identified.

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Diagnosis

OCC syndrome may be diagnosed at or shortly after birth based upon a thorough clinical evaluation, identification of characteristic physical findings, and specialized imaging techniques. Some investigators have suggested that minimal diagnostic criteria for OCC syndrome must include the presence of characteristic findings in at least two of the three systems typically involved (eye, skin, brain).

Specialized tests detect and/or characterize certain abnormalities associated with the disorder, including ocular defects, cerebral malformations, and seizure activity. These may include advanced imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI); or electroencephalography (EEG).

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Standard Therapies

Treatment

The management of OCC syndrome is directed toward the specific signs apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals who may need to plan an affected child’s treatment systematically and comprehensively. These professionals may include pediatricians; surgeons; physicians who specialize in disorders of the skin (dermatologists); physicians who diagnose and treat neurological disorders (neurologists and neurosurgeons); eye specialists (ophthalmologists); and/or others.

Specific therapies for OCC syndrome are symptomatic and supportive. Intervention may include drainage of orbital cysts; surgical removal (excision) of orbital cysts, hamartomas, or skin tags; or surgical repair of certain abnormalities, such as colobomas of the lids or the cleft palate. The specific surgical interventions will depend on the severity of the anatomical abnormalities, their associated signs, and other factors.

Treatment may include medications to prevent, reduce, or control seizures (anticonvulsant drugs). Those with hydrocephalus may have a specialized device (shunt) surgically implanted to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed.

Genetic counseling may be recommended for the families of affected individuals. Other treatment for OCC syndrome is symptomatic and supportive.

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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: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Moog U, Dobyns WB. An update on oculocerebrocutaneous (Delleman-Oorthuys) syndrome. Am J Med Genet C Semin Med Genet. 2018 Dec;178(4):414-422.

INTERNET
Oculocerebrocutaneous Syndrome. Genetic and Rare Diseases Information Center (GARD). Last update Feb 2023. Oculocerebrocutaneous syndrome – About the Disease – Genetic and Rare Diseases Information Center (nih.gov) Accessed June 6, 2023.

McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Entry Number: 164180; Last Edit Date: 02/19/2015. https://www.omim.org/entry/164180 Accessed June 6, 2023.

Moog,Ute. Oculocerebrocutaneous syndrome. Orphanet. August 2019; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1647 Accessed June 6, 2023.

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