Oculocerebral Syndrome with Hypopigmentation

Disease Overview

Oculocerebral syndrome with hypopigmentation is an extremely rare genetic disorder characterized by the lack of normal color (hypopigmentation) of the skin and hair and abnormalities of the central nervous system that affect the eyes and certain parts of the brain (oculocerebral).

Some signs and symptoms are evident at birth (congenital) and may include an unusually light skin color and silvery-gray hair, small eyes (microphthalmia) and other eye abnormalities as clouding (opacities) of the front, clear portion of the eye (cornea) and/or rapid, involuntary eye movements (nystagmus). Additional symptoms that may develop during infancy include involuntary muscle contractions, associated loss of muscle function (spastic paraplegia), developmental delays and/or intellectual disability.

Inheritance is thought to be autosomal recessive, but the underlying genetic cause of this condition is still unknown. Treatment is directed toward the specific symptoms that the affected person has.

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Synonyms

• oculocerebral syndrome hypopigmentation syndrome, Cross type
• Cross-McKusick-Breen syndrome
• Cross syndrome
• depigmentation-gingival fibromatosis-microphthalmia
• Kramer syndrome

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Signs & Symptoms

Oculocerebral syndrome with hypopigmentation, also known as Cross syndrome, is an extremely rare genetic disorder that may be apparent at birth (congenital) or during early infancy.

Abnormally small eyes and lack of skin and hair color are usually apparent at birth. Neurological abnormalities may become apparent by three months of age. Some affected infants have abnormally enlarged gums (gingival fibromatosis) when the first teeth emerge from the gums (at age six months to three years). Other symptoms may become apparent later during infancy or childhood.

Reported signs and symptoms include:

• Decreased color (hypopigmentation) or total lack of color (depigmentation) of the skin and hair
  • The skin is usually very light and may be extremely sensitive to exposure to the sun (photosensitivity)
  • In most affected children the hair is often silvery or silvery gray in color at birth
• Slow involuntary purposeless movements of various muscles, especially in the hands (athetoid movements)
• Difficulty coordinating voluntary movements (ataxia)
• Movement of the head beyond the normal range of motion (hyperextension)
• Increased rigidity in some muscles causing stiffness and limitation of movement
• Lack of voluntary movements of the arms and legs (spastic tetraplegia) in more severely affected people
• Increased reflexes
• Fixation of several joints in a permanently flexed position (joint contractures), especially affecting the legs, arms, shoulders and hips
• High-pitched cry or constant sucking sounds
• Eye abnormalities that may result in varying degrees of visual difficulties or, in some patients, blindness, depending upon the severity and/or combination of eye abnormalities present which may include:
  • Abnormally small eyes (microphthalmia)
  • Abnormally small cornea (microcornea), the clear layer in front of the eye that covers the iris and the pupil and allows light to enter the eye
  • Abnormal clouding (opacity) of the corneas
  • Rapid side-to-side involuntary eye movements (horizontal nystagmus)
  • Outward turning of the eyelids, exposing the delicate membranes that line the inside of the eyelids (ectropion palpebral conjunctivae)
  • Loss of transparency (opacity) of the lenses of the eyes, the clear layer of the eye located behind the iris (the colored part of the eye) known as cataracts
  • Wasting away (atrophy) of the iris and/or the optic nerve (optic atrophy)
• Intellectual disability
• Slow physical development (growth delay)
• Delay in reaching developmental milestones (such as holding up the head, sitting, walking, etc.) and/or a delay in the acquisition of skills requiring the coordination of muscular and mental activity (psychomotor delay)
• Abnormally large gums (gingival fibromatosis) between the ages of six months to three years, when the baby teeth emerge from the gums
  • The overgrown gums may be pink and leathery and have small pebble-like bumps on the surface
  • Rarely, the gums may completely cover the teeth and protrude from the mouth
• Speech problems, which, if not corrected may interfere with breathing and swallowing in severely affected people
• A long appearance to the head (dolichocephaly)
• Highly arched roof of the mouth (palate)
• Widely spaced teeth
• Underdevelopment of a muscle that separated the thorax from the abdomen (diaphragm) that is necessary for proper breathing (oligophrenia) which may result in breathing difficulties
• Urinary tract abnormalities, described in one person

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Causes

The gene involved in this syndrome is not yet known, but one report suggested that the gene associated with this condition is located on chromosome 3 at 3q27.1q29.

Inheritance

Oculocerebral syndrome with hypopigmentation is thought to be inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Parents of several individuals with this disorder have been closely related by blood (consanguineous). In these families, there is a higher-than-normal chance that both parents carry, and consequently may pass on, the gene variants that cause this disorder.

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Affected populations

Oculocerebral syndrome with hypopigmentation is an extremely rare disorder that affects males and females in equal numbers. It was first reported in 1967 and, as of 2024, fewer than 20 cases have been described, without an ethnic preference. Most reported cases occurred within families.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of oculocerebral syndrome with hypopigmentation. Comparisons may be useful for a differential diagnosis:

Chediak-Higashi syndrome is a rare inherited disorder characterized by the lack of normal color of the skin and eyes (oculocutaneous albinism), visual difficulties, and/or abnormalities affecting certain white blood cells (leukocytes) that may result in immune system deficiencies. The hair is typically blond or light brown with a silvery tint. Affected infants may also have abnormal sensitivity to light (photosensitivity), rapid involuntary eye movements (nystagmus) and/or an impaired ability to coordinate voluntary movements (ataxia). Chediak-Higashi syndrome is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “Chediak Higashi” as your search term in the Rare Disease Database.)

Hermansky-Pudlak syndrome is a rare inherited disorder characterized by lack of normal skin pigmentation (albinism), blood platelet dysfunction with prolonged bleeding, visual difficulties and abnormal storage of a fatty-like substance in various tissues of the body. The skin, hair, and eyes may vary in color from very pale to almost normal coloring. Other symptoms may include easy bruising, bleeding gums, and excessive bleeding after surgery or accidents. Hermansky-Pudlak syndrome is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “Hermansky Pudlak” as your search term in the Rare Disease Database.)

Albinism is a group of rare inherited disorders characterized by decreased color (hypopigmentation) or complete absence of color (depigmentation) in the skin, hair and eyes at birth. Albinism may be associated with many different syndromes. In individuals with albinism, the skin and the eyes are generally extremely pale or white. This may result in abnormal sensitivity to light, abnormal eye movements, crossed eyes and/or nearsightedness (myopia). Some people with albinism may be at an increased risk of developing skin cancer. The range and severity of symptoms and physical characteristics associated with albinism depend upon the type of albinism present. (For more information on this disorder, choose “Albinism” as your search term in the Rare Disease Database.)

Menkes disease is a rare genetic disorder of copper metabolism beginning before birth. Copper accumulates in excessive amounts in the liver and is deficient in most other tissues of the body. Structural changes occur in the hair, brain, bones, liver and arteries. Physical findings may include poorly pigmented, frail hair and lack of normal skin color (hypopigmentation). (For more information on this disorder, choose “Menkes” as your search term in the Rare Disease Database.)

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Diagnosis

Oculocerebral syndrome with hypopigmentation may be suspected in infants with characteristic neurological and ocular abnormalities occurring in association with the presence of abnormally light skin and silvery-gray hair.

Abnormal lack of skin color (cutaneous hypopigmentation) and abnormally small eye(s) are usually obvious at birth or in early infancy. Ultrasonography may be used to confirm a diagnosis of small eyes (microphthalmia). Horizontal side-to-side eye movements (nystagmus) and outward turning of the eyelids (ectropion palpebral conjunctivae) may also be observed at birth. Enlarged gums (gingival fibromatosis) may develop when the first teeth emerge from the gums (usually around six months to three years of age). Neurological abnormalities, such as athetoid movements and ataxia, may become apparent around three months of age. Other symptoms (e.g., developmental delays, intellectual disability, etc.) may not become apparent until late infancy or childhood.

Internal abnormalities such as an underdeveloped diaphragm (oligophrenia) may be detected through a combination of observation and internal imaging techniques, such as computerized tomography (CT) scanning. CT scanning is an imaging technique in which a computer and X-rays are used to create a film showing cross-sectional images of certain organs.

Diagnosis of oculocerebral syndrome with hypopigmentation may be confirmed based upon a thorough clinical evaluation and detailed patient history, characteristic physical findings, specialized laboratory tests and imaging techniques.

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Standard Therapies

There is no cure or specific treatment. The treatment is symptomatic and supportive, and it is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, dentists, physicians who specialize in disorders of the eyes (ophthalmologists), physicians who specialize in skin disorders (dermatologists), and other health care professionals may need to plan an affected child’s treatment systematically and comprehensively.

An affected child’s skin may be highly sensitive to sun exposure; therefore, sunscreen, hats, and long sleeves may be recommended to avoid sunburn. Wearing sunglasses and other preventative measures may also be recommended to protect affected individuals from the sun.

Corrective glasses or contact lenses may be used to help improve vision. In some patients, eye surgery may be performed.

The size of the gums may be reduced with surgery. However, the enlargement may recur as more teeth emerge and/or when secondary teeth grow in, requiring other surgeries.

Early intervention is important to ensure that affected children reach their potential. Special services that may be beneficial to affected children may include special remedial education and other medical, social and/or vocational services.

Genetic counseling is recommended for families of affected children.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://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:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

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:
https://www.centerwatch.com/

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

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References

TEXTBOOKS

Scriver CR, et al., eds. The Metabolic and Molecular Basis of Inherited Disease. 7th Ed. New York, NY; McGraw-Hill Companies, Inc; 1995:4379.

Champion RH, et al., eds. Textbook of Dermatology. 5th ed. Cambridge, MA: Blackwell Scientific Publications; 1992:1605, 2668, 2705.

Buyse ML, ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:81, 660-62, 775, 778-79.

JOURNAL ARTICLES

Liu S, Kuht HJ, Moon EH, Maconachie GDE, Thomas MG. Current and emerging treatments for albinism. Surv Ophthalmol. 2021 Mar-Apr;66(2):362-377. https://www.sciencedirect.com/science/article/abs/pii/S0039625720301454

Gironi LC, Zottarelli F, Savoldi G, Notarangelo LD, Basso ME, Ferrero I, Timeus F, Fagioli F, Maiuri L, Colombo E, Savoia P. Congenital hypopigmentary disorders with multiorgan impairment: A case report and an overview on gray hair syndromes. Medicina (Kaunas). 2019 Mar 25;55(3):78. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473230/

Chabchoub E, Cogulu O, Durmaz B, Vermeesch JR, Ozkinay F, Fryns JP. Oculocerebral hypopigmentation syndrome maps to chromosome 3q27.1q29. Dermatology. 2011;223(4):306-10. https://pubmed.ncbi.nlm.nih.gov/22327602/

Tezcan I, et al. A new case of oculocerebral hypopigmentation syndrome (Cross syndrome) with additional findings. Clin Genet. 1997;51:118-21.

Lerone M, et al. Oculocerebral syndrome with hypopigmentation (Cross syndrome): report of a new case. Clin Genet. 1992;41:87-89.

De Jong G, et al. Oculocerebral syndrome with hypopigmentation (Cross syndrome): the mixed pattern of hair pigmentation as an important diagnostic sign. Genet Couns. 1991;2:151-55.

Ozkan H. Oculocerebral hypopigmentation syndrome (Cross syndrome). Turk J Pediatr. 1991;33:247-52.

Courtens W, et al. Oculocerebral hypopigmentation syndrome (Cross syndrome) in a gipsy child. Acta Pediatr Scand. 1989;78:806-10.

Castle DJ, et al. The oculocerebral syndrome in association with generalised hypopigmentation. A case report. S Afr Med J. 1989;76:35-56.

Fryns JP, et al. Oculocerebral syndrome with hypopigmentation (Cross syndrome). Report of two siblings born to consanguineous parents. Clin Genet. 1988;34:81-84.

Patton MA, et al. An oculocerebral hypopigmentation syndrome: a case report with clinical, histochemical, and ultrastructural findings. J Med Genet. 1987;24:118-22.

Preus M, et al. An oculocerebral hypopigmentation syndrome. J Genet Hum. 1983;31:323-28.

Cross HE, et al. A new oculocerebral syndrome with hypopigmentation. J Pediatr. 1967;70:398-406.

INTERNET

Oculocerebral syndrome with hypopigmentation. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 257800; Last Update: 11/11/2013. https://www.omim.org/entry/257800 Accessed March 4, 2024.

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