NORD gratefully acknowledges Heng Wang, MD, PhD, Medical Director, DDC Clinic Center for Special Needs Children, Middlefield, Ohio, for assistance in the preparation of this report.
The signs and symptoms of Cohen syndrome may vary from one individual to another. Although researchers have been able to establish a clear syndrome with characteristic or “core” features, much about the disorder is not fully understood. Several factors including the small number of identified cases and the lack of large clinical studies, prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.
Newborns with Cohen syndrome usually have diminished muscle tone (hypotonia). Feeding and breathing difficulties due to hypotonia may be present in the first few days of life. Some newborns may have a weak or high-pitched cry. Some infants may exhibit a failure to gain weight and grow as would otherwise be expected based upon gender and age (failure to thrive). An infant’s joints may be ‘loose’, meaning that they have an abnormally large range of motion (joint hypermobility). Mild to moderate microcephaly often develops within the first year of life and continues into adulthood.
As infants grow older, they may exhibit delays in reaching normal developmental milestones such as sitting up or rolling over (developmental delays). The degree of such delays is highly variable, even among members of the same family. Walking is often delayed until 2-5 years of age. Speech delays are also common; an infant’s or child’s first words or ability to speak in sentences are often delayed.
Mild to moderate intellectual disability is non-progressive and affected individuals show an ability to learn new concepts. Most children are described as sociable with a cheerful disposition. In some instances, children may exhibit behavioral issues that fall within the autistic spectrum. Although rare, seizures have been reported in a minority of individuals.
During childhood, often around the age of 5, distinctive facial features may become apparent. Such features include large ears; a prominent root of the nose (the part of nose between the eyes); a low hairline; highly-arched or wave-shaped eyelids; long, thick eyelashes; thick eyebrows; a high, narrow roof of the mouth (palate); an abnormally short groove in the middle of the upper lip (philtrum); and prominent upper central incisors. Some individuals may develop recurrent, small rounded ulcers in the mouth (aphthous ulcers) and inflammation or infection of the gums (gingivitis) may occur. In the medical literature, the range of distinctive facial features is highly variable and specific features appear to be more likely to occur in individuals of specific ethnic backgrounds.
Affected individuals often develop a variety of abnormalities affecting the eyes and may experience vision problems early in childhood. Such abnormalities include decreased clarity of vision (visual acuity), nearsightedness (myopia), and crossed eyes (strabismus). Myopia usually becomes progressively worse throughout childhood.
Affected individuals may also have chorioretinal dystrophy, a condition characterized by abnormalities affecting the choroid and retina including degeneration of the retina. The choroid is the middle layer of the eye that consists of blood vessels that supply blood to the retina. The retina is a membranous layer of light-sensing cells in the back of the eye that converts light to specific nerve signals, which are then transmitted to the brain to form images. Chorioretinal dystrophy is progressive and can cause poor vision in dim light and eventually night blindness (nyctalopia) and a decreased field of vision with a decreased ability to see to the left or right when looking straight ahead (constriction of the peripheral field of vision; sometimes referred to as tunnel vision). Loss of peripheral vision may cause individuals to trip or fall easily.
Less often, additional abnormalities of the eyes are associated with Cohen syndrome including abnormal curvature of the cornea (astigmatism), reduced size of the cornea (microcornea), abnormally small eyeballs (microphthalmia), clouding (opacity) of the lenses, degeneration of the iris (iris atrophy), degeneration of the optic nerve, which carries impulses from the eyes to the brain (optic atrophy), and a cleft of missing tissue (colobomas) in the retina or eyelids.
Some individuals develop obesity of the trunk or torso of the body that occurs during mid-childhood. The arms and legs can remain slender or thin. Individuals may be below average height for their age and gender (short stature). Some individuals may also have small, narrow hands and feet. Delayed puberty has also been reported and some males exhibit undescended testicles (cryptorchidism).
Abnormal curvature of the spine is common. Affected individuals may develop abnormal front-to-back curvature of the spine (kyphosis), or a combination of kyphosis with abnormal sideways curvature of the spine (scoliosis).
Individuals with Cohen syndrome may have a condition called neutropenia, in which there are abnormally low levels of certain white blood cells called neutrophils. Neutrophils are essential in helping the body to fight off infection by surrounding and destroying bacteria that enter the body. Episodes of neutropenia are usually mild or moderate. Some individuals may experience repeated infections such as respiratory infections or minor skin infections. Children with Cohen syndrome may be prone to developing middle ear infections (otitis media). Chronic development of aphthous ulcers and gingivitis may be partly due to neutropenia.
Individuals with Cohen syndrome appear to be at an increased risk of developing autoimmune disorders, especially diabetes mellitus, but also thyroid disorders and celiac disease. Autoimmune disorders occur when the body’s immune system mistakenly attacks healthy tissue.
Cohen syndrome is caused by alterations in the COH1 gene. This gene is also known as the VPS13B gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When an alteration of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
Alterations of the COH1 gene in Cohen syndrome are inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same trait, one from each parent. If an individual inherits one normal gene and one altered gene for the disease, the person will be a carrier for the disease but will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have 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.
Researchers have determined that the protein product of the COH1 gene is involved in glycosylation, the process by which sugar ‘trees’ (glycans) are created, altered and chemically attached to certain proteins or fats (lipids). When these sugar molecules are attached to proteins, they form glycoproteins; when they are attached to lipids, they form glycolipids. Glycoproteins and glycolipids have numerous important functions in all tissues and organs. Glycosylation involves many different genes, encoding many different proteins such as enzymes. A deficiency or lack of one of these enzymes can lead to a variety of symptoms potentially affecting multiple organ systems, and there is nearly always an important neurological component. Symptoms and can vary in severity.
Cohen syndrome affects males and females in about equal numbers. It appears to occur more frequently in people of Finnish, Amish, Greek/Mediterranean and Irish ancestry. More than 150 cases have been reported in the medical literature and an estimated 500-1,000 individuals have been diagnosed with the disorder worldwide. However, instances of Cohen syndrome often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of the disorder in the general population.
The treatment of Cohen syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, orthopedists, ophthalmologists, psychiatrists, speech pathologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is recommended for affected individuals and their families.
Treatment options that may be used to treat individuals with Cohen syndrome are complex and varied. The specific treatment plan will need to be highly individualized. Decisions concerning the use of specific treatments should be made by physicians and other members of the health care team in careful consultation with an affected child’s parents or with an adult patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.
Specific treatments for Cohen syndrome include spectacles and eyeglasses to help with vision. In later years, low vision training as needed in individuals with visual impairment. Recurrent infections can be treated with standard therapies including antibiotics.
In some instances, neutropenia may be treated with the administration of granulocyte-colony stimulating factors (G-CSF). G-CSF is a manufactured version of the natural hormones that stimulate the bone marrow to produce neutrophils. G-CSF increases the number of neutrophils generated by the bone marrow and improves the efficacy of their bacteria-killing ability.
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