Cohen Syndrome - Symptoms, Causes, Treatment - NORD

19/12/23, 16:46 Cohen Syndrome - Symptoms, Causes, Treatment | NORD
Home / Rare Diseases / Cohen Syndrome
Cohen Syndrome
Last updated: 05/23/2023

Years published: 1990, 1995, 1996, 1997, 2005, 2016, 2019, 2023
Acknowledgment
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.
DISEASE OVERVIEW
Cohen syndrome is a variable genetic disorder characterized by
diminished muscle tone (hypotonia), abnormalities of the head, face,
hands and feet, eye abnormalities, and non-progressive intellectual
disability. Affected individuals usually have microcephaly, a condition
that indicates that head circumference is smaller than would be
expected for an infant’s age and sex. In many older patients, obesity is
present, especially around the torso and is associated with slender
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arms and legs. A lowered level of certain white blood cells known as
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caused by changes (variants or mutations) in the VPS13B/COH1 gene.
SYNONYMS
Pepper Syndrome
SIGNS & SYMPTOMS

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
https://rarediseases.org/rare-diseases/cohen-syndrome/ 1/12
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 sex 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
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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.
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(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. Neutropenia is 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.
CAUSES
Cohen syndrome is caused by changes (variants or mutations) 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 protein, this can affect many organ systems of the
body.
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
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there is nearly always an important neurological component.
Symptoms can vary in severity.
Cohen syndrome is inherited in an autosomal recessive manner.
Recessive genetic disorders occur when an individual inherits a
mutated gene from each parent. If an individual receives one normal
gene and one mutated gene for the disease, 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 mutated gene 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.
AFFECTED POPULATIONS
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 over 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.
DISORDERS WITH SIMILAR SYMPTOMS

Symptoms of the following disorders can be similar to those of Cohen
syndrome. Comparisons may be useful for a differential diagnosis:
Prader-Willi syndrome (PWS) is a genetic multisystem disorder
characterized during infancy by lethargy, diminished muscle tone
(hypotonia), feeding difficulties and poor weight gain. In childhood,
features of this disorder include short stature, small genitals and an
excessive appetite because affected individuals do not feel satisfied
after completing a meal (satiety). Without intervention, this can lead to
overeating and the gradual onset of obesity. Food compulsion requires
constant
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increased
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individuals with PWS have some cognitive impairment that ranges from
low normal intelligence with learning disabilities to mild to moderate
intellectual disability. Behavioral problems are common and can include
temper tantrums, obsessive/compulsive behavior and skin picking.
Motor milestones and language development are often delayed. PWS
occurs due to alterations affecting certain genes in a specific region of
chromosome 15. These abnormalities usually result from random
(sporadic) errors in development but are sometimes inherited. (For
more information on this disorder, choose “Prader-Willi” as your search
term in the Rare Disease Database.)
Angelman syndrome (AS) is a rare genetic neurological disorder
characterized by severe developmental delays and learning disabilities;
the absence or near absence of speech; an inability to coordinate
voluntary movements (ataxia) and tremulous, jerky movements of the

arms and legs and a distinct behavioral pattern characterized by a
happy disposition and unprovoked episodes of laughter and smiling,
often at inappropriate times. Although affected individuals may be
unable to speak, many gradually learn to communicate through other
means such as gesturing. In addition, children may have enough
receptive language ability to understand language to understand
simple commands. Additional symptoms may occur in some children
inluding seizures, sleep disorders and feeding difficulties. Some
affected children may have distinctive facial features. Angelman
syndrome is caused by deletion of or abnormal expression of the
UBE3A gene that is located on the long arm (q) of chromosome 15
(15q11-q13), the PWS/AS region. (For more information on this disorder,
choose “Angelman” as your search term in the Rare Disease Database.)
Several other genetic disorders can have signs and symptoms that are
similar to or overlap with those seen in Cohen syndrome. These
disorders include Alstrom syndrome, Cri-du-chat syndrome, Williams
syndrome, Bardet-Biedl syndrome and hypothyroidism. (For more
information, choose the specific disorder name as your search term in
the Rare Disease Database.)
STANDARD THERAPIES
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,
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pathologists and other healthcare professionals may need to
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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.
Genetic counseling is recommended for families with an affected child.
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.
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
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Some current clinical trials also are posted on the following page on
the NORD website:
https://rarediseases.org/for-patients-and-families/information-
resources/news-patient-recruitment/
For information about clinical trials sponsored by private sources,
contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:

https://www.clinicaltrialsregister.eu/
REFERENCES
TEXTBOOKS
Chandler K, Clayton-Smith J. Cohen Syndrome. In: Management of
Genetic Syndromes, 3rd edition. Cassidy SB, Allanson JE, editors. 2011
Wiley-Blackwell, Hoboken, NJ.
Gunay-Aygun M. Cohen Syndrome. In: NORD Guide to Rare Disorders.
Lippincott Williams & Wilkins. Philadelphia, PA. 2003:172-73.
Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Cohen syndrome. In:
Syndromes of the Head and Neck. 4th ed. Oxford University Press,
London, UK; 2001:424-426.
JOURNAL ARTICLES
Limoge F, Faivre L, Gautier T, et al. Insulin response dysregulation
explains abnormal fat storage and increased risk of diabetes mellitus
type 2 in Cohen syndrome. Hum Mol Genet. 2015;24:6603-6613.
http://www.ncbi.nlm.nih.gov/pubmed/26358774
Duplomb L, Duvet S, Picot D, et al. Cohen syndrome is associated with
major glycosylation defects. Hum Mol Genet. 2014;23:2391-2399.
Gueneau L, Duplomb L, Sarda P, et al. Congenital neutropenia with
retinopathy, a new phenotype without intellectual disability or obesity
secondary to VPS13B mutations. Am J Med Genet A. 2014;164:522-
527. http://www.ncbi.nlm.nih.gov/pubmed/24311531
El Chehadeh-Djebbar S, Blair E, Holder-Espinasse M, et al. Changing
facial phenotype in Cohen syndrome: towards clues for an earlier
diagnosis. Eur J Hum Genet. 2013;21:736-742.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3722949/
Douzgou S, Petersen MB. Clinical variability of genetic isolates of
Cohen syndrome. Clin Genet. 2011;79:501-506.
Donadieu J, Fenneteau O, Beaupain B, Mahlaoui N, Chantelot CB.
Congenital neutropenia: diagnosis, molecular diagnosis, molecular
bases and patient management. Orphanet J Rare Dis. 2011;6:26.
Balikova I, Lehesjoki AE, de Ravel TJ, et al. Deletions in the VPS13B

(COH1) gene as a cause of Cohen syndrome. Hum Mutat.
2009;30:E845-854. http://www.ncbi.nlm.nih.gov/pubmed/19533689
Taban M, Memoracion-Peralta DS, Wang H, Al-Gazali LI, Traboulsi EI.
Cohen syndrome: report of nine cases and review of the literature, with
emphasis on ophthalmic features. J AAPOS. 2007;11:431-437.
Seifert W, Holder-Espinasse M, Spranger S, et al. Mutational spectrum
of COH1 and clinical heterogeneity in Cohen syndrome. J Med Genet.
2006;43:e22. http://www.ncbi.nlm.nih.gov/pubmed/16648375
Falk MJ, Feiler HS, Neilson DE, et al. Cohen syndrome in the Ohio
Amish. Am J Med Genet. 2004;128A:23-28.
Hennies HC, Rauch A, Seifert W, et al. Allelic heterogeneity in the
COH1 gene explains clinical variability in Cohen syndrome. Am J Hum
Genet. 2004;75:138-45.
Kolehmainen J, Wilkerson R, Lehesjoki AE, et al. Delineation of the
Cohen syndrome following a large-scale genotype-phenotype screen.
Am J Hum Genet. 2004;75:122-27.
Karpf J, Turk J, Howlin P. Cognitive, language, and adaptive behavior
profiles in individuals with a diagnosis of Cohen syndrome. Clin Genet.
2004;65:327-32.
Terms of Service http://www.ncbi.nlm.nih.gov/pubmed/15025727
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Kolehmainen J, Black GC, Saarinen A, et al. Cohen syndrome is caused I Agree
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by mutations in a novel gene, COH1, encoding a transmembrane
protein with a presumed role in vesicle-mediated sorting and
intracellular protein transport. Am J Hum Genet. 2003;72:1359-69.
Chandler KE, Kidd A, Al-Gazali L, et al. Diagnostic criteria, clinical
characteristics, and natural history of Cohen syndrome. J Med Genet.
2003;40:233-41. http://www.ncbi.nlm.nih.gov/pubmed/12676892
Chandler KE, Biswas S, Lloyd IC, et al. The ophthalmic findings in Cohen
syndrome. Br J Ophthalmol. 2002;86:1395-98.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1771382/
Kivitie-Kallio S, Norio R. Cohen syndrome: essential features, natural

history, and heterogeneity. Am J Med Genet. 2001;102:125-35.
Kivitie-Kallio S, Larsen A, Kajasto K, et al. Neurological and
psychological findings in patients with Cohen syndrome: a study of 18
patients aged 11 months to 57 years. Neuropediatrics. 1999;30:181-89.
INTERNET
Wang H, Falk MJ, Wensel C, et al. Cohen Syndrome. 2006 Aug 29
[Updated 2016 Jul 21]. In: Adam MP, Mirzaa GM, Pagon RA, et al.,
editors. GeneReviews® [Internet]. Seattle (WA): University of
Washington, Seattle; 1993-2023. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK1482/ Accessed May 9, 2023.
Wang H. Cohen syndrome. Orphanet Encyclopedia, February 2013.
Available at: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?
Expert=193 Accessed May 9, 2023.
Cohen Syndrome. Online Mendelian Inheritance in Man (OMIM). Entry
No:216550; Last Update: 03/18/2020. Available at: Entry – #216550 –
COHEN SYNDROME; COH1 – OMIM Accessed May 9, 2023.
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PATIENT ORGANIZATIONS
Cohen Syndrome Association

Phone: 410-632-1668 Fax: 410-632-1697
https://rarediseases.org/organizations/cohen-syndrome-
association/
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Phone: 202-534-3700 Email: info@thearc.org
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19/12/23, 16:46 Cohen Syndrome - Symptoms, Causes, Treatment | NORD

Home / Rare Diseases / Cohen Syndrome

Last updated: 05/23/2023

SIGNS & SYMPTOMS

number of identified cases and the lack of large clinical studies,

Affected individuals often develop a variety of abnormalities affecting

individuals may experience repeated infections such as respiratory

DISORDERS WITH SIMILAR SYMPTOMS

voluntary movements (ataxia) and tremulous, jerky movements of the

Early developmental intervention is important to ensure that affected

CLINICAL TRIALS AND STUDIES

For more information about clinical trials conducted in Europe, contact:

Balikova I, Lehesjoki AE, de Ravel TJ, et al. Deletions in the VPS13B

Kivitie-Kallio S, Norio R. Cohen syndrome: essential features, natural

Programs & Resources

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new

Rare Disease Educational Support Program

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers

Cohen Syndrome Association

VISIONS Services for the Blind and Visually Impaired

Understanding Living with a Community Advancing Driving Get

Terms of Service & Privacy Policy

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