Cohen syndrome, also known as Norio syndrome in Finnish populations, is a rare autosomal recessive genetic disorder that affects multiple body systems—hence it is classified as a syndrome. It is caused by mutations in the VPS13B gene (also known as COH1). This multivariate disease mainly causes developmental delays (and consequent growth deficiencies), facial deformities, intellectual disabilities, obesity, poor muscle tone (hypotonia), and vision problems. Fewer than 1000 cases of Cohen have been reported until now. The highest number of cases is seen in the Amish population.¹

It is sometimes incorrectly referred to as Pepper syndrome, but this is actually a separate neonatal condition involving metastatic neuroblastoma in infants. Doctors usually diagnose the syndrome at an early age in the patient. However, most experts suspect that Cohen syndrome is underdiagnosed worldwide. Like the majority of inherited disorders, currently, there is no cure for Pepper syndrome. While most patients need medical assistance throughout their lives, the life expectancy of Cohen syndrome is good.

Cohen Syndrome Symptoms

As it affects a variety of organs, a long list of symptoms is seen in Cohen syndrome. The most commonly observed symptoms of the disorder include:

Facial Disfigurement:

Patients suffering from this inherited disease present with typical facial features. Youngsters suffer from microcephaly, i.e., a small head size, which contributes to mental developmental difficulties. There is thickening of eyebrows and lengthening of eyelashes. The eyes of patients have unusual shapes and slant downwards in a wave-shaped pattern. The tip of the nose is bulbous, and the philtrum (area between the nose and upper lip) is shortened. A highlighting feature of the syndrome is prominent upper central incisors.

As per the latest findings, infants with Cohen syndrome have small jaws (micrognathia) and round faces with full cheeks. However, the shape of the face changes as the child grows. Beyond 4 years of age, the face elongates gradually, and the nose becomes beak-shaped. The prominent upper incisors impart an open-mouth appearance, which becomes evident at 9 years of age.²

Developmental Delays:

The genetic changes brought about by the disorder lead to developmental delays in children. Affected kids are late in developing skills like rolling over, walking, and speaking, etc. However, most patients are sociable and cheerful, rather overly sociable. Physical examinations of patients have revealed significant developmental delays and speech disorders in conjunction with joint hypermobility, microcephaly, and limb anomalies.³ Patients may also suffer from delayed puberty along with undescended testicles in males.

Such individuals have poor growth, but there is no growth hormone deficiency. Growth retardation leads to a short stature. Abnormal growth of the spine can lead to abnormal curvatures, i.e., scoliosis or kyphosis. Some patients experience incomplete growth of hands and feet, which may lead to narrowing. Patients often have slender fingers.

Obesity:

Another salient feature of the syndrome is obesity. Kids are born with a normal size but rapidly gain weight in the early years (especially within the first year) of life, leading to obesity. Researchers have noted that most patients have fat deposition in the torso, i.e., truncal obesity. This is different from general obesity, as there is no fat deposition on the limbs. Truncal obesity is considered a characteristic feature of the genetic syndrome.⁴

Hypotonia:

In addition to other features, there is poor muscle tone. When you observe a Cohen syndrome patient, you will find hypotonia and weak muscles. This is accompanied by a strange finding, i.e., hypermobility of joints. The excessive movement of the joints may be accompanied by pain. Joint hypermobility is also seen in other disorders like Down syndrome. The co-occurrence of facial deformities, intellectual disabilities, and vision disturbances with hypermobility helps healthcare professionals in diagnosing Cohen syndrome.

Vision Problems:

There are marked vision difficulties in Cohen syndrome patients. Nearsightedness (myopia) is a common problem encountered by individuals. The condition worsens with age. In addition to sight problems, there is damage to the retina as well. Damage to the retina is seen in the form of retinal dystrophy or chorioretinitis (inflammation of the retina and choroid of the eye). Reports suggest that myopia and retinochoroid dystrophy are very common complications associated with this syndrome and develop at an early age.⁵ Other eye problems include:

Ptosis
Strabismus
Lens opacities

Ophthalmic analyses of young patients reveal peripheral retinal regeneration, which may be asymptomatic but increases the risk of retinal detachment.⁶

Neutropenia:

The low levels of white blood cells, i.e., neutropenia, expose patients to recurrent infections. High frequency of infections is a reason for frequent hospitalization of infants (and adolescent patients).

Infant Symptoms:

The genetic disease starts manifestation in early life. Infants present with feeding difficulties and usually have high-pitched cries. Patients have difficulty gaining weight due to compromised feeding. Breathing difficulties also accompany feeding issues, which are major concerns for the parents.

Cohen Syndrome Causes

It arises due to a mutation in the VPS13B gene (also known as the COH1 gene). This gene is a part of the Golgi apparatus of the cell. The Golgi apparatus is the cell’s protein packaging factory. It modifies the protein before sending it to different parts. It is responsible for the process of glycosylation, i.e., attaching sugar molecules to the proteins. Experts believe that impairment of the normal glycosylation leads to a wide variety of symptoms. It also plays a part in the organization of nerve cells and fat cells. Therefore, abruption of the gene-controlled process leads to intellectual disabilities and fat deposition.

Genetic mutaion in Cohen syndrome — A genetic mutation in the VPS13B gene causes Cohen syndrome.

It is an autosomal recessive inherited disorder, which means that it develops only when a child receives two copies of the mutated gene (one from each parent). Thus, biological parents can be Cohen syndrome carriers without having the disease themselves. If one of your children is affected by the disease, each sibling has:

a 25% chance of being unaffected or being a carrier
a 50% chance of being an asymptomatic carrier
a 25% chance of being affected

Thus, prenatal testing for pregnancies and carrier testing for at-risk family members are important steps.

Risk Factors:

The following ancestries are at a higher risk of developing the genetic mutations for Cohen syndrome:

Amish
Greek
Irish
Finnish

Cohen Syndrome Diagnosis

After taking a history of the symptoms, your healthcare provider will start a physical examination to test different organs. Identifying characteristic features like truncal obesity, prominent incisors, myopia, and joint hypermobility with neutropenia is crucial in diagnosis. A history of developmental delays also helps reach a diagnosis.

Blood genetic testing is done for most genetic disorders. Molecular genetic testing involves identifying faulty genes. Single-gene testing begins with sequence analysis of the VPS13B gene, followed by a deletion/duplication analysis. Targeted analysis and multigene panel tests are also done to identify problems in the genes of interest.

Differential Diagnosis:

Diagnosing Cohen syndrome is a difficult task because of its rare occurrence and similar symptoms. The following symptoms have presentations similar to Cohen syndrome:

Cohen-like syndrome
Prader-Willi syndrome
Bardet-Biedl syndrome
Angelman syndrome
Williams syndrome

Infants suffering from Prader-Willi syndrome have hypotonia (severe) and feeding difficulties. Morbid obesity and delayed development are also seen in such individuals. However, unlike Cohen syndrome, Prader-Willi patients are stubborn (with temper tantrums) and lack retinal dystrophy. This sets the disease apart.

Cohen Syndrome Treatment

No exact treatment for this genetic disorder exists currently. Genetic counseling provides information to individuals/families regarding genetic conditions. This helps the layman understand the implications (physiological, physical, and medical) of the disease and how they can find support.

Management of Cohen syndrome involves a team of specialists to cater to the wide variety of problems. The following therapies play a crucial role in improving the quality of life of the patients:

Occupational Therapy (OT):

This mode of treatment has been indicated for a number of chronic infirmities. This therapy, provided by healthcare professionals, enables patients to perform daily activities independently and thus improves the quality of life. Therapists help young patients with Cohen syndrome who have mental and physical deficits overcome the barriers to independence.

Physical Therapy:

Physiotherapy can aid in improving joint hypermobility and hypotonia. Weekly sessions of physical therapy in infants and young children help with independent walking.⁷ The latest clinical research shows that there is some advantage of occupational and physical therapy in patients with hypotonia.⁸

Speech Therapy:

Language delays are common in kids affected with Cohen syndrome. Therefore, a speech therapist can help your child with his/her speech impediments. Early intervention has been shown to be beneficial. In some cases, therapists help develop oral motor skills and aid in solving swallowing issues.

Vision Training:

Low vision training is done to maximize the residual sight and improve functional vision in individuals with genetic disorders like Cohen syndrome. This type of rehabilitation improves the quality of life for visually impaired adults.⁹

A little boy wearing spectacles to treat vision myopia in Cohen syndrome — Spectacles help correct nearsightedness in children.

Patients may also need spectacles (eyeglasses) for better vision.

Infection & Neutropenia Management:

Frequent infections plague the growing child, which is attributed to a low white blood cell count. Doctors prescribe antibiotics for most infections. To treat the underlying neutropenia, healthcare providers inject granulocyte-colony stimulating factor (G-CSF) into the skin. This glycoprotein promotes white blood cell production from your bone marrow. Studies show that this treatment type helps in the production of WBCs and minimizes the associated risk of infections.¹⁰

Dental Management:

Management of the prominent upper incisors is done by a dentist. Orthodontic treatment can help align the teeth and improve the appearance of the patient.

Cohen Syndrome Complications

There are multiple complications associated with Cohen syndrome. Due to the low levels of protective white blood cells, patients persistently fall prey to infections and issues related to weak immunity. A major complication of the syndrome is infection of the middle ear, i.e., otitis media. Individuals may also suffer from chronic gingivitis and recurrent oral sores.

Final Word

Cohen syndrome is an autosomal recessive genetic disorder caused by a mutation in the VPS13B gene (COH1 gene). It causes a variety of symptoms, including truncal obesity, developmental delays (speech, motor skills), muscle hypotonia, vision impairments, and typical facial features (microcephaly, prominent incisors, etc.). In several cases, neutropenia (low white blood cell count) causes recurrent infections at an early age. Infants display breathing and feeding difficulties in early life. Genetic testing is done to reach a diagnosis. Management aims at improving quality of life and involves the collaboration of different therapies, including occupational, physical, and speech therapies. Low vision training helps with sight, while dental treatment improves appearance.

Refrences

1
Ishikawa, E., Shibuya, M., Kimura, Y., Kamekura, N., & Fujisawa, T. (2022). A Cohen syndrome patient whose muscle-relaxant effect may have been prolonged during general anesthesia: a case report. Journal of dental anesthesia and pain medicine, 22(2), 155.
2
Güneş, N., Alkaya, D. U., Demirbilek, V., Yalçınkaya, C., & Tüysüz, B. (2023). Early diagnostic signs and the natural history of typical findings in Cohen syndrome. The Journal of Pediatrics, 252, 93-100.
3
Momtazmanesh, S., Rayzan, E., Shahkarami, S., Rohlfs, M., Klein, C., & Rezaei, N. (2020). A novel VPS13B mutation in Cohen syndrome: a case report and review of literature. BMC Medical Genetics, 21, 1-6.
4
Milhem, F. S., Awashra, A., Hamshary, H., Sawaftah, Z., Khaled, A., Nabresi, N., … & Nabresi, N. N. (2024). Cohen Syndrome With Complex Medical Complications: A Case Report. Cureus, 16(8).
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Quinn, M. P., MacKeen, L. D., Vincent, A., & Strube, Y. N. J. (2021). Early ocular findings in Cohen syndrome: Case report and Canadian survey study. Canadian Journal of Ophthalmology, 56(1), e26-e28.
6
Kim, D. A., & Kim, J. (2023). Ophthalmic findings in Cohen syndrome patient without subjective ophthalmic complaints: A case report. Medicine, 102(46), e35945.
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Mintz-Itkin, R., Lerman-Sagie, T., Zuk, L., Itkin-Webman, T., & Davidovitch, M. (2009). Does physical therapy improve outcome in infants with joint hypermobility and benign hypotonia?. Journal of Child Neurology, 24(6), 714-719.
8
Paleg, G. S., Hidalgo Robles, Á., Govender, P., & Livingstone, R. W. (2025). Occupational and Physical Therapy Interventions for Young Children with Developmental Central Hypotonia: An Overview of Systematic Reviews.
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Hoeben, M., Langelaan, M., Klevering, J., Keunen, J. E., & van Rens, G. H. (2020). Low vision rehabilitation for better quality of life in visually impaired adults. Cochrane Database of Systematic Reviews, (1).
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Cetean, S., Căinap, C., Constantin, A. M., Căinap, S., Gherman, A., Oprean, L., … & Oprean, R. (2015). The importance of the granulocyte-colony stimulating factor in oncology. Clujul medical, 88(4), 468.

Cohen Syndrome: Rare Genetic Disorder Explained

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