Cohen syndrome

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Cohen syndrome

Definition

Cohen syndrome is a very rare genetic disorder characterized by infantile hypotonia (a weakening of the skeletal muscles), childhood obesity, and several malformations.

Description

Cohen syndrome was first described in 1973 by Dr. M. M. Cohen, Jr. in three children with distinct physical and developmental observations. Since then, over 100 cases have been reported throughout the world, offering the picture of an extremely rare disease with a wide range of clinical characteristics. The initial description given by Cohen included obesity, mental retardation, low muscle tone, narrow hands and feet, and distinctive facial features with prominent upper central teeth. As of 2001, the underlying cause of the disease remains unknown.

Cohen syndrome has also been referred to as Pepper syndrome, Hypotonia-Obesity-Prominent Incisors syndrome, Obesity-Hypotonia syndrome, and Mirhosseini-Holmes-Walton syndrome.

Genetic profile

Research has suggested that the gene for Cohen syndrome lies between 8q21.3 and 8q22.1. This refers to a location on the long arm of chromosome 8 between positions 21.3 and 22.1 and is a rough estimate of where the gene may lie. This region was originally referred to as CHS1 but has since become known as COH1. The phrase 'COH1 gene region' is often used due to the fact that the exact location of the gene still remains to be discovered.

Chromosomes are the genetic material passed down from generation to generation that tell a person's body how to work and how to grow. Each chromosome is composed of smaller pieces known as genes. A person inherits one set of 23 chromosomes from both the egg and the sperm of the parents. These chromosomes can then be matched into pairs, giving two copies of each chromosome and likewise two copies of each gene.

Cohen syndrome is an autosomal recessive disorder. Recessive means that both copies of the COH1 gene region must have a change or mutation for a person to be affected. An individual with only one changed COH1 gene region is not affected by the disease but can pass the disease on to a future child. These individuals are called carriers. If two carriers have a child there is a 25% chance with each pregnancy that the child will be affected. At this time prenatal diagnosis is not available.

Demographics

While Cohen syndrome affects all races and genders, several small samplings of affected populations have been studied around the world. Interestingly, it has been found that Cohen syndrome manifests in these populations in distinctly different ways, with certain clinical findings being family- or ethnic-specific.

For example, Cohen syndrome has been studied extensively in Finland. In the populations studied, individuals diagnosed with the syndrome typically have fewer white blood cells than normal (granulocytopenia), a specific eye abnormality called mottled retina, and mental retardation. As a rule, they do not have truncal obesity, a common characteristic of Cohen syndrome in other populations. Although the symptoms of Cohen syndrome are known to vary widely between affected individuals within the same family, affected people within the Finnish populations are very similar to each other in their presentation.

Due to the extreme rarity of the disease, the exact incidence of Cohen syndrome is not known. A relatively high frequency of the disease has also been noted in Israel. However, earlier reports suggesting a possible increase in the frequency of Cohen syndrome among Ashkenazi Jews no longer seems to be true.

Signs and symptoms

Four main areas are affected by Cohen syndrome: physical appearance, mental function, vision, and hematology (blood function). The list of possible conditions is extensive however, and it is important to remember that each case is different. While a given characteristic may be common to the syndrome, not all affected individuals have been found to have it.

Physical appearance

When they are born, babies with Cohen syndrome usually look just like babies without the syndrome, although they are typically born at a low birth weight. As they grow, the various physical signs associated with the syndrome become increasingly obvious.

Narrow hands and feet with long slender fingers are a hallmark feature, found in approximately 89% of diagnosed individuals. Truncal obesity, or the abnormal deposition of fat around the mid-section of the body, has been observed in roughly 70% of patients. Most individuals with Cohen syndrome have large and rather noticeable front teeth, referred to as prominent upper central incisors. In general, the teeth are abnormal in shape and position. A majority of individuals with Cohen syndrome are also short, with many experiencing growth deficiency at all stages of life. Microcephaly (small head) is another common feature of the syndrome.

In addition, there are many other associated physical characteristics that occur less often. The palate (roof of the mouth) may be overly high, arched, and narrow. The mid-face can have an underdeveloped appearance and the area below the nose to the upper lip (philtrum) may be very short. The eyes can be down-slanting and thick hair and eyebrows may be observed.

Mental dysfunction

It is thought that every individual with Cohen syndrome experiences some level of developmental delay. Mental retardation can range from mild to severe. Even from infancy many are obviously behind in developmental milestones and are not able to sit up or roll over within the same time frame as their peers.

Most children with Cohen syndrome do learn to walk, although there have been a few reported cases of individuals who were wheelchair-bound. There is usually a noticeable delay, with affected children not learning to walk independently until much later than their peers (the normal average age for walking independently is 12 months).

Language deficiencies are also a common occurrence. Many affected individuals never learn to talk or have a vocabulary limited to a few singular words and two-word phrases. In general an IQ of less than 50 is considered average for Cohen syndrome.

Visual deficiencies

Vision is affected to varying degrees. Severe limitation in eyesight due to myopia is often observed. Several other dysfunctions and defects of the eyes causing low visual clarity have been reported including retinal dystrophy, strabismus, astigmatism, microphthalmia, and coloboma of the iris.

Hematologic abnormalities

Cohen syndrome can have a profound effect on the composition of the blood. Abnormally low counts of white blood cells, referred to as granulocytopenia, was once thought to be a standard symptom. It was hoped that it could help in early diagnosis because it can be tested for at birth. However, further studies have shown that not all affected individuals suffer from granulocytopenia. Some individuals have no blood disorders associated with their disease at all while others have various forms of white blood cell problems, such as a reduction in the number of white blood cells in the blood (leucopenia) or of neutrophils, which are specialized white blood cells (neutropenia).

Other deficiencies

Hypotonia, or low muscle tone, is found in 90-100% of the persons diagnosed with Cohen syndrome. Babies with hypotonia are described as "floppy" due to their lack of muscle strength. Although the observed hypotonia is not thought to be associated with any nervous system disorder, it does delay the overall development of the child, most notably in slowing the development of motor skills.

Social skills

Many studies have described Cohen syndrome patients as being outgoing and friendly with mild hyperactivity and severe attention deficits. There are a few reports of diagnosed individuals showing signs of autism , an extreme form of centering attention and interest on the self only.

Diagnosis

In 1972, Dr. Mirhosseini and others described two patients with symptoms similar to those observed in Cohen syndrome. These patients and a few subsequent cases were given a diagnosis of Mirhosseini-Holmes-Walton syndrome. Over the years, scientific opinion has come to consider Mirhosseini-Holmes-Walton syndrome and Cohen syndrome as different manifestations of the same disease.

Diagnosis of Cohen syndrome is difficult due to the varied nature of the symptoms. Most features of Cohen syndrome are not evident in the newborn and many symptoms, such as truncal obesity and visual deficits are not easily observed until early childhood. In the past, the average age of diagnosis was approximately 6-8 years. However, as physicians become more aware of the disorder it is hoped that diagnosis will occur at earlier ages, offering affected individuals the opportunity for rapid intervention and treatment.

Incorrect diagnosis is not uncommon in patients with Cohen syndrome. Affected individuals may be misdiagnosed with Marfan syndrome , Sotos syndrome , hypothyroidism, Prader-Willi syndrome , or mental retardation of an unknown nature.

A correct and early diagnosis is important to ensure the favorable prognosis of the patient and so that the family can receive appropriate genetic counseling concerning the affected child or the risks involved in future pregnancies.

Treatment and management

Treatment of Cohen syndrome is focused on improving or alleviating symptoms as they arise. There is no cure for Cohen syndrome.

Early correction of vision problems, usually with glasses, often leads to general improvement of cognitive skills, an area of marked deficit in affected individuals.

As is the case for many disorders involving hypotonia and slowed development, physical and occupational therapy are invaluable tools. These treatment strategies are important at any age, but should be started as early as possible. There is no need to wait for a definitive diagnosis of Cohen syndrome as any child with hypotonia can benefit from physical and occupational therapy.

Prognosis

Varying symptoms lead to varying prognosis. Mental retardation can range from mild to severe. However, there is no way to predict the level of developmental delay a specific child will experience. Language deficiencies also vary a lot, with some children never learning to speak at all and others speaking full sentences. The hypotonia observed in infancy may persist and moderate obesity usually develops in mid-childhood.

As of 2001, there has been one reported case of a woman with Cohen syndrome giving birth. The child had some developmental delays but was thought not to have Cohen syndrome.