What are the other Names for this Condition? (Also known as/Synonyms)

• ARID1B Gene Syndrome

What is ARID1B Syndrome? (Definition/Background Information)

• ARID1B Syndrome is a rare genetic abnormality that involves the ARID1B gene located on chromosome 6. In this disorder, either the gene function is disrupted, or the gene is missing, resulting in a set of associated signs and symptoms that typically involve the neurological system
• This chromosomal anomaly may develop from sporadic mutations (some cases), or it may be inherited from one’s parents (in many cases). ARID1B Syndrome may be diagnosed through specialized genetic testing. In some children, the condition may be mild and hence can also remain undiagnosed. Features that often occur include seizures, vision and hearing impairment, speech and learning delays, and intellectual disability
• Following a diagnosis, the condition may be managed based on the presenting symptoms and extent of involvement of the body systems. The treatment may involve physician experts from several specialties, and can include the use of speech and language therapy, physiotherapy, and use of hearing and vision aids, as needed
• The prognosis is primarily dependent on the severity of the disorder, and it varies from one child to another. Many children with ARID1B Syndrome are able to cope well through adequate treatment and supportive care. Some of the signs and symptoms associated with the condition are known to improve with time

Who gets ARID1B Syndrome? (Age and Sex Distribution)

• The incidence of ARID1B Syndrome is presently unknown. It is an extremely rare and recently discovered disorder with only about 25 cases reported in the medical literature
• In many cases, individuals with mild signs and symptoms may be undiagnosed in their lifetime. Hence, a true incidence of the disorder may be difficult to estimate
• ARID1B Syndrome is a congenital disorder, and the presentation of symptoms may occur at or following the birth of the child
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for ARID1B Syndrome? (Predisposing Factors)

In many individuals, there are no identified risk factors for ARID1B Syndrome.

• In a few individuals, a positive family history is noted, which may be an important risk factor for the syndrome
• Currently, no environmental and lifestyle (including dietary) factors have been implicated
• The syndrome is not caused by what the expectant mother does or does not do, either prior to or during pregnancy

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of ARID1B Syndrome? (Etiology)

ARID1B Syndrome is caused by abnormalities involving the ARID1B gene. In a majority of cases, this disorder is caused by abnormal changes/mutations to the ARID1B gene that is located on the long arm (q) of chromosome 6, specifically in the band q25.3.

• The changes result in abnormal functioning of one of the two copies of the gene leading to associated signs and symptoms. In some cases, one copy of the gene on chromosome 6 may be missing or absent
• The role of the ARID1B (AT-rich interactive domain 1B) gene is very complex. It provides instruction for the production of a protein component that form part of the SWI/SNF protein complexes
• These protein complexes are responsible for regulating gene activity, including DNA repair and the growth and division of cells

There are two chromosomes numbered 6. Children with ARID1B Syndrome typically will have one (chromosome 6) in normal condition, while the other may be abnormal. The abnormality is characterized by a loss of chromosomal material.

• Many cases of the disorder develop sporadically (de novo) during embryonic development. This means that no deletion of genetic material is observed in either of the parents
• However, in some few cases, ARID1B Syndrome may be an inherited condition

It is important to note that a child’s development and future is not only influenced by the chromosome material duplicated/deleted and genes involved, but also by other factors such as one’s environment, involvement of other genes, and unique personality.

Additional (general) information on chromosomes, which is helpful in understanding the disorder:

Chromosomes are microscopic thread-like protein structures present in each cell nucleus that carry genetic information in the form of DNA (deoxyribonucleic acid). DNAs are nucleic acids that encodes the genetic information of any organisms; a basic unit of the DNA is termed a gene with a specific set of instructions and a defined function. Each chromosome is “X” shaped with a center, called the centromere, and two short arms (termed p arms) and two long arms (termed q arms).

Humans have 46 chromosomes in the cell nucleus, in 23 pairs, of which one pair is named the sex chromosome. In males, it is designated XY, for chromosome X and chromosome Y; while, in females, it is designated XX, for a pair of chromosome X. The other 22 pairs of chromosomes are numbered chromosome 1 through 22, approximately according to size (with chromosome 1 being the largest; chromosome 21 being the smallest) and are referred to as autosomes or somatic chromosomes. During conception, the embryo inherits one copy of each chromosome from each parent (i.e., mother and father). Any alteration in the chromosome numbers or structure, such as via addition or deletion of chromosomal material, can result in mild to severe genetic abnormalities that may manifest as birth defects, growth delays, and intellectual disabilities.

What are the Signs and Symptoms of ARID1B Syndrome?

The signs and symptoms of ARID1B Syndrome may be significantly different from one individual to another. The degree of signs and symptoms are often related to the amount of chromosome material deleted and the number of genes affected.

The commonly noted signs and symptoms of ARID1B Syndrome include:

• Development delays
• Short stature in some cases
• Mild to moderate learning disabilities; speech delays
• Seizures are noted in some cases, typically in children
• Vision defects usually include shortsightedness that may be severe and strabismus
• Some children report mild hearing loss that may be bilateral
• Feeding difficulties are seen in nearly 50% of the cases
• Speech and learning disabilities that may be mild to severe
• Behavioral issues

How is ARID1B Syndrome Diagnosed?

Children can have varying signs and symptoms. Some children with mild signs and symptoms may go undiagnosed in their lifetimes. Given the rarity of the condition, the healthcare provider should have a high index of suspicion to consider ARID1B Syndrome in the differential diagnosis. Often, specialized tests are necessary to confirm the disorder.

ARID1B Syndrome is diagnosed on the basis of the following information:

• Complete physical examination and thorough medical history evaluation, including family medical history
• Assessment of the presenting signs and symptoms, including evaluation of body systems such as vision, hearing, muscles, heart, kidneys, central nervous system, genitalia, and immune system
• Hearing assessment through various tests
• Eye and vision assessment through:
  • General eye exam
  • Visual acuity test using a special and standardized test chart (Snellen chart)
  • Refraction studies using various instruments
  • Fundoscopic (ophthalmoscopic) examination by an eye specialist, who examines the back part of the eye (or the fundus)
  • Slit-lamp examination
• Laboratory tests, as needed, such as electrolyte levels, serum calcium levels, thyroid function test, kidney function test, urine tests, sex hormone studies, etc.
• Radiological studies of the affected regions, as needed
• Assessment of cardiac and renal function
• Neurological examination that involves the central nervous system (brain and spinal cord)
• Behavioral studies
• Prenatal studies including abdominal ultrasonography
• Specialized genetic testing techniques are often required to confirm the diagnosis. This may include:
  • Fluorescence in situ hybridization (FISH) testing
  • Array comparative genomic hybridization (array-CGH)
  • DNA sequencing

Often, karyotyping of the chromosome is not adequate to diagnose the condition, since individuals with this condition can have normal karyotype chromosomal studies.

A differential diagnosis to eliminate Coffin-Siris syndrome (CSS) that presents similar signs and symptoms may be considered prior to establishing a diagnosis of ARID1B Syndrome.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of ARID1B Syndrome?

The complications of ARID1B Syndrome may include:

• Severe emotional stress for parents and caregivers
• Pregnancy complications
• Increased risk for infections
• Occasionally, heart and/or kidney abnormalities are seen
• Delay in achieving milestones, such as rolling, sitting, and walking, have been reported; children tend to walk at age 30 months (on an average)
• Intellectual challenges and low IQ levels
• Reduced quality of life

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is ARID1B Syndrome Treated?

There is no cure for ARID1B Syndrome since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops. It also depends on the severity of the signs and symptoms and the body systems affected. Individuals with mild signs and symptoms may require periodic monitoring without significant medical intervention. Often, a multidisciplinary team of specialists including pediatricians, ophthalmologists, otolaryngologists, neurologists, internists, cardiologists, endocrinologists, surgeons, and other healthcare professionals are involved in managing the condition.

The treatment measures for ARID1B Syndrome may involve:

• For feeding difficulties, use of feeding tubes (temporary nasogastric or gastrostomy tubes), medications, feed thickeners, bottle-feeding expressed milk, including special diets and nutritional supplements
• Seizure control using anticonvulsant medication, vitamin supplements, and ketogenic diet: Seizure control is important to ensure that the child’s learning ability is not significantly affected
• Special education: Employing suitable learning strategies via music therapy, visual and tactile books, touch screen computers, etc.
• Speech and language therapy; the use of sign language may be beneficial
• Physiotherapy for weakened muscles, including incorporating daily exercise regimen
• Development of motor skills via daily exercises, swimming, and other adapted activities; use of specially-designed toys and daily-used items (such as spoons and cups)
• Use of walking aids
• Use of suitable glasses and surgical correction of vision defects, as needed
• Psychotherapy, behavior modification, and establishing discipline techniques, as necessary

Regular medical screening at periodic intervals with tests and physical examinations are necessary and highly recommended.

How can ARID1B Syndrome be Prevented?

ARID1B Syndrome may not be preventable since many of these genetic disorders are diagnosed at or following the birth of the child. Also, some cases are sporadic occurrences, which means there is no family history of the condition.

In many cases, the condition is familial, meaning they occur within families. In expecting parents with a familial history:

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy), if available, may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

It is important to note that the chances of both the parents with normal chromosomes having another child with ARID1B Syndrome is highly unlikely. This may be confirmed via specialized prenatal testing and preimplantation genetic diagnosis (PGD), if needed. Prenatal tests may include chorionic villus sampling (CVS) and amniocentesis.

What is the Prognosis of ARID1B Syndrome? (Outcomes/Resolutions)

The prognosis of ARID1B Syndrome is dependent upon the severity of the signs and symptoms and associated complications, if any. It may be assessed on a case-by-case basis, but it is generally difficult to predict the long-term outlook.

• Children with mild conditions are generally able to cope well via appropriate treatment and adaptive behaviors as they get older
• Most children are healthy and no major birth defects and development challenges are seen. However, some children may require prolonged medical support and care

Additional and Relevant Useful Information for ARID1B Syndrome:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/