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

• GATA6 Gene Syndrome

What is GATA6 Syndrome? (Definition/Background Information)

• GATA6 Syndrome is an uncommon genetic disorder that presents pregnancy complications, congenital heart defects, and severe pancreatic dysfunction. It develops when the normal function of the GATA6 gene, which is responsible for the development of various organs (heart and pancreas) and located on chromosome 18, is affected
• GATA6 Syndrome is a progressive condition, and the presentation of signs and symptoms are noted at birth. The syndrome may develop from sporadic mutations (vast majority of cases), or it may be inherited from one’s parents (very rarely). GATA6 Syndrome may be diagnosed through specialized genetic testing. In some children, the condition may be mild and hence can also remain undiagnosed
• Following a diagnosis, the condition may be managed based on the presenting symptoms and extent of involvement of the body systems. The treatment of GATA6 Syndrome may involve physician experts from several specialties, and can include the administration of medications, diabetes control, physiotherapy, and surgery to correct the defects. The prognosis is primarily dependent on the severity of the disorder, and it varies from one child to another

Who gets GATA6 Syndrome? (Age and Sex Distribution)

• The incidence of GATA6 Syndrome is presently unknown; only around 50 cases are 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
• GATA6 Syndrome is a congenital disorder, and the presentation of symptoms may occur at or following the birth of the child
• Both males and females are equally affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for GATA6 Syndrome? (Predisposing Factors)

In a vast majority of individuals, there are no identified risk factors for GATA6 Syndrome.

• A positive family history may be an important risk factor, since some cases of GATA6 Syndrome are reportedly inherited
• 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 GATA6 Syndrome? (Etiology)

GATA6 Syndrome is caused when the normal functioning of the GATA6 gene (or GATA-binding factor 6 gene) is affected resulting in a variable set of signs and symptoms. This gene dysfunction may take place in the following manner:

• Loss of one copy of the gene due to deletion of chromosomal material on which it is located
• The copy of the gene is altered leading to a loss of function or abnormal function. The changes may be a result of genetic inheritance (family history) or taking place spontaneously (de novo) in the absence of any family history. A vast majority of cases occur de novo

GATA6 gene dysfunction causes many developmental abnormalities that may be mild or severe depending on the extent of dysfunction.

• The GATA6 gene, located on chromosome 18, contains instructions for the GATA6 protein that is involved in pancreatic agenesis and congenital heart defects
• Thus, any disruption to this process may compromise the health and functioning of the organs leading to a set of associated abnormalities
• There are two chromosomes numbered 18. Children with GATA6 Syndrome typically will have one (chromosome 18) in normal condition, while the other is abnormal

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 GATA6 Syndrome?

The signs and symptoms of GATA6 Syndrome may be significantly different from one individual to another, but predominantly involve the nervous system. The degree of signs and symptoms are often related to the amount of chromosome material deleted and the genes affected and/or its dysfunction. However, apart from the brain, spinal cord, and the nervous system, no other body systems are known to be affected.

The commonly noted signs and symptoms of GATA6 Syndrome include:

• Low birth weight
• Intrauterine growth retardation (IUGR) during pregnancy
• Underdeveloped or absent pancreas causing neonatal diabetes
• Congenital heart defects: Heart abnormalities can result in associated signs and symptoms, such as chest pain, shortness of breath, dizziness, fainting, palpitations, and tiredness, among others
• Hernias at birth
• Underactive thyroid gland
• Developmental delays; delays in reaching milestones
• Intellectual disabilities
• Behavioral issues
• Speech and learning disabilities is observed in some children

How is GATA6 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 GATA6 Syndrome in the differential diagnosis. Often, specialized tests are necessary to confirm the disorder.

GATA6 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
• Laboratory tests, as needed, such as electrolyte levels, serum calcium levels, thyroid function test, kidney function test, urine tests, sex hormone studies, etc.
• Oral glucose tolerance test in pregnant women
• Radiological studies of the affected regions, as needed
• Assessment of cardiac function
• Brain scans: These may include prenatal ultrasounds and MRI scans, and CT/MRI scans after development of the child
• 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.

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 GATA6 Syndrome?

The complications of GATA6 Syndrome may include:

• Severe emotional stress for parents and caregivers
• Pregnancy complications including preterm or premature birth
• Delayed milestone achievement that may affect when a child rolls, sit, crawl, or walk
• Defective bile duct development
• Pancreatic insufficiency
• Absence of gallbladder
• Severe heart anomalies
• Overall reduced quality of life

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

How is GATA6 Syndrome Treated?

There is no cure for GATA6 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, surgeons, and other healthcare professionals are involved in managing the condition.

The treatment measures for GATA6 Syndrome may involve:

• Diabetes control via medications (insulin therapy) and healthy lifestyle including food control
• Surgery to treat heart abnormalities
• Treatment with fat soluble vitamins for children on pancreatic enzyme replacement
• Hormone replacement therapy for underactive thyroid gland
• Employing suitable learning strategies
• Speech and language therapy
• Physiotherapy for weakened leg muscles, including incorporating daily exercise regimen
• Psychotherapy, behavior modification, and establishing discipline techniques, as necessary
• Occupational therapy

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

How can GATA6 Syndrome be Prevented?

GATA6 Syndrome may not be preventable since many of these genetic disorders are diagnosed at or following the birth of the child. A majority of cases are sporadic occurrences, which means there is no family history of the condition.

In some rare cases, the condition may be familial, meaning they occur within families. In expecting parents with a familial history:

• Genetic (chromosome) 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

What is the Prognosis of GATA6 Syndrome? (Outcomes/Resolutions)

The prognosis of GATA6 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
• Children usually require extended medical support and care

Additional and Relevant Useful Information for GATA6 Syndrome:

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

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