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

• DDX3X Gene Syndrome

What is DDX3X Syndrome? (Definition/Background Information)

• DDX3X Syndrome is an uncommon and recently recognized genetic disorder that manifests as developmental delays, intellectual disabilities, poor muscle tone, and autism spectrum disorder in newborn girls. It develops when the normal function of the DDX3X gene, which is responsible for various cellular processes and located on chromosome X, is disrupted
• This chromosomal anomaly is usually known to develop from sporadic mutations; presently, no cases of inheritance (from one’s parents) is reported. DDX3X Syndrome may be diagnosed through specialized genetic testing. In some girls, the condition may be mild and hence can also remain undiagnosed
• Following a diagnosis of DDX3X Syndrome, 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 speech and language therapy, use of walking aids, behavior modification, and surgery (if needed)
• The prognosis is primarily dependent on the severity of the disorder, and it varies from one child to another. Many children with DDX3X Syndrome are able to cope well through adequate treatment and lifelong supportive care. Some of the signs and symptoms associated with the condition are known to improve with time

Who gets DDX3X Syndrome? (Age and Sex Distribution)

• The incidence of DDX3X Syndrome is presently unknown, and around 300 cases have been 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
• DDX3X Syndrome is a congenital disorder, and the presentation of symptoms may occur at or following the birth of the child
• The condition is almost only observed in females since the anomaly involves chromosome X. Very rarely males are affected by abnormalities in the DDX3X gene; although in such cases, the signs and symptoms are typically mild
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for DDX3X Syndrome? (Predisposing Factors)

In a vast majority of individuals, there are no identified risk factors for DDX3X Syndrome.

• A positive family history may be an important risk factor, since DDX3X Syndrome can be inherited. However, presently no cases of family inheritance is reported
• 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 DDX3X Syndrome? (Etiology)

DDX3X Syndrome is caused when the normal functioning of the DDX3X gene (or DEAD-box helicase 3 X-linked 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. A vast majority of cases occur de novo i.e., spontaneously, in the absence of any family history
• A positive family history (genetic inheritance) in DDX3X Syndrome is currently not recorded in the medical reports

DDX3X gene dysfunction results in the disruption of several cell processes in the nucleus and cytoplasm that may be mild or severe depending on the extent of disruption.

• The DDX3X gene on chromosome X is involved in transcriptional regulation, splicing, RNA transport, translation, cellular signaling, and viral replication
• There are two chromosomes numbered X. Children with DDX3X Syndrome typically will have one (chromosome X) 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 DDX3X Syndrome?

The signs and symptoms of DDX3X Syndrome may be significantly different from one girl child to another. The degree of signs and symptoms are often related to the amount of chromosome material involved and the genes affected and/or its dysfunction.

The commonly noted signs and symptoms of DDX3X Syndrome in girls and women include:

• Developmental delays; delays in reaching milestones
• Small-sized head (microcephaly), which is noted in nearly 35% of the cases
• Feeding difficulties; sucking and swallowing may be difficult
• Girls are usually underweight, although their height may be normal for age
• Brain abnormalities that include underdeveloped corpus callosum, enlarged brain ventricles, and disruption in the formation of the grey matter
• Seizures may be noted in some girls
• Intellectual disabilities and cognitive impairment can be mild, moderate, or severe
• Speech and learning disabilities that may be mild or severe; language delays
• Hearing and vision impairment is generally uncommon
• Low muscle tone (hypotonia) resulting in floppiness
• Some children present increased muscle tone resulting in spasticity in the lower limbs
• Hypermobile joints are commonly noted
• Movement disorders
• Behavioral issues that include short attention span, hyperactivity, anger, and aggression
• Autism and attention-deficit hyperactivity disorder (ADHD)

How is DDX3X 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 DDX3X Syndrome in the differential diagnosis. Often, specialized tests are necessary to confirm the disorder.

DDX3X 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 and vision assessment
• 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
• 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.

Due to its rarity and relative newness, the syndrome is known to be misdiagnosed as:

• Autism spectrum disorder
• Cerebral palsy
• Dandy Walker syndrome
• Rett 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 DDX3X Syndrome?

The complications of DDX3X Syndrome may include:

• Severe emotional stress for parents and caregivers
• Pregnancy complications
• Delayed milestone achievement that may affect when a child rolls, sit, crawl, or walk
• Some individuals may have significant mobility issues
• Severe brain anomalies
• Mental health deficiencies (below average to low IQ levels)
• Overall reduced quality of life

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

How is DDX3X Syndrome Treated?

There is no cure for DDX3X 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 DDX3X Syndrome may involve:

• Use of hearing and vision aids, as needed
• Employing suitable learning strategies
• Speech and language therapy
• For feeding difficulties, medications, feed thickeners, bottle-feeding expressed milk, including special diets and nutritional supplements
• Physiotherapy for stiff muscles, including incorporating daily exercise regimen
• Development of motor skills via daily exercises, swimming, and other adapted activities
• Use of walking aids
• Psychotherapy, behavior modification, and establishing discipline techniques, as necessary
• Occupational therapy
• Social skills training support groups and exercises

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

How can DDX3X Syndrome be Prevented?

DDX3X 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 DDX3X Syndrome? (Outcomes/Resolutions)

The prognosis of DDX3X 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
• Some children usually require prolonged medical support and care

Additional and Relevant Useful Information for DDX3X Syndrome:

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

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