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

• 3q29 Duplications and Microduplications Syndrome

What is Chromosome 3q29 Duplications and Microduplications Syndrome? (Definition/Background Information)

• Chromosome 3q29 Duplications and Microduplications Syndrome is a rare condition caused by the presence of an extra copy of a small piece of chromosome 3 in the cells of the body. This condition can occur sporadically as a de novo mutation or can be inherited in an autosomal dominant manner from a parent. The syndrome may be diagnosed through specialized genetic testing
• The signs and symptoms of Chromosome 3q29 Duplications and Microduplications Syndrome can vary widely among affected individuals; but in many children, major birth defects are not noted. Some individuals also have no symptoms, while others may have features such as a large head size (macrocephaly), mild to moderate developmental delay and learning difficulties, heart anomalies, and seizures
• 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 seizure control, physiotherapy, and surgery for correction of physical defects
• The prognosis is primarily dependent on the severity of the disorder, and it varies from one child to another. Many children with Chromosome 3q29 Duplications and Microduplications 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 Chromosome 3q29 Duplications and Microduplications Syndrome? (Age and Sex Distribution)

• Chromosome 3q29 Duplications and Microduplications Syndrome is a rare congenital disorder; the presentation of symptoms may occur at or following the birth of the child
• 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
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Chromosome 3q29 Duplications and Microduplications Syndrome? (Predisposing Factors)

In a vast majority of individuals, there are no identified risk factors for Chromosome 3q29 Duplications and Microduplications Syndrome.

• In some individuals, a positive family history may be an important risk factor for 3q29 Duplications and Microduplications 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 Chromosome 3q29 Duplications and Microduplications Syndrome? (Etiology)

Chromosome 3q29 Duplications and Microduplications Syndrome is caused by an extra copy of genetic material on the long arm (q) of chromosome 3 and at band q29. The amount of chromosome material added/duplicated varies widely from one individual to another resulting in a variable set of signs and symptoms.

• Most cases of the disorder develop sporadically (de novo) during embryonic development. This means that no duplication of genetic material at 3q29 is observed in either of the parents. When the condition is inherited, it occurs in an autosomal dominant manner
• There are two chromosomes numbered 3. Children with 3q29 Duplications and Microduplications Syndrome typically will have one (chromosome 3) in normal condition, while the other is abnormal. The abnormality is characterized by a gain of chromosomal material
• The chromosomal abnormality is termed a duplication when the duplicated material is large enough to be visible under a microscope with normal magnification
• However, in microduplication, a very tiny part of the chromosome is duplicated, and it is not even visible under a microscope with high magnification. In such cases, cytogenetic fluorescent in situ hybridization (FISH) or array comparative genomic hybridization (array-CGH) studies may be necessary to detect the duplications

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.

A chromosome duplication disorder indicates that a certain portion of the chromosomal material is duplicated, which may be detected through molecular genetic testing. Depending on the nature and amount of extra material, the manifestation of a set of signs and symptoms are noted.

What are the Signs and Symptoms of Chromosome 3q29 Duplications and Microduplications Syndrome?

The signs and symptoms of Chromosome 3q29 Duplications and Microduplications 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 gained and the number of genes affected. As a general rule, a small loss of chromosome material generally results in milder signs and symptoms. Conversely, larger duplications of the chromosome material generally results in severe signs and symptoms. It is important to note that exceptions may also occur, where individuals with small amount of chromosomal gains, may have disproportionately severe presentations.

The associated signs and symptoms depend on what material is duplicated, how much duplication has occurred (quantity), where the duplications occurs, and if the involvement of other chromosomes are noted.

The commonly noted signs and symptoms of Chromosome 3q29 Duplications and Microduplications Syndrome include:

• Global development delays
• Feeding difficulties due to swallowing difficulties, vomiting, and gastroesophageal reflux disease
• Presence of abnormal hands and feet (such as slender hands, conjoined toes, unusual placement of digits, extra digits, etc.)
• Gross and fine motor skills may be affected in a minor way
• Seizures may be rarely observed
• In some children, vision defects may include:
  • Cataracts resulting from clouding of the lens causing blurry vision
  • Small eyes (microphthalmia)
  • Coloboma
  • Corneal clouding
• Increased risk for becoming overweight or obese
• Congenital hip dislocation that may involve one or both hips may be seen in few cases
• Hearing impairment including:
  • Recurrent ear infections (in some children)
  • Glue ear - fluid buildup in middle ear
• In some cases, heart abnormalities may be observed. This can result in associated signs and symptoms, such as chest pain, shortness of breath, dizziness, fainting, palpitations, and tiredness, among others
  • Valve defects, such as ventricular septal defects (VSD) or atrial septal defects (ASD), is uncommon
  • Bicuspid aortic valve
  • Tetralogy of Fallot, an abnormality that consists of four heart defects, namely subpulmonic stenosis, ventricular septal defect, overriding aorta, and right ventricular hypertrophy
• Speech and learning disabilities; speech skills may be affected
• Minor genital abnormalities, which mostly affect boys:
  • Cryptorchidism (undescended testes)
  • Hypospadias
  • Underdeveloped or large labia in girls
• Umbilical hernias
• Facial features are generally normal
• Sleep disturbances that can affect one’s physical and mental health
• Constipation that may be moderate to severe is rarely noted
• Behavioral problems that include communication difficulties and social awkwardness

Major birth defects are not usually noted. Children are healthy in most cases and life expectancy is mostly normal.

How is Chromosome 3q29 Duplications and Microduplications 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 3q29 Duplications and Microduplications in the differential diagnosis. Often, specialized tests are necessary to confirm the disorder.

Chromosome 3q29 Duplications and Microduplications 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 including:
  • Otoscopy: Examination using an instrument that allows the physician to look inside the ear
  • Weber test: A test in which a vibrating tuning fork is placed on the midline of the head
  • Rinne test: A test in which a vibrating tuning fork is held next to the ear and then in front of the ear, until the individual no longer hears the sound
  • Audiometric test: Hearing tests that involve listening to different tones
  • Tympanometry: A test that puts air pressure in the ear canal in order to move the eardrum, and then measures the eardrum mobility (movement)
• 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
  • Alignment and focusing testing
  • Fundoscopic (ophthalmoscopic) examination by an eye specialist, who examines the back part of the eye (or the fundus)
  • Slit-lamp examination
  • Visual evoked potential (VEP) test
  • Fundus fluorescein angiography
  • Optical coherence tomography (OCT) of eye
• Evaluation of heart defects through:
  • Chest X-rays
  • Echocardiogram
  • Electrocardiogram (EKG)
  • Cardiac catheterization
  • Fetal ultrasound for heart defects
• 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
• Kidney and urinary tract scans
• Brain scans (to determine corpus callosum): 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 Chromosome 3q29 Duplications and Microduplications Syndrome?

The complications of Chromosome 3q29 Duplications and Microduplications Syndrome may include:

• Severe emotional stress for parents and caregivers
• Pregnancy complications
• Intrauterine growth retardation (IUGR); some babies are underweight at birth
• Failure to thrive
• Patent urachus (bladder defect)
• Rarely, birth defects may include absence or underdeveloped of limb
• Delayed milestone achievement that may affect when a child rolls, sits, crawls, or walks
• Sleep (infantile) apnea may be associated with seizures (night-time seizures)
• Poor growth due to malnutrition caused by weak suckling
• Spinal curve abnormalities, such as scoliosis, which mostly develops from hypotonia; this may be mild or severe
• Brain abnormalities such as Dandy Walker syndrome, cerebellar vermis, and Arnold Chiari malformation
• Risk of falls and injury due to seizures
• Increased risk for aspiration pneumonia
• Deafness
• Thyroid dysfunction leading to hypothyroidism
• Recurrent infections
• Autism spectrum disorders
• Severe heart anomalies
• Severe cognitive impairment; low IQ levels
• Reduced quality of life

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

How is Chromosome 3q29 Duplications and Microduplications Syndrome Treated?

There is no cure for Chromosome 3q29 Duplications and Microduplications 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 Chromosome 3q29 Duplications and Microduplications Syndrome may involve:

• Use of hearing aids and cochlear implants; in case of fluid buildup in the middle ear, some children may require the placement of a small ventilation tubes to help with improved fluid drainage
• Seizure control using anticonvulsant medication, vitamin supplements, and ketogenic diet
• Employing suitable learning strategies via music therapy, visual and tactile books, learning through fun and play, and lots of repetition. Writing by holding a pencil may be very difficult; but touchscreen computers and keyboards are known to be easier to use and learn
• Speech and language therapy; the use of sign language may be beneficial; rectification of hearing impairment may improve speech and language development
• Physiotherapy for weakened muscles, including incorporating daily exercise regimen
• Development of motor skills via daily exercises, swimming, hydrotherapy, and other adapted activities; use of specially-designed toys and daily-used items (such as spoons and cups)
• 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
• A surgical procedure named fundoplication may be necessary in some children with severe GERD. Milder GERD cases can be generally well-controlled by giving feeds slowly and positioning the baby in a semi-upright. And, where necessary, raising the head of the end of the bed for sleeping is also recommended
• Heart abnormalities may require surgical correction in some cases; some defects tend to improve over time without any invasive procedures
• Surgical correction of physical defects, as assessed by a healthcare expert, such as surgical repair of cleft lip
• Use of padded brace for abnormal spinal curvature and posture management, including surgical correction of severe cases. Also, children may be provided specially designed furniture, such as chairs, tables, and beds, for spine support while sitting and sleeping
• Pavlik harness may be used for children with congenital hip dislocation; in some, surgery may be needed to reposition the hip, followed by the use of padded braces
• Use of suitable glasses and surgical rectification of vision defects, if necessary
• Surgical correction (orchiopexy) of undescended testicles and other genital defects
• Controlling weight gain through physical exercise and providing a healthy diet
• Sleep disorders may require medication; daytime naps may be advised
• Hernia repair surgery for umbilical hernias, as needed
• Psychotherapy, behavior modification, and establishing discipline techniques, as necessary
• Social skills training support groups and exercises
• Occupational therapy

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

How can Chromosome 3q29 Duplications and Microduplications Syndrome be Prevented?

Chromosome 3q29 Duplications and Microduplications 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 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 Chromosome 3q29 Duplications and Microduplications 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 Chromosome 3q29 Duplications and Microduplications Syndrome? (Outcomes/Resolutions)

The prognosis of Chromosome 3q29 Duplications and Microduplications 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.

• Children with mild conditions (usually from small duplications) are generally able to cope well via appropriate treatment and adaptive behaviors as they get older. Some of the abnormalities are known to resolve or improve with time
• In a majority of individuals, the condition is reportedly mild with few to no birth defects observed. In such individuals, the life expectancy is also normal
• Rarely, some children require extended medical support and care; it may also take some children a long time (several years) to gain a measure of independence

Additional and Relevant Useful Information for Chromosome 3q29 Duplications and Microduplications Syndrome:

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

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