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

• Duplication 4q Syndrome
• Partial Trisomy 4q Syndrome
• Trisomy 4q Syndrome

What is Chromosome 4q Duplication Syndrome? (Definition/Background Information)

• Chromosome 4q Duplication Syndrome is a chromosome abnormality that occurs when there is an extra copy of genetic material on the long arm (q) of chromosome 4. The severity of the condition and the signs and symptoms depend on the size and location of the duplication and which genes are involved. If large segments of the chromosome are duplicated, then the child may have severe abnormalities
• The condition affects newborn children (congenital manifestation. Chromosome 4q Duplication Syndrome can result in physical and mental developmental delays, poor motor skills, heart abnormalities, and vision impairment. This chromosomal anomaly may develop from sporadic mutations (vast majority of cases), or it may be inherited from one’s parents (very rarely). 4q Duplication 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 may involve physician experts from several specialties, and can include the use of vision aids, speech and language therapy, 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 4q Duplication 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 4q Duplication Syndrome? (Age and Sex Distribution)

• Chromosome 4q Duplication 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 4q Duplication Syndrome? (Predisposing Factors)

In a vast majority of individuals, there are no identified risk factors for Chromosome 4q Duplication Syndrome.

• In some individuals, a positive family history may be an important risk factor for 4q Duplication 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 4q Duplication Syndrome? (Etiology)

• Chromosome 4q Duplication Syndrome may be caused by:
  • De-novo duplication of genetic material in the long arm (q) of chromosome 4 (most common cause)
  • Inheritance of duplicated genetic material in the long arm of chromosome 4 (in rare cases)
• The amount of chromosome material added/duplicated varies widely from one individual to another resulting in a variable set of signs and symptoms
• Some cases of 4q duplications are not described as “pure” duplications, since the involvement of another chromosome(s) may be noted
• The duplications may be distal (occurring nearer to the end of the chromosome) or proximal (occurring near to the centromere)

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 4q Duplication Syndrome?

The signs and symptoms of Chromosome 4q Duplication 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 added and the number of genes affected. As a general rule, a small gain in chromosome material generally results in milder signs and symptoms. Conversely, larger gains/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 (such as at the tip or center of the chromosome), and if the involvement of another chromosome is noted (known to occur in some cases).

The commonly noted signs and symptoms of Chromosome 4q Duplication Syndrome include:

• Abnormal facial features that include:
  • Small-sized head (microcephaly)
  • Facial asymmetry; in some children, the back of the head is flat (brachycephaly)
  • Hair growth on the forehead
  • Thick eyebrows
  • Up or down slanting eyes; eyes set wide apart or unusually close
  • Skinfolds across the inner corners of the eye
  • High nose bridge
  • Protruding upper lip; unusually short or long groove between the nose and upper lip
  • Very small mouth; slack muscles around the mouth
  • Low-set and abnormally-formed ears
  • Small and receding lower jaw
  • Short neck
• Poor muscle tone (hypotonia) causing motor delays that can be mild or severe
• In many children, feeding problems (sucking and swallowing) leading to small and underweight children
• Hand and foot abnormalities that usually involve the fingers and toes
• Eye-hand coordination may be poor
• Developmental delays; short stature
• Vision defects observed in the affected children may include:
  • Strabismus (most common vision abnormality)
  • Shortsightedness or longsightedness
• Breathing issues in some of the children (mostly sleep apnea)
• Dental and teeth abnormalities
• Hearing impairment
• Umbilical hernia in some cases
• Heart abnormalities can result in associated signs and symptoms, such as chest pain, shortness of breath, dizziness, fainting, palpitations, and tiredness, among others. The following heart defects may be noted:
  • Valve defects, such as ventricular septal defect (VSD) or atrial septal defect (ASD)
  • Patent ductus arteriosus (PDA)
• Seizures are not commonly noted
• Minor genital anomalies, mostly in boys
• Intellectual disability
• In rare cases, sleep disturbances that can affect one’s physical and mental health
• Behavioral problems
• Speech, communication, and learning delays

How is Chromosome 4q Duplication 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 Chromosome 4q Duplication Syndrome in the differential diagnosis. Often, specialized tests are necessary to confirm the disorder.

4q Duplication 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
• 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 4q Duplication Syndrome?

The potential complications of Chromosome 4q Duplication Syndrome may include the following:

• Severe emotional stress for parents and caregivers
• Pregnancy complications
• Intrauterine growth retardation (IUGR); some babies are underweight at birth
• Delayed milestone achievement; rolling, sitting, and walking may be significantly delayed
• Poor growth due to malnutrition caused by weak suckling
• Increased risk for recurrent ear and chest infections
• Spinal curve abnormalities, such as scoliosis, which mostly develops from hypotonia; this may be mild or severe
• Severe intellectual deficiency
• Kidney and urinary bladder defects
• Decreased cognitive function (low IQ levels)
• Physical abnormalities that can cause difficulties in day-to-day living
• Reduced quality of life

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

How is Chromosome 4q Duplication Syndrome Treated?

There is no cure for Chromosome 4q Duplication 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 4q Duplication Syndrome may involve:

• Use of hearing aids; 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: Seizure control is important to ensure that the child’s learning ability is not significantly affected
• 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
• Heart abnormalities may require surgical correction in some cases; some defects, such as patent ductus arteriosus, tend to improve over time without any invasive procedures
• Surgical correction of physical defects, as assessed by a healthcare expert
• 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
• Sleep disorders may require medication; daytime naps may be advised
• Antibiotic treatment, including prophylactic therapy for frequent infections
• 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 Chromosome 4q Duplication Syndrome be Prevented?

Chromosome 4q Duplication 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) 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 4q Duplication 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 4q Duplication Syndrome? (Outcomes/Resolutions)

The prognosis of Chromosome 4q Duplication 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 (usually from small duplications) are generally able to cope well via appropriate treatment and adaptive behaviors as they get older
• Some of the abnormalities involving the heart, recurrent infections, motor skills, communication and behavioral issues are known to resolve or improve with time
• Some children with severe signs and symptoms may require prolonged medical support and care

Additional and Relevant Useful Information for Chromosome 4q Duplication Syndrome:

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

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