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

• 4p Duplication Syndrome
• Trisomy 4p Syndrome

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

• Chromosome 4p Duplication Syndrome is a rare chromosome abnormality that occurs when there is an extra copy of genetic material on the short arm (p) of chromosome 2. The severity of the condition and the signs and symptoms depend on the size and location of the duplication and which genes are involved
• The condition affects newborn children (congenital manifestation). This chromosomal anomaly may develop from sporadic mutations (vast majority of cases), or it may be inherited from one’s parents (very rarely). 4p Duplication Syndrome may be diagnosed through specialized genetic testing. In some children, the condition may be mild and hence can also remain undiagnosed
• The signs and symptoms that are commonly observed in individuals with Chromosome 4p Duplication Syndrome include developmental delay, congenital heart defects, intellectual disability, behavioral issues, vision impairment, and distinctive facial features. The 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 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 4p 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 4p Duplication Syndrome? (Age and Sex Distribution)

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

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

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

Chromosome 4p Duplication Syndrome is caused by an extra copy of genetic material on the short arm (p) of chromosome 4. 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 4p is observed in either of the parents. When inherited in rare cases, the parents are noted to present with a balanced translocation or pericentric inversion of the chromosome
• There are two chromosomes numbered 4. Children with 4p Duplication Syndrome typically will have one (chromosome 4) in normal condition, while the other is abnormal. The abnormality is characterized by a gain of chromosomal material. Also, a loss of genetic material of other chromosomes may be observed in 4p Duplication Syndrome
• It is observed that when the duplication of material occurs at the tip of the chromosome, the conditions are generally mild. In severe cases, where large duplications are noted (or the centromere is involved), the child may be severely affected

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 4p Duplication Syndrome?

The signs and symptoms of Chromosome 4p Duplications 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 (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 4p Duplications Syndrome include:

• Developmental delays (even though the child may have normal weight at birth)
• Poor muscle tone (hypotonia) causing motor delays that can be mild or severe, and include:
  • Feeding problems (sucking and swallowing) leading to small and underweight children
  • Difficulty in holding small items such as a cup or spoon
  • Drawing and writing difficulties
  • Difficulty in climbing stairs and difficulty in sitting without support
  • Standing and walking difficulties
  • Help needed for wearing clothes and undressing
• Some children may present stiff and rigid muscles (hypertonia)
• Presence of abnormal hands and feet; contracted joints
• Seizures may be observed in infants and young children
• Vision defects may include:
  • Shortsightedness or longsightedness
  • Strabismus
  • Astigmatism: It is an eye disorder caused by the irregular shape and curvature of the cornea or lens
  • Small eyes (microphthalmia) and coloboma
• Heart abnormalities may be observed that can result in associated signs and symptoms, such as chest pain, shortness of breath, dizziness, fainting, palpitations, and tiredness, among others
• Speech and learning disabilities; speech skills may be significantly affected
• Minor genital abnormalities, which mostly affect boys:
  • Cryptorchidism (undescended testes)
  • Hypospadias
  • Small penis
• Digestive system abnormalities
• Teeth abnormalities in some children, including misaligned teeth
• Distinctive facial features may include:
  • A small head with a prominent forehead
  • A prominent bone between the eyebrows (glabella)
  • A ridge across the eyebrows
  • Widely-spaced eyes with a frequent squint (strabismus)
  • Large and low-set ears
  • A broad bridge to the nose and a bulbous tip
  • A small mouth with thin lips and receding, pointed chin
  • Chubby cheeks
  • A low hairline
• High-arched palate
• Sleep disturbances that can affect one’s physical and mental health
• Constipation that may be moderate to severe
• Behavioral problems

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

Chromosome 4p Duplications 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
• 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 4p Duplications Syndrome?

The complications of Chromosome 4p Duplications Syndrome may include:

• Severe emotional stress for parents and caregivers
• Pregnancy complications are not very commonly noted
• Intrauterine growth retardation (IUGR); some babies are underweight at birth
• Failure to thrive
• Delayed milestone achievement that may affect when a child rolls, sits, crawls, or walks
• Some children grow to be short, while some may be tall
• 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
• Risk of falls and injury due to seizures
• Deafness
• Frequent respiratory infections
• Blocked nasal passage (choanal atresia)
• 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 4p Duplications Syndrome Treated?

There is no cure for Chromosome 4p Duplications 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 4p Duplications Syndrome may involve:

• 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)
• Use of walking aids including foot orthotics and special footwear and shoe inserts
• 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
• Severe constipation may require dietary changes, including increased intake of fiber and wholegrains, along-with the administration of laxatives
• 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
• 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
• Use of suitable glasses and surgical rectification of vision defects, if necessary
• Surgical correction (orchiopexy) of undescended testicles and other genital defects
• Sleep disorders may require medication; daytime naps may be advised
• 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 4p Duplication Syndrome be Prevented?

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

The prognosis of Chromosome 4p 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 children may require lifelong medical support and care

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

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

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