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

• 4q Deletions Between 4q21 and 4q31

What is Chromosome 4q Deletions Between 4q21 and 4q31? (Definition/Background Information)

• Chromosome 4q Deletions Between 4q21 and 4q31 is a chromosome abnormality that affects many different parts of the body. People with this condition are missing genetic material located on the long arm (q) of chromosome 4 in the region between q21 and q31. The severity of the condition and the associated signs and symptoms vary based on the size of the deletion and the genes that are involved
• Most cases of 4q Deletions Between 4q21 and 4q31 are not inherited, although affected people can pass the deletion on to their children. Common features observed in individuals with this deletion include distinctive craniofacial features, poor muscle tone, Rieger syndrome, heart defects, feeding difficulties, developmental delays, and short stature
• Following a diagnosis of Chromosome 4q Deletions Between 4q21 and 4q31, 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, speech and language therapy, physiotherapy, and surgery for correction of heart and other physical defects, if any
• The prognosis is primarily dependent on the severity of the disorder, and it varies from one child to another. Many children with Chromosome 4q Deletions Between 4q21 and 4q31 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 Deletions Between 4q21 and 4q31? (Age and Sex Distribution)

• Chromosome 4q Deletions Between 4q21 and 4q31 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 Deletions Between 4q21 and 4q31? (Predisposing Factors)

In a vast majority of individuals, there are no identified risk factors for Chromosome 4q Deletions Between 4q21 and 4q31.

• In some individuals, a positive family history may be an important risk factor for Chromosome 4q Deletions Between 4q21 and 4q31
• 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 Deletions Between 4q21 and 4q31? (Etiology)

Chromosome 4q Deletions Between 4q21 and 4q31 are caused by the deletion of genetic material from chromosome 4. The amount of missing chromosome material varies widely from one individual to another resulting in a variable set of signs and symptoms.

• In this disorder, there is a variable loss of chromosomal material between the regions marked q21 and q31 on the long arm (q) of chromosome 4
• The type of deletion that mostly occurs is known as an interstitial deletion. The term “interstitial” means that the chromosome material on the q arm broke at two locations (q21 and q31) and the broken ends joined together; and, the segment between q21 and q31 is lost or missing
• The severity of the condition and the associated signs and symptoms vary depending on the size of the deletion (whether small or large), the breakpoints involved, and the genes that are affected/lost. It is observed that individuals with the following specific deletions have wide-ranging and more severe signs and symptoms:
  • 4q25q27 deletion - deletion between bands q25 and q27. When genetic material on the 4q25q26 band, particularly when a copy of the PITX2 gene, is lost, it can result in Rieger syndrome
  • 4q27q31 deletion - deletion between bands q27 and q31
• Most cases of the disorder develop sporadically (de novo) during embryonic development. This means that no deletion of genetic material at 4q is observed in either of the parents. However, in rare cases, the disorder may be inherited

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

What are the Signs and Symptoms of Chromosome 4q Deletions Between 4q21 and 4q31?

The signs and symptoms of Chromosome 4q Deletions Between 4q21 and 4q31 may be significantly different from one individual to another. The degree of signs and symptoms are often related to the amount of chromosome material deleted 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 deletion 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 loss, may have disproportionately severe presentations.

The associated signs and symptoms depend on what material is lost/missing, how much deletion has occurred (quantity), where the deletions occur, and if the involvement of other chromosomes are noted.

The commonly noted signs and symptoms of 4q Deletions Between 4q21 and 4q31 include:

• Growth and developmental delays
• Short stature
• Speech, communication, and learning difficulties
• Congenital hypotonia (reduced muscle tone) resulting in a soft and floppy body of the infant; many children present hypotonia
• Feeding difficulties; sucking and swallowing may be difficult
• Gastroesophageal reflux disease (GERD)
• Rieger syndrome: In this syndrome, the teeth, eye, and skin around the umbilicus are involved
• Seizures (seizure-like activity) may be present in some children
• Congenital heart defects in some children such as:
  • Atrial septal defect (ASD)
  • Ventricular septal defect (VSD)
  • Patent ductus arteriosus (PDA)
• Minor genital abnormalities, particularly in boys
• Dental abnormalities are generally observed; these include missing teeth or overcrowding of teeth within a small jaw
• Hand and feet abnormalities; several limb abnormalities are noted, including clubfoot
• Skeletal anomalies, including missing rib and split or incompletely developed vertebra
• Distinctive craniofacial features such as:
  • Abnormally-shaped large head with prominent forehead
  • Small eyes that are set wide apart; additional skin folds around the eyes and drooping eyelids (ptosis)
  • Depressed, wide nasal bridge; small nose
  • Abnormally-shaped low-set ears
  • Cleft palate
  • Small mouth with down-turned corners; high palate
  • Small receding chin and jaw; lower jaw is set backwards with respect to the upper jaw
• Vision may be affected; many children may present strabismus, some have droopy upper eyelid
• Fontanelle: A large soft spot on head/skull that closes slowly
• Behavioral issues are usually not significant

How is Chromosome 4q Deletions Between 4q21 and 4q31 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 4q Deletions Between 4q21 and 4q31 in the differential diagnosis. Often, specialized tests are necessary to confirm the disorder.

Chromosome 4q Deletions Between 4q21 and 4q31 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
• Assessment of hearing and vision of the affected child
• 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
• 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 Deletions Between 4q21 and 4q31?

The complications of Chromosome 4q Deletions Between 4q21 and 4q31 may include:

• Severe emotional stress for parents and caregivers
• Pregnancy complications
• Intrauterine growth retardation (IUGR)
• Delayed milestone achievement
• Rieger syndrome may sometimes cause permanent hearing loss; even functioning of the pituitary gland may be affected
• Severe vision impairment
• In rare cases, endocrine abnormalities
• Intellectual impairment (low IQ levels)
• Severe heart anomalies
• Reduced quality of life

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

How is Chromosome 4q Deletions Between 4q21 and 4q31 Treated?

There is no cure for Chromosome 4q Deletions Between 4q21 and 4q31 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, otolaryngologists, neurologists, internists, cardiologists, endocrinologists, surgeons, and other healthcare professionals are involved in managing the condition.

The treatment measures for Chromosome 4q Deletions Between 4q21 and 4q31 may involve:

• Use of hearing aids
• 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
• Employing learning strategies via music therapy, visual and tactile books, learning through fun and play, and lots of repetition
• Speech and language therapy; the use of sign language may be beneficial; rectification of hearing impairment may improve speech and language development
• Seizure control using anticonvulsant medication, vitamin supplements, and ketogenic diet
• 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)
• Surgical correction of physical defects, as assessed by a healthcare expert
• Surgical correction (orchiopexy) of undescended testicles and other genital defects
• Heart abnormalities may require surgical correction in some cases
• 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 Deletions Between 4q21 and 4q31 be Prevented?

Chromosome 4q Deletions Between 4q21 and 4q31 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 deletions 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 Deletions Between 4q21 and 4q31? (Outcomes/Resolutions)

The long-term outlook (prognosis) for people with Chromosome 4q Deletions Between 4q21 and 4q31 varies from one individual to another.

• The severity of the condition and the associated signs and symptoms largely depend on the size of the deletion, the breakpoints, and the genes involved
• Weak muscle tone (hypotonia) severity may determine motor function delays; it improves with physiotherapy and as the child gets older
• Some children require lifelong medical support and care

Additional and Relevant Useful Information for Chromosome 4q Deletions Between 4q21 and 4q31:

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

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