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

• Duplication 5q35 Syndrome
• Partial Trisomy 5q35 Syndrome

What is Chromosome 5q35 Duplication Syndrome? (Definition/Background Information)

• Chromosome 5q35 Duplication Syndrome is a rare chromosome abnormality that occurs when there is an extra (duplicated) copy of genetic material on the long arm (q) of chromosome 5, specifically at the location q35. The severity of the condition and the signs and symptoms depend on the size and location of the duplication and which genes are involved
• Chromosome testing of both parents can provide more information on whether or not the duplication was inherited. Features that are often noted in individuals with Chromosome 5q35 Duplication Syndrome include developmental delay, intellectual disability, behavioral issues, and rarely, heart and brain anomalies
• This chromosomal anomaly may develop from sporadic mutations (vast majority of cases), or it may be inherited from one’s parents (very rarely). 5q35 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 hearing and vision aids, 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 5q35 Duplications 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 5q35 Duplication Syndrome? (Age and Sex Distribution)

• Chromosome 5q35 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 equally affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Chromosome 5q35 Duplication Syndrome? (Predisposing Factors)

In a majority of individuals, there are no identified risk factors for Chromosome 5q35 Duplication Syndrome.

• In some individuals, a positive family history may be an important risk factor for 5q35 Duplication Syndrome
• Having a parent with a balanced translocation involving chromosome 5q35 may be an important risk factor for the syndrome in the subsequent (next) generation
• 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 5q35 Duplication Syndrome? (Etiology)

Chromosome 5q35 Duplication Syndrome is caused by an extra copy of genetic material on the long arm (q) of chromosome 5, in the q35 region. Most cases are not inherited, but parents can pass on the duplication to their children.

• There are two chromosomes numbered 5. Children with the syndrome typically have one (chromosome 5) 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. Nevertheless, in some cases, microduplications are noted (such as 5q35.1 or 5q35.2 microduplication)
• 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
• The involvement of the NSD1 gene is believed to play a significant role in the features associated with this syndrome. This gene is known to regulate another gene called the APC2 gene that is involved in brain development. According to researchers, there may be other (as yet unidentified) genes that contribute to the syndrome presentations
  • When the NSD1 gene is deleted or mutated, the disorder is called Sotos syndrome 1
  • When the NSD1 gene is duplicated, the disorder is known as reversed Sotos syndrome

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 5q35 Duplication Syndrome?

The signs and symptoms of Chromosome 5q35 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 (quantity) and where the duplications occurs.

The commonly noted signs and symptoms of Chromosome 5q35 Duplication Syndrome include:

• Stunted growth and developmental delays; delayed bone growth
• Short stature
• Feeding difficulties, including sucking, swallowing, and breathing difficulties
• Gastroesophageal reflux disease (GERD)
• Constipation is commonly noted
• Abnormal facial features such as:
  • Small-sized head and prominent forehead
  • Widely-spaced eyes
  • Broad nose
  • Abnormally-shaped and low-set ears
  • Thin lips
  • Cleft lip
  • Small jaw
• Vision and hearing impairment due to:
  • Longsightedness, strabismus, coloboma, and astigmatism
  • Glue ear (fluid buildup in the middle ear)
• Seizures are occasionally reported
• Eczema
• Hand and foot abnormalities, including loose joints
• Heart abnormalities such as valvular defects, heart murmur, and persistent foramen ovale. These may result in associated signs and symptoms, such as chest pain, shortness of breath, dizziness, fainting, palpitations, and tiredness, among others
• Brain anomalies are rarely noted, but may include ectopic neurohypophysis, periventricular leukomalacia, and cerebellar vermis hypoplasia, which may affect brain function
• Inguinal and umbilical hernias
• Poor muscle tone (hypotonia) causing motor delays and mobility issues
• Hand-eye coordination difficulties
• Behavioral issues, including mood swings, social isolation, and anxiety disorders
• Dental abnormalities, such as tooth cavities, are commonly noted
• Speech and learning disabilities that may be mild or severe
• Intellectual disabilities that may be severe in some children

How is Chromosome 5q35 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 5q35 Duplication Syndrome in the differential diagnosis. Often, specialized tests are necessary to confirm the disorder.

5q35 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
• Tests and exams to asses heart function
• 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
• 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 5q35 Duplication Syndrome?

The complications of Chromosome 5q35 Duplication Syndrome may include:

• Severe emotional stress for parents and caregivers
• Pregnancy complications
• Intrauterine growth retardation (IUGR)
• Failure to thrive
• Delayed milestone achievement
• Frequent ear and chest infections
• Severe brain or heart anomalies
• Autism and Asperger’s disorder
• Intellectual impairment
• Inability to live independently
• Reduced quality of life

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

How is Chromosome 5q35 Duplication Syndrome Treated?

There is no cure for Chromosome 5q35 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 5q35 Duplication Syndrome may involve:

• Use of hearing aids, if required
• Special education: Employing learning strategies via music therapy, visual and tactile books, touch screen computers, etc.
• Speech and language therapy; the use of sign language may be beneficial
• Physiotherapy for weakened muscles, including incorporating daily exercise regimen
• Development of motor skills via daily exercises, swimming, 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
• For feeding difficulties, use of feeding tubes (temporary), medications, feed thickeners, including special diets and nutritional supplements
• A surgical procedure named fundoplication may be necessary in some children with severe gastroesophageal reflux disease (GERD). Milder GERD cases can be generally well-controlled by giving feeds slowly and positioning the baby in a semi-upright position
• 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 suitable glasses and surgical rectification of vision defects, if necessary
• Surgical correction of genital defects
• Dental care and hygiene
• Sleep disorders may require medication; daytime naps may be advised
• For eczema, the treatment may involve the use of moisturizing creams and emollients and steroid creams as necessary; many children overcome the condition as they get older
• Hernia repair surgery for umbilical and inguinal hernias, as needed. In many cases, the condition resolves over 3-4 years, as the child develops
• 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 5q35 Duplication Syndrome be Prevented?

Chromosome 5q35 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 5q35 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 5q35 Duplication Syndrome (Outcomes/Resolutions)

The prognosis of Chromosome 5q35 Duplication Syndrome is dependent upon the severity of the signs and symptoms and associated complications, if any.

• Children with mild conditions 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. Children with severe heart or brain defects may have worser prognosis

Additional and Relevant Useful Information for Chromosome 5q35 Duplication Syndrome:

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

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