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

• 1q21.1 Microdeletion Syndrome
• Monosomy 1q21.1 Syndrome

What is Chromosome 1q21.1 Microdeletion Syndrome? (Definition/Background Information)

• Chromosome 1q21.1 Microdeletion Syndrome is a rare chromosome abnormality that develops when there is missing genetic material on chromosome 1 leading to a set of associated signs and symptoms. Specifically, a segment of genetic material on the long arm (or q arm) of chromosome 1 at position 21.1 is missing or is deleted
• Some individuals with this deletion have no observable features, while others have variable presentations that can include a small head (microcephaly), developmental delay (speech and motor delays), mild intellectual disability, distinctive facial features, and eye abnormalities. Other findings can include seizures as well as abnormalities of the heart, skeleton, and urinary system
• This chromosomal anomaly is usually known to develop from sporadic mutations in a vast majority of cases. 1q21.1 Microdeletion 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, speech and language therapy, physiotherapy, and surgery for correction of heart and other defects
• The prognosis is primarily dependent on the severity of the disorder, and it varies from one child to another. Many children with Chromosome 1q21.1 Microdeletion 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 1q21.1 Microdeletion Syndrome? (Age and Sex Distribution)

• The incidence of Chromosome 1q21.1 Microdeletion Syndrome is presently unknown
• 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
• 1q21.1 Microdeletion Syndrome is a congenital disorder, and the presentation of symptoms may occur at or following the birth of the child
• 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 1q21.1 Microdeletion Syndrome? (Predisposing Factors)

In a vast majority of individuals, there are no identified risk factors for Chromosome 1q21.1 Microdeletion Syndrome.

• In some individuals, a positive family history may be an important risk factor for 1q21.1 Microdeletion 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 1q21.1 Microdeletion Syndrome? (Etiology)

Chromosome 1q21.1 Microdeletion Syndrome is caused by a deletion of genetic material in the long arm of chromosome 1. The deletion typically occurs in one of the 2 copies of chromosome 1, in all cells of the individual.

• In microdeletion, a very tiny part of the chromosome is lost or missing; when it is not even visible under a microscope with high magnification. In such cases, FISH or array-CGH studies may be necessary to detect the deletions
• Even though termed microdeletion, relatively smaller or larger deletions may take place, based on the amount of genetic material lost. In 1q21.1 Microdeletion Syndrome, two deletion sizes are noted:
  • Class I microdeletion that occurs distal to the chromosome tip and is typically smaller in size. It is documented that around 9 genes may be lost in this form of deletion
  • Class II microdeletion that includes the above region and the TAR region, containing around 25 known genes. Abnormalities involving the TAR region is known to result in a disorder known as thrombocytopenia-absent radius (TAR) syndrome
• The involvement of HYD1N gene (influencing head growth), GJA5 gene (associated with heart development), and GJA8 gene (causing cataracts and also involved in schizophrenia) is noted
• 1q21.1 Microdeletion Syndrome can occur in an individual as a consequence of the following:
• A random event in the egg or sperm in a parent 
• A random event in the early stages of embryonic development
• An inherited deletion from a parent
• When inherited, 1q21.1 Microdeletion Syndrome is transmitted in an autosomal dominant manner

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition, or pass it on to their offspring.

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 1q21.1 Microdeletion Syndrome?

The signs and symptoms of Chromosome 1q21.1 Microdeletion 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 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 signs and symptoms of 1q21.1 Microdeletion Syndrome may vary from one individual to another and may include:

• Abnormal facial features that include:
  • Small-sized head is seen in nearly 65% of the cases; while some children present abnormally large-sized head
  • Prominent forehead
  • Deeply set eye
  • Wide nasal bridge
  • Large-sized nose
  • High palate
• Short stature
• Hand and foot deformities such as clubfoot, extra digits, curved fingers/toes, and webbed toes 
• Loose joints (seen in 25% of the cases)
• Psychiatric and behavioral features can include:
  • Autism spectrum disorders
  • Anxiety and mood disorders
  • Schizophrenia
  • Attention-deficit hyperactivity disorder (ADHD)
  • Sleep disorders
  • Depression
• Global developmental delay, which can be mild or moderate
• Intellectual disability
• Vision impairment in the form of cataracts, shortsightedness and longsightedness, double vision, strabismus, and Duane anomaly
• Hearing impairment due to glue ear (fluid build-up in the middle ear)
• Heart abnormalities can result in associated signs and symptoms, such as chest pain, shortness of breath, dizziness, fainting, palpitations, and tiredness, among others. The heart defects noted may include:
  • Aortic and aortic valve abnormalities including interrupted aortic arch and coarctation of the aorta
  • Atrial septal defects (ASD)
  • Patent ductus arteriosus (PDA)
  • Tetralogy of Fallot (rarely noted)
  • Transposition of the great arteries 
  • Truncus arteriosus
  • Ventricular septal defect (VSD)
• Low muscle tone (hypotonia), observed in around 25% of the cases
• Feeding difficulties due to swallowing difficulties, vomiting, and gastroesophageal reflux disease
• Epileptic seizures
• Agenesis of corpus callosum
• Sleep disturbance
• Minor genital anomalies

In some children, the condition may be very mild that no visible symptoms, such as abnormal features or behavioral issues, may be noted.

How is Chromosome 1q21.1 Microdeletion 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 1q21.1 Microdeletion Syndrome in the differential diagnosis. Often, specialized tests are necessary to confirm the disorder.

1q21.1 Microdeletion 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: 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 1q21.1 Microdeletion Syndrome?

The potential complications of Chromosome 1q21.1 Microdeletion Syndrome may include:

• Severe emotional stress for parents and caregivers
• Pregnancy complications
• Intrauterine growth retardation (IUGR)
• Failure to thrive
• Hydrocephalus due to increased CSF in the brain
• Delay in achieving developmental milestones
• Frequent infections
• Intellectual disability
• Compromised vision; vision loss
• Irreversible hearing loss
• Behavioral issues including low self-esteem
• If scoliosis is present, then it may result in back pain, damage to lungs and heart, etc.
• Risk of falls and injuries in affected individuals with seizures
• Lennox-Gastaut syndrome
• Abnormally-developed lungs and kidneys
• 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 1q21.1 Microdeletion Syndrome Treated?

There is no cure for Chromosome 1q21.1 Microdeletion 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 1q21.1 Microdeletion 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
• Speech and language therapy; the use of sign language may be beneficial; rectification of hearing impairment may improve speech and language development
• Employing suitable learning strategies via music therapy, visual and tactile books, touch screen computers, etc.
• 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; wheelchair assistance may be necessary
• 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
• 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
• Sleep disorders may require medication; daytime naps may be advised
• 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 1q21.1 Microdeletion Syndrome be Prevented?

Chromosome 1q21.1 Microdeletion 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 1q21.1 Microdeletion 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 1q21.1 Microdeletion Syndrome? (Outcomes/Resolutions)

The prognosis of Chromosome 1q21.1 Microdeletion 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 are generally able to cope well via appropriate treatment and adaptive behaviors as they get older
• Some of the abnormalities involving the heart, seizures, recurrent infections, motor skills, communication and behavioral issues are known to resolve or improve with time
• Children usually require lifelong medical support and care; it may also take children a long time (several years) to gain a measure of independence

Additional and Relevant Useful Information for Chromosome 1q21.1 Microdeletion Syndrome:

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

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