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

• 1q42 (and beyond) Deletions
• Chromosome 1q4 Deletions from 1q42 and beyond
• Terminal 1q Deletion

What are Chromosome 1q42 (and beyond) Deletions? (Definition/Background Information)

• Chromosome 1q42 (and beyond) Deletions are rare chromosomal disorders that develop when there is missing genetic material on chromosome 1 (at band q4) leading to a set of associated signs and symptoms. These may be mild or severe, depending on several factors such as the amount of genetic material lost, the number of genes affected, and the function of the affected genes. The condition affects newborn children (congenital manifestation); if large segments of the chromosome are missing, then the child may have severe abnormalities
• Chromosome 1q42 (and beyond) Deletions can result in developmental delays, poor motor skills, heart and brain abnormalities, seizures, and vision and hearing impairment. 1q42 (and beyond) Deletions may present complications such as malnutrition due to feeding difficulties, delayed achievement of milestones, abnormal spinal curvature, and reduced quality of life
• This chromosomal anomaly may develop from sporadic mutations (vast majority of cases), or it may be inherited from one’s parents (very rarely). 1q42 (and beyond) Deletions 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 and hearing aids, seizure control, speech and language therapy, physiotherapy, and surgery for correction of heart and other 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 1q42 (and beyond) Deletions 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 1q42 (and beyond) Deletions? (Age and Sex Distribution)

• The incidence of Chromosome 1q42 (and beyond) Deletions is presently unknown. Presently, over 50 cases have been reported
• 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
• 1q42 (and beyond) Deletions is a congenital disorder and the presentation of symptoms may occur at or following the birth of the child
• Both males and females are equally affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Chromosome 1q42 (and beyond) Deletions? (Predisposing Factors)

In a vast majority of individuals, there are no identified risk factors for Chromosome 1q42 (and beyond) Deletions.

• In some individuals, a positive family history may be an important risk factor for 1q42 (and beyond) Deletions
• 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 1q42 (and beyond) Deletions? (Etiology)

Chromosome 1q42 (and beyond) Deletions are caused by the deletion of genetic material from the long arm (q) of chromosome 1; the amount of missing chromosome material varies widely from one individual to another resulting in a variable set of signs and symptoms.

• Majority of deletions involve the tip of the long arm (q) chromosome, called terminal 1q deletion (or 1qter deletion)
• The deletions may be terminal or interstitial (where a certain length of the long arm of chromosome is missing, but the tip/end is still present)
• The deletion may be very small, called microdeletions, 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
• The deletions may be termed proximal or distal. When deletions occur closer to the center (centromere), it is termed proximal deletions. When deletions occur near the end of the chromosome, it is termed distal deletions

There are two chromosomes numbered 1. Children with Chromosome 1q42 Deletions typically will have one (chromosome 1) in normal condition, while the other is abnormal. The abnormality is characterized by a loss of chromosomal material.

• Most cases of the disorder develop sporadically (de novo) during embryonic development. This means that no deletion of genetic material at 1q42 (and beyond) is observed in either of the parents. However, in rare cases, Chromosome 1q42 (and beyond) Deletions may be inherited
• In many individuals, apart from 1q42 deletions, there is gain or loss of genetic material from another chromosome. The gain (duplication) of material has been noted from chromosomes 3, 8, 9, 12, 13, 14 and 16
• One of the genes involved in 1q42 (and beyond) Deletions include the AKT3 gene, which is strongly associated with agenesis of the corpus callosum 

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 1q42 (and beyond) Deletions?

The signs and symptoms of Chromosome 1q42 (and beyond) Deletions 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 commonly noted signs and symptoms of Chromosome 1q42 (and beyond) Deletions include:

• Agenesis of the corpus callosum (ACC), birth defect involving the brain, is seen in nearly 90% of the children. This can cause:
  • Small-sized head (microcephaly)
  • Delays in reaching developmental milestones
  • Feeding issues
  • Low muscle tone (hypotonia)
  • Speech and language delays
  • Behavioral issues
  • Intellectual disabilities
• Poor muscle tone (hypotonia) causing motor delays that can be mild or severe. It is observed in 80-90% of the individuals causing a variety of issues including:
  • Feeding problems (sucking and swallowing) leading to small and underweight children
  • Constipation
  • 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
• Seizures, observed in 80-85% affected children, from age 6 months to 3 years
• Over 70% may have gastroesophageal reflux disease (GERD)
• Mild or severe eczema is noted in 60% of the children that gets worse during summers
• Vision defects observed in nearly 60% of the affected children may include:
  • Strabismus (most common vision abnormality)
  • Shortsightedness or longsightedness
  • Astigmatism: It is an eye disorder caused by the irregular shape and curvature of the cornea or lens
• Breathing issues in 40% of the children (mostly sleep apnea); 20% may have asthma that is known to improve with age
• 20% show congenital hip dislocation that may involve one or both hips 
• Hearing impairment including:
  • Recurrent ear infections
  • Glue ear - fluid buildup in middle ear
• The following heart abnormalities may be observed in nearly 50% of the cases. This can result in associated signs and symptoms, such as chest pain, shortness of breath, dizziness, fainting, palpitations, and tiredness, among others
  • Valve defects, such as ventricular septal defects (VSD) or atrial septal defects (ASD), is usually present at birth
  • Persistence of patent ductus arteriosus (PDA) is noted
  • Pulmonary stenosis or sub-aortic stenosis is rarely seen
  • Tetralogy of Fallot, an abnormality that consists of four heart defects, namely subpulmonic stenosis, ventricular septal defect, overriding aorta, and right ventricular hypertrophy
• Speech and learning disabilities; speech skills may be significantly affected
• Minor genital abnormalities, which mostly affect boys:
  • Cryptorchidism (undescended testes), and hypospadias in boys
  • Underdeveloped or large labia in girls
• Umbilical and inguinal hernias
• Hand/finger abnormalities including short thumb, fused fingers, and incurving fingers
• Feet abnormalities such as flatfeet, clubfoot, rocker bottom feet, overlapping toes, and inwards curving feet
• Teeth abnormalities in some children, including slow eruption of teeth
• Cleft and high palate leading to feeding and speaking challenges
• Distinctive facial features may include prominent forehead; abnormal and low set ears; flat short nose, eyes wide apart and deeply set; thin upper lip, receding lower jaw; short neck - some features improve change over time, but head may be still smaller in size
• Short stature
• Sleep disturbances that can affect one’s physical and mental health

In general, children are well-behaved, sociable, affectionate, and determined.

How are Chromosome 1q42 (and beyond) Deletions 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 1q4 Deletions in the differential diagnosis. Often, specialized tests are necessary to confirm the disorder.

1q42 (and beyond) Deletions 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 1q42 (and beyond) Deletions?

The complications of Chromosome 1q42 (and beyond) Deletions may include:

• Severe emotional stress for parents and caregivers
• Pregnancy complications in some cases
• Intrauterine growth retardation (IUGR); some babies are underweight at birth
• Delayed milestone achievement: Children may learn to roll around 14 months, many children sit at age 22 months, while some may never learn to crawl, but may “bottom shuffle”. The average age at which children walk is around 3 years
• Brain anomalies including hydrocephalus, large brain ventricles, and delayed myelination
• Vision loss; cortical visual impairment resulting in partial or total blindness
• Sleep (infantile) apnea may be associated with seizures (night-time seizures)
• 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
• Kidney defects may be noted in 1 in 5 children. These include kidney reflux (urine flows back into the kidney from the urinary bladder), and rarely, single kidney or horseshoe kidney
• Deafness due to persistent fluid in middle ear
• In small number of cases, autism spectrum disorders may be observed
• Intellectual disability
• Puberty delays, menstrual abnormalities, and infertility may be noted
• Lennox-Gastaut syndrome from severe and chronic seizures
• Severe heart anomalies
• Reduced quality of life

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

How are Chromosome 1q42 (and beyond) Deletions Treated?

There is no cure for Chromosome 1q42 (and beyond) Deletions 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 1q4 Deletions 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. Each child may have specific learning needs, and thus, unique teaching techniques may be necessary. Parents and teachers have to recognize this and approach the child with patience, cheer, and encouragement. Rarely, children may become seizure-free into late childhood or early adulthood
• Special education: Employing learning strategies via music therapy, visual and tactile books, learning through fun and play, and lots of repetition. Children are known to like music and singing. 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; wheelchair assistance may be necessary. Clubfoot may require surgery to correct the abnormal feet positioning
• 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 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. And, where necessary, raising the head of the end of the bed for sleeping is also recommended
• 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, such as surgical repair of cleft lip
• 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
• Surgical correction (orchiopexy) of undescended testicles and other genital defects
• Surgical correction of kidney reflux via ureteral reimplantation procedure
• 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 1q42 (and beyond) Deletions be Prevented?

Chromosome 1q42 (and beyond) Deletions 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 (chromosome) testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy), if available, 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 1q4 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 1q42 (and beyond) Deletions? (Outcomes/Resolutions)

The prognosis of Chromosome 1q42 (and beyond) Deletions 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 deletions) 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
• Weak muscle tone (hypotonia) severity may determine motor function delays; it improves with physiotherapy and as the child gets older
• Children usually require lifelong medical support and care; it may also take some children a long time (several years) to gain a measure of independence
• Also, since children are known to resist changes in their lifestyle, it is helpful to establish a set (daily) routine for them, to make them feel comfortable and secure

Nevertheless, in a majority of cases, pregnant women with children having Chromosome 1q4 Deletions are known to have normal deliveries.

Additional and Relevant Useful Information for Chromosome 1q42 (and beyond) Deletions:

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

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