12 Key Symptoms of DiGeorge Syndrome (22q11.2 Deletion Syndrome) You Should Know

DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a genetic disorder caused by the deletion of a small piece of chromosome 22. This condition affects approximately 1 in 4,000 to 6,000 live births, making it one of the most common deletion syndromes. The syndrome can affect multiple body systems, leading to a wide range of symptoms that vary greatly in severity from person to person.

The condition was first described by Dr. Angelo DiGeorge in 1965 and is characterized by a combination of medical problems that may include heart defects, immune system dysfunction, developmental delays, and distinctive facial features. Because the symptoms can be so varied, some individuals may have severe complications while others experience only mild effects. Early recognition and proper management of symptoms are crucial for improving quality of life and long-term outcomes.

Understanding the symptoms of DiGeorge syndrome is essential for early diagnosis and intervention. Below, we explore the most common symptoms associated with this genetic condition.

1. Congenital Heart Defects

Heart defects are among the most common and serious symptoms of DiGeorge syndrome, affecting approximately 75% of individuals with the condition. These cardiac abnormalities are typically present from birth and can range from mild to life-threatening.

The most frequently observed heart defects include:

• Tetralogy of Fallot: A combination of four heart defects that affects normal blood flow through the heart
• Interrupted aortic arch: A potentially life-threatening condition where the aorta doesn’t form completely
• Ventricular septal defect (VSD): A hole in the wall separating the heart’s lower chambers
• Truncus arteriosus: A single large vessel leading out of the heart instead of two separate arteries

Symptoms of heart defects may include bluish skin color (cyanosis), rapid breathing, poor feeding, fatigue during feeding, and failure to gain weight appropriately. These heart conditions often require surgical intervention shortly after birth or during infancy to prevent serious complications.

2. Immune System Dysfunction

Individuals with DiGeorge syndrome frequently experience immune system problems due to underdevelopment or absence of the thymus gland, an organ critical for T-cell production and immune function. The severity of immune dysfunction varies widely among affected individuals.

The immune system complications manifest as:

• Increased susceptibility to viral, fungal, and bacterial infections
• Recurrent respiratory infections such as pneumonia, bronchitis, and ear infections
• Chronic sinusitis and frequent colds
• Slower recovery from common illnesses
• Increased risk of autoimmune disorders

Children with significant immune deficiency may require special precautions to avoid infections, including limiting exposure to sick individuals and maintaining up-to-date vaccinations (though live vaccines may need to be avoided in severe cases). The degree of immune impairment can range from mild to severe, with some individuals having nearly normal immune function while others require more intensive monitoring and intervention.

3. Hypocalcemia and Parathyroid Gland Problems

Hypocalcemia, or low calcium levels in the blood, is a common symptom of DiGeorge syndrome caused by underdeveloped or absent parathyroid glands. These small glands regulate calcium and phosphorus levels in the body, and their dysfunction can lead to significant complications.

Signs and symptoms of hypocalcemia include:

• Muscle spasms, cramps, or tetany (involuntary muscle contractions)
• Tingling sensations in the fingers, toes, and around the mouth
• Seizures, particularly in infants and young children
• Irregular heartbeat or arrhythmias
• Fatigue and weakness
• Developmental delays if left untreated

Hypocalcemia can occur during the newborn period or may not become apparent until later in childhood or even adulthood. Regular monitoring of calcium levels is essential, and affected individuals may require lifelong calcium and vitamin D supplementation under medical supervision.

4. Palatal Abnormalities

Palatal abnormalities are present in approximately 70% of individuals with DiGeorge syndrome and can significantly impact feeding, speech development, and quality of life. These structural differences affect the roof of the mouth and related structures.

Common palatal abnormalities include:

• Cleft palate: An opening or split in the roof of the mouth that may involve the soft palate, hard palate, or both
• Submucous cleft palate: A hidden cleft covered by the mouth’s lining that may not be visible but affects function
• Velopharyngeal insufficiency (VPI): Incomplete closure between the mouth and nose during speech, leading to hypernasal speech
• Bifid uvula: A split uvula (the hanging tissue at the back of the throat)

These abnormalities can cause feeding difficulties in infants, including problems with sucking and swallowing, nasal regurgitation of liquids, and poor weight gain. Speech problems are also common, including hypernasal speech quality, difficulty pronouncing certain sounds, and delayed speech development.

5. Distinctive Facial Features

Many individuals with DiGeorge syndrome have characteristic facial features that may be subtle or more pronounced. While these features alone are not diagnostic, they can provide important clues when combined with other symptoms.

Common facial characteristics include:

• Small, low-set ears with squared upper ear (abnormal folding)
• Hooded eyelids with narrow eye openings
• A bulbous nasal tip with a squared nasal root
• Small mouth with thin upper lip
• Facial asymmetry, with one side of the face appearing slightly different from the other
• Micrognathia (small jaw) in infancy
• Short philtrum (the vertical groove between nose and upper lip)

It’s important to note that these facial features are often subtle and may not be immediately apparent. They tend to be more noticeable in infancy and early childhood and may become less distinctive with age. Not all individuals with DiGeorge syndrome will have all of these features, and their presence or absence doesn’t correlate with the severity of other symptoms.

6. Developmental and Learning Delays

Developmental delays and learning difficulties are common in DiGeorge syndrome, affecting the majority of individuals to varying degrees. These challenges can impact multiple areas of development and learning throughout childhood and into adulthood.

Developmental concerns include:

• Motor delays: Later achievement of milestones such as sitting, crawling, walking, and fine motor skills like grasping and manipulating objects
• Speech and language delays: Late onset of first words, difficulty with articulation, and challenges in expressive and receptive language
• Cognitive challenges: Mild to moderate intellectual disability in some cases, though many individuals have normal intelligence
• Learning disabilities: Difficulties with mathematics, reading comprehension, and abstract reasoning
• Attention problems: Higher incidence of attention deficit hyperactivity disorder (ADHD)

While some children may have significant delays requiring substantial support, others may have only mild learning differences. Early intervention services, including physical therapy, occupational therapy, and speech therapy, can help children reach their full potential.

7. Feeding Difficulties

Feeding problems are extremely common in infants and young children with DiGeorge syndrome, often presenting as one of the earliest signs of the condition. These difficulties can result from multiple factors, including structural abnormalities, muscle weakness, and coordination problems.

Feeding challenges manifest as:

• Poor sucking ability and weak feeding in newborns
• Difficulty coordinating sucking, swallowing, and breathing
• Nasal regurgitation of liquids due to palatal abnormalities
• Gagging or choking during feeds
• Prolonged feeding times (more than 30-40 minutes per feed)
• Poor weight gain and failure to thrive
• Food aversions and selective eating patterns in older children
• Gastroesophageal reflux

These feeding issues may require specialized feeding techniques, modified bottle nipples, thickened liquids, or in severe cases, temporary tube feeding to ensure adequate nutrition and growth. A multidisciplinary approach involving pediatricians, feeding specialists, and speech therapists is often necessary to address these challenges.

8. Hearing Loss

Hearing problems affect a significant proportion of individuals with DiGeorge syndrome, with studies suggesting that up to 60% experience some degree of hearing loss. This symptom can have profound effects on speech and language development if not identified and addressed early.

Hearing issues associated with DiGeorge syndrome include:

• Conductive hearing loss: Most commonly caused by chronic ear infections (otitis media) and fluid buildup in the middle ear
• Sensorineural hearing loss: Less common but can occur due to nerve damage or inner ear abnormalities
• Mixed hearing loss: A combination of both conductive and sensorineural components
• Structural abnormalities of the ear canal or middle ear bones

The hearing loss may be mild to moderate and can fluctuate, particularly when associated with ear infections. Regular hearing evaluations are crucial for early detection, as even mild hearing loss can significantly impact language development and learning. Many children benefit from interventions such as ear tube placement to reduce fluid accumulation and recurrent infections.

9. Genitourinary Abnormalities

Kidney and urinary tract problems occur in approximately 30-40% of individuals with DiGeorge syndrome. These abnormalities can range from minor structural differences to significant malformations requiring medical intervention.

Common genitourinary symptoms include:

• Kidney malformations such as absent kidney (renal agenesis), multicystic dysplastic kidney, or horseshoe kidney
• Vesicoureteral reflux (backward flow of urine from bladder to kidneys)
• Hydronephrosis (swelling of the kidney due to urine backup)
• Recurrent urinary tract infections
• Structural abnormalities of the ureters or bladder
• In males, undescended testicles (cryptorchidism) or hypospadias

Many of these abnormalities are asymptomatic and only discovered during routine imaging studies. However, some may cause recurrent infections, pain, or impaired kidney function. Early ultrasound screening of the kidneys and urinary tract is recommended for all children diagnosed with DiGeorge syndrome to identify any abnormalities that may require monitoring or treatment.

10. Behavioral and Psychiatric Disorders

Individuals with DiGeorge syndrome have a significantly increased risk of developing behavioral, emotional, and psychiatric disorders, particularly as they grow older. These mental health challenges can substantially impact quality of life and require ongoing attention and support.

Psychiatric and behavioral symptoms include:

• Anxiety disorders: Generalized anxiety, social anxiety, and phobias are particularly common
• Attention deficit hyperactivity disorder (ADHD): Difficulties with attention, hyperactivity, and impulse control
• Autism spectrum disorder: Present in approximately 20-50% of individuals with DiGeorge syndrome
• Schizophrenia: Individuals with 22q11.2 deletion syndrome have a 25-30% risk of developing schizophrenia, particularly in adolescence or early adulthood
• Depression: Increased rates of depressive symptoms and major depressive disorder
• Obsessive-compulsive behaviors: Repetitive thoughts and behaviors

Early behavioral screening and mental health support are essential components of comprehensive care. Many individuals benefit from behavioral interventions, counseling, and in some cases, consultation with psychiatrists experienced in treating individuals with genetic syndromes.

11. Skeletal and Musculoskeletal Abnormalities

Bone and muscle-related symptoms are relatively common in DiGeorge syndrome, affecting posture, movement, and overall physical function. These abnormalities can range from minor variations to more significant structural problems.

Musculoskeletal manifestations include:

• Hypotonia (low muscle tone) in infancy and early childhood, causing floppiness and delayed motor milestones
• Scoliosis (curvature of the spine) or other spinal abnormalities
• Rib abnormalities or chest wall deformities
• Tapered or slender fingers and toes
• Joint hypermobility or laxity
• Short stature compared to family members
• Flat feet and other foot abnormalities
• Butterfly vertebrae or other vertebral malformations

The low muscle tone present in many infants can contribute to feeding difficulties, delayed motor development, and coordination problems. Physical therapy and occupational therapy can be beneficial in addressing these challenges. Skeletal abnormalities typically require monitoring and may need intervention if they progress or cause functional limitations.

12. Endocrine and Growth Problems

Hormonal and growth-related issues can affect individuals with DiGeorge syndrome, impacting their overall development, metabolism, and long-term health. These endocrine problems may not be apparent at birth but can emerge during childhood or adolescence.

Endocrine symptoms include:

• Growth hormone deficiency: Contributing to short stature and slower growth velocity
• Thyroid dysfunction: Both hypothyroidism and hyperthyroidism have been reported, though hypothyroidism is more common
• Hypoparathyroidism: Leading to the calcium imbalances discussed earlier
• Delayed puberty: Later onset of puberty compared to peers
• Autoimmune thyroid disease: Increased risk of conditions like Hashimoto’s thyroiditis or Graves’ disease

Regular monitoring of growth parameters and endocrine function is important for identifying these problems early. Growth charts specific to DiGeorge syndrome are available and can help distinguish between normal variation within the syndrome and true growth hormone deficiency. Thyroid function tests should be performed periodically, as thyroid problems can develop at any age.

What Causes DiGeorge Syndrome?

DiGeorge syndrome is caused by a deletion of genetic material from a specific region of chromosome 22, specifically at location 22q11.2. This chromosomal deletion results in the loss of approximately 30 to 40 genes, though not all of these genes’ functions are completely understood.

Genetic Mechanism: The deletion occurs during the formation of egg or sperm cells, or very early in fetal development. In most cases (approximately 90%), the deletion happens spontaneously with no family history of the condition. This is called a de novo (new) mutation. In the remaining 10% of cases, one parent carries the deletion and passes it to their child in an autosomal dominant pattern.

Risk Factors: In most cases, there are no identifiable risk factors, and the deletion occurs randomly. Parents of a child with a de novo deletion do not have an increased risk of having another child with the condition. However, if a parent carries the 22q11.2 deletion, there is a 50% chance with each pregnancy of passing the deletion to their child.

Critical Genes: Several genes within the deleted region are thought to be particularly important in causing the syndrome’s features. The TBX1 gene is considered one of the most critical genes, as it plays a vital role in the development of structures affected in DiGeorge syndrome, including the heart, face, and glands.

Developmental Impact: The deletion affects the development of structures that arise from the pharyngeal pouches during early embryonic development (around the third and fourth week of pregnancy). This explains why the syndrome affects multiple, seemingly unrelated body systems—they all originate from the same embryonic structures.

Frequently Asked Questions

Can DiGeorge syndrome be detected before birth?

Yes, DiGeorge syndrome can sometimes be detected during pregnancy through prenatal testing. Non-invasive prenatal testing (NIPT) may suggest the possibility of a 22q11.2 deletion, though it is not diagnostic. Definitive diagnosis requires amniocentesis or chorionic villus sampling (CVS) with chromosomal microarray analysis or fluorescence in situ hybridization (FISH) testing. Additionally, some features like heart defects may be visible on detailed prenatal ultrasounds, prompting further genetic testing.

Is DiGeorge syndrome the same as 22q11.2 deletion syndrome?

Yes, DiGeorge syndrome and 22q11.2 deletion syndrome are the same condition. The term “22q11.2 deletion syndrome” is increasingly preferred because it accurately describes the genetic cause. Other historical names for the same condition include velocardiofacial syndrome (VCFS) and conotruncal anomaly face syndrome (CTAFS). All these terms refer to disorders caused by deletion of the same chromosomal region.

Do all people with DiGeorge syndrome have the same symptoms?

No, DiGeorge syndrome is highly variable. Even within the same family, individuals with the same genetic deletion can have very different symptoms. Some people may have severe heart defects and significant intellectual disability, while others may have only mild learning difficulties and no major health problems. More than 180 different clinical features have been associated with the syndrome, and no single symptom is present in all affected individuals.

Will my child with DiGeorge syndrome be able to live independently as an adult?

Many individuals with DiGeorge syndrome can live independently or semi-independently as adults, though this varies greatly depending on the severity of their symptoms. Those with mild cognitive impairment and well-managed health problems often complete education, hold jobs, and live on their own. Others with more significant intellectual disabilities or complex medical needs may require ongoing support. Early intervention, appropriate therapies, and good medical management significantly improve long-term outcomes.

Is there a cure for DiGeorge syndrome?

There is currently no cure for DiGeorge syndrome, as it is a genetic condition present from conception. However, many of the symptoms and complications can be effectively managed with appropriate medical care. Treatment is tailored to each individual’s specific needs and may include surgery for heart defects or cleft palate, calcium and vitamin D supplementation for hypocalcemia, speech and developmental therapies, educational support, and monitoring for complications. With comprehensive care, many individuals with DiGeorge syndrome lead fulfilling lives.

Should siblings of a child with DiGeorge syndrome be tested?

Testing of siblings depends on whether the affected child has a de novo deletion or inherited the deletion from a parent. If genetic testing confirms that neither parent carries the deletion, siblings have a very low risk (close to the general population risk) and routine testing is not necessary. However, if one parent carries the deletion, each sibling has a 50% chance of also having the deletion and should be offered testing. A genetics counselor can help families understand their specific situation and testing recommendations.

Can people with DiGeorge syndrome have children?

Yes, many individuals with DiGeorge syndrome can have children, though fertility may be affected in some cases. It’s important to understand that if a person has DiGeorge syndrome, there is a 50% chance of passing the genetic deletion to each of their children. Genetic counseling is strongly recommended before pregnancy to discuss these risks, available prenatal testing options, and reproductive alternatives such as preimplantation genetic diagnosis (PGD) for those who wish to avoid passing the condition to their children.

How is DiGeorge syndrome diagnosed?

DiGeorge syndrome is diagnosed through genetic testing that identifies the deletion on chromosome 22. The most common tests are fluorescence in situ hybridization (FISH) or chromosomal microarray analysis (CMA). The diagnosis may be suspected based on clinical features such as heart defects, hypocalcemia, immune problems, or characteristic facial features, which then prompts genetic testing. Some cases are now identified through expanded newborn screening programs or prenatal testing.

What is the life expectancy of someone with DiGeorge syndrome?

Life expectancy for individuals with DiGeorge syndrome varies depending on the severity of symptoms, particularly heart defects and immune system problems. Those with severe heart defects that are not corrected may have reduced life expectancy, but with modern surgical techniques and medical management, many individuals survive well into adulthood. Those with mild symptoms and well-managed health issues can have a normal or near-normal life expectancy. Advances in medical care continue to improve outcomes for people with this condition.

References:

• Mayo Clinic – DiGeorge syndrome (22q11.2 deletion syndrome)
• National Heart, Lung, and Blood Institute – DiGeorge Syndrome
• National Human Genome Research Institute – 22q11.2 Deletion Syndrome
• National Organization for Rare Disorders (NORD) – DiGeorge Syndrome
• Children’s Hospital of Philadelphia – Chromosome 22q11.2 Deletion Syndrome
• MedlinePlus – 22q11.2 deletion syndrome