Chromosome 22q11 deletion syndrome

Introduction

Chromosome 22q11 deletion syndrome, sometimes called 22q11.2 deletion syndrome or DiGeorge syndrome in its classic form, is a genetic condition caused by the loss of a small piece of chromosome 22. It’s surprisingly common—occurring in about 1 in 3,000 to 1 in 6,000 births—but its impacts vary widely. Some folks only have mild heart or immune quirks, while others face learning delays, speech differences, or psychiatric concerns. In this article we’ll explore symptoms, underlying causes, diagnostic steps, treatment approaches, and what the long-term outlook looks like.

Definition and Classification

Chromosome 22q11 deletion syndrome refers to the absence (deletion) of a small segment on the long arm (q arm) of chromosome 22 at position 11.2. Medically, it’s classified as a microdeletion syndrome. Depending on the organs or systems affected, doctors sometimes group it under:

• DiGeorge syndrome – prominent cardiac defects and thymic hypoplasia leading to immune deficiency.
• Velocardiofacial syndrome (VCFS) – chiefly palate abnormalities, facial features, and learning challenges.
• Conotruncal Cardiac Anomalies Face (CATCH-22) – catchy acronym denoting Cardiac defects, Abnormal facies, Thymus hypoplasia, Cleft palate, Hypocalcemia, all linked to chromosome 22q11.

Organs involved include the heart, immune system (thymus), parathyroid glands, palate, and sometimes kidneys. Clinically relevant subtypes are based on which organ systems are most disrupted, but they all share the same underlying genetic loss.

Causes and Risk Factors

The root cause of 22q11 deletion syndrome is the spontaneous loss of about 1.5 to 3 million base pairs on chromosome 22. In about 90–95% of cases, this microdeletion occurs de novo – meaning neither parent carries it, it’s a new event in the child. Roughly 5–10% of cases are inherited from an affected parent.

Key risk factors and elements include:

• Genetic predisposition: If a parent has the deletion, each child has a 50% chance of inheriting it. Family history is the main non-modifiable risk.
• Environmental triggers: No specific environmental exposures (like toxins or infections) have been proven to cause the deletion itself. However, maternal health (e.g., uncontrolled diabetes) can worsen certain outcomes in a baby who already has the deletion, especially heart development.
• Age of parents: Unlike some chromosomal anomalies (like Down syndrome), advanced maternal age isn’t strongly linked to 22q11 deletions. Likewise, paternal age seems not to play a big role.
• Epigenetic factors: There’s ongoing research into whether certain epigenetic changes can influence severity, particularly in psychiatric manifestations.

While genetic causes are clear, the exact triggers for why the deletion happens during cell division are not fully understood. Researchers suspect that repetitive DNA sequences flanking the deleted region make it prone to misalign during meiosis, leading to the deletion. Distinguishing modifiable from non-modifiable risks is tricky here – you can’t modify a spontaneous chromosomal event, but good prenatal care may help optimize outcomes once a fetus is affected.

Pathophysiology (Mechanisms of Disease)

Biologically, the 22q11 deletion removes several genes important for normal development. Among the most studied are TBX1, COMT, and PRODH. TBX1 plays a crucial role in the development of the pharyngeal arches in early embryos—these structures give rise to the heart’s outflow tract, thymus, and parathyroid glands.

When TBX1 is missing or under-expressed:

• Cardiac neural crest cells fail to migrate properly, resulting in conotruncal heart defects (e.g., tetralogy of Fallot, interrupted aortic arch).
• Thymus formation is incomplete, impairing T-cell development and leading to immune deficiency.
• Parathyroid glands may be hypoplastic, causing hypocalcemia (low calcium levels) and associated muscle twitching or seizures.

Other genes in the deleted region influence neurological pathways. COMT regulates dopamine catabolism in the prefrontal cortex; its reduced activity correlates with higher risk of psychiatric issues (anxiety, ADHD, psychosis). PRODH affects proline metabolism, linked to cognitive function and seizure threshold.

In short, a missing chunk of DNA leads to a cascade where structural, immunological, endocrine, and neurochemical systems are disrupted in tandem, accounting for the syndrome’s multi-system presentation.

Symptoms and Clinical Presentation

Presentation is famously variable. Some infants are diagnosed in the newborn period for life-threatening heart defects; others may not come to medical attention until childhood speech delays become obvious. Here’s a broad overview:

• Cardiac issues: Conotruncal anomalies, such as tetralogy of Fallot, ventricular septal defects, truncus arteriosus. Roughly 75–80% of children have some heart defect.
• Immune dysfunction: Mild-to-moderate T cell deficiency; recurrent ear infections, pneumonia; rarely, severe immunodeficiency.
• Endocrine and metabolic: Hypocalcemia, especially in the neonatal period, presenting with jitteriness, seizures, or tetany; sometimes thyroid abnormalities.
• Craniofacial: A long face, hooded eyelids, small chin, ear anomalies; submucous cleft palate or overt clefts in ~70% of cases.
• Neurologic/developmental: Speech delays, motor coordination issues, mild global developmental delay in infancy; later, learning disabilities (often in math).
• Psychiatric: Elevated risk of anxiety disorders, ADHD in childhood; about 25–30% develop psychotic disorders like schizophrenia in adolescence or early adulthood.
• Renal and skeletal: Structural kidney anomalies in 30%; scoliosis or other bone issues occasionally.

Early signs in newborns often include feeding difficulties, low calcium symptoms, or noticeable heart murmurs. As children grow, parents may notice speech articulation problems (“you have a cleft palate speech”), behavioral patterns like social anxiety, or school struggles. Adults sometimes present for the first time with psychiatric symptoms or mild immune complaints, having never been recognized earlier.

Warning signs: Neonatal seizures from hypocalcemia, severe infections beyond routine childhood illnesses, or cyanotic spells due to heart defects warrant urgent evaluation.

Diagnosis and Medical Evaluation

Diagnosis usually starts with clinical suspicion based on characteristic findings—heart defects seen on fetal ultrasound, cleft palate, low calcium, or immune issues. Genetic confirmation requires specialized testing:

• Fluorescence in situ hybridization (FISH): Traditional method to spot the microdeletion.
• Chromosomal microarray analysis (CMA): High-resolution screen detecting submicroscopic deletions across all chromosomes, now the gold standard in many centers.
• MLPA (Multiplex Ligation-dependent Probe Amplification): Another technique confirming the precise breakpoints.

Additional workup includes:

• Echo-cardiography to define heart anatomy.
• Immunological assays – T cell subsets, immunoglobulin levels.
• Calcium and parathyroid hormone levels for endocrine assessment.
• Renal ultrasound if kidney anomalies are suspected.
• Neurodevelopmental evaluation – speech, motor skills, behavior screening.

Differential diagnoses might include other microdeletion/duplication syndromes like 10p13 deletion, Smith-Lemli-Opitz syndrome, or isolated DiGeorge-like presentations from TBX1 variants. But the combination of heart, palate, immune, and endocrine findings strongly points to 22q11 deletion syndrome.

Typically, a pediatric geneticist or genetic counselor coordinates testing and interprets results, collaborating with specialists as needed.

Which Doctor Should You See for Chromosome 22q11 Deletion Syndrome?

If you or your child is suspected of having 22q11 deletion syndrome, the first step is usually a referral to a clinical geneticist or genetic counselor, who’ll guide testing. But because this condition affects multiple systems, care often involves a multidisciplinary team:

• Cardiologist – for heart defects, surgical planning, and follow-up.
• Immunologist or allergist – to monitor immune function, manage infections, and advise on vaccines.
• Endocrinologist – for hypocalcemia, thyroid evaluation, and growth monitoring.
• Otolaryngologist/plastic surgeon – for cleft palate repair and speech-related issues.
• Speech therapist and developmental pediatrician – for early intervention and school support.

Which doctor to see first? After a pediatrician flags potential signs, telemedicine can help you get initial genetic counseling, interpret lab results, and clarify next steps—super convenient if you live far from a specialty center. But remember, nothing replaces in-person evaluations for physical exams, surgeries, or emergency interventions (e.g., severe hypocalcemia seizures or cyanotic spells). Online care is best for second opinions, follow-up questions, or genetic result explanations.

Treatment Options and Management

Treatment is tailored to each person’s mix of symptoms and severity. Here’s the broad approach:

• Cardiac: Surgical correction for septal defects or conotruncal anomalies—often during infancy. Lifelong cardiology follow-up is key.
• Immune support: Mild T-cell deficits may only need infection vigilance; severe cases sometimes require thymus transplant or immunoglobulin replacement.
• Endocrine: Acute hypocalcemia is managed with calcium and active vitamin D analogues; long-term monitoring of serum calcium and parathyroid function.
• Palate and speech: Early cleft repair plus speech therapy; hearing evaluations due to frequent ear infections.
• Developmental: Early intervention programs (OT, PT, speech), individualized education plans (IEPs), behavioral therapy for ADHD or anxiety as indicated.
• Psychiatric: Evidence-based medications (SSRIs, stimulants, antipsychotics) plus psychotherapy for mood, anxiety, or psychosis. COMT status might influence drug choice in the future.

Lifestyle measures such as a balanced diet (to support calcium levels), regular immunizations, and protective infection protocols (hand hygiene, avoiding live vaccines if severe immune compromise) help reduce complications. Every therapy has pros/cons: surgeries carry risk, immunoglobulin infusions can be time-consuming, and psychotropic meds need close monitoring, so shared decision-making is vital.

Prognosis and Possible Complications

Long-term outlook depends on the severity of heart and immune involvement, plus early intervention for development and learning. Many children with mild-to-moderate presentations grow into independent adults with good quality of life. Factors influencing prognosis include:

• Complexity of cardiac defects—uncorrected severe anomalies raise mortality risk in infancy.
• Degree of immune dysfunction—recurrent severe infections can be life-threatening.
• Cognitive and psychiatric issues—untreated psychiatric illness worsens functional outcomes.
• Access to multidisciplinary care—early intervention, educational support, and specialist follow-up improve success.

Untreated complications may include chronic lung disease from recurrent infections, developmental delays that limit independence, persistent hypocalcemia causing seizures, or psychiatric crises in adolescence. Yet with modern, coordinated care, many live well into adulthood, holding jobs, relationships, and families of their own. Regular surveillance for cardiac, endocrine, and psychiatric issues remains essential.

Prevention and Risk Reduction

Because 22q11 deletion syndrome stems from a structural chromosomal change, primary prevention (i.e., preventing occurrence) isn’t feasible currently. However, risk reduction and early detection strategies include:

• Prenatal screening: Noninvasive prenatal testing (NIPT) can flag 22q11 deletions, prompting confirmatory amniocentesis or CVS and early care planning.
• Genetic counseling: Parents with a known deletion can discuss family planning, prenatal options, and recurrence risk (50% if parent is affected).
• Fetal echocardiography: In pregnancies at risk, a detailed fetal echo at 18–22 weeks can identify heart defects early, allowing neonatal NICU planning.
• Newborn screening: While no universal screen for 22q11 exists yet, heightened awareness of hypocalcemia seizures or immune deficiencies in newborns can hasten testing.
• Vaccination planning: Immunization schedules adapted to immune status reduce severe infections.

Although we can’t stop the deletion from happening, early recognition and proactive management blunt many complications, ensuring better developmental, cardiac, and psychiatric trajectories.

Myths and Realities

There’s a lot of confusion around 22q11 deletion syndrome. Let’s debunk some myths:

• Myth: “It’s extremely rare; I’ll probably never see it.”
  Reality: With prevalence around 1:3,000, even general pediatricians encounter cases occasionally.
• Myth: “All kids have severe heart problems requiring multiple surgeries.”
  Reality: Cardiac defects affect ~75%, but some are mild and need only observation or minor repair.
• Myth: “If speech is clear by age 5, there’s no learning or psychiatric risk.”
  Reality: Learning disabilities or psychiatric issues (anxiety, ADHD, psychosis) can emerge later, even in verbally fluent individuals.
• Myth: “It always causes intellectual disability.”
  Reality: IQ ranges widely; many have average intelligence but specific learning challenges in math, executive function, or social skills.
• Myth: “Once you’ve repaired the heart, that’s it.”
  Reality: Lifelong surveillance—cardiac, immune, endocrine, psychiatric—is crucial, as issues can arise or evolve.

By understanding evidence-based facts rather than popular misconceptions, families and clinicians can tailor realistic expectations and support strategies.

Conclusion

Chromosome 22q11 deletion syndrome is a multi-system genetic condition with a wide spectrum—from mild cardiac or immune quirks to significant developmental and psychiatric challenges. Accurate diagnosis via chromosomal microarray, early multidisciplinary interventions, and lifelong surveillance form the cornerstone of care. While there’s no cure for the underlying deletion, evidence-based treatments—surgical, medical, therapeutic—greatly improve outcomes. If you suspect 22q11 deletion syndrome, seek evaluation by genetics specialists and work closely with cardiology, immunology, endocrinology, and developmental teams. With timely intervention and coordinated support, many individuals lead fulfilling, productive lives.

Frequently Asked Questions (FAQ)

1. What is Chromosome 22q11 deletion syndrome?

A genetic disorder caused by the loss of a small segment on chromosome 22, affecting heart, immune, endocrine, and neurodevelopment.

2. How common is 22q11 deletion syndrome?

It occurs in approximately 1 in 3,000 to 1 in 6,000 births, making it one of the more frequent microdeletion syndromes.

3. What are the first signs in newborns?

Common initial signs include heart murmurs, low calcium seizures, feeding issues, or recurrent infections.

4. How is the condition diagnosed?

Diagnostic tests include chromosomal microarray analysis (CMA), FISH, or MLPA to confirm the microdeletion.

5. Which specialists manage 22q11 deletion syndrome?

Care is multidisciplinary: geneticists, cardiologists, immunologists, endocrinologists, ENT surgeons, speech therapists, and mental health professionals.

6. Can parents pass it to their children?

Yes—if a parent carries the deletion, there’s a 50% chance of transmission to each child; most cases, however, are new mutations.

7. What treatment options exist?

Treatments include cardiac surgery, calcium supplementation, immunoglobulin or thymus transplant if needed, palate repair, therapies for speech and development, and psychiatric care.

8. Is there a cure?

There is no cure for the deletion itself, but targeted interventions can manage and mitigate symptoms effectively.

9. What is the long-term outlook?

Prognosis depends on severity. Many lead independent, fulfilling lives with appropriate medical and developmental support.

10. Can adults be diagnosed later?

Yes—some adults only get diagnosed when they face psychiatric issues, mild immune problems, or have a child with the syndrome.

11. Are there support groups available?

Yes—organizations like the International 22q11.2 Foundation offer resources, local chapters, and online communities.

12. Do all affected individuals have intellectual disability?

No—IQ varies widely. Many have average intelligence but specific learning or social challenges.

13. Should siblings be tested?

If one child has a confirmed deletion, siblings may be offered genetic testing in case they are asymptomatic carriers.

14. How can telemedicine help?

Online genetic counseling, result interpretation, care coordination, and mental health follow-up can complement in-person visits.

15. When should I seek emergency care?

Urgent care is needed for neonatal seizures, severe hypocalcemia, life-threatening infections, or acute cardiac decompensation.