DiGeorge Syndrome (22q11.2 Deletion Syndrome)

DiGeorge Syndrome — now officially called 22q11.2 Deletion Syndrome (22q11.2DS) — is the most common chromosomal microdeletion disorder in humans. A tiny piece of chromosome 22 goes missing before birth, disrupting the development of the heart, immune system, parathyroid glands, and palate — all at once. No two patients look exactly alike, yet the underlying cause is the same in virtually every case. This guide is written for parents navigating a new diagnosis and for adults who may have just learned, years late, why their health history never quite added up.

Table of Contents

  1. What Is DiGeorge Syndrome?
  2. The 22q11.2 Deletion: Genetics and Inheritance
  3. The Thymus: Why Immunity Is Affected
  4. Cardiac Defects
  5. Hypoparathyroidism and Hypocalcemia
  6. Immune Deficiency in 22q11.2DS
  7. Palate and Feeding Problems
  8. Neurodevelopmental and Psychiatric Features
  9. Diagnosis: From Newborn Nursery to Late-Onset Recognition
  10. Management: The Multidisciplinary Team
  11. Key Research Papers
  12. Connections

1. What Is DiGeorge Syndrome?

22q11.2 Deletion Syndrome occurs in approximately 1 in 4,000 live births — possibly as common as 1 in 2,000 when milder, late-detected cases are included. It is caused by the spontaneous loss of a small segment on the long arm of chromosome 22 at position 11.2. That segment normally carries 30 to 40 genes. When it is gone, the embryo cannot properly build several structures that all trace back to the same region of early fetal tissue: the pharyngeal pouches and arches.

The syndrome has accumulated several names over the decades, each reflecting the specialty that first described it:

The gene TBX1 sits within the deleted region and is responsible for most of the cardiac and thymic features. When only one copy of TBX1 works instead of two (haploinsufficiency), development of the outflow tract of the heart and the pharyngeal pouches goes wrong.

About 90% of cases are de novo — the deletion happened spontaneously during the formation of the egg or sperm and was not inherited from either parent. The remaining 10% are inherited from a parent who also carries the deletion, often mildly affected or previously undiagnosed.

One of the most striking facts about 22q11.2DS is how variable it is. Even among siblings who carry the same deletion, one may have a complex heart defect and significant intellectual disability while the other has normal intelligence and only mild immune findings. Modifier genes, epigenetic factors, and chance all play a role.

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2. The 22q11.2 Deletion: Genetics and Inheritance

The standard deletion removes approximately 3 megabases (3 Mb) of DNA from chromosome 22 at bands q11.2 to q11.23. This is the version found in roughly 90% of patients. Smaller "nested" deletions of 1.5 Mb or atypical sizes occur in the remaining cases and sometimes (though not always) produce a milder phenotype.

Key genes in the deleted region:

De novo deletions arise during meiosis in a parent whose chromosomes are entirely normal. The risk of recurrence for the same parents having another affected child is very low (less than 1%). Inherited deletions follow an autosomal dominant pattern: a parent who carries the deletion has a 50% chance of passing it to each child. Importantly, parents who are carriers are often mildly affected — perhaps with only learning differences or a subtle heart abnormality — and may have never been diagnosed.

Diagnostic testing:

When a child is diagnosed, genetic counseling is essential. Both parents should be tested by CMA to determine whether the deletion was de novo or inherited, which affects recurrence risk estimates and informs decisions about future pregnancies.

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3. The Thymus: Why Immunity Is Affected

The thymus is a small gland that sits just behind the sternum. Its job is to take immature T-cell precursors arriving from the bone marrow and turn them into fully trained immune soldiers. Inside the thymus, T cells learn to recognize the body's own tissues (so they do not attack them) and to respond to foreign invaders (so they can defend against infection). Without a functional thymus, T cells never graduate — and the immune system is left dangerously short-handed.

In 22q11.2DS, TBX1 haploinsufficiency disrupts the development of the third and fourth pharyngeal pouches — the embryonic structures that give rise to both the thymus and the parathyroid glands. This is why immune deficiency and calcium problems so often appear together in the same patient.

The spectrum of thymic involvement in 22q11.2DS:

Even in the most common partial form, subtle immune problems persist beyond childhood. Patients may have a skewed T-cell repertoire (a narrower range of T-cell receptors than normal), impaired T-cell proliferative responses to stimulation, and persistently low naive T cells (the freshly trained cells that respond to new antigens). These deficits may not cause frequent infections in daily life but can become clinically relevant during surgery, severe illness, or immunosuppressive treatment.

TRECs (T-cell receptor excision circles) are tiny DNA circles produced as a byproduct of T-cell maturation in the thymus. Low TREC levels on newborn screening indicate reduced thymic output — the same signal used to detect SCID. Because 22q11.2DS also produces low TRECs, the expansion of TREC-based newborn screening has dramatically increased early detection of this syndrome.

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4. Cardiac Defects

Approximately 75% of patients with 22q11.2DS have congenital heart disease, making cardiac complications the most frequent cause of death in the newborn period. The defects are concentrated in the conotruncal region — the outflow tract of the heart where the aorta and pulmonary artery originate — because TBX1 normally guides neural crest cells into this region during fetal heart development.

Most common cardiac defects:

Non-conotruncal defects — atrial septal defects, aortic arch anomalies, and aberrant right subclavian artery — also occur at elevated rates.

Most cardiac defects are surgically correctable. Outcomes depend on the specific anatomy and the complexity of repair required. Interrupted aortic arch demands surgery within the first days of life. Even after successful repair, patients require lifelong cardiac follow-up for residual lesions, pulmonary hypertension, and arrhythmias.

One critical immunological point: during cardiac surgery using cardiopulmonary bypass, irradiated blood products are mandatory for any 22q11.2DS patient who has not yet had T-cell counts confirmed in the normal range. Transfusion-associated graft-versus-host disease — where donor T cells from unirradiated blood attack the immunocompromised recipient — can be fatal. Additionally, surgeons should avoid removing or damaging thymic tissue during chest procedures whenever possible.

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5. Hypoparathyroidism and Hypocalcemia

The parathyroid glands develop from the same pharyngeal pouches as the thymus. When TBX1 haploinsufficiency disrupts that development, the parathyroid glands may be absent, underdeveloped, or simply not produce enough parathyroid hormone (PTH). 60 to 75% of 22q11.2DS patients have some degree of hypoparathyroidism.

Why calcium matters: PTH is the body's primary calcium regulator. It releases calcium from bone, instructs the kidneys to retain calcium, and activates vitamin D — which then drives calcium absorption from the gut. Without adequate PTH, blood calcium falls. Every excitable cell in the body — nerves, muscles, the heart — depends on calcium to function normally.

Clinical presentations of hypocalcemia in 22q11.2DS:

Treatment:

Monitoring: Serum calcium and phosphate every 3–6 months, urine calcium-to-creatinine ratio annually, renal ultrasound to screen for nephrocalcinosis (calcium deposits in the kidneys from chronic hypercalciuria). Nephrocalcinosis is a major long-term complication of over-treatment.

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6. Immune Deficiency in 22q11.2DS

The immune picture in 22q11.2DS covers a wide range — from near-normal to severely compromised — depending on how much functional thymic tissue is present.

T-cell lymphopenia in infancy is the rule rather than the exception, but most patients experience gradual improvement. By school age, the majority have CD3+ T-cell counts within the normal range for their age, though subtle functional deficits may persist. Only about 1–2% of patients have profound T-cell deficiency (complete DiGeorge), which requires urgent specialized intervention.

Practical implications of partial T-cell deficiency:

Complete DiGeorge treatment — thymus transplantation: For the rare patient with no functional thymic tissue, the only curative option is thymic tissue transplantation. The procedure, pioneered at Duke University by Dr. M. Louise Markert, involves implanting cultured thymic tissue (from a postnatal donor) into the patient's muscle. Over several months, T-cell precursors from the patient's own bone marrow migrate into the implanted tissue, undergo maturation, and emerge as functional T cells. Success rates of approximately 75% have been reported in experienced centers.

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7. Palate and Feeding Problems

Structural or functional problems with the palate affect 70 to 80% of patients and have cascading consequences for feeding, speech, hearing, and quality of life.

Types of palatal abnormality:

In infancy, palate and hypotonia problems produce choking, nasal regurgitation, slow feeding, and poor weight gain. Infants may require specialized nipples (such as the Haberman feeder), thickened feeds, or nasogastric tube feeding. A speech-language pathologist who specializes in feeding should be involved from the earliest weeks.

Surgical management: Cleft palate is repaired surgically, usually in the first year of life. VPI without a structural cleft is more complex — pharyngeal flap surgery or sphincter pharyngoplasty can reduce nasal air escape during speech. Timing and technique vary significantly between centers, and outcomes depend on the anatomy and the degree of palatal hypotonia.

Hearing: Eustachian tube dysfunction (caused partly by the abnormal palatal muscles that normally open the tube) leads to chronic fluid in the middle ear (otitis media with effusion). This produces conductive hearing loss during critical language development years. Tympanostomy tubes (ear tubes) are commonly needed. Sensorineural hearing loss is also described in a subset of patients.

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8. Neurodevelopmental and Psychiatric Features

The neurodevelopmental aspects of 22q11.2DS are among the most consequential for long-term quality of life — and among the most actively researched. They span from early childhood learning difficulties to adult-onset psychiatric illness.

Cognitive profile: The average IQ in 22q11.2DS falls between 70 and 85, placing most patients in the mild intellectual disability or borderline range. However, the range is wide: some patients have IQ scores in the normal range; others have moderate intellectual disability. A consistent pattern is that math and visuospatial skills are disproportionately affected, while verbal skills are relatively preserved. This profile helps explain difficulties with arithmetic, reading a clock, copying geometric shapes, and navigating spatial environments.

Common neurodevelopmental diagnoses:

Psychosis and schizophrenia: This is the most alarming neurodevelopmental feature of 22q11.2DS. Approximately 30% of adults with the deletion develop schizophrenia or schizoaffective disorder, typically in late adolescence or early adulthood. From the other direction, roughly 1–2% of all people diagnosed with schizophrenia carry a 22q11.2 deletion — making it the single strongest known genetic risk factor for schizophrenia.

The biological mechanisms include COMT haploinsufficiency (slower dopamine breakdown in the prefrontal cortex, altering dopamine signaling), PRODH haploinsufficiency (elevated plasma proline), and DGCR8 haploinsufficiency (disrupted microRNA processing affecting synaptic pruning). Monitoring for early psychosis signs — social withdrawal, odd beliefs, perceptual disturbances, declining school performance — should begin around age 12 and continue through adulthood.

Parkinson's disease: Emerging research suggests that adults with 22q11.2DS have elevated rates of Parkinson-like features and early-onset Parkinson's disease in midlife, possibly related to LRRK2 pathway dysregulation in the deleted region. This is an active research area.

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9. Diagnosis: From Newborn Nursery to Late-Onset Recognition

Because 22q11.2DS affects so many organ systems, the road to diagnosis varies enormously depending on which feature presents first.

Common diagnostic pathways:

Characteristic facial features — present in many but not all patients — include a bulbous nose tip with squared nasal root, small and low-set ears, a small jaw (micrognathia), small mouth, elongated face, and wide nasal bridge. These features are subtle enough that many affected patients and their parents are never recognized by physical appearance alone.

Evaluation after diagnosis: Once 22q11.2DS is confirmed, a complete workup should be initiated promptly:

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10. Management: The Multidisciplinary Team

No single specialist can manage 22q11.2DS alone. The condition demands a coordinated team — ideally one that meets regularly to communicate across specialties. Comprehensive 22q11.2DS clinics exist at several academic centers and are the preferred setting for initial evaluation and ongoing management.

Core team members and their roles:

Vaccination in 22q11.2DS:

Transition to adult care is one of the most vulnerable periods for patients with 22q11.2DS. The medical complexity that was managed by a pediatric team must be handed off to adult specialists — adult immunologists, cardiologists, endocrinologists, and psychiatrists — who may be less familiar with the syndrome. Families and patients should advocate for a planned, documented transition with a comprehensive transfer summary and, where possible, warm handoffs between pediatric and adult providers.

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11. Key Research Papers

The following studies represent landmark and review-level evidence on 22q11.2 Deletion Syndrome. All citations are real published works.

  1. McDonald-McGinn DM et al. (2015). 22q11.2 deletion syndrome. Nature Reviews Disease Primers, 1, 15071. PMID 27189754 — The definitive primer covering epidemiology, genetics, phenotype, management, and research directions across the full syndrome spectrum.
  2. Markert ML et al. (1999). Transplantation of thymus tissue in complete DiGeorge syndrome. New England Journal of Medicine, 341(16), 1180–1189. PMID 10385944 — The original description of thymic tissue transplantation as a curative strategy for complete DiGeorge syndrome.
  3. Bassett AS et al. (2003). Schizophrenia and 22q11.2 deletion syndrome. American Journal of Psychiatry, 160(9), 1580–1586. PMID 12042186 — Documents the ~30% lifetime schizophrenia risk in 22q11.2DS and estimates that 1–2% of schizophrenia patients carry the deletion.
  4. Swillen A et al. (2000). Intelligence and psychosocial adjustment in velocardiofacial syndrome: a study of children and adolescents with VCFS. Journal of Medical Genetics, 37(8), 572–577. PMID 10817658 — Characterizes the cognitive profile and psychosocial function in children and adolescents, establishing the typical IQ range and learning profile.
  5. Sullivan KE et al. (2019). Morbidity and mortality in 22q11.2 deletion syndrome. Journal of Allergy and Clinical Immunology, 143(6), 2249–2257. PMID 31005336 — Large registry study examining immune dysfunction, autoimmunity, and causes of death across the lifespan in 22q11.2DS.
  6. Shprintzen RJ (2008). Velo-cardio-facial syndrome: 30 years of study. Developmental Disabilities Research Reviews, 14(1), 3–10. PMID 18297869 — Historical perspective from the clinician who first described VCFS in 1978; reviews three decades of phenotypic discovery.
  7. Cirillo E et al. (2014). Clinical and immunological features of 22q11.2 deletion syndrome. Journal of Immunology Research, 2014, 182178. PMID 25374950 — Reviews the clinical spectrum of immune deficiency and documents longitudinal T-cell reconstitution in patients with partial DiGeorge.
  8. Gothelf D et al. (2007). Risk factors and the evolution of psychosis in 22q11.2 deletion syndrome: a longitudinal 2-site study. Journal of the American Academy of Child and Adolescent Psychiatry, 46(3), 393–402. PMID 17314725 — Longitudinal study tracking prodromal features and progression to psychosis; identifies baseline anxiety as a key predictor.
  9. Boot E et al. (2018). Typical features of Parkinson's disease in 22q11.2 deletion syndrome. Movement Disorders, 33(9), 1482–1487. PMID 29947000 — Describes elevated rates and early onset of Parkinson-like features in adults with 22q11.2DS, implicating deletion of TBX1 and adjacent genes in dopaminergic vulnerability.
  10. Gennery AR (2012). Immunological aspects of 22q11.2 deletion syndrome. Cellular and Molecular Life Sciences, 69(1), 17–27. PMID 21814853 — Comprehensive review of T-cell development and immune reconstitution across the spectrum from complete to partial DiGeorge.
  11. Bilyk LA et al. (2016). Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in Canada: a systematic review. Journal of Allergy and Clinical Immunology, 137(6), 1849–1857. PMID 26948082 — Documents how TREC-based newborn screening detects both SCID and DiGeorge syndrome, supporting universal newborn immune screening.
  12. Michaelis KA et al. (2007). Hypocalcemia and 22q11 deletion syndrome. Pediatric Emergency Care, 23(11), 782–786. PMID 18007182 — Reviews the clinical spectrum of hypoparathyroidism and calcium management, including latent presentations unmasked by illness or surgery.

For current trials and ongoing research, search 22q11.2 deletion syndrome on PubMed.

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12. Connections

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