OVERVIEW

What is DiGeorge Syndrome?

In 1965, Dr. Angelo DiGeorge reported a group of congenital disorders characterized by the absence of the thymus and thyroid glands, naming it DiGeorge Syndrome (DGS).

The classic triad of DGS includes conotruncal heart defects, thymic hypoplasia, and hypocalcemia, with varying severity. Treatment requires a multidisciplinary approach, including correcting hypocalcemia, repairing heart and other organ abnormalities, thymus transplantation, and hematopoietic stem cell transplantation.

What are the types of DiGeorge Syndrome?

In the 1980s, studies found that most DGS patients and those with similar syndromes, such as velocardiofacial syndrome (VCFS), had heterozygous deletions in chromosome 22q11.2 (DGS locus 1). Thus, DGS can be divided into two main categories:

• DGS with chromosome 22q11.2 deletion: Accounts for the majority of cases, with specific manifestations related to genes like TBX1.
• DGS without chromosome 22q11.2 deletion: A minority of cases.

In addition to chromosome 22q11.2, 2%–5% of patients have heterozygous deletions in chromosome 10p13-14 (DGS locus 2), often presenting with sensorineural hearing loss.

Some patients show no chromosomal abnormalities but instead have isolated mutations in genes like TBX1.

Is DiGeorge Syndrome common?

A U.S. study found that 1 in 5,950 live births had a chromosome 22q11.2 deletion. Two other studies reported incidences of 1 in 4,000 and 1 in 1,000 live births, respectively.

However, these figures may not fully represent DGS prevalence, as some fetuses with chromosome 22q11.2 deletions are lost to spontaneous miscarriage.

Research in low-risk pregnancies suggests a rate of 1 in 400 fetuses with chromosome 22q11.2 deletions.

SYMPTOMS

What symptoms does DiGeorge syndrome cause?

The classic "triad" of DGS manifests as:

• Cardiac conotruncal anomalies;
• Thymic hypoplasia;
• Hypocalcemia due to parathyroid abnormalities.

Symptoms vary significantly among DGS patients, even within the same family.

What cardiac abnormalities does DiGeorge syndrome cause?

• Interrupted aortic arch: Presents with "differential cyanosis," where the upper body appears pink while the lower body is blue;
• Persistent truncus arteriosus: May cause neonatal cyanosis due to hypoxia;
• Tetralogy of Fallot: May cause neonatal cyanosis;
• Atrial septal defect (ASD);
• Ventricular septal defect (VSD);
• Vascular ring: Severe cases may lead to critical airway obstruction, stridor, or feeding difficulties;
• Congenital coronary anomalies.

How does hypocalcemia present in DiGeorge syndrome?

Hypocalcemia results from parathyroid hypoplasia and can be life-threatening. It occurs in 60% of neonates with DiGeorge syndrome, manifesting as tremors, tetany, seizures, low serum calcium, elevated serum phosphorus, and extremely low parathyroid hormone levels.

After the neonatal period, hypocalcemia becomes rare, likely due to compensatory hyperplasia of parathyroid tissue. However, severe stress (e.g., infections, major surgery, burns, or extreme psychological stress) can trigger it. Some undiagnosed DGS patients may present with hypocalcemia in adulthood.

How does thymic hypoplasia present in DiGeorge syndrome?

Some DGS patients lack a thymus entirely, while others have a reduced thymus size. Both conditions cause immunodeficiency, though severity varies.

DGS is classified based on thymic hypoplasia severity:

• Complete DGS

Complete DGS is a severe combined immunodeficiency (SCID) and can be fatal. Patients have T-cell counts >3 standard deviations below normal for their age, with naive CD3+ T-cells typically <50/mm³. Affected infants may present with recurrent severe infections, chronic diarrhea, and failure to thrive.

Among DGS patients with 22q11.2 deletion, <1% have complete DGS. About 48% of complete DGS cases show no chromosomal abnormalities, possibly linked to TBX1 gene mutations.

• Atypical complete DGS

These patients lack a thymus and exhibit lymphadenopathy and eczematous dermatitis but have detectable oligoclonal T-cell populations, resulting in higher T-cell counts than typical complete DGS. Symptoms include erythroderma, T-cell oligoclonal expansion, lymphadenopathy, and elevated IgE.

• Partial DGS

75% of DGS cases with 22q11.2 deletion involve thymic insufficiency rather than complete absence. These patients have mild immunodeficiency, not SCID, and rarely suffer life-threatening infections. Features include IgA deficiency and impaired antibody function (e.g., polysaccharide antibody deficiency).

Many partial DGS patients have recurrent sinopulmonary infections, such as bronchitis, pneumonia, sinusitis, or otitis media.

What autoimmune/atopic manifestations occur in DiGeorge syndrome?

Patients are prone to autoimmune hemolytic anemia (AIHA), autoimmune cytopenias, arthritis, inflammatory bowel disease, autoimmune thyroid disorders, eczema, and asthma. Interestingly, allergic rhinitis incidence is not increased—the reason remains unclear.

What craniofacial anomalies are common in DiGeorge syndrome?

These anomalies are not unique to DGS and occur in other 22q11.2 deletion disorders. Features include low-set posteriorly rotated ears, hypertelorism, bulbous nasal tip, overt or submucosal cleft palate, and velopharyngeal insufficiency causing hypernasal speech and nasal regurgitation. Facial features may become less prominent with age.

What developmental and behavioral issues does DiGeorge syndrome cause?

Most patients exhibit developmental delays, especially in language. Moderate intellectual disability may occur, though some have normal cognition. Emotional dysregulation, behavioral inhibition deficits, attention disorders, and psychiatric conditions (e.g., schizophrenia, major depression) are also reported.

CAUSES

What is the cause of DiGeorge Syndrome (DGS)?

DGS results from abnormal development of the embryonic pharyngeal system, leading to disruptions in the formation and morphogenesis of the thymus, thyroid, parathyroid glands, maxilla, mandible, aortic arch, cardiac outflow tract, and external/middle ear.

The abnormal development of the embryonic pharyngeal system is associated with chromosomal abnormalities or gene mutations in the affected fetus:

• Most DGS patients have a heterozygous deletion of chromosome 22q11.2 (DGS locus 1);
• 2%–5% of DGS patients exhibit a heterozygous deletion of chromosome 10p13-14 (DGS locus 2);
• A small subset of DGS patients show no chromosomal deletions but have isolated gene mutations, such as in TBX1.

Is DiGeorge Syndrome (DGS) hereditary?

Yes.

Most cases of DGS are caused by a deletion of chromosome 22q11.2, which follows an autosomal dominant inheritance pattern. If a parent carries the 22q11.2 deletion, the child has a 50% risk of inheriting it.

However, in clinical cases, 90% of 22q11.2 deletions are not inherited from parents but occur de novo during fetal development.

DIAGNOSIS

What conditions must be met for a definitive diagnosis of DiGeorge syndrome?

• Reduced CD3+ T-cell count to <500/mm³ (mandatory condition);
• Conotruncal cardiac defects (truncus arteriosus, tetralogy of Fallot, interrupted aortic arch, or aberrant right subclavian artery);
• Hypocalcemia lasting more than three weeks requiring treatment;
• Detection of a 22q11.2 chromosomal deletion.

In addition to the mandatory condition, at least two of the other three conditions must be met to confirm a diagnosis of DiGeorge syndrome.

What conditions must be met for a preliminary diagnosis of DiGeorge syndrome?

• Reduced CD3+ T-cell count to <1,500/mm³;
• 22q11.2 chromosomal deletion.

Meeting both of these conditions allows for a presumptive diagnosis of DiGeorge syndrome.

What conditions must be met for a suspected diagnosis of DiGeorge syndrome?

• Reduced CD3+ T-cell count to <1,500/mm³ (mandatory);
• Cardiac malformations;
• Hypocalcemia lasting more than three weeks requiring treatment;
• Craniofacial anomalies/palate-related issues.

In addition to the mandatory condition, at least one of the other conditions must be met for a suspected diagnosis of DiGeorge syndrome.

TREATMENT

Which department should DiGeorge syndrome (DGS) patients consult?

The treatment of DGS requires multidisciplinary collaboration, including otolaryngology, plastic surgery, oral and maxillofacial surgery, immunology, cardiac surgery, neurology, psychiatry, and endocrinology. It also involves speech pathologists, genetic specialists, and ideally social workers and nutritionists.

How is DiGeorge syndrome (DGS) treated?

Treatment strategies vary depending on the disease stage. Below are the approaches for "acute infant treatment" and "long-term follow-up treatment."

How is acute DiGeorge syndrome (DGS) treated in infants?

For newborns meeting the suspected diagnosis criteria, the following issues should be prioritized for identification and treatment:

• Hypocalcemia
• Congenital heart abnormalities
  • Severe congenital heart defects such as interrupted aortic arch or tetralogy of Fallot may require emergency corrective surgery, necessitating intervention by cardiologists and cardiac surgeons.
  • For infants with feeding and swallowing difficulties, slow weight gain, or frequent reflux and aspiration, careful evaluation for palatal and gastrointestinal defects is needed, requiring specialist involvement. Multidisciplinary collaboration is crucial in such cases.
• Severe immunodeficiency
  • Complete DGS must be identified, as it is a severe combined immunodeficiency requiring protective isolation to prevent life-threatening infections. For example, newborns needing blood transfusions for heart surgery should receive leukocyte-depleted, cytomegalovirus-negative, and irradiated blood products rather than standard ones.
  • In addition to protective isolation, complete DGS infants require intravenous immunoglobulin and prophylactic antibiotic therapy.
  • Thymus or hematopoietic stem cell transplantation is then performed, as untreated infants rarely survive beyond one year.

Why is thymus or hematopoietic stem cell transplantation necessary for DiGeorge syndrome?

Complete DiGeorge syndrome patients have T-cell immunodeficiency, making thymus transplantation the optimal treatment to correct immune dysfunction. If thymus transplantation is unavailable, hematopoietic stem cell transplantation with memory T-cell retention (i.e., without donor T-cell depletion) can be an alternative.

Partial DiGeorge syndrome patients, despite having humoral and cellular immune deficiencies, usually do not require hematopoietic stem cell or thymus transplantation.

What are the long-term treatments for DiGeorge syndrome?

After correcting hypocalcemia and heart defects, the following aspects should be monitored and treated as needed:

• Hearing assessment, especially for those with 10p13-14 heterozygous deletions;
• Language ability evaluation;
• Monitoring thyroid and growth hormones;
• Assessing learning, developmental, and behavioral disorders;
• Identifying schizophrenia, schizoaffective disorder, or major depression;
• Checking for palatal defects;
• Evaluating immune function (T-cell and humoral immunity) every 6–12 months.

DIET & LIFESTYLE

Can patients with DiGeorge syndrome (DGS) receive vaccinations?

DGS patients have T-cell abnormalities. It was once believed that live vaccines were contraindicated for such patients, but this view has been increasingly questioned. After all, T-cell dysfunction varies in severity. Based on this, an immunology specialist should be consulted to determine vaccination suitability.

Due to humoral immune deficiencies in DGS patients, the protective antibodies they produce after vaccination may not last as long as in healthy individuals. Therefore, they often require more frequent vaccinations to reduce infection risks.

What dietary and lifestyle precautions should DiGeorge syndrome patients take?

Maintain hygiene to minimize infection risks. Early feeding may involve issues like food reflux and aspiration, so expert guidance should be sought.

PREVENTION

Can DiGeorge Syndrome (DGS) Be Prevented? How to Prevent It?

It is difficult to prevent.

Currently, there are no feasible prenatal genetic tests for the fetus. Prenatal examinations such as fetal cardiac ultrasound can help doctors screen for fetal heart abnormalities to some extent, indirectly suggesting DGS, but they cannot detect all DGS cases.

After identifying a child with DGS, genetic testing can be performed on the parents. If either parent carries the same chromosomal or genetic mutation, there is a 50% risk of future children inheriting the condition. Parents can weigh the pros and cons before deciding whether to have another child. During pregnancy, close monitoring is recommended, and termination may be considered if necessary.