DiGeorge syndrome

Did You Know?

• The syndrome was originally classified under separate names including velocardiofacial syndrome, Shprintzen syndrome, Sedlackova syndrome, and conotruncal anomaly face syndrome.
• The International 22q11.2 Foundation advocates for the name 22q11.2 deletion syndrome through its 'Same Name Campaign'.

Signs and symptoms

The features of DiGeorge syndrome vary widely, even among family members, and affect many parts of the body. Common signs include congenital heart disease, palate defects (often velopharyngeal insufficiency), learning disabilities, mild facial differences, and recurrent infections due to T-cell immune problems from an absent or hypoplastic thymus. Newborns may present with heart defects or convulsions from hypocalcemia caused by malfunctioning parathyroid glands.

Other birth defects can include kidney abnormalities and feeding difficulties. Gastrointestinal issues, such as constipation from digestive motility problems, are common. Late-occurring features include hypothyroidism, hypoparathyroidism, thrombocytopenia, and psychiatric illnesses. The 22q11.2 deletion is associated with a 20- to 30-fold increased risk of schizophrenia; about 1% of schizophrenia patients have this deletion, compared to 0.025% in the general population.

The mnemonic CATCH-22 summarizes salient features: Cardiac abnormality, Abnormal facies, Thymic aplasia or hypoplasia, Cleft palate, and Hypocalcemia/hypoparathyroidism. The syndrome has incomplete penetrance, making early diagnosis difficult.

Genetics

DiGeorge syndrome is caused by a heterozygous deletion of part of the long arm of chromosome 22 at 22q11.2. About 80-90% of patients have a 3 Mb deletion, and 8% have a 1.5 Mb deletion, affecting approximately 30 to 50 genes. Rarely, similar features arise from deletions on the short arm of chromosome 10. The disorder follows autosomal dominant inheritance.

A French study of 749 people diagnosed between 1995 and 2013 found the mutation was inherited in 15% of patients, with 85.5% of those from the mother; other studies report inheritance rates of 6–10%. Most cases are de novo deletions, as the 22q11 region is prone to rearrangements during sperm or egg formation. The exact mechanism causing all features is unknown, but haploinsufficiency of the TBX1 gene is thought to produce some symptoms. Point mutations in TBX1 have also been observed.

TBX1 is a T-box transcription factor important in embryonic tissue and organ formation, and may regulate differentiation of neural crest cells, which form structures affected in the syndrome—skull bones, facial mesenchyme, heart outflow tract, thymus, and parathyroid stroma. Loss of FGF18 expression during pharyngeal arch development leads to neural crest cell death; TBX1 may regulate FGF18 expression. Mouse models with TBX1 deletion show defects similar to human symptoms, mainly affecting great artery and thymus development.

Diagnosis

Diagnosis of DiGeorge syndrome can be difficult due to variable symptoms and phenotypes. It is suspected in patients with one or more signs of the deletion, and confirmed by detecting a deletion at 22q11.2. Genetic analysis typically uses fluorescence in situ hybridization (FISH), which detects microdeletions missed by standard karyotyping. Newer methods include multiplex ligation-dependent probe amplification (MLPA) and quantitative polymerase chain reaction (qPCR), which can detect atypical deletions not found by FISH; qPCR is also faster, with a turnaround of 3 to 14 days.

A 2008 study found a high-definition MLPA probe as reliable as FISH for detecting normal deletions and able to detect smaller atypical deletions, potentially replacing FISH. BACs-on-Beads testing has successfully detected deletions prenatally. Array-comparative genomic hybridization (array-CGH) screens the entire genome for deletions or duplications and can be used post- and prenatally. Fewer than 5% of individuals with symptoms have normal cytogenetic studies and negative FISH; in these cases, atypical deletions are the cause. Some cases involve deletions on other chromosomes, notably 10p14.

Treatment

While there is no cure for DiGeorge syndrome, its various symptoms can be managed with standard treatments. The most important step is to identify each health issue early. For instance, immune system problems require special care with blood transfusions and live vaccines. A missing thymus in the rare complete form can be treated with a transplant. Antibiotics handle bacterial infections, and heart defects often need surgery. Lifelong calcium and vitamin D supplements are usually necessary for hypoparathyroidism. Specialty clinics, like the 22q Deletion Clinic at SickKids Hospital in Toronto, coordinate care from a team of specialists. For psychosis linked to the syndrome, the drug metirosine (methyltyrosine) is used off-label.