Introduction

DiGeorge first recognised this congenital syndrome in 1965. He described congenital heart malformations, hypoparathyroidism and absent thymus. A wider phenotype is recognised today including congenital heart defects, abnormal facies, hypoparathyroidism with hypocalcaemia, lack of resistance to infection and cognitive, behavioural and psychiatric problems.

Those areas depend on migration of neural crest cells to the region of the third and fourth pharyngeal pouches embryologically. It is thought that the underlying gene deletion affects that development.

Many phenotypically similar syndromes have now been described (see 'Synonyms', above) and they have been given the acronym CATCH-22 (= cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcaemia resulting from 22q11.2 deletions).^[1]

Genetics

Most cases result from a deletion of chromosome 22q11.2 - the DiGeorge syndrome chromosomal region. This is also known as the DiGeorge sequence. Chromosome 22 has been fully sequenced and the gene mainly responsible for the phenotypic features identified as TBX1.^[2]

DiGeorge syndrome has been established to have an autosomal dominant mode of inheritance. Penetrance is 100% with highly variable expression.^[3] Variable expression is evident even in cases with the same deletion. The large majority of cases are de novo mutations. Neither parent is affected in over 90% of cases. Although the majority of affected individuals have identical 3 megabase deletions, fewer than 10% of cases have smaller deletions of 1.5 or 2.0 megabases.

Epidemiology

Prevalence appears to be at least 1 in 4,000.^[2] The prevalence has been shown to be approximately 1 in 2,000 in the USA.^[3] This may reflect increased awareness and a lower threshold for testing.

75% of patients with 22q11.2 deletion have a cardiac abnormality making it the second most common cause of congenital heart disease after Down's syndrome.

Presentation

The expression is highly variable, with some individuals being essentially normal at the mildest end of the spectrum, and the most severe cases having life-threatening and life-impairing problems. There is no clinical feature that occurs in 100% of cases and there is no reported case of the syndrome that has all or even most of the clinical findings.^[4]

Cardiac

Cardiac malformations are seen in approximately 75% of patients with 22q11.2 deletion.^[1] They particularly affect the outflow tract. They include Fallot's tetralogy, type B interrupted aortic arch, truncus arteriosus, right aortic arch and aberrant right subclavian artery. Cases presenting later tend to have a milder spectrum of cardiac defect with ventricular septal defect being common.

Endocrine

Neonatal hypocalcaemia, which may present as tetany or seizures, due to hypoplasia of the parathyroid glands.

Immune deficiency

Susceptibility to infection due to a deficit of T cells. The immune deficit is caused by hypoplasia or aplasia of the thymus gland.

Facies

The ears are typically low set and smaller in the vertical diameter with abnormal pinna folding. Telecanthus with short palpebral fissures is seen. Both upward and downward slanting eyes have been described. The philtrum is short and the mouth relatively small with micrognathia also common.

Speech

75% of affected individuals have hypernasal speech and a high percentage having severe articulation impairment. DiGeorge syndrome is the most frequent clefting syndrome and may be responsible for up to 8% of children with palatal clefts seen in some hospitals.^[5]

Psychiatric problems

A variety of psychiatric disorders has been described in a small proportion of adult cases, including paranoid schizophrenia and major depressive illness. More than 40% of patients meet the criteria for either autistic spectrum disorder, attention deficit/hyperactivity disorder, or both.^[5]

The risk for severe psychiatric illness is 25 times higher than in the general population.^[3]

Other features

Short stature and variable mild-to-moderate learning difficulties are common. Nearly 50% of patients have microcephaly. Clinical features seen more rarely include hypothyroidism, cleft lip, and deafness. 10% of patients have sensorineural hearing loss and 45% have conductive loss.^[1]

Renal agenesis, duplicated kidneys, dysplastic kidneys, duplicated ureters and other minor malformations are seen in about a third of patients. These rarely require medical intervention.

Differential diagnosis

• Conotruncal anomaly face syndrome.
• Cayler syndrome.
• Opitz GBBB syndrome.
• CHARGE (coloboma (eye), heart anomaly, atresia (choanal), retardation (mental and growth), genital anomaly, ear anomaly) syndrome.^[6]

Investigations

• Fluorescent in situ hybridisation (FISH) - a DNA probe determines if a specific region of the genome (in this case, the 22q11.2 region) is present in two copies in a chromosome preparation obtained from peripheral blood.^[7] This test is quite expensive and takes 2-3 days. Work is currently underway to develop a polymerase chain reaction (PCR)-based method which will be faster and cheaper to deliver.
• Multiplex ligation-dependent probe amplification (MLPA) single tube assay is the equivalent of FISH. This method has been designed to be performed on DNA extracted from dried blood spot samples as obtained from Guthrie cards.
• Calcium levels and parathyroid function.
• Flow cytometry (to estimate the number of T cells in peripheral blood and their responses).
• Echocardiography.

Management

As there is a wide spectrum of phenotypes, this should be tailored to the individual. The following are typical of what may be required, but the list is not exhaustive.^[1]

• Cardiac defects are the usual focus of clinical management, unless very mild. Surgery does not carry a worse prognosis.^[8]
• Calcium supplements and 1,25-colecalciferol may be needed to treat hypocalcaemia.
• Thymic transplantation has been tried.^[9] However, it is difficult to assess, as children tend to improve with age anyway.
• Any affected child undergoing major surgery should have a supply of irradiated blood to avoid graft-versus-host disease (until immunocompetence has been demonstrated).
• Clefts may be submucous. They should be sought.
• Infants may have feeding problems. Gastrostomy should not be necessary if good coping techniques are used:
  • Upright positioning during feeding.
  • Increasing the flow from the bottle by enlarging the hole in the nipple.
  • Treating constipation vigorously.
  • Resolving any airway issues.
• Management shifts to cognitive, behavioural, and learning disorders during school years. Speech therapy and additional educational assistance may be needed.
• In late adolescence and adult years the potential for psychiatric disorders (including psychosis) requires vigilance.

Genetic counselling

Fewer than 10% of the patients show familial transmission of 22q11.2 deletion.^[3]

Because subjects with 22q11.2 deletion have a 50% risk of transmitting the deletion, they should be offered genetic counselling and FISH for prenatal detection (at 10-12 weeks of gestation) by chorionic villus sampling.

Prognosis

Cardiac malformations are the main cause of death for patients with DiGeorge syndrome. The prognosis for the resolution of heart, speech, and immune problems is good. The large majority of babies have successful corrections of their heart disease and will live normal life spans.

Immune problems subside with time, and endocrine problems tend to be intermittent and treatable with appropriate medications.

Speech problems respond well to speech therapy and surgery.