22q11.2 deletion syndrome
22q11.2 deletion syndrome (also known as DiGeorge syndrome and velocardiofacial syndrome) is a highly variable multisystem genetic condition associated with learning difficulties, congenital heart defects, palatal anomalies, immunodeficiency and hypocalcaemia.
Overview
22q11.2 deletion syndrome is the most common microdeletion syndrome. It is a multi-system condition with an increased prevalence of a variety of health problems, including structural heart defects, palatal dysfunction (such as cleft palate), hearing loss and immune system dysfunction. The eyes, nervous system, skeleton and genitourinary system can also be affected. Affected individuals have an increased risk of psychiatric illnesses and autoimmune conditions.
Clinical features
22q11.2 deletion syndrome is highly variable and may present with any combination of the features listed below.
| Commonly associated features | |
| Congenital heart disease | Often conotruncal, ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, truncus arteriosus. |
| Palatal anomalies | Velopharyngeal insufficiency, hypernasal speech, cleft palate (typically submucosal), bifid uvula, dysphagia. |
| Laryngotracheoesophageal anomalies | Laryngomalacia, vascular ring, subglottic stenosis. |
| Developmental delay and/or learning difficulties | Variable, even within families; more significant speech delay. |
| Neuropsychiatric | Autism spectrum disorder, attention deficit disorder, schizophrenia, anxiety. |
| CNS | Hypotonia, microcephaly, seizures (may be associated with hypocalcaemia). |
| Gastrointestinal | Hernias, constipation (with or without a structural cause). |
| Immunological | Frequent infections and/or immune deficiency (thymic hypoplasia and subsequent impaired T-cell production), predisposition to autoimmune conditions. |
| Ophthalmologic and audiological | Ptosis, strabismus, coloboma, cataract, hearing loss (sensorineural and/or conductive). |
| Facial features (variable and not always present) | Hooded eyelids, flat nasal bridge, bulbous nasal tip, micrognathia, asymmetric crying facies, craniosynostosis, small and low-set ears, overfolding, cupped shape, preauricular tags and pits. |
| Skeletal | Occipital-cervical anomaly, rib and vertebral anomalies, scoliosis, clubfoot, extra fingers. |
| Genitourinary | Renal anomalies, cryptorchidism, hypospadias. |
| Endocrine | Hypoparathyroidism and hypocalcaemia, hypothyroidism, growth hormone deficiency. |
Genomics
22q11.2 deletion syndrome is caused by a microdeletion at chromosome position 22q11.2. The microdeletion is typically 2.54 Mb in size. Individuals with 22q11.2 deletion syndrome have one, rather than the usual two, copies of a number of genes, including TBX1.
Note that significantly smaller or larger deletions in (and distal to) this region do occur and can cause different medical problems.
Diagnosis
- 22q11.2 deletion syndrome can be diagnosed in a variety of ways. Clinical suspicion may arise prenatally because of congenital malformations such as a facial cleft, or because of congenital heart disease. Please see Fetus with facial clefts and Fetus with an isolated congenital anomaly.
- Postnatally, suspicion may arise because of the presence of some of the features outlined above.
- Alternatively, individuals may be tested due to a known risk in the family. For example, a parent with a 22q11.2 deletion will have a 50% chance of passing on the condition to each child they have. As the condition is highly variable, a lack of associated features is not a sufficient reason to rule out a diagnosis: additional screening should still take place for people with 22q11.2 deletions, so genomic testing should be offered to at-risk individuals even if there are few or no associated features.
Inheritance and genomic counselling
- Most cases of 22q11.2 deletion syndrome arise because of a new (de novo) microdeletion occurring in the egg or sperm.
- The features of this condition can be extremely variable, however, even within members of the same family. As such, it is important to offer testing to parents of an affected child, even if they do not have any apparent symptoms. If a parent is found to have a 22q11.2 deletion, they should be offered the opportunity to access genomic counselling and health screening.
- When an individual with 22q11.2 deletion syndrome has children, there is a 50% chance of them passing on the microdeletion in each pregnancy. If a parent is found to have a 22q11.2 deletion, existing and future siblings may be affected. Individuals with 22q11.2 deletion syndrome may wish to discuss reproductive options, which could include testing in pregnancy (non-invasive prenatal testing) or preimplantation genetic testing.
Management
Management of children with 22q11.2 deletion syndrome is complex and should be delivered via a multidisciplinary team. Detailed suggested approaches have been published by several authors (see the resources for clinicians below).
Resources
For clinicians
- Gene Reviews: 22q11.2 deletion syndrome
- Genetic and Rare Diseases Information Center: 22q11.2 deletion syndrome
- NHS England: National Genomic Test Directory
References:
- Habel A, Herriot R, Kumararatne D and others. ‘Towards a safety net for management of 22q11.2 deletion syndrome: Guidelines for our times‘. European Journal of Pediatrics 2014: volume 173, issue 6, pages 757–765. DOI: 10.1007/s00431-013-2240-z
For patients
- International 22q11.2 Foundation
- Max Appeal (UK patient support charity)