22q11.2 deletion syndrome
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22q11.2 deletion syndrome (DS) is a chromosomal anomaly which causes a congenital malformation disorder whose common features include cardiac defects, palatal anomalies, facial dysmorphism, developmental delay and immune deficiency.
The worldwide incidence is estimated at 1/2,000-1/4,000 live births.
22q11.2 DS shows a variable clinical phenotype that can range from mild to severe. Congenital heart defects (77% of cases) include mainly conotruncal malformations such as truncus arteriosus, tetralogy of Fallot and vetricular septal defect. More than 75% of patients present with palatal anomalies (e.g. overt cleft palate, cleft lip and palate, velopharyngeal incompetence) that may lead to hypernasal speech, feeding and swallowing difficulties. Developmental delay is frequent. Many patients present with mild facial dysmorphism (e.g. malar flatness, ptosis, hypertelorism, epicanthal folds, prominent nasal root) and vertebral anomalies (e.g. butterfly vertebrae, hemivertebrae). 75% of patients have an immune deficiency due to thymic aplasia/hypoplasia that renders them susceptible to various infections. Patients also have a higher risk of developing an autoimmune disease such as idiopathic thrombocytopenic purpura and juvenile idiopathic arthritis (see these terms). Neonatal hypocalcemia is observed in 50% of cases. It usually resolves but can reappear at any age or after an infection, surgery or pregnancy. Additional clinical findings may include gastrointestinal anomalies (intestinal malrotation, imperforate anus), hearing loss, renal anomalies (renal agenesis), dental anomalies (enamel hypoplasia), learning problems and/or psychiatric disorders (attention deficit hyperactivity disorder, schizophrenia). The broad spectrum of clinical phenotypes that the syndrome encompasses was previously divided into distinct syndromes (e.g. DiGeorge syndrome, velocardiofacial syndrome, cardiofacial syndrome) but are now known to be etiologically identical and are referred to as 22q11.2 DS.
In most cases, the syndrome is due to a 3 million base pair (Mb) deletion on the chromosomal region 22q11.2 that is flanked by low copy number repeats. The deletion is due to a non-allelic meiotic recombination during spermatogenesis or oogenesis. In ~15% of cases, the deletion is within the 3 Mb region and varies in size. There are also atypical deletions which are nested within the DiGeorge critical region. Some of them include the TBX1 gene that has been shown to be implicated in cardiac, parathyroid, thymus and facial structure development. The variable expression of the 22q11.2 phenotype is thought to be due to genetic modifiers on either the other 22q11.2 allele or on other chromosomes.
Diagnosis is suspected upon clinical examination and detection of anomalies (e.g. cardiac defects by echocardiography, vertebral anomalies by cervical spine X-rays). It is confirmed by detection of the 22q11.2 deletion, using fluorescence in situ hybridization (FISH), MLPA, aCGH or genome-wide SNP microarrays.
Differential diagnosis includes Smith-Lemli-Opitz syndrome, CHARGE syndrome, Alagille syndrome, VATER syndrome, Goldenhar syndrome and isotretinoin embryopathy (see these terms).
Prenatal diagnosis is possible in familial cases by chorionic villus sampling or amniocentesis, and in pregnancies where associated anomalies have been noted by fetal echocardiography. Preimplantation genetic diagnosis is possible.
The deletion arises de novo in ~90% of the cases. There is a 50% recurrence risk for affected individuals.
Treatment depends on the associated abnormalities. It may consist of heart and/or palate surgery, speech therapy, nasogastric feeding, calcium supplementation, and psychological therapy. A regular immunologic surveillance is necessary.
The prognosis is variable and depends on the severity of the disease. The infant mortality rate is relatively low (~4%); in adults mortality is higher than that of the rest of the adult population.