Genetic defect leading to a wide range of phenotypic
presentations, mainly developmental defects in the outflow tract of the
heart, hypoparathyroidism with hypocalcemia, and thymic hypoplasia/aplasia
with immune defects.
Pharyngeal Pouch Syndrome; Thymic Aplasia.
Both sexes are equally affected. Deletion of 22q11 is
estimated to occur in approximately 1:3000-5000 live births. It is more
frequent in children with congenital cardiac defects (up to 25% of these
patients) and with cleft lip/palate (up to 8% of children with a cleft
reportedly have this deletion).
Autosomal dominant; possibly a contiguous gene
syndrome. Only 25% of 22q deletions are inherited, and most cases of
DiGeorge Syndrome are isolated. In 90% of cases, DiGeorge syndrome is
related to a monoallelic microdeletion of 22q11.2 (so-called DiGeorge
syndrome critical region [DGCR]). This is the most frequent human gene
deletion and, after trisomy 21, the second most common genetic cause of
congenital heart defect. A few patients with DiGeorge syndrome have defects
in other chromosomes (10p13, 18q21.33, 4q21.3-q25). In noninherited cases,
maternal alcohol abuse, isotretinoin exposure, and uncontrolled diabetes
mellitus during pregnancy have been considered risk factors.
The chromosomal deletion leads to an abnormal
migration of the cephalic and cardiac neural crest cells in the fourth week
of embryogenesis, causing a developmental field defect that involves the
third and fourth pharyngeal pouches. The developmental field defect theory
is used to explain the narrow range of clinical expression of the different
causes of DiGeorge syndrome. The principal basic defect leads to thymic
aplasia or hypoplasia, heart defects, and hypoparathyroidism.
The finding of thymic aplasia or hypoplasia
radiologically, intraoperatively (for correction of congenital cardiac
defect), or on autopsy, combined with the clinical features, confirms the
diagnosis. However, immune function correlates poorly with thymus size.
Measurement of the CD4+ subset of white cells, standard karyotype to exclude
major rearrangements, and fluorescent in situ hybridization using probes
from within the deletion segment (close to translocation breakpoint site
preferably) finalize the diagnosis. Although CD3+, CD4+, and CD8+
T-lymphocyte counts are abnormally low, the number of natural killer cells
and B lymphocytes is normal.
Severe cases present with neonatal hypocalcemia
(caused by hypoplasia of the parathyroid glands), which may result in tetany
or seizures (presenting symptom in approximately 10% of patients) and
susceptibility to infection as a consequence of a deficit of T cells
(hypoplasia or aplasia of the thymus gland). Several cardiac malformations
(tetralogy of Fallot, type B interrupted aortic arch [typical], persistent
truncus arteriosus, double-outlet right ventricle, transposition of the
great arteries, ventriculoseptal defect, pulmonary stenosis, right
infundibular stenosis, right aortic arch, aberrant right subclavian artery)
are common and the main cause of death during the first weeks of life.
Recurrent infections start in the first 6 months of life. Cases with delayed
diagnosis (late childhood) present usually with a milder spectrum of cardiac
defects (mainly membranous ventricular septal defect), absence of, hypocalcemia and nearly normal immune function.
Facial abnormalities ...