*188400 DIGEORGE SYNDROME; DGS
Alternative
titles; symbols
HYPOPLASIA OF THYMUS AND PARATHYROIDS
THIRD AND FOURTH PHARYNGEAL POUCH SYNDROME
DIGEORGE SYNDROME CHROMOSOME REGION, INCLUDED;
DGCR, INCLUDED
SHPRINTZEN VCF SYNDROME, INCLUDED
TAKAO VCF SYNDROME, INCLUDED
CONOTRUNCAL ANOMALY FACE SYNDROME, INCLUDED
VELOCARDIOFACIAL SYNDROME, INCLUDED
CATCH22, INCLUDED
table OF
CONTENTS
Gene Map Locus: 22q11
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TEXT
DESCRIPTION
- DiGeorge syndrome (DGS) comprises
hypocalcemia arising from parathyroid
hypoplasia, thymic hypoplasia, and outflow tract
defects of the heart. Disturbance of cervical
neural crest migration into the derivatives of
the pharyngeal arches and pouches can account
for the phenotype. Most cases result from a
deletion of chromosome 22q11.2 (the DiGeorge
syndrome chromosome region, or DGCR). Several
genes are lost including the putative
transcription factor TUPLE1 which is expressed
in the appropriate distribution. This deletion
may present with a variety of phenotypes:
Shprintzen syndrome (192430);
conotruncal anomaly face (or Takao syndrome);
and isolated outflow tract defects of the heart
including tetralogy of Fallot, truncus
arteriosus, and interrupted aortic arch. A
collective acronym CATCH22 has been proposed for
these differing presentations. A small number of
cases of DGS have defects in other chromosomes,
notably 10p13. In the mouse, a transgenic Hox A3
(Hox 1.5) knockout produces a phenotype similar
to DGS as do the teratogens retinoic acid and
alcohol.
-
NOMENCLATURE
- DiGeorge syndrome overlaps clinically with
the disorder described by the Japanese as
'conotruncal anomaly face syndrome' (Kinouchi
et al., 1976; Takao
et al., 1980; Shimizu
et al., 1984), where the cardiovascular
presentation is the focus of attention. The term
conotruncal anomaly face syndrome is cumbersome
and has the disadvantage of using embryologic
assumptions as a title. It would be appropriate
to use Takao syndrome for those cases with a
preponderant cardiac presentation in contrast to
the low T cell and hypocalcemic presentation in
infancy of DiGeorge syndrome and the
craniofacial and palatal abnormalities typical
of Shprintzen syndrome. These 3 phenotypes may
be seen in the same family and most cases of all
3 categories have been shown to have a 22q11
deletion. This led Wilson
et al. (1993) to propose the acronym CATCH22
(Cardiac Abnormality/abnormal facies, T cell
deficit due to thymic hypoplasia, Cleft palate,
Hypocalcemia due to hypoparathyroidism resulting
from 22q11 deletion) as a collective acronym for
those with the common genetic etiology.
Shprintzen (1994)
objected to 'lumping' velocardiofacial syndrome
with the DiGeorge anomaly, arguing that there is
'no valid evidence to suggest that
velocardiofacial syndrome is etiologically
heterogeneous...[whereas] the DiGeorge
anomaly is known to be so.' Hall
(1993) cited data of Driscoll
et al. (1993) indicating that
velocardiofacial syndrome is etiologically
heterogeneous. She stated that '...68% of
Shprintzen syndrome patients...have been
recognised to have deletions of 22q11.'
Shprintzen (1994)
refuted her statement, maintaining that it could
accurately be stated that deletion was found in
68% of patients sent to the Driscoll laboratory
with a diagnosis of velocardiofacial syndrome
made by other clinicians. Shprintzen
(1994) said that in his sample, 100% had
deletion.
-
CLINICAL
FEATURES
- DiGeorge syndrome is characterized by
neonatal hypocalcemia, which may present as
tetany or seizures, due to hypoplasia of the
parathyroid glands, and susceptibility to
infection due to a deficit of T cells. The
immune deficit is caused by hypoplasia or
aplasia of the thymus gland. A variety of
cardiac malformations are seen in particular
affecting the outflow tract. These include
tetralogy of Fallot, type B interrupted aortic
arch, truncus arteriosus, right aortic arch and
aberrant right subclavian artery. In infancy,
micrognathia may be present. The ears are
typically low set and deficient in the vertical
diameter with abnormal folding of the pinna.
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. In the older child
the features overlap Shprintzen syndrome
(velocardiofacial syndrome) with a rather
bulbous nose and square nasal tip and hypernasal
speech associated with submucous or overt
palatal clefting. Cases presenting later tend to
have a milder spectrum of cardiac defect with
ventricular septal defect being common.
Short stature and variable mild-to-moderate
learning difficulties are common. A variety of
psychiatric disorders have been described in a
small proportion of adult cases of
velocardiofacial syndrome. These have included
paranoid schizophrenia and major depressive
illness. Clinical features seen more rarely
include hypothyroidism, cleft lip, and deafness.
Goodship et al.
(1995) described monozygotic twin brothers
with precisely the same 22q11.2 deletion but
somewhat discordant clinical phenotype. Both
twins had a small mouth, square nasal tip, short
palpebral fissures, and small ears with
deficient upper helices. Twin 1 had bilateral
hair whorls and twin 2 had a right-sided hair
whorl. Toes 4 and 5 were curled under
bilaterally in both boys, this being more marked
in twin 1. The twins were said to have had a
single placenta although the findings of a
detailed examination were not recorded. Twin 1
weighed 2,200 g and twin 2 weighed 2,800 g. Twin
1 had tetralogy of Fallot, which was repaired at
1 year of age. Twin 2 had a normal
cardiovascular system. Twin 1 started taking
steps at 24 months of age, while his brother
stood at 13 months and walked steadily at 18
months. These observations indicated to
Goodship et al.
(1995) that differences in deletion size and
modifying genetic loci are not responsible for
all the phenotypic differences observed in CATCH
22.
Novak and Robinson
(1994) reported a male fetus and a female
infant with the association of DiGeorge anomaly
(including absence of thymus and parathyroid
glands in both cases) and bilateral renal
agenesis. Karyotypes were normal. The mother of
the male fetus had insulin-dependent diabetes
mellitus (IDDM). Novak
and Robinson (1994) found 2 other reported
cases of this association; the mother in each
case had IDDM.
De Silva et al.
(1995) reported 3 children with phenotypic
manifestations varying from typical DiGeorge
syndrome to association of hypocalcemia,
hypoparathyroidism, and facial dysmorphism. All
3 patients had deletions of 22q11. The same
deletion was found in the mothers of 2 of them.
One of these mothers was diagnosed with
schizophrenia and had cleft palate and
hypocalcemia (in infancy); the other had no
manifestations of DiGeorge syndrome but did have
mild craniosynostosis and short terminal
phalanges of the thumbs (these abnormalities,
most likely independent of the 22q11 deletion,
were found also in her child with typical
DiGeorge syndrome). De
Silva et al. (1995) emphasized heterogeneity
of clinical manifestations associated with
deletions of 22q11.
Gripp et al.
(1997) described 2 patients with a 22q11.2
deletion and a dimpled nasal tip. They suggested
that this may be the extreme of the broad or
bulbous nose commonly found in the 22q11.2
deletion syndrome, and should not be confused
with the more severe nasal abnormalities seen in
frontonasal dysplasia (136760,
305645).
Ryan et al. (1997)
reported a European collaborative study of 558
patients with deletions of 22q11. In 204 of the
285 patients for whom parental deletion status
was available, neither parent had the deletion.
Of the 81 inherited deletions, the sex of the
parent with the deletion was known in 79 cases,
with 61 maternal and 18 paternal deletions.
Growth data were available for 131 of 158
patients whose heights and/or weights were less
than the fiftieth centile; 57 of 158 were below
the third centile for either height or weight.
Forty-four patients had died, and of the 29 for
whom age of death was available, 16 had died
within 1 month and 25 within 6 months as a
consequence of congenital heart disease. There
was 1 death from severe immune deficiency. A
total of 107 of 338 cases were developmentally
normal, although 37 of these had speech delay.
Of 231 patients with abnormal development, 102
had mild delay and 60 had either moderate or
severe learning difficulties. Twenty-two of 252
children in the study had behavioral or
psychiatric problems, including 2 with episodes
of psychosis; 11 of 61 adults had a psychiatric
disorder, 4 of whom had had at least 1 episode
of psychosis. Cardiac studies were recorded in
545 patients, of whom 409 had significant
cardiac pathology, most commonly tetralogy of
Fallot, ventricular septal defect, interrupted
aortic arch, pulmonary atresia/ventricular
septal defect, and truncus arteriosus. A total
of 242 of 496 patients had otolaryngeal
abnormalities, with 72 having either an overt
cleft palate or submucous cleft; 161 patients
had velopharyngeal insufficiency without
clefting. Of 159 patients in whom data on
hearing were available, 52 had abnormal hearing,
with data on the type of hearing loss available
in only 17, in all of whom this was conductive
in type. A total of 49 of 136 patients had renal
abnormalities, with absent, dysplastic, or
multicystic kidneys in 23, obstructive
abnormalities in 14, and vesicoureteric reflux
in 6. A total of 203 of 340 had recorded
hypocalcemia; 108 of this group had a history of
seizures, and 42 of these had had seizures
secondary to hypocalcemi a. Most hypocalcemia
was reported in the neonatal period, but 1
patient presented at 18 years of age. Laboratory
and clinical immune function and thymus status
were available in 218 patients. Only 4 of these
were classified as having a major immune
function abnormality. Two of these had died,
with severe immunodeficiency being the cause of
death in 1. A total of 94 of 548 patients had
minor abnormalities of the skeletal system, and
39 of 548 had ocular anomalies. Ten offspring
comparisons showed that 27 of 35 children had
more severe congenital heart disease than their
parents, with 8 of 35 having the same degree of
severity. Developmental status was worse in 9 of
17 and the same in 7 of 17. Palatal
abnormalities were better in 10 of 22 children
and similar to the parents in 12 of 22 children.
Sibship comparisons in 26 sibs from 12 families
showed considerable variation in heart
abnormalities between sibs, and development
status was similar in most cases. Ryan
et al. (1997) concluded that most of the
clinical findings in their study reflected
previous reports; however, fewer immunologic
problems and more renal problems than were
expected were found. Ryan
et al. (1997) therefore recommended that
abdominal ultrasound be carried out in all
patients with 22q11 deletions. They also
recommended that both parents be studied when a
child is found to have a deletion.
BIOCHEMICAL
FEATURES
- Hypocalcemia secondary to hypoparathyroidism
is the key biochemical feature and may be
sufficiently severe to be symptomatic.
Resolution in early childhood is typical,
although the deficient function of the
parathyroids may be exposed in adulthood by
infusion of disodium edetate (EDTA) (Gidding
et al., 1988).
The patient of Gidding
et al. (1988) had isolated conotruncal
cardiac defect and, despite normal baseline
ionized calcium and midmolecule parathyroid
hormone levels, she failed to increase the
secretion of midmolecular parathyroid hormone
appropriately in response to a hypocalcemic
challenge. They speculated that this combination
of latent-hypoparathyroidism (LHP) and
conotruncal cardiac defects should be included
in the clinical spectrum of DiGeorge anomaly.
Indeed, this woman's fourth child died with
DiGeorge anomaly. Seven years after the report
by Gidding et al.
(1988), Cuneo et al.
(1997) restudied the index patient with LHP
and evaluated 3 generations of her family for
parathyroid dysfunction, cardiac anomalies, and
del22q11. Deletions were found in 6 relatives, 3
with conotruncal cardiac defects and 3 with a
structurally normal heart. They found
significant transgenerational noncardiac
phenotypic variability, including learning
difficulties, dysmorphic facial appearance, and
psychiatric illness. A spectrum of parathyroid
gland dysfunction associated with the del22(q11)
was seen, ranging from hypocalcemic
hypoparathyroidism to normocalcemia with
abnormally low basal intact parathyroid hormone
levels. In addition, LPH found in the index
patient 7 years previously had evolved to frank
hypocalcemic hypoparathyroidism.
OTHER
FEATURES
- The deficit in thymic function results in a
lack of T cells which may be demonstrated by
measuring the proportion of CD4 cells (Wilson
et al., 1993). Immunohistochemical analysis
of the parathyroids reveals a deficit of
thyrocalcitonin immunoreactive cells (C cells)
(Palacios et al.,
1993).
Levy et al. (1997)
stated that, of parents of patients with DGS,
10% to 25% exhibit the 22q11 deletion but are
nearly asymptomatic. The authors described 2
female patients carrying a 22q11 microdeletion
and presenting with idiopathic thrombocytopenic
purpura. Both had children with typical
manifestations of DGS. The possibility that
defective thymic function predisposes patients
with DGS to autoimmune diseases was raised.
-
INHERITANCE
- DiGeorge syndrome is usually sporadic and
results from de novo 22 deletion. A long series
of reports has recognized the variable features
resulting from this deletion in multiple family
members with the variable phenotype behaving as
an autosomal dominant trait (Steele
et al., 1972; Raatikka
et al., 1981; Atkin et
al., 1982; Rohn et
al., 1984; Keppen et
al., 1988; Stevens et
al., 1990). Stevens
et al. (1990) suggested that such familial
cases should be regarded as being
velocardiofacial syndrome. The variable
phenotype was described by Strong
(1968) prior to the recognition of DGS. The
mother in that family developed a psychotic
illness. The first dominant pedigree in which
marked clinical variability was associated with
dominant transmission of a 22q11 deletion was
reported by Wilson et al.
(1991); the mother had the typical
dysmorphic features. Of the 3 affected
offspring, one had coarctation of the aorta, one
a ventricular septal defect, and one DGS.
Wilson et al. (1991)
found 5 of 9 families ascertained on the basis
of familial outflow tract defects to have 22q11
deletion. Subtle dysmorphic features typical of
those seen in DGS were apparent in several of
these affected family members.
-
CYTOGENETICS
- De la Chapelle et al.
(1981) suggested that DiGeorge syndrome may
be due to a deletion within chromosome 22 or
partial duplication of 20p, based on finding the
syndrome in members of a family with a 20;22
translocation. Specifically, they observed DGS
in 4 members of 1 family and demonstrated
monosomy of 22pter-q11 and 20p duplication.
Their interpretation that DGS might result from
monosomy for 22q11 was confirmed by Kelley
et al. (1982) in 3 patients with
translocation of 22q11-qter to other
chromosomes.
Greenberg et al.
(1984) observed partial monosomy due to an
unbalanced 4;22 translocation in a 2-month-old
male with type 1 truncus arteriosus and features
of DGS. The asymptomatic mother showed partial
T-cell deficiency and the same unbalanced
translocation with deletion of proximal
22q11.
Augusseau et al.
(1986) observed telecanthus,
microretrognathia, severe aortic coarctation
with hypoplastic left aortic arch, decreased E
rosettes, and mild neonatal hypocalcemia. The
same translocation was present in the clinically
normal mother and maternal aunt. The latter had
had her fourth pregnancy aborted because of
cardiac and other malformations detected on
ultrasound. This translocation has proved
important in analysis of the expressed sequences
in the deleted segment.
The recognition of the importance of 22q11
deletion grew with improving techniques.
Greenberg et al.
(1988) found chromosome abnormalities in 5
of 27 cases of DGS, 3 with 22q11 deletion though
only one of these was an interstitial
deletion.
Wilson et al.
(1992) reported high resolution banding
(more than 850 bands per haploid set) in 30 of
36 cases of DGS and demonstrated 9 cases of
interstitial deletion. All other cases were
apparently normal. Use of molecular dosage
analysis and fluorescence in situ hybridization
with probes isolated from within the deleted
area revealed deletion in 21 of the 22 cases
with normal karyotypes (Carey
et al., 1992) giving pooled results of 33
deleted among the consecutive series of 35
cases. Driscoll et al.
(1992) also found deletions at the molecular
level in all 14 cases studied.
Whereas 90% of cases of DGS may now be
attributed to a 22q11 deletion, other chromosome
defects have been identified. In the report of
Greenberg et al.
(1988), there was 1 case of DGS with
del10p13 and one with a 18q21.33 deletion.
Monaco et al. (1991)
and Lai et al. (1992)
among others have reported DGS features in cases
of 10p deletion. Fukushima
et al. (1992) found a female infant with a
deletion of 4q21.3-q25 associated with
interrupted aortic arch, VSD, ASD, and PDA; T
cell deficit and a small thymus at surgery;
absent corpus callosum; and dysmorphic features.
The possibility of an unrecognized
submicroscopic deletion of 22q11 should be
considered in such cases, although it is clear
that the disturbance of neural crest migration
presumed to underlie DGS may be caused by
several distinct defects at the molecular level.
Pinto-Escalante et al.
(1998) described a premature male infant
with mosaic monosomy of chromosome 22. His
facial appearance was similar to that in
DiGeorge syndrome; hypertonicity, limitation of
extension of major joints, and flexion
contracture of all fingers were also present.
They found previous reports of monosomy 22 in 6
cases, 3 of which were nonmosaic and 3 mosaic.
There was great variability in anomalies in
these patients; however, the most common
anomalies were in the face and joints.
Gottlieb et al.
(1998) determined the location and extent of
the deletion on chromosome 10 in 5 DiGeorge
syndrome patients by means of a combination of
heterozygosity tests and fluorescence in situ
hybridization analysis. The results did not
support the existence of a single, commonly
deleted region on 10p in these 5 patients.
Rather, they suggested that deletion of more
than 1 region on 10p could be associated with
the DGS phenotype. Furthermore, there was no
obvious correlation between the phenotypic
traits of the patients and the extent of the
deletion. The patient with the largest deletion
exhibited 1 of the less severe phenotypes. The
authors commented that the lack of a correlation
between the size of a deletion and the phenotype
is observed also with deletions on chromosome 22
and may be a characteristic of
haploinsufficiency disorders.
-
MAPPING
- A large series of polymorphic markers and
some expressed sequences have now been
identified in the critical region (Fibison
and Emanuel, 1987; Fibison
et al., 1990; Scambler
et al., 1990). The deletion lies proximal to
the breakpoint critical region (151410).
Details of the mapping of DGS to 22q11 are
located in the Molecular Genetics and
Cytogenetics sections of this entry.
Galili et al.
(1997) documented homology of synteny
between a 150-kb region on mouse chromosome 16
and the portion of 22q11.2 most commonly deleted
in DiGeorge syndrome and VCFS. They identified 7
genes, all of which are transcribed in the early
mouse embryo.
-
MOLECULAR
GENETICS
- Several expressed sequences have been
identified in the region commonly deleted.
Aubry et al. (1993)
have identified a zinc finger gene ZNF74,
Halford et al. (1993)
reported the expressed sequence T10. The gene
TUPLE1 (TUP-like enhancer of split gene 1;
600237)
reported by Halford et
al. (1993) is an attractive candidate for
the central features of the syndrome. This
putative transcription factor shows homology to
the yeast transcription factor TUP, and to
Drosophila enhancer of split. It contains four
WD40 domains and shows evidence of expression at
the critical period of development in the
outflow tract of the heart and the neural crest
derived aspects of the face and upper thorax.
The gene localizes to the critical DiGeorge
region but was not disrupted by the
translocation breakpoint described by Augusseau
et al. (1986). The possibility of this being
a contiguous gene syndrome remains.
Augusseau et al.
(1986) described a patient (ADU) with
'partial' DGS. She had telecanthus,
microretrognathia, severe aortic coarctation
with hypoplastic left aortic arch, decreased E
rosettes, and mild neonatal hypocalcemia. The
apparently balanced translocation involved
chromosomes 2 and 22: t(2;22)(q14;q11). The same
translocation was present in her mother (VDU).
The original paper reported that VDU had no
features of DGS. However, Budarf
et al. (1995) observed that subsequent
publications cited VDU as mildly affected with
hypernasal speech, micrognathia, and inverted
T4/T8 ratio, which are all features seen in VCFS
and DGS. The DGS phenotype in ADU, the VCFS
phenotype in VDU, and a balanced translocation
of chromosome 22 in both led Budarf
et al. (1995) to clone the translocation,
sequence the region containing the breakpoint,
and analyze the DNA sequence for transcript
identification. A gene disrupted by the
rearrangement was identified. Their analysis
suggested that there are at least 2 transcripts
on opposite strands in the region of the t(2;22)
breakpoint. The breakpoint disrupted a predicted
ORF of one of these genes, deleting 11
nucleotides at the translocation junction.
Additional fluorescence in situ hybridization
studies and Southern blot analysis demonstrated
that the deletions in chromosome 22
deletion-positive patients with DGS/VCFS include
both of the transcripts at the t(2;22)
breakpoint. Support that either of these
putative genes is of significance in the
etiology of DGS might come from determining
whether all deleted patients are hemizygous for
these loci and whether mutations in these genes
are detectable in non-deleted patients with
features of DGS. Lacking such evidence, the
possibility remains that the translocation
separates a locus control region from its target
gene or produces a position effect. This has
been suggested for the role of translocations
seen in association with autosomal sex reversal
and campomelic dysplasia (CMD1; 114290),
where several disease-causing translocation
breakpoints map 50 kb or more 5-prime of the
SOX9 gene.
Demczuk et al.
(1995) pointed to the existence of a strong
tendency for 22q11.2 deletions in DGS, VCFS, and
isolated conotruncal cardiac disease to be of
maternal origin. With their experience of 22
cases in which parental origin could be
determined, combined with recent results from
the literature, 24 cases were found to be of
maternal origin and 8 of paternal origin,
yielding a probability of less than 0.01.
Demczuk et al.
(1995) reported the isolation and cloning of
a gene encoding a potential adhesion receptor
protein (600594)
in the DGCR. They designated the gene DGCR2 and
suggested DGCR1 as a symbol for the TUPLE1
gene.
Pizzuti et al.
(1996) described the cloning and tissue
expression of a human homolog of the Drosophila
'dishevelled' gene (601225),
a gene required for the establishment of fly
embryonic segments. The 3-prime untranslated
region of the gene was positioned within the DGS
critical region and was found to be deleted in
DGS patients. The authors stated that the gene
may be involved in the pathogenesis of DGS.
Demczuk et al.
(1996) described the cloning of a gene,
which they referred to as DGCR6 (601279),
from the DGS critical region. The putative
protein encoded by this gene shows homology with
Drosophila melanogaster gonadal protein (gdl)
and with the gamma-1 chain of human laminin
(150290), which maps to chromosome 1q31.
HETEROGENEITY
- The association of the DiGeorge syndrome
with at least 2 and possibly more chromosomal
locations suggests strongly that several genes
are involved in control of migration of neural
crest cells and their subsequent fixation and
differentiation at different sites. In the
mouse, Chisaka and
Capecchi (1991) described a knockout of Hox
A3(1.5) which produced a recessive phenocopy of
DGS. This gene maps to human chromosome 7, an
area not yet implicated in the cause of the
human syndrome.
One explanation for the wide variation in
phenotype would be the need for more than 1 gene
defect to produce the severe version. Thus, for
example, impaired signal and receptor may be
needed to produce the full phenotype.
Environmental factors could also play an
additive role. Features of DGS have been
described in children with clinical evidence of
fetal alcohol syndrome. Ammann
et al. (1982) found 4 children among a
referral population with immunodeficiency who
had hypocalcemia with decreased levels of
parathormone, and T cell rosette formation of
between 9 and 50% (normal over 65%). All 4 had
cardiovascular lesions compatible with DGS; VSD
with right aortic arch, truncus arteriosus and
pulmonary stenosis, aberrant subclavian artery
and pulmonary valve stenosis respectively. Two
of the children had absent thymus at direct
examination. The alcohol may have directly
disrupted neural crest migration or have exposed
a genetic predisposition. Among a series of
pregnancies exposed to the teratogen
isotretinoin (vitamin A) reported by Lammer
et al. (1985) 21 malformed infants were
investigated; 8 had conotruncal defects or
aortic arch anomalies, 6 had micrognathia, 3 had
cleft palate and 7 had thymic defects. Several
of these children would satisfy the diagnostic
criteria of DGS. Again, it is likely that this
environmental challenge is exposing the same
susceptible pathways of development as are
impaired by the 22q11 deletion though the
possibility of an interaction between the insult
and genotype remains open.
-
DIAGNOSIS
- The dysmorphic facial appearance in an
individual with a major outflow tract defect of
the heart or a history of recurrent infection
should raise suspicion. In infancy, hypocalcemia
is a characteristic feature although this may be
intermittent and has a tendency to resolve
during the first year. Immunological assessment
relies on chest radiography to detect a thymic
shadow, a notoriously unreliable investigation,
particularly in the stressed infant, and
measurement of the CD4-positive subset of white
cells. With the rapid progress in molecular
cytogenetics, the investigation of choice is now
a standard karyotype to exclude major
rearrangements and fluorescence in situ
hybridization using probes from within the
deletion segment, preferably those close to the
translocation breakpoint site. Where cell
suspension or fresh blood cannot be obtained for
karyotype, allele loss may be sought with a
series of the hypervariable probes in the
region. Parents should be screened for carrier
status.
-
CLINICAL
MANAGEMENT
- Calcium supplements and 1,25-cholecalciferol
may be needed to treat hypocalcemia. Thymic
transplantation has been employed though this is
difficult to assess since children tend to
improve with age. 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 and should be sought. Speech
therapy and additional educational assistance
may be needed. Cardiac defects are the usual
focus of clinical management. Early
echocardiography is essential in any child where
other features suggest the diagnosis.
-
POPULATION
GENETICS
- A preliminary population study in the
Northern region of England, which has a birth
population of 40,000 per annum, revealed 9 cases
born in 1993 with 22q11 deletions who presented
with neonatal features. One of these was
familial with an asymptomatic carrier father.
The overall birth prevalence appeared to be at
least 1 in 4,000 (Burn et al., 1995).
Goodship et al.
(1998) presented prospective prevalence data
derived from the same health region. Since
approximately 75% of patients with 22q11
deletion have a cardiac abnormality, all infants
with significant congenital heart disease born
in 1994 and 1995 who were referred to the
Northern (United Kingdom) Genetics Service were
screened for 22q11 deletion. Significant
congenital heart disease was defined as major
structural malformation or disease requiring
early invasive investigation or intervention.
Additional cases born during this period without
apparent heart malformation in whom a diagnosis
of 22q11 deletion was made by a clinical
geneticist were included. Among 69,129 live
births there were 207 babies with significant
congenital heart disease; fluorescence in situ
hybridization analyses were performed in 170 of
these. Five of these had 22q11 deletions. One
baby with type B interruption of the aortic
arch, ventricular septal defect, and 22q11
deletion was diagnosed at autopsy following
sudden death at 11 days. Three further infants
were diagnosed on the basis of a laryngeal web
and hypocalcemia, dysmorphism, and dysmorphism
with nasal voice, respectively. The minimum
birth prevalence from this data was 13 per
100,000 live births, making 22q11 deletion the
second most common cause of congenital heart
disease after Down syndrome.
HISTORY
- The original description of the syndrome was
derived from a published discussion at an
immunology meeting (Cooper
et al., 1965). DiGeorge
(1968) published a formal report 3 years
later. The report by Strong
(1968) predated this formal report and
probably represents the same variable disorder.
Kimura (1977)
reported velopharyngeal deficiency in a series
of patients without cleft palate. The Japanese
language report by Kinouchi
et al. (1976) and the English reports, by
Takao et al.
(1980)and Shimizu et
al. (1984), delineated the syndrome in the
Japanese population. The acronym CATCH22 derives
from the phrase Catch 22, which was used by
Joseph Heller as the title of his book
(Heller, 1962).
-
SEE ALSO
- Burn et al. (1995)
; Radford et al.
(1988)
REFERENCES
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PubMed ID : 1747284
CLINICAL
SYNOPSIS
View
Clinical Synopsis Entry
Paul Brennan - updated : 2/18/1999
Michael J. Wright - updated : 6/5/1998
Victor A. McKusick - updated : 4/14/1998
Victor A. McKusick - updated : 3/27/1998
Victor A. McKusick - updated : 5/27/1997
Victor A. McKusick - updated : 5/16/1997
Victor A. McKusick - updated : 4/7/1997
Mark H. Paalman - updated : 1/23/1997
Iosif W. Lurie - updated : 1/23/1997
Iosif W. Lurie - updated : 8/11/1996
Moyra Smith - Updated : 5/25/1996
Mark H. Paalman - updated : 4/25/1996
John Burn - updated : 5/11/1994
Victor A. McKusick : 6/2/1986
EDIT HISTORY
alopez : 2/18/1999
terry : 7/29/1998
terry : 7/24/1998
alopez : 6/17/1998
terry : 6/5/1998
terry : 5/28/1998
carol : 5/27/1998
carol : 4/14/1998
carol : 4/7/1998
joanna : 3/27/1998
terry : 9/12/1997
alopez : 8/4/1997
mark : 7/16/1997
terry : 7/8/1997
alopez : 6/3/1997
jenny : 5/30/1997
terry : 5/27/1997
mark : 5/16/1997
terry : 5/12/1997
mark : 5/6/1997
mark : 4/7/1997
terry : 4/2/1997
mark : 1/23/1997
mark : 1/23/1997
mark : 1/23/1997
carol : 1/23/1997
carol : 8/11/1996
carol : 6/19/1996
carol : 5/29/1996
carol : 5/25/1996
mark : 4/25/1996
joanna : 2/21/1996
joanna : 1/25/1996
mark : 10/22/1995
mimadm : 5/10/1995
carol : 12/13/1994
pfoster : 10/26/1994
davew : 8/16/1994
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