The study of the specific "cardiac phenotype" in patients with Del22
shows that a particular cardiac anatomy can be identified.15
In fact, patients with conotruncal heart defect and Del22 have often additional
CHDs as a distinctive recognizable pattern.
Tetralogy of Fallot:Additional cardiac defects are found in
the half of the patients with this TF and Del22.17,18 The associated
cardiac defects include: 1) right or cervical aortic arch with or without
aberrant left subclavian artery; 2) hypoplasia or absence of the infundibular
septum; 3) absence of the pulmonary valve; 4) discontinuity and diffuse
hypoplasia of the pulmonary arteries.
Pulmonary atresia with ventricular septal defect: Considering
the pattern of pulmonary blood supply, among children with pulmonary atresia
with ventricular septal defect two major groups of patients can be recognized:
1) children with a single ductus arteriosus that usually presents confluent
and well formed pulmonary arteries (also called tetralogy of Fallot with
pulmonary atresia), and 2) children with major aortopulmonary collateral
arteries (MAPCA) frequently associated with discontinuity, hypoplasia or
absence of the central pulmonary arteries. In children with pulmonary atresia
with ventricular septal defect and Del22 the pattern of pulmonary blood
supply provided by the MAPCA is prevalent.19-22 Additionally,
a high prevalence of right aortic arch and of discontinuity and defects
of arborization of the pulmonary arteries can be found.
Truncus arteriosus: Del22 is prevalent in patients with TA with
nonconfluent pulmonary arteries (Type 3 of van Praagh), in which the right
pulmonary artery arises from the TA near to the truncal valve, and the
left pulmonary artery is supplied by the ductus arteriosus.23-25
Additional CHDs to TA are: 1) interruption or right aortic arch; 2) discontinuity,
stenosis, or crossing of the pulmonary arteries; 3) severe dysplasia of
the truncal valve; 4) origin of the TA from the right ventricle.
Interrupted aortic arch: Del 22 is particularly common in patients
with IAA type B.26-30 In these cases the infundibular septum
is often hypoplastic or absent and is deviated posteriorly and to the left;
the VSD results in a subarterial position doubly committed with the pulmonary
and aortic valves.
Ventricular septal defect: The type of VSD in patients with Del22
is prevalently subarterial doubly committed.16,31 Right or cervical
aortic arch may be associated.
Two thirds of the patients with Del22 are found to have palatal anomalies,
and the spectrum of malformations is wide.2,3,40 The majority
have velopharyngeal insufficiency in the absence of cleft palate, but overt
clefts, bifid uvula and cleft lip may also be present. Palatal function
plays an important role in the development of speech.
The immunodeficiency in Del22 syndrome is due to poor formation of
thymic tissue and impaired production of T-cells. The most common immunologic
abnormality is low number of T-cell, and functional T-cell deficiency is
found in a minority of all patients.41 Nevertheless, the spectrum
of immunocompromise in the Del22 patient population is broad. Children
with Del22 have a significant risk of infection due to anatomical effects
such as CHD and cleft palate. The additional risk associated with immunodeficiency
may represent a critical factor in the management of these patients. Fortunately,
the T-cell number usually increases by time and the cell function is not
altered. Usually, patients with del22 are at most risk for repeated infections
in the first years of life, but older children and adults do generally
not have recurrent infections.
Neonatal hypocalcemia is recognized in most of children with Del22.2
This symptom is related to hypoparathyroidism due to absence or underdevelopment
of parathyroid glands, which leads to low blood calcium levels.42,43
Hypocalcemia may cause tremors, seizures, and arrhythmia. Calcium
supplementation leads to normalization of blood calcium levels. The development
of hypoparathyroidism later in life is rarer.
Speech / Learning impairment
Developmental delays can be present in children with del22, including
delays in the motor, linguistic and cognitive domains.44,45
Delayed motor development is mainly attributed to the hypotonia present
in more than half of the patients with del22. Psychomotor therapy is therefore
recommended from an early age. Difficulties in expressive language are
generally evident in preschooler children. This delayed speech development
is prevalently due to the concomitance of velopharyngeal insufficiency
and developmental delay. Speech difficulties related to velo-palatal abnormalities
may become clearly manifest late, particularly when speech has fully developed.
During childhood, the majority of the children has learning problems, especially
in the area of reading comprehension, arithmetic and problem-solving. Common
problems seen in these patients are impulsivity, distractibility, perseveration,
and hyperactivity. Several common behavioural and temperamental features
have been observed in children and adolescents with del22, including a
predisposition to show a withdrawn behavior, depression, anxiety and a
tendency to engage in obsessive and/or compulsive behaviours. Therefore,
good monitoring and follow up of the socio-emotional development is important
in all ages.
Skeletal anomalies and deformations have been detected in patients
with del22.46-48 In the first reports, a variety of hand malformations
and clubfoot have been described. Thereafter, scoliosis and vertebral maformations,
including butterfly vertebrae and vertebral coronal cleft, have been added
to the list. As characteristic diagnostic marker, most of del22 patients
have long tapered fingers (Figure 3).
Figure 3: Long tapering fingers characteristics of Del22 syndrome
Asymmetric crying face
Unilateral partial facial palsy due to hypoplasia of the depressor
anguli oris muscle (DAOM) results in asymmetry of the lower lip, especially
evident in smiling and crying. The eye on the affected side usually closes
normally. DAOM can be detected in about 20% of neonates with del22.49
Hearing impairment is documented in 60% of patients with del22.2,50
Hearing loss is conductive in the majority of the cases, probably
related to chronic otitis media with effusion and upper respiratory tract
infections. Nevertheless, congenital sensorineural deafness is also diagnosed
in some cases. Audiological evaluation is recommended in Del22 children,
in order to reduce the risk of speech deficit.
A specific pattern of growth is identifiable in patients with Del22.51
Weight deficiency is frequent in the first years of age, being prevalently
related to feeding difficulties. The growth in weight improves with time
leading to overweight and obesity in adolescence. On the contrary, short
stature is present in a minority of the patients. In fact, adolescent patients
have prevalently normal height, with a small group of patients showing
a constitutional delay in height growth.
In 1992, a microdeletion of chromosome 22 at the q11.2 band was reported.52
The critical region has been subsequently defined (Figure 4).
Figure 4: The 22q11 critical region commonly deleted in DiGeorge/velocardiofacial
The majority of the patients carry a common 3 Mb deletion, but smaller
deletions have also been found. To date, the size of the deletion has not
been correlated with the phenotypical expression of the syndrome. Fluorescent
in situ hybridization (FISH) is used as genetic laboratory test for 22q11.2
microdeletion detection (Figure 5).
Figure 5: Fluorescent in situ hybridization showing Del22
At least 30 genes have been mapped in the typical deleted region. Among
genes located in the "critical" chromosomal region, TUPLE1, UFD1L and TBX1
have been particularly studied.53-55 Athough TBX1 mutations
have been recently detected in rare patients with clinical features of
DiGeorge/Velo-Cardio-Facial syndrome without an identifiable Del22,56
it remains unclear whether several genes must be haploinsufficient
to cause a clinical phenotype or whether a single locus predominates.
The Del22 is a "de novo" occurrence in the family in most of the cases.
Nevertheless, inheritance of the microdeletions from one of the parents
is possible, the frequency varying from 6% to 28% in different series.2,9,57-59
The affected parent often demonstrates a milder phenotype. Various
genetic and non-genetic factors, including modifier genes, mosaicism, unstable
mutations, allelic variations chance and environmental interactions, can
be hypothesized to be involved in variable clinical expression of the syndrome
in the same family.
Non-syndromic conotruncal heart defects
Several observations suggesting that del22 could be associated with
"non-syndromic" CHDs can be found in the previous literature on this argument.32,33
However, 80% of these patients, reported as apparently "isolated"
CHD, had in fact extracardiac features fitting within the del22 syndrome
phenotype. Other investigations have shown that Del22 is virtually never
found in non-syndromic patients with conotruncal CHDs.34-38 In
a personal series of 305 patients with true non-syndromic CHD, we detected
only one deleted patient.14 Thus, we believe that, in clinical
practice, genetic tests searching for del22 are not indicated in all patients
with conotruncal CHDs, but only in subjects with clinical anomalies of
del22 syndrome. Classic or subtle facial anomalies are fundamental useful
tools for selecting children who should be tested for Del22.14,39
In this regard, also patients with distinct anatomic conotruncal
defect subtypes must be included.14,39
Clinical expression of Del22 syndrome can be extremely variable and
the degree of various organ systems involved is wide. Early recognition
of the deletion is important, so that the treatment of involved organ anomalies
can be initiated, screening for associated malformations performed and
prevention of neuropsychological problems provided. In fact, as occurrs
in several multiple system clinical conditions, the care of patients with
Del 22 can be very complex. A multidisciplinary approach is fundamental
to ensure that the patient will be able to attain his or her maximal potential.
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Cast a wide FISHing net! Genet Med 2001;3:23-29.
Dr. Maria Cristina Digilio
Bambino Gesù Hospital
Piazza S. Onofrio 4
00165, Rome - Italy