Introduction
Named after the Italian American physician and pediatric endocrinologist Dr. Angelo
M. DiGeorge (1965), DiGeorge syndrome (DGS) is a combination of signs and symptoms
caused by a defect in the pharyngeal pouch structure during human embryo development.[1] Statistically, more than 90% of cases with deletion(del) 22q11.2 are sporadic and
only a few are inherited,[2]
[3]
[4] which can easily be diagnosed by fluorescence in situ hybridization (FISH) or microarray
based comparative genomic hybridization (aCGH).[5] Prenatal ultrasound (US) is a valuable tool in the detection of sporadic cases of
DGS with sonographic features like cardiovascular abnormalities, thymic hypoplasia/aplasia,
genitourinary anomalies, central nervous system (CNS) defects, skeletal deformities,
fetal growth restriction (FGR), increased nuchal translucency (NT), and abnormal amniotic
fluid levels. Among these, conotruncal cardiac defects are a prominent feature and
are found in more than 90% of the cases.[6]
[7]
[8] Additionally, the detection of thymic and genitourinary abnormalities, along with
other less frequently associated findings on US can enhance the detection rate of
22q11.2(del). Owing to the phenotypic diversity of DGS, a prompt and early prenatal
diagnosis of 22q11.2(del) would help obstetricians, surgeons, pediatric cardiologists,
neonatologists, and geneticists to plan an optimum management strategy for prenatal,
perinatal, and postnatal care. We share our experience in sonographic-based prenatal
diagnosis and outcomes of eight patients from a single tertiary center in South India.
We also highlight a unique case diagnosed based on a clue from subtle US findings
in the absence of congenital heart disease (CHD).
Materials and Methods
This was a retrospective study of eight patients who visited the feto maternal unit
in a single tertiary care center in Kerala, South India, between 2012 and 2020. We
analyzed the hospital database and identified eight prenatally diagnosed DGS fetuses.
All patients underwent detailed anomaly scans and fetal echocardiography (ECHO) by
dedicated feto maternal specialists and pediatric cardiologists using Voluson P8 and
E10 machines. Genetic counseling was offered to all families by an experienced clinical
geneticist at our institute concerning prenatal and postnatal care and to devise a
treatment strategy. Data regarding maternal age, consanguinity, parity, inheritance,
family history, sonographic findings, gestational age, mode of delivery, and postnatal
outcomes were analyzed. All patients underwent amniocentesis for confirmation of 22q11.2del
either by FISH with a probe specific for the TUPLE I region or microarray.
Results
All of the fetuses were diagnosed in the mid trimester following anatomic scans except
one with a strong family history of DGS, who was offered genetic counseling in the
early second trimester ([Table 1]). With a mean gestational age of 19 weeks 3 days (16 weeks 05 days to 26 weeks 06
days), the majority (87.5%, 7 of 8) of the cases were singleton pregnancies excluding
one which was a case of dichorionic diamniotic (DCDA) twins wherein one fetus had
DGS. The mean maternal age was 33.4 years (25–36 years). Fifty percent (4 of 8) of
the patients were primigravida, 25% (2 of 8) were second gravida, and the remaining
25% (2 of 8) were third gravida. Note that 87.5% (7 of 8) were nonconsanguineously
married, while 12.5% (1 of 8) were married consanguineously (third degree). The 11
to 14 weeks scan of 5 patients was normal and data of 3 patients was unavailable for
evaluation.
Table 1
Overview of indications, obstetric history, prenatal scan findings, and outcomes of
prenatal diagnosed 22q11.2DS
|
Patient no.
|
Indication
|
Obstetric history and consanguinity
|
Gestation
|
Scan findings
|
Microarray/FISH result
|
Outcome
|
|
P1
|
CHD
|
G1, NCM
|
Singleton, 20W4D
|
EICF, right aortic arch
|
Deletion of 22q11.2
|
TOP
|
|
P2
|
CHD
|
G3P2L2, NCM
|
Singleton, 25W2D
|
DORV with severe PS, PLSVC, clenched fists and pointing index finger, polyhydramnios,
SGA
|
Deletion of 22q11.2
|
FTND, male/2.6 kg, micropenis with hypoplastic scrotum and imperforate anus, karyotype:
46 XY, permanent colostomy. Staged correction of CHD done with fair outcome, mild
developmental delay. Alive
|
|
P3
|
CHD
|
G1, 3rd degree consanguinity
|
Singleton, 22W5D
|
DORV-TGA like, severe pulmonary stenosis, ARSA
|
Deletion of 22q11.2
|
Preterm 32 weeks (PPROM) cesarean, female/1.5 kg, CHD corrected with fair outcome.
Expired at 3 years of age due to aspiration pneumonia
|
|
P4
|
CHD
|
G3P1L1A1, NCM
|
Singleton, 26W6D
|
TOF, SGA
|
Deletion of 22 q 11.2
|
Preterm delivery at 32 weeks. Expired on day 14 due to failure to thrive
|
|
P5
|
CTEV
|
G1, NCM
|
DCDA, 20W
|
Polyhydramnios, dilated CSP, cavum vergae, thymic hypoplasia, bilateral CTEV, SGA
|
Deletion of 22q11.2
|
Preterm 36 weeks cesarean delivery at, male/1.95 kg, low set ears, squared nasal tip,
micrognathia. Laryngomalacia, CTEV, hypoparathyroidism, status post tendo-Achilles
tenotomy. Mild developmental delay. Alive
|
|
P6
|
CHD
|
G1, NCM
|
Singleton, 21W6D
|
TOF with pulmonary atresia, CP cysts
|
Deletion of 22q11.2
|
TOP
|
|
P7
|
Family history (husband and previous child with DGS)
|
G2P1L1, NCM
|
Singleton, 20W5D
|
PLSVC draining into CS, dilated CSP, thymic hypoplasia
|
Deletion of 22q11.2
|
TOP
|
|
P8
|
CHD
|
G2P1L1, NCM
|
Singleton, 20W5D
|
TOF with pulmonary atresia, MAPCAs, tortuous DA, thymic hypoplasia
|
Deletion of 22q11.2
|
TOP
|
Abbreviations: A, abortion; ARSA, aberrant right subclavian artery; CHD, congenital
heart disease; CP, choroid plexuses; CS, coronary sinus; CSP, cavum septum pellucidum;
CTEV, congenital talipes equinovarus; DA, ductus arteriosus; DCDA, dichorionic diamniotic;
DGS, DiGeorge syndrome; DORV, double outlet right ventricle; EICF, echogenic intracardiac
foci; FISH, fluorescence in situ hybridization; FTND, full-term normal delivery; G,
gravida; L, living; MAPCAs, multiple aortopulmonary collaterals; NCM, nonconsanguineous;
P, para; PLSVC, persistent left superior vena cava; PPROM, preterm premature rupture
of membranes; PS, pulmonary stenosis; SGA, small for gestational age; TGA, transposition
of great arteries; TOF, tetralogy of Fallot; TOP, termination of pregnancy.
In most patients (75%, 6 of 8), CHD was the primary indication for DGS evaluation.
Note that 12.5% (1) had a family history of DGS (wherein her husband and previous
child were affected), and the remainder 12.5% (1) had an unusual case diagnosed on
the basis of subtle US features in the absence of CHD. Most of the fetuses with CHD
exhibited conotruncal anomalies (62.5%, 5 of 8), of which 37.5% (3 of 8) had tetralogy
of Fallot, and 25% (2 of 8) had double outlet right ventricle (DORV). Echogenic intracardiac
foci (EICF) with the right aortic arch was seen in 12.5% (1) and variants in normal
cardiac anatomy like persistent left superior vena cava draining into the coronary
sinus were seen in 12.5% (1). Among the fetuses with conotruncal anomalies, 25% (2
of 8) had other associated cardiac findings such as aberrant right subclavian artery
seen in 12.5% (1) and pulmonary atresia with multiple aortopulmonary collaterals in
12.5% (1) ([Table 1]). Thymic hypoplasia and small for gestation (SGA) fetuses were each identified in
37.5% (3 of 8) cases. Other extracardiac findings were seen in varying combinations
in 37.5% (3 of 8) cases. CNS findings were noted in 37.5% (3 of 8) (dilated cavum
septum pellucidum [CSP] in 25% [2 of 8], choroid plexus cyst in 12.5% [1]). Polyhydramnios
and skeletal abnormalities were documented in 25% (2 of 8) each. Among the skeletal
findings, bilateral congenital talipes equinovarus (CTEV) and clenched fists with
pointing index fingers were identified in 12.5% (1) each.
Half (50%, 4 of 8) of the prenatally diagnosed DGS patients decided to terminate their
pregnancy after comprehensive counseling by a multidisciplinary team of experts and
none of them opted for fetal autopsy. Among the patients who continued their pregnancy,
25% (2 of 8) born at other centers, expired. One of them expired due to failure to
thrive on day 14 of life and the other death, at 3 years of age, was attributed to
aspiration pneumonia post CHD correction. Among the remaining 25% (2 of 8) alive babies
born at our center, one has facial dysmorphism, mild developmental delay, hypoparathyroidism,
stridor, and CTEV. This patient is subsequently described as a unique case and is
detailed below. The other baby was born with ambiguous genitalia (micropenis and hypoplastic
scrotum) along with high anorectal malformation (imperforate anus), who underwent
permanent sigmoid colostomy on day 5 of life and was eventually operated on for DORV
with a favorable outcome.
Here, we highlight an unusual case of a 28 year old primigravida with DCDA twins at
20 weeks 4 days, who reported to us for a second opinion for bilateral CTEV in one
fetus. She was nonconsanguineously married for 2.5 years and conceived this pregnancy
following intrauterine insemination. Her NT scan was normal, but the anomaly scan
done elsewhere revealed bilateral CTEV in one fetus.
Detailed anatomic scan done at our center showed twin A with EICF in the left ventricle
and twin B had dilated CSP ([Figs. 1] and [2]) with prominent cavum vergae, bilateral CTEV ([Fig. 4]), and hypoplastic thymus ([Fig. 3]). With a provisional diagnosis of 22q11.21(del) in twin B, amniocentesis for aCGH
confirmed our diagnosis. Subsequent scans at 24 and 29 weeks additionally revealed
polyhydramnios and at 36 weeks 2 days the estimated fetal weight for twin B was < 10th
centile (SGA).
Fig. 1 Dilated cavum septum pellucidum (yellow arrow) in a fetus (twin b) with 22q11.2 deletion
syndrome and normal cavum septum pellucidum (white arrow) in a normal fetus (twin
a) in axial view.
Fig. 2 Dilated cavum septum pellucidum (yellow arrow) in a fetus (twin b) with 22q11.2 deletion
syndrome and normal cavum septum pellucidum (white arrow) in a normal fetus (twin
a) in sagittal view.
Fig. 3 Three vessel cardiac view showing hypoplastic thymus (yellow arrow) in twin b and
normal thymus (white arrow) in twin a.
Fig. 4 Bilateral lower limbs show congenital talipes equinovarus in a fetus with DiGeorge
syndrome (twin b).
She underwent an emergency cesarean for breech presentation and delivered a normal
female baby weighing 2.76 kg and a DGS affected male baby weighing 1.95 kg. The affected
baby had phenotypic features of DGS, viz., hypertelorism, bilateral dysplastic pinna,
squared nasal tip, long fingers, micrognathia, and bilateral CTEV. Biochemical investigations
revealed normal serum calcium, phosphorus, thyroid, and parathyroid levels. US abdomen,
neurosonogram, and ECHO were all normal. Both neonates were discharged after an uneventful
stay in the neonatal intensive care unit.
After 2 weeks, the affected baby boy was brought back to the neonatal unit with feeding
difficulty and stridor. He was detected to have hypoparathyroidism and was initiated
on medications. An ear, nose, and throat specialist opined the possibility of laryngomalacia
as the cause for stridor and he is under follow up for the same. At 2 months of age,
he underwent bilateral tendo Achilles tenotomy for CTEV. During his last visit at
the age of 22 months, he was fully immunized for his age and is doing well with near
normal developmental milestones.
Discussion
DGS occurs in 1 in 4,000 to 6,000 live births and is one of the most common survivable
deletion syndromes in humans.[1]
[8] With other syndromes like velocardiofacial syndrome, Cayler cardio facial syndrome,
Shprintzen-Goldberg syndrome, Sedlackova syndrome, and conotruncal anomaly face syndrome,
DGS is historically grouped under a broad genetic diagnosis of 22q11.2 deletion syndrome.
The names of these syndromes can be used interchangeably as they denote a common underlying
genetic etiology.[5] The variety of phenotypic expressions has supported the use of different nomenclatures
for the same entity.[9]
Etiologically, DGS is a result of 1.5-3 megabase deletion on the long arm(q) of chromosome
22 at 11.2 locus; hence, labeled as 22q11.2(del) which causes defective development
of the third and fourth pharyngeal pouches and the fourth aortic arch which are embryologic
precursors for development of the middle and external ear, maxilla, mandible, palatine
tonsils, thymus, thyroid, parathyroids, aortic arches, and cardiac outflow tracts.
This leads to abnormal facies, cleft palate, speech abnormalities, recurrent infections
due to immunodeficiency secondary to thymic aplasia/hypoplasia, hypocalcemia due to
small/absent parathyroid glands, developmental delay, seizures, and most frequently,
cardiac anomalies.[5]
Predominantly, DGS occurs de novo and less than 10% are inherited as autosomal dominant.[2]
[3]
[4] Astonishingly, Besseau-Ayasse et al reported a higher incidence of inheritance in
a 2014 study, wherein 27% of the cases were inherited from either one of the parents.[7] The recurrence risk for unaffected parents to have another affected child is low;
nevertheless, prenatal testing should be offered to such families due to the possibility
of germline mosaicism. Out of > 90 genes encoded in 22q11.2, T box transcription factor
1 (TBX-1) gene abnormality correlates with several prominent phenotypes of DGS, as confirmed
by researchers in mouse and zebrafish knockout models.[10]
[11]
Although DGS affects 1:1,000 of fetuses, the actual prenatal and postnatal prevalence
may be higher,[1]
[10] possibly due to underestimation of lethal phenotypes remaining undiagnosed and due
to the postnatal phenotypic variability, children with subtle anomalies may be underdiagnosed.[12] Third, unavailability of genetic expertise in most centers could also lead to underrepresentation
of these cases.
Currently, indications for prenatal evaluation for DGS are abnormal sonographic findings
and positive family history. The primary indication for evaluation in our series was
CHD (75%). This is in accordance with prior studies, which reported 76 to 100% of
fetuses with CHD ([Table 2]). It is well established that the frequently associated CHD in DGS is conotruncal
defects.[8] We documented the majority (62.5%) to have conotruncal anomalies in the current
series, in similarity to other cohorts.[8] DGS is commonly seen in CHD patients with aortic arch malformation. Interrupted
aortic arch is seen in 50 to 80% of cases and common arterial trunk in 35% of cases.[2]
[13] However, in the current study, we prenatally diagnosed a fetus with DGS who had
right aortic arch without any CHD or other fetal markers. Surprisingly, hypoplastic
left heart syndrome has also been reported to be associated with 22q11.2(del) in a
study by Noël et al.[6]
Table 2
Literature review of prenatally diagnosed 22q11.2 deletion syndrome
|
Case series
|
Current study
(N = 8)
|
Schindewolf et al.[8]
(N = 42)
|
Besseau-Ayasse et al.[7]
(N = 228)
|
Noël et al.[6]
(N = 74)
|
Bretelle et al.[21]
(N = 8)
|
|
Prenatal US finding
|
|
Cardiac
|
6 (75%)
|
40 (95%)
|
228 (83%)
|
56 (76%)
|
8 (100%)
|
|
CNS
|
2 (25%)
|
16 (38%)
|
n/a
|
4 (5%)
|
n/a
|
|
Skeletal
|
2 (25%)
|
8 (19%)
|
n/a
|
2 (2.7%)
|
2 (25%)
|
|
GI
|
n/a
|
4 (9.5%)
|
n/a
|
2 (2.7%)
|
n/a
|
|
Pulmonary
|
n/a
|
3 (7%)
|
n/a
|
n/a
|
n/a
|
|
GU
|
n/a
|
7 (17%)
|
25 (11%)
|
14 (19%)
|
|
|
Facial
|
n/a
|
9 (21%)
|
16 (7%)
|
3 (4%)
|
n/a
|
|
Thymic hypoplasia
|
2 (25%)
|
11 (26%)
|
10 (4%)
|
2 (2.7%)
|
n/a
|
|
Polyhydramnios
|
2 (25%)
|
13 (31%)
|
25 (9.2%)
|
11 (15%
|
n/a
|
|
FGR/SGA
|
3 (37.5%)
|
0%
|
n/a
|
6 (8%)
|
n/a
|
|
Other findings
|
n/a
|
SUA 1 (3%)
|
Increased NT 20 (8.7%)
|
Increased NT 11 (15%)
|
n/a
|
|
Live birth
|
4 (50%)
|
42 (100%)
|
67 (25%)
|
1 (1.35%)
|
0
|
Abbreviations: CNS, central nervous system; FGR/SGA, fetal growth restriction/small
for gestational age; GI, gastrointestinal; GU, genitourinary; n/a, not applicable;
NT, nuchal translucency; SUA, single umbilical artery; US, ultrasound.
A large prenatal series reported conotruncal heart defects to be the most common finding
(92%), followed by thymic hypoplasia (86%) and urinary tract anomalies (34%).[6] Other extracardiac anomalies include CNS anomalies (15.4–38%), polyhydramnios (9.2–30%),
facial dysmorphism (5.9–21%), skeletal defects (16.9–19%), genitourinary disorders
(10–33.8%), gastrointestinal (GI) anomalies (14%), and pulmonary disorders (7%).[6]
[7]
[8]
Interestingly, 90% of the fetuses were identified to have extracardiac manifestations
in a 2018 study.[6] Cleft lip/palate are considered to be markers for DGS when associated with other
defects.[8] However, it is an uncommon finding as cleft palate is seen in < 10% of children
and merely 1 to 2% present with cleft lip.[1]
[6]
[14] No fetus in our series had cleft lip/palate, restating the rarity of this finding,
though it is an important marker for DGS. Hypoplastic thymus was noted in 25% (2/8)
of fetuses in our cohort, which is kindred to a study by Schindewolf et al, whereas
various other studies reported a lower prevalence of 2.7 to 4%[6]
[7]
[8] ([Table 2]). Increased NT and FGR can also be inconsistently associated with DGS.[6]
[7] The NT scan was essentially normal in our series, though 37.5% of fetuses were SGA.
Polyhydramnios is a nonspecific finding and can be present in various conditions.
DGS is thought to be associated with GI tract anomaly or weak laryngopharyngeal musculature,
causing defective swallowing in the fetus, eventually leading to polyhydramnios.[12] Hence, the occurrence of polyhydramnios with other fetal markers should point toward
the diagnosis of DGS.
Over 67% of fetuses with DGS were reported to have dilated CSP in a previous study.[8] Neural tube defects and asymmetric ventriculomegaly, which are atypical findings
of DGS, have also been reported.[6]
[8] In the current series, we identified 25% with skeletal findings. Of these, one had
clenched fists with pointing index fingers, which, to our knowledge, is by far the
first such case to be reported in DGS. Furthermore, the unique case we encountered
had bilateral CTEV, which prompted us to look for other associated anomalies, such
as hypoplastic thymus and dilated CSP. CTEV is an uncommon finding and is seen in
only 3.3% of 22q11.2(del) affected children, highlighting the rarity of this finding.[15] As these findings are strongly linked to DGS, we confirmed our diagnosis by direct
testing. From this, we can infer the importance of identifying additional fetal markers
in the absence of CHD which can help us in the diagnosis and management.
22q11.2(del) can be detected either by FISH, multiplex ligation dependent probe amplification,
or aCGH but cannot be identified by karyotype. However, the availability and cost
effectiveness of these tests may limit their implementation in resource poor countries.[5] DGS manifests in childhood with developmental delay, learning disability, recurrent
infections, and psychiatric disorders like schizophrenia.[1]
[16] Twenty five percent of fetuses in our cohort succumbed due to DGS. Among the surviving
infants (25%), one child has a permanent sigmoid colostomy and surgical corrected
CHD, and the other has hypoparathyroidism with craniofacial features of DGS, which
were not identified antenatally, as it is difficult to ascertain facial dysmorphism
in a fetus. Both infants are thriving well with mild developmental delay. One of them
had stridor due to laryngomalacia, which is a well known association of DGS.
Management of DGS involves a multidisciplinary team consisting of pediatric cardiologist,
otolaryngologist, geneticist, pediatric surgeon, endocrinologist, and psychiatrists
formulated to ensure optimal postnatal outcome.[17]
[18]
[19]
[20] There are various DGS support groups around the globe to support families affected
with this condition, to provide useful advice on various aspects pertaining to this
disorder.
Conclusion
This prenatal series of DGS reiterates the importance of evaluating fetuses with conotruncal
anomalies. Additionally, prenatal findings like poor growth velocity, CTEV, polyhydramnios,
clenched fists with pointing index finger, and wide CSP in the absence of CHD should
raise a high index of suspicion of DGS, warranting genetic analysis, preferably microarray,
when a combination of multisystem involvement is detected for early diagnosis and
optimum management. From our experience, we highly recommend to meticulously evaluate
a fetus for subtle sonographic findings, even in the absence of CHD, which would warrant
for invasive testing. Timely diagnosis avoids unwanted surprises to the parents and
enables them to seek knowledge, anticipate the outcome, make reproductive decisions,
and find out ways of coping with the challenges in the management of these children.
