3. Discussion
The general features of 22q11.2 DS vary widely (more than 180 phenotypic
presentations) and includes Di George’s syndrome, Shprintzen’s syndrome
as well as Cayler cardio-facial syndrome. The syndromes were named
separately after their first description by the author. Later, with the
advancements in the diagnostic methods in the field of genetics, it was
found that 22q11.2 chromosome was deleted in all these syndromes. They
are currently grouped under “the 22q11.2 deletion syndromes”, as it is
difficult to choose a single term.
22q11.2 DS is one of the most frequently encountered interstitial
deletion syndromes in the population, with an estimated frequency of
1/4000-5000 (Scambler, 2000). Though usually sporadic and autosomal
dominant inheritance, it has been reported in 10-20% of the patients
(Bassett et al., 2011).
The chromosome 22q11 region is very unstable with misalignment of
chromosome-specific low-copy repeats (LCR22A-H) during nonallelic
homologous recombination, leading to the deletion of 22q11.2 region
(Burnside, 2015). Approximately 90% of patients with 22q11DS have a
1.5~3Mb deletion (Burnside, 2015; Yagi et al., 2003).
The haploinsufficiency of genes located at 22q11.2, especiallyTBX1 , can disturb the early morphogenesis of many organs
including the thymus, parathyroid gland and facial structures. This
explains as to why there are wide clinical manifestations like cardiac
defects, thymic hypoplasia, abnormal facial features, cleft palate, and
hypocalcemia associated with it (Yagi et al., 2003).
The cause of hypoplasia of the depressor anguli oris muscle still
remains to be elusive, though previous studies postulated intrauterine
molding or subclinical viral infections as the cause. This finding needs
further confirmation. Lahat et al. (Lahat, Heyman, Barkay, & Goldberg,
2000) reported a prospective study, wherein 17 out of 5532 infants had
ACF. There were no noxious obstetric perinatal factors identified and no
family history of hereditary diseases in all the cases. In our case, we
also found no maternal infection and no family history of hereditary or
systemic diseases associated with ACS.
Hypoparathyroidism and hypothyroidism are commonly observed in patients
with 22q11.2 deletion and requires much attention. Hypoparathyroidism is
the first hormonal disturbance recognized in DGS and is documented by
aplasia and hypoplasia of the parathyroid glands during surgery or
autopsy. Furthermore, hypocalcemia can occur transiently during the
neonatal stage with symptoms of seizures, tremors, or tetany, which
mainly occur due to low parathyroid reserve and abrupt cessation of
maternal calcium supply after birth. In our case, serum calcium level
was normal (2.3mmol/L, reference rage, 2.1-2.7 mmol/L), no hypocalcemic
symptoms of seizures, tremors, or tetany were observed on admission,
which ruled out the possibility of hypocalcemia due to
hypoparathyroidism. Although hypocalcemia may not be present during the
neonatal period (Pawar, Sharma, Srilakshmi, Reddy Chejeti, & Pandita,
2015), studies have shown that it can occur at any time during childhood
(Friedman, Rienstein, Yeshayahu, Gothelf, & Somech. 2016; Fu, Leung,
Kao, & Yeh, 2015), adolescence (Yoo, Kim, Cho, Kwon, & Yoo, 2017) and
even in adulthood (Fung et al., 2015; Maldjian & Sanders, 2018). This
is likely due to the recurrence of hypoparathyroidism precipitated by
increased metabolic demand and acute illness during pregnancy, surgery,
infection, or any physiologic stress conditions. Regular lifelong
follow-up of calcium, magnesium, and PTH levels are required in patients
with 22q11DS (Cheung, George, Costain, Andrade, Chow, Silversides, &
Bassett, 2014). Calcium and vitamin D supplements are recommended to
patients with 22q11DS, regardless of whether they have been diagnosed
with hypocalcaemia or not. However, iatrogenic hypercalcemia resulted in
renal calculi and renal failure, and so should be avoided (Fung et al.,
2015).
Immunodeficiency has been reported in 80% of the patients with 22q11
syndrome. As a result of thymic hypoplasia, cell-mediated immunity is
usually involved with 22q11DS, decreasing the T-cell numbers and
functions. However, disorders of humoral immunity might also occur.
Waters et al. (Waters, Peterson, & LaRussa, 2007) reported a case of
pneumonia in a 13-month-old male child with partial DGS, and the child
died after inadvertently receiving live viral vaccines. Recently,
Matsuoka (Matsuoka et al., 2019) reported the first case of a teenage
patient with chromosome 22q11.2 DS who died due to overwhelming
post-splenectomy infection (OPSI) by Streptococcus pneumoniaedespite appropriate prevention by pneumococcal vaccine. As such, it is
appropriate to check immunoglobulin levels in the patient before
vaccinations.
Congenital heart defects are one of the main clinical features of
22q11DS. Although serious cardiac anomalies were present in most of the
patients in earlier studies, their prevalence accounted for about 40%
according to the recent papers (Fung et al., 2015). Interestingly, our
patient had ventricular septal defect and two atrial septal defects
which warranted ongoing follow-up visists.
Some follow-up studies revealed that the frequency of psychomotor
retardation and speech disorders was increased (Cancrini et al., 2014).
However, information regarding long-term outcomes and older age ranged
in ACS has been limited in China. Our patient showed a normal neonatal
behavioral neurological assessment (NBNA) score at a corrected
gestational age of 41 weeks and his physical index was between P10-P90,
but he still had ACF. During the final evaluation, he was aged 2 years 6
mo, had developmental delay (height: 80cm; and body weight: 11kg) and
speech deficits. However, the patient’s intellectual level, cognitive
and adaptive functioning and motor function were normal. The patient had
undergone intracardiac repair the prior month which necessitated ongoing
follow-up visits. The best case scenario involves early interventions
for developmental delay and learning difficulties. Parents required
counseling due to long-term outcomes, as deletion of 22q11.2 is
associated with learning difficulties and mental retardation.
Previously, karyotyping results by GTG banding were normal in most of
the ACF patients. Recently, more sophisticated techniques such as FISH
have been replaced by karyotyping studies in most of the laboratories.
It is therefore not surprising that several ACF cases with chromosome
22q11 microdeletions have been or continue to be reported (Pawar,
Sharma, Srilakshmi, Reddy Chejeti, & Pandita, 2015). Some authors,
therefore, suggested that newborns with ACF require additional screening
of 22q11.2 DS (Pasick, McDonald-McGinn, Simbolon, Low, Zackai, &
Jackson, 2013). In our case, genetic investigations were performed to
exclude any underlying syndrome caused by 22q11 deletion. Notably, DNA
high throughput sequencing analysis revealed two microdeletions of
chromosomes 22q11.21 and 11p15.4, respectively. This, coupled with the
clinical presentation confirmed the diagnosis of ’ACF’ as a result of
hypoplasia of the depressor anguli oris muscle.
Previous studies have reported that children diagnosed with Cayler
Cardio-facial syndrome have an underlying condition called 22q11.2 DS,
in which a small part of chromosome 22 is absent. More importantly, we
detected additional chromosomal microdeletions in 11p15.4 in our
patient. ACS is traditionally diagnosed using FISH with commercial
probes. It is extremely accurate but limited to only one single-target
sequence. Interestingly, our results showed the effectiveness of DNA
high throughput sequencing, which overcame the limitations of FISH in
terms of diagnostic yield and allowed whole genome screening and
detection of a larger number of deletions and/or duplications in ACS
patients.
In conclusion,our report reinforces that facial phenotypic and cardiac
anomalies are manifestations associated with ACS. However, confirmation
of this disease requires further genetic investigations. Apart from a
microdeletion of chromosome 22q11.21, a novel microdeletion of
chromosome 11p15.4 was found in our case. We, therefore, suggest that
newborns with ACS should be screened with DNA high throughput sequencing
analysis across the whole genome, which is more advantageous over FISH
technique and could contribute to further research.