COMPREHENSIVE GENETIC EVALUATION
OF BULGARIAN CHILDREN WITH
SYNDROMIC CRANIOSYNOSTOSIS
Delchev T.1, Hadjidekova S.2, Bichev S.3, Veleva Ts.1, Boneva I.4, Avdjieva-Tzavella D.1
*Corresponding Author: Trayan Delchev, MD, PhD, Department of Clinical genetics, University
Children Hospital, Medical University of Sofia; Sofia, Bulgaria, Ivan Geshov blvd. No 11,
tel: +359883482376, e-mail: trayan_delchev@abv.bg
page: 6
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DISCUSSION
The distribution of suture involvement in syndromic
craniosynostosis in the literature [4-6] is sagittal in about
50-60%, followed by coronal in 20-25%, metopic in 15%
and lambdoid in approximately 5% of all cases. This differs
from our findings (see Results). This is probably due
to the limited size of our sample.
Patient 2 (Table 1) had normal results from conventional
chromosome analysis and MLPA while aCGH
revealed a pathogenic duplication of the long arm of chromosome
1 (1q21.1) (Table 2). The parents were not available
for segregation analysis. None of the genes within
this region have been associated with CRS so far. Rare,
recurrent chromosome 1q21.1 duplications and deletions
have been linked with developmental delay, autism, congenital
heart anomalies and macrocephaly in children [7].
Our patient was diagnosed with ASD, which is consistent
with the literature we found on duplication 1q21.1. The
aforementioned duplication also includes the 1q21.1 recurrent
(TAR – Thrombocytopenia Absent Radius syndrome) region (proximal, BP2-BP3). However, there is insufficient
evidence for triplosensitivity, explaining why we found
no phenotypic features of TAR syndrome in our patient.
Intriguingly, patients 2 and 25 (see Discussion, Patient 25)
were found to have partially overlapping duplications of
1q21.1. This warrants a further and more detailed investigation
of this chromosomal region.
In patient 8 (Table 1), conventional cytogenetics and
MLPA showed normal results. The patient was screened
for submicroscopic rearrangements using aCGH, yielding
one likely pathogenic, homozygous deletion of 14q32.33
(177.93Kb). Several gene sequences have been mapped
on this region, none of which have been connected to
craniosynostosis. Submicroscopic deletions of the long
arm of chromosome 14 are associated with two conditions
– Dubowitz syndome [8] and 14q32.3 deletion syndrome
[9]. Due to patient 8’s facial dysmorphism and the presence
of gastrointestinal symptoms as well as brachydactyly, we
are inclined towards Dubowitz symdrome (Tables 1 and 2).
As far as we know, neither Dubowitz syndrome nor
14q32.3 deletion syndrome have ever been associated with
craniosynostosis. We were not able to obtain information
regarding the biologicical parents of this patient.
In patient 22 (Table 1), aCGH revealed a heterozygous
deletion of the 5q35 region (5q35.2-5q35.3). The
deletion was 1.665 Mb in size (Table 2), encompassing 40
HGNC and 24 OMIM genes, including NSD1 and FGFR4.
The array CGH results were confirmed by MLPA. The
patient‘s parents were unavailable for testing. This result
is consistent with Sotos syndrome (SoS). It is a rare but
well-known disorder causing overgrowth in childhood.
Ten percent of affected individuals have 5q35 microdeletions
[10]. The size and mechanism of formation of 5q35
microdeletions differ depending on the ethnic origin of
the patients [11]. The presented features of our patient
(Table 1) are typical for SoS, although the overgrowth was
absent. Our patient’s microdeletion includes the NSD1 and
FGFR4 genes. Overall, the individuals with microdeletions have less prominent overgrowth than patients with NSD1
variants [12]. Douglas et al. also described a patient with
5q35 microdeletion involving NSD1 and FGFR4 genes and
craniosynostosis [13]. Fibroblast growth factor (FGF) and
fibroblast growth factor receptor (FGFR) signaling pathways
play essential roles in the earliest stages of skeletal
development, thus mutations in these genes can cause
differenent bone diseases, including craniosynostosis [14].
Nie et al. speculated that FGFR4 is involved in growth
regulation of face and head structures, although the effect
of FGFR4 on bone development remains unknown and
needs further elucidation [15].
The genetic evalutaion of patient 25 (Table 1) began
with chromosome analysis and MLPA, both showing normal
results. Array CGH, however, revealed a pathogenic
microduplication of chromosme 1 (1q12q21.2) spanning
across 4.62 Mb (Table 2). None of the genes within this
chromosome region have been associated with craniosynostosis
so far. Brisset et al. present a complex finding of
paternally inherited duplication 1q12q21.2 (5.8 Mb) in
combination with maternally inherited deletion of 16p11.2
of 545 Kb in a child with several malformations, psychomotor
delay, seizures and overweight [16]. Brisset’s finding
clearly differs from our patient 25, most likely due to
the additional deletion of 16p. It is interesting to note that
this patient’s duplication (which overlaps incompletely
with the finding in patient 2) also partially includes 1q21.1
recurrent region (BP3-BP4, distal) but without the GJA5
gene, thus possibly explaining the absence of congenital
heart disease in this patient. To our knowledge, the findings
in patients 2 and 25 are the first reported associations
between microduplications of 1q12q21.2 and 1q21.1 and
syndromic craniosynostosis.
Patient 29 (Table 1) presented with a pathological
female karyotype - 46,ÕÕ,t(2;7)(q14;q35). The same translocation
was found in her mother (who presented with
mild facial dysmorphism). The father had a normal male
karyotype. MLPA revealed a microduplication of the short
arm of chromosome 2 - dupl 2p16.1. Several cases with de
novo interstitial microduplications involving 2p16.1-p15
are reported in literature with facial dysmorphism, intellectual
disability, developmental delay, congenital heart
defects and various additional nonspecific features [17].
No associations with craniosynostosis were found. Finally,
aCGH was performed, which revealed a large pathogenic
duplication of 2p - dupl 2p22-3p16.1 (25.19 Mb). This
region is fairly large, containing a significant number of
genes which are unrelated to craniosynostosis, with one exception
– the SIX2 gene. This gene encodes a transcription
factor associated with cell differentiation and migration,
crucial for the development of several organs (including
the cranium). The increased dosage of SIX2 could lead to
early and pronounced ossification of cranial sutures, linking
with the craniofacial dysmorphism in our patient, making
this finding possibly causative. Hufnagel et al. report a case
with frontonasal dysplasia with sagittal craniosynostosis
due to microdeletion of the SIX2 gene [18]. These findings
reaffirm the complex role of the SIX2 gene in the etiology
of SC, making it a potential candidate for further study.
In patient 34 (Table 1) the conventional cytogenetic
analysis showed a normal male karyotype – 46,XY. MLPA
revealed a terminal deletion of the long arm of chromosome
4 - del 4q (TRIML2) which has no associations with
SC, as far as we know [19]. Array CGH, however, showed
a submicroscopic duplication of the short arm of 1st chromosome
- dupl 1p22.1 (378.47 Kb). This was classified as a
likely pathogenic variant. This chromosme region contains
5 gene sequences including the TGFBR3 gene (Table 2). It
encodes the transforming growth factor (TGF)-beta type
III receptor. These receptors, along with the FGF receptor
family are widely expressed in bone cells and in the bone
matrix and play an important role in premature pathological
suture closure [20-21]. Based on this finding, we
hypothesize that the duplication of 1p22.1 containing the
TGFBR3 gene links with the metopic craniosynostosis in
our patient, making the finding potentially causative. This
particular chromosome region is a promising candidate for
further investigation into syndromic craniosynostosis. Additionally,
our patient presented with hypoplasia of corpus
callosum which is characteristic of 1p22 duplications.
The disparity between the MLPA and aCGH findings is a
result of method limitations. The patient‘s parents were
unavailable for further testing.
In conclucion, we tried to elucidate various genetic
factors involved in the pathogenesis of syndromic craniosynostosis
by screening 39 children with a combination of
cytogenetics, MLPA, and array CGH. In total, we found 6
patients with significant genetic variations. This constitutes
15.3% of the children in our sample, corresponding with
the data we observed in the literature. In our study, aCGH
had the highest detection rate proving that submicroscopic
chromosomal rearrangements play an important role in the
pathogenesis of syndromic craniosynostosis. MLPA and
conventional karyotyping yielded respectively 7.7% and
2.5% pathological findings. Duplications were found to be
more common than the deletions, underlining the importance
of increased dosage of certain genes in syndromic
craniosynostosis. Coronal synostosis was the most common
anatomical variant we found, which differs from the
established suture involvement distribution in literature,
probably due to sample size limitations. Several genetic
variations already connected to different pathological conditions
were found in children with syndromic craniosynostosis.
Those findings reaffirm the complex role of various genetic factors in cranial suture patency regulation and
warrant further investigation.
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