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SHORT COMMUNICATION
Syndromic craniosynostosis associated with
microdeletion of chromosome
19p13.12e19p13.2
Sarah M. Lyon
a
, Darrel Waggoner
b
, Sara Halbach
b
,
Erik C. Thorland
c
, Leila Khorasani
d
, Russell R. Reid
d,
*
a
Pritzker School of Medicine, University of Chicago, United States
b
Department of Human Genetics and Pediatrics, University of Chicago, 5841 S. Maryland Ave,
M/C 0077, Chicago, IL 60637, United States
c
Lab Medicine & Pathology, 200 First St SW, Hilton 970, Rochester, MN 55905-0001, United States
d
Department of Surgery, University of Chicago, 5841 S. Maryland Ave, M/C 0077, Chicago, IL 60637,
United States
Received 27 July 2015; accepted 9 September 2015
KEYWORDS
Chromosome 19;
Craniofacial
syndrome;
Craniosynostosis;
Microarray;
Microdeletion
Abstract Craniosynostosis, a condition in which the cranial sutures pr ematurely fuse, can
lead to elevated intracranial pressure and craniofacial abnormali ties in yo ung children.
Currently surgical intervention is the only therapeutic option for patients with this condition.
Craniosynostosis has been associated with a variety of different gene mutations and chromo-
some anomalies. Here we describe three cases of partial deletion of chromosome 19p. Two of
the cases present with syndromic craniosynostosis while one has metopic ridging. A review of
the genes involved in the rearrangements between the three cases suggests several gene can-
didates for craniosynostosis. CALR and DAND5, BMP regulators involved in osteoblast differen-
tiation, and MORG1, a mediator of osteoclast dysregulation may play a role in abnormal cranial
vault development. Additionally, CACNA1A, a gene that when mutated is associated with ep-
ilepsy and CC2D1A, a gene associated with non-syndromic mental retardation may contribute
to additional phenotypic features seen in the patients we describe. In addition, these findings
further support the need for genetic testing in cases of syndromic craniosynostosis.
Copyright ª 2015, Chongqing Medical University. Production and hosting by Elsevier B.V. This is
an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).
* Corresponding author. Section of Plastic Surgery, 5841 S. Maryland Avenue, M/C 6035, Chicago, IL 60637, United States. Tel.: þ1 773 702
6302; fax: þ1 773 702 1634.
E-mail addresses: slyon@uchicago.edu (S.M. Lyon), dwaggone@geneti cs.uchicago.edu (D. Waggoner), shalbach@bsd.uchicago.edu (S .
Halbach), thorland.erik@mayo.edu (E.C. Thorland), rreid@surgery.bsd.uchicago.edu (R.R. Reid).
Peer review under responsibility of Chongqing Medical University.
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Please cite this article in press as: Lyon SM, et al., Syndromic craniosynostosis associated with microdeletion of chromosome
19p13.12e19p13.2, Genes & Diseases (2015), http://dx.doi.org/10.1016/j.gendis.2015.09.001
http://dx.doi.org/10.1016/j.gendis.2015.09.001
2352-3042/Copyright ª 2015, Chongqing Medical University. Production and hosting by Elsevier B.V. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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Genes & Diseases (2015) xx,1e6
Introduction
The premature fusion of cranial sutures affects approxi-
mately 1 in 2500 newborns in a condition known as cra-
niosynostosis.
1,2
Craniosynostosis can lead to elevated
intracranial pressure, developmental delay and ocular/vi-
sual compromise.
3
Craniosynostosis can be characterized as either syn-
dromic or non-syndromic. Approximately 80% of cases are
non-syndromic and there is no common genetic basis.
4
In
isolated (non-syndromic) craniosynostosis the sagittal su-
ture is most commonly affected, followed by the metopic
and coronal sutures. Closure of the metopic suture can
result in metopic ridging and metopic craniosynostosis
which can be difficult to differentiate but which have
importance for treatment.
5
Syndromic cases can be
inherited but are often sporadic and are the result of de
novo autosomal dominant mutations commonly involving
fibroblast growth factor receptors (FGFRs) and TWIST gen-
es.
6e8
Gain-of-function mutations in FGFR1 to 3 have been
associated with Crouzon, Pfeiffer, Apert and Muenke syn-
dromes, among others. More than 180 syndromes have been
reported to manifest craniosynostosis.
4
Here we describe
three cases of patients with deletions in the region of
chromosome 19p13.12ep13.2. Two of the cases with over-
lapping deletion have developmental delay and craniosy-
nostosis, whereas the other patient with a unique deletion
in the region has physiologic closure of the metopic suture
with ridging without craniosynostosis. These cases along
with one additional case from the literature help define
genes that may be associated with syndromic craniosynos-
tosis. Approval of this case series was obtained from the
University of Chicago Institutional Review Board (IRB#14-
0489). Parental consent forms, which included permission
for the use of the facial images of the affected individuals,
were obtained for the reported work.
Case 1
The first patient was born to healthy parents after a preg-
nancy complicated by antenatal ultrasound findings of
ventriculomegaly. The patient was born via elective ce-
sarean section at 38 weeks with a birth weight of 2365 g
(<5th percentile) and occipitofrontal circumference (OFC)
of 36.5 cm (95th percentile). In the newborn period, she
developed oxygen desaturations and feeding difficulties.
Clinical examination at that time revealed micrognathia,
frontal bossing, low set ears, a high palate and scaphoce-
phaly (Fig. 1). A CT scan of the cranial bones revealed
partial posterior sagittal craniosynostosis and micrognathia
(Fig. 1). Magnetic resonance (MR) imaging of the brain
revealed an immature brain with thickened cortex and
decreased gyral pattern suggestive of a cortical brain
malformation. An ophthalmology examination revealed
bilateral optic nerve hypoplasia.
Due to her severe obstructive sleep apnea (OSA)dwith a
presurgical apneaehypopnea index (AHI) of 60dthe patient
underwent multiple interventions (tongue lip adhesion and
mandibular distraction osteogenesis) to improve her airway
obstruction. This markedly reduced the patient’s supple-
mental oxygen requirement. With improvement in her
airway and nutrition, the patient underwent a subsequent
subtotal calvarial vault reconstruction for sagittal cranio-
synostosis (Fig. 1 ).
Her growth and development continued to be delayed.
At 8 months of age, her weight was 6.61 kg (2nd percen-
tile), and height was 68.2 cm (40th percentile) and OFC was
44.5 cm (75th percentile). At 11 months of age she had
developmental delays of gross and fine motor as well as
speech. At 20 months of age she developed seizures, which
were treated with anti-epileptic medication.
At 26 months of age, 20 months post initial cranial vault
expansion, the patient’s head circumference failed to
progress over a 9-month period. The patient presented with
turribrachycephaly and computed tomography (CT) scan
evaluation revealed clear signs of craniocerebral mismatch
with no identifiable cranial suture patent (Fig. 1). These
radiographic signs corroborated the clinical presentation,
as the patient was found to have signs and symptoms of
increased intracranial pressure. These findings necessitated
a revision cranial vault expansion via multidirectional pos-
terior vault distraction.
Microarray results. Cytogenomic microarray revealed a
2.2 Mb microdeletion of chromosome 19p: arr
19p13.12ep13.2 (12,552,241e14,714,485) (National Center
for Biotechnology Information (NCBI) build 36.1) containing
approximately 73 known genes.
Case 2
The second patient is an international case of a 10-month-
old Scandinavian child who is the product of a first preg-
nancy to healthy parents. She was born following induction
of labor for low amniotic fluid at gestational age 41 weeks 3
days. Birth weight was 3 465 g and length was 51 cm. There
were no complications at birth. An abnormal head shape,
with occipital flattening, was noted by the parents and the
pediatrician, but this was thought to be related to posi-
tional molding.
She developed persistent vomiting/reflux, necessitating
hospitalization on three separate occasions (starting at 2
months of age). Secondary to the reflux and developmental
delays a cytogenomic microarray revealed a 700 kb deletion
of chromosome 19p13.2 (chr. 19: 13,041,835e13,740,519
NCBI Build 36.1). Parental studies were not obtained.
Her head circumference measured 38.1 cm at 4 weeks of
age, 42 cm at 4 months of age, and 44.5 cm at 9 months of age
(all at the 75th percentile for age). Digital photography (not
shown) reveals bitemporal retrusion, mild brachycephaly,
and right posterior plagiocephaly. Interestingly, craniofacial
CT scan with 3D reformations demonstrates partial synos-
tosis of the bilateral coronal suture systems (Fig. 2). No other
findings were remarkable on these imaging studies.
Case 3
The third patient is a female 7-month-old fraternal twin
born via cesarean section at 36 weeks gestation following a
pregnancy in which serial ultrasonography identified ven-
triculomegaly and hydronephrosis. The patient had respi-
ratory distress and cyanosis and feeding difficulties. Birth
weight was 2060 g (<5th percentile), length was 41 cm
2 S.M. Lyon et al.
+ MODEL
Please cite this article in press as: Lyon SM, et al., Syndromic craniosynostosis associated with microdeletion of chromosome
19p13.12e19p13.2, Genes & Diseases (2015), http://dx.doi.org/10.1016/j.gendis.2015.09.001
(<5th percentile), and head circumference (HC) was
31.5 cm (<5th percentile). A brain MRI confirmed the
enlarged ventricles and, additionally, showed a hypoplastic
corpus callosum.
At 6 months of age she was noted to have significant
proximal and peripheral hypotonia as well as symmetrically
decreased reflexes in the upper and lower extremities. Her
ears were slightly low set and posteriorly rotated with
mildly pointed superior helices, and her head was triangular
shaped with a flat occiput, severe plagiocephaly, biparietal
peaking, and bitemporal narrowing. Her skin showed a 1 cm
cafe
´
-au-lait spot in the right groin, a tiny skin tag at the
coccyx without dimple, and a 2.5 cm brown flat macule
with clear borders on the center of the abdomen. Her
weight was 6.5 kg (14th percentile), length was 62.0 cm
(8th percentile), and HC was 42.3 cm (41st percentile).
Developmentally she had delays in gross motor skills.
Based on her head shape described above a CT scan was
done and showed features consistent with physiologic
closure of the metopic suture with ridging, and no cranio-
synostosis ( Fig. 3).
Chromosomal single nucleotide polymorphisms (SNP)
array analysis was ordered with showed a 19p13.12 deletion
(14,144,824e14,787,018, hg19). This 642 kb deletion was
maternally inherited.
Methods
Cytogenomic array analysis was performed using either a
custom Agilent oligonucleotide microarray with 180,000
probes and analyzed on human genome build hg18 or the
Affymetrix CytoScan HD array including 750,000 SNP probes
and 1.9 million non-polymorphic probes analyzed on hg19.
Base pair coordinates were estimated from the microarray
and the coordinates from hg18 were converted to hg19 for
comparison.
Discussion
Microdeletions in the small arm of chromosome 19 are rare
and described deletions have significant phenotypes that
Figure 1 Case 1. I: A, B; Photos of patient 1 before calvarial vault reconstruction. A. Photo shows typical compensatory sca-
phocephaly and micrognathia, as well as dysmorphic features including low set ears, frontal bossing of the cranial vault secondary
to sagittal suture fusion. C,D; 24 months of age demonstrating turribrachycephaly. II: A, B; CT scan at birth showing the micro-
gnathia (A) and the partial sagittal craniosynostosis (B). C, D; Axial T2 FLAIR MRI at birth shows adequate brain growth. Scan is
notable for mild lissencephaly. III: A, B; CT scan at 5 months post mandibular distraction showing persistent micrognathia and
progression of the sagittal craniosynostosis. C, D; CT scan at 24 months of age demonstrating craniocerebral mismatch with
effacement of the sagittal suture and the coronal sutures.
Syndromic craniosynostosis 3
+ MODEL
Please cite this article in press as: Lyon SM, et al., Syndromic craniosynostosis associated with microdeletion of chromosome
19p13.12e19p13.2, Genes & Diseases (2015), http://dx.doi.org/10.1016/j.gendis.2015.09.001
are often terminal in utero.
9
The clinical phenotypes of
patients with chromosome 19p deletions are difficult to
compare and variable as the deletions are of different sizes
and involve different regions of chromosome 19. Many re-
ported cases were described based on karyotype abnor-
malities with poor resolution of breakpoints. The recent
advance of cytogenomic microarray technology has allowed
for higher resolution studies and characterization of the
exact genomic composition including specific genes within
genomic rearrangements.
Three patients with overlapping 19p13.12 microdeletions
have been described with mental retardation, ear malfor-
mations, brachycephaly and anteverted nares.
10
Addition-
ally, an 834 kb deletion in 19p13.2 was described in a five-
year-old boy with intellectual disability, febrile seizures and
minor dysmorphic features including a slightly protruding
forehead, short fingers and ears with overfolded helices.
11
An additional case bearing common deletions within the
same region to our case series is a case of complex syn-
dromic craniosynostosis (fused left coronal, lambdoid and
parieto-temporal sutures) described by Lysy et al.
12
The patient reported by Lysy et al and two of the three
patients we describe (Cases 1 and 2 herein) all share de-
letions of CALR and DAND5 (Fig. 4)dregulators of bone
morphogenetic proteins (BMPs) essential for bone
metabolism, organ and skeletal formation and differentia-
tion of osteoblastic cells.
13,14
These common deletions
suggest that the absence of these BMP regulatory genes
could cause abnormalities in calvarial development leading
to craniosynostosis.
12
Additionally, MORG1, a gene whose
product associates with components of the extracellular
signal-regulated kinase (ERK) pathway integral to osteo-
clast development and activity, is deleted in the patient
described by Lysy et al and in our first case.
15,16
Deletion of
this helper protein may disrupt the ERK signaling pathway
that leads to osteoclast dysregulation.
17
This gene was not
deleted in the second case reported herein who similarly
presents with a 700 kb deletion in chromosome 19p13.2
(within that of Case 1), partial synostosis and develop-
mental delay. Deletion of coding regions on the 5
0
end of
the gene, however, could affect MORG1 expression. The
microdeletion described in this second case is on the 3
0
end
of the gene, which suggests that MORG1 is not implicated in
the craniosynostotic phenotype (Fig. 4). Interestingly, both
cases described herein had partial involvement of a
particular suture system, whether sagittal (Case 1)or
bilateral coronal (Case 2). In the case described by Lysy
et al, there is pansynostosis (left unicoronal, lambdoid, and
parieto-temporal) which, to our review of the figures in
their manuscript, represents a partial, “skip-lesion”
Figure 2 Case 2. Three-dimensional reformatted CT scan imaging demonstrates partial synostosis of bilateral coronal sutures.
A. Frontal view; B. Right lateral view; C. Posterior view; D. Left lateral view. Arrows denote areas of abnormal bridging ossification
(synostosis) of coronal sutures.
4 S.M. Lyon et al.
+ MODEL
Please cite this article in press as: Lyon SM, et al., Syndromic craniosynostosis associated with microdeletion of chromosome
19p13.12e19p13.2, Genes & Diseases (2015), http://dx.doi.org/10.1016/j.gendis.2015.09.001
phenotype. The authors also comment in their case that the
craniosynostosis, in certain areas, is partial. The fact that
our first case had craniocerebral disproportion with
elevated intracranial pressure, and required revision cra-
nioplasty to expand the cranial vault, corroborates the
syndromic nature of this presentation and points to po-
tential lesions in the molecular pathways described above.
Further implicating this region’s significance in suture
homeostasis is the third case presented in this study.
Microarray analysis of this patient revealed a deletion distal
to the other patients, and therefore not involving the pu-
tative genes described above. Despite clinical findings of
severe plagiocephaly, biparietal peaking, and bitemporal
narrowing, suggestive of premature metopic closure, the
patient failed to demonstrate the formal radiographic signs
characteristic of metopic craniosynostosis: her findings are
Figure 3 Case 3. Three-dimensional reformatted CT scan imaging demonstrates head shape and lack of findings consistent with
craniosynostosis and consistent with physiologic closure of the metopic suture. A. Frontal view; B. Right lateral view; C. Posterior
view; D. Left lateral view. Note occipital flattening and biparietal peaking, physiologic closure of metopic suture and patency of
other cranial sutures.
Figure 4 Genomic overlap A. Ideogram of chromosome 19 at
850 band stage. B. Zoomed in view of deletions showing the
regions of overlap between the cases and the genes of interest.
Dotted lines represent minimum region of overlap between the
patients with craniosynostosis.
Syndromic craniosynostosis 5
+ MODEL
Please cite this article in press as: Lyon SM, et al., Syndromic craniosynostosis associated with microdeletion of chromosome
19p13.12e19p13.2, Genes & Diseases (2015), http://dx.doi.org/10.1016/j.gendis.2015.09.001
more indicative of physiologic closure of the metopic suture
with ridging.
5
Lastly, the deletion described in our first and second
cases also included the CACNA1A and the first and third
case included the CC2D1A gene. CACNA1A is a gene
encoding a voltage dependent calcium channel subunit
expressed in neuronal tissue and mutations in this gene are
associated with epilepsy.
16,18
CC2D1A is a gene that regu-
lates the expression of serotonin receptors in neuronal
tissue and mutations in this gene have been associated with
non-syndromic mental retardation.
16
Deletion of these
genes likely contributes to the patient’s phenotype of
developmental disability and seizures.
Conclusion
We now add to the growing body of evidence in the liter-
ature supporting the association of specific chromosomal
19p microdeletions (19p13.12e13.2) and cranial suture
dysmorphology. Specifically, two craniosynostotic patients
are described: one with sagittal craniosynostosis, micro-
gnathia, seizure disorder, hypotonia and developmental
delay, and another patient with bilateral coronal synostosis
and mild developmental delays. Our third case in this se-
ries, with a deletion distal to the first two cases and only
hypotonia, plagiocephaly and developmental delay, further
targets a putative gene locus, which affects suture ho-
meostasis. Of particular interest, the first two patients
described in this report, and that described by Lysy et al,
demonstrate initial partial involvement of some sutures,
suggesting a progressive process and therefore point to
genetic and epigenetic causal factors. The craniosynostosis
in the first case required multiple surgeries secondary to
craniocerebral mismatch, which is unusual outside the
syndromes associated with FGFR. The second case demon-
strates bilateral coronal synostosis, which is partial in na-
ture. The genes in the deleted region are associated with
seizures, developmental disability and a disruption in the
balance between osteoblastic and osteoclastic activity
essential for proper bone growth and remodeling. This
report not only helps expand the phenotypic characteriza-
tion of 19p deletions, but also reinforces the importance of
cytogenomic microarray in the setting of suspected syn-
dromic craniosynostosis.
Acknowledgments
The authors would like to thank James Cao, Administrative
Specialist in the Section of Plastic Surgery, University of
Chicago, for his assistance with obtaining test results and
figures from Case 2 and with consent form procurement.
Conflict of interest
None of the authors have any financial conflicts of interest
to disclose.
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Please cite this article in press as: Lyon SM, et al., Syndromic craniosynostosis associated with microdeletion of chromosome
19p13.12e19p13.2, Genes & Diseases (2015), http://dx.doi.org/10.1016/j.gendis.2015.09.001
