ACHONDROGENESIS TYPE 2 IN A NEWBORN WITH
A NOVEL MUTATION ON THE COL2A1 GENE
Dogan P1,*, Varal IG1, Gorukmez O2, Akkurt MO3, Akdag A1
*Corresponding Author: Pelin Dogan, M.D., University of Health Sciences, Bursa Yuksek Ihtisas
Teaching Hospital, Department of Pediatrics, Division of Neonatology, Yıldırım, Bursa, Turkey.
Tel.: +90-505-316-4268. Fax: +90-224-294-4000. E-mail: pelin_akbas@yahoo.com
page: 89
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DISCUSSION
In this report, we present a case with a heterozygous
missense variation on the COL2A1 gene, c.2546G>A,
p.Gly849Asp mutation, being a different genetic variant
of ACG2 syndrome that has rarely been reported in the
literature. A definitive molecular diagnosis was made in
the patient through the application of clinical exome and
Sanger sequencing. The fact that the present patient was diagnosed
with targeted exome sequencing allowed a shorter
diagnostic process than with whole exome sequencing
(WES) [7].
The COL2A1 gene located on chromosome 12 encodes
polypeptide chains of type 2 collagen. A glycine
substitution in the triplehelical domain is the most common
type of pathogenic mutation on the COL2A1 gene
[8]. Even though 570 different changes on the COL2A1
gene have so far been reported, the genetic variation in our case has not been previously reported (c.2546G>A,
p.Gly849Asp mutation) (HGMD). Genetic variations on
the COL2A1 gene are clinically heterogeneous and were
associated with 15 different phenotypes (omim.org). In a
previous study, it was reported that glycine to asparagine
substitutions in COL1A2 resulted in a severe short stature,
whereas in another study, it was reported that patients with
glycine to asparagine mutations were rather tall [9,10].
In the presented case, a glycine to asparagine substitution
was observed and a phenotype presented with short
structure and shortening of the limbs. In another case,
similar to ours, a p.Gly1122Arg mutation was observed as
phenotype generalized broadening and shortening of the
phalanges were reported [10]. Studies showed that severe
ocular phenotype was observed in patients with glycine to
aspartic acid and glycine to arginine mutations, but in the
presented case, a glycine to asparagine substitution was
observed, however, the ophthalmological examination of
the patient was normal. The presence of severe mutations
affecting glycine is frequent in ACG2 and the frequent
mutation was p.(Gly1110Cys) c.3328G>T. Death occurs
mostly in utero or during the early neonatal period [11].
Similarly, in the present case, we observed a glycine to
asparagine substitution (c.2546G>A, p.Gly849Asp) and
the patient died on postnatal day 25. A broad spectrum of
disorders occur as a result of mutations on the COL2A1
gene. Milder clinical forms of skeletal dysplasia, such as
the Czech dysplasia (OMIM 609192), premature onset
arthritis (OMIM 604864), bilateral hip disease and short
stature, can occur, but lethal skeletal dysplasias such as
ACG2 may also occur [12]. Type 2 collagen is present
in the hyaline cartilage and vitreous humor, leading to
spinal, epiphyseal and ocular anomalies in COL2A1 gene
mutations.
Dysostoses are constitutional disorders of the bone
that take the form of malformations of single or multiple
bones in combination. Based on genetic mutations and
variations in blastogenesis, they affect normal bone or
cartilage development and cause bone defects and skeletal
dysplasias [13]. Achondrogenesis comes in three forms,
being ACG1A (Houston-Harris type), ACG1B (Parenti-
Fraccaro type) and ACG2 (Langer-Saldino), with differential
diagnoses made based on clinical, radiological and
molecular findings. The various forms of ACG have identical
phenotypic characteristics, such as hydrops fetalis,
short neck and trunk, small chest (bell-shaped), prominent
abdomen and severe micromyelia, which are typically observed
in the all three groups, while there are radiological
and molecular differences between the three [13]. The skull
is not ossified in ACG1A, whereas there are mildly low
ossified areas in ACG1B. Skull ossification is normal in
ACG2, alongside decreased ossification in the pelvis and
spine. Rib fractures are common in ACG1A, whereas short
ribs are often without fractures in ACG2 [2,4,13]. The present
case of ACG2 had typical phenotypic characteristics,
including short trunk, small chest, distinctive abdomen and
micromyelia, and a radiologic examination revealed short
tubular bones with widened metaphyses and non ossified
cervical vertebrae, short unfractured ribs, a narrow bellshaped
chest, lack of ossification in the pelvis and normal
ossification of the skull (Figures 1 and 2).
Apart from skeletal anomalies, severe pulmonary
hy-poplasia occurs in ACG2 due to the underlying defects
in collagen expression, and respiratory distress can occur
immediately after birth with severe forms of the disorder
[2,14]. The present case had significant respiratory distress
immediately after birth, was followed with HFOV due to
persistent respiratory distress during mechanical ventilation
using conventional settings and the patient died of
respiratory insufficiency on postnatal day 25.
In conclusion, we present a patient with ACG2 and
a novel mutation on the COL2A1 gene, identified through
NGS. Our findings expand the spectrum of causative mutations
and clinical findings in ACG2. The authors suggest
that the recognition of ACG2 in the prenatal and neonatal
period may enable the earlier prediction of the anomaly,
and may prolong survival through genetic counseling provided
to the family before and after birth.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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