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
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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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