OP-03 Osteogenesis Imperfecta Type 3 with COL1A1 mutation Prenatal diagnosis and management

Objective

Osteogenesis Imperfecta (OI) is a rare genetic disease group consisting of defects in collagen synthesis. This disease is characterized by alteration of connective tissue structure of exposed patients, usually caused by mutation of type I collagen. Altered connective tissue structure leads to low bone mineral density, defective bone structure and strength, and multiple fractures, which are usually obtained after low-impact trauma.[1] It is a rare disease that is seen in 0.5-1 per 10000 live births in general.[2] There are several types of OI, type I being the mildest form of OI, which is usually asymptomatic, sometimes with scoliosis due to compression fractures of the vertebrae in adults. Type II is the most severe form and is generally incompatible with life, while type III is the most severe form in surviving patients.[2-4] OI is inherited in an autosomal dominant manner and heterozygous mutation in one of the COL1A1 or COL1A2 genes is the cause in more than 90% of cases. [2,5] Type III constitutes 5% of all OI cases.[5] With this case report, we aimed to present the antenatal findings and clinical management of an OI type III case diagnosed during the antenatal period.

Methods

Computer-based and ultrasonography records of a case of osteogenesis imperfecta who applied to the Perinatology outpatient clinic of Prof. Dr. Cemil Taşçıoğlu City Hospital at the 8th week of pregnancy were retrospectively scanned from the hospital system and the history of the ultrasonography device. Fetal ultrasonography examination was performed using Mindray Resona 7 device and its 1.2-6 MHz convex abdominal probe. Ultrasonography findings and patient history were noted.

Case

A 40-year-old primagravid patient who became pregnant by in vitro fertilization first applied to our clinic for an 11-14 week ultrasound examination at 14 weeks of age. In the patient’s anamnesis, it was learned that he had a brain aneurysm 2 years ago and had hypothyroidism. The result of the non-invasive prenatal test performed by the patient in an external center was reported as normal. In the ultrasound examination of the patient at the 14th week, hypomineralization was observed in the skull bones (Figure 1). It was observed that the head shape was deformed by the compression of the ultrasound probe. Osteogenesis imperfecta, hypophosphatasia and achondrogenesis were considered as the differential diagnosis in the patient. The patient was informed and called for follow-up 2 weeks later. In the ultrasound examination performed at the 16th week, hypomineralization was observed in the skull bones, the mineralization of the vertebral column was normal, shortness in all long bones, contractures in the hands and feet, and short costa were observed (Figure 2). The family was informed about amniocentesis and amniocentesis was performed. A heterozygous variant in the COL1A1 gene was detected in the fetus in wholeexome sequencing analysis, and this variant was reported as a pathogenic variant associated with Osteogenesis Imperfecta Type 3. The family decided to terminate. Termination was performed at 20 weeks (Figure 3,4). The patient, who had no bleeding or complaints after termination, was discharged with recommendations.

Results

OI is a persistent connective tissue disease with autosomal dominant inheritance. OI Type III is shown as the most severe form in survivors.[2] Although there are treatment options such as pamidronate, zolidronate or risedronate in the postnatal period, these patients are faced with nearly 100 bone fractures and the necessity of many operations both during birth and until adolescence. For these reasons, the family should be informed in detail about the prognosis and possible risks in patients diagnosed with OI Type III, who were diagnosed with invasive diagnostic tests during the antenatal period, and the decision to continue or terminate the pregnancy should be made and managed together. 

Keywords

Osteogenesis imperfecta, COL1A1, collagen, bone mineralization, fetal anomalies

1. Shapiro JR, Byers P, Glorieux F, Sponsellor P (2014) Osteogenesis imperfecta: a translational approach to brittle bone disease. Elsevier, New York.
2. Sinikumpu JJ, Ojaniemi M, Lehenkari P, Serlo W. Severe osteogenesis imperfecta Type-III and its challenging treatment in newborn and preschool children. A systematic review. Injury. 2015 Aug;46(8):1440–6.
3. Amor B, Mouna I, Roughley P, Glorieux F, Rauch F. Skeletal clinical characteristics of osteogenesis imperfecta caused by haploinsufficiency mutations in COL1A1. J Bone Miner Res 2013;28:2001–7.
4. Georgescu I, Vlad C, Gavriliu TS, Dan S, Parvan AA. Surgical treatment in osteogenesis imperfecta – 10 years experience. J Med Life 2013;6:205–13.
5. Reeder J, Orwoll E. Adults with Osteogenesis Imperfecta. New England Journal of Medicine. 2006 Dec 28;355(26):e28.

	File/Dsecription
	Figure 1 Hypomineralitation of skull bones during ultrasonoghrapic examination
	Figure 2 Sagittal section of columnna vertebralis (Mineralization of columnna vertebralis as it should be.)
	Figure 3 Post-termination view of the case
	Figure 4 X-ray of the case after termination