We present the case of a 34-year-old woman with a prenatally diagnosed osteogenesis imperfecta type II of one fetus of a diamniotic-dichorionic twin pregnancy at 28 weeks and 2 days of gestation. The diagnosis was suspected after a routine ultrasound examination, specified by 3D-ultrasound and confirmed with moleculargenetic analyses of COL1A1 with DNA of fetal cells obtained after amniotic drainage. Since a premature rupture of membranes occurred a cesarean section was performed at 36 weeks of gestation. Both newborns received primary medical care by neonatologists. The affected child received further treatment initially stationary, later as an ambulant patient. Even though ultrasound is a powerful tool to identify clinical features of osteogenesis imperfecta, the condition can finally only be confirmed by collagen or DNA analyses. We discuss the possibilities and limits of prenatal diagnosis, treatment options as well as issues that are relevant for genetic counseling.
Osteogenesis imperfecta (OI) is a rare congenital disorder of the heterogeneous group of skeletal dysplasias. It is characterized by brittle bones prone to fractures. Referring to Forlino  11 classified types and three unclassified OI-like or collagen-based disorders can be identified, of which type II, also called the “lethal type”, presents the most severe form. De novo mutations as well as autosomal recessive inheritance are described , however, most cases of OI type II are caused by autosomal-dominant mutations of the COL1A1 (17q21.33–q22) and COL1A2 (7q21.3) genes . Ultrasound is currently the gold standard for antenatal, non-invasive diagnosis of OI. A prenatal diagnosis allows the appropriate delivery of an affected unborn child and furthermore the parents to prepare to care for a child with OI.
We present the case of a 34-year-old gravida II para 0. Besides one miscarriage her medical as well as family history was unremarkable. The pregnancy resulted from a non-consanguineous partnership. She first presented at our department at 13 weeks and 4 days of gestation for a first trimester screening, which showed no abnormalities including a normal nuchal translucency (NT) measurement (Fet I: 1.6 mm, Fet II: 2.0 mm). At 28 weeks and 2 days of gestation she was referred back to our department by her gynecologist with suspected OI of the second fetus.
At this point ultrasound examinations (Toshiba Aplio XG, 6.5-MHz, Transducer; Medical Systems Corp., Otawa, Tochigi, Japan) presented a eutrophic, normally developed first twin, but abnormalities of the second twin. Beside a difference of growth, the affected twin showed slight pyelectasia, cysts of the plexus choroideus, hypoplasia of the thorax, short long bones with fractures, pes equinovarus and a polyhydramnion. The doppler indices of the umbilical arteries, the middle cerebral arteries and the uterine arteries were within normal ranges.
Three further ultrasound examinations were done at 28 weeks and 6 days, 30 weeks and 2 days and 31 weeks and 6 days of gestation (Figures 1–3). The parents agreed to perform an amniotic drainage to reduce the risk of premature birth. At this consultation 1600 mL of amniotic fluid were drained, and respective cells were used for the consecutively followed molecular and cytogenetic analyses. With sequence analyses of the COL1A1 gene the variant c.4237G>A (p.Asp1413Asn) was detected for the affected fetus (Figure 4).
The mother was admitted to our tertiary center with premature rupture of membranes at 36 weeks of gestation and a cesarean section was performed the same day. The affected newborn girl was delivered without complications. Respiration started promptly and sufficiently under supplemental oxygen. The birth weight was 2070 g, the Apgar scores were 9/9/9, umbilical artery blood pH 7.32, venous blood pH 7.37 and base excess –6.6 mmL/L. The X-rays performed after birth confirmed the prenatal ultrasound findings: fractured long bones and clavicle with callus formations as well as deformed extremities in false postures. Furthermore, very soft bones of the cranium, so-called “wormian bones”, blue sclera and poor muscle tone were noticed as characteristics of OI.
A therapy with Neridronat (Nerixia®), a recently authorized bisphosphonate for the intravenous application for children with OI was started 2 weeks after birth. The initial dose of 2 mg was given intravenous. The next therapy cycles followed every 3 months were tolerated well. In comparison to other bisphosphonates the advantage of Neridronat is based on its less complicated form of application: it is applied every 3 months in contrast to every 3 days. Currently, no guidelines exist for the therapy of OI for children under the age of 3 years. In addition to the bisphosphonates, the child received 500 IU of vitamin D3 as well as calcium and phosphate orally.
Her further development was satisfying. She was discharged from hospital after 6 weeks with a remaining metabolically compensated tachypnea. We contacted the parents again after 15 months, she was developing well with a good state of health.
Patients with OI are unable to produce functionally normal connective tissue, in the majority of cases due to a deficiency of type-I collagen. The result of either defective or missing type-I-collagen is a susceptibility to fractures, deflection of the long bones, probably a bell shaped chest and other malformations as well as micromelia . In most cases the diagnosis of OI type II leads to intrauterine or early postnatal death. If the newborn survives the early postnatal phase, death often occurs within the first year.
Ultrasound is a simple, cost-effective and sensitive examination tool for the detection of some or all of the above-mentioned abnormalities. 2D-ultrasound is a tool sensitive enough to suspect the diagnosis of OI. A 3D-ultrasound should be performed to obtain additional information concerning the malformations, as it was the case for the situation we described here (Figures 2 and 3). In principle, a 3D-computed tomography (CT) can also be done to get an adequate resolution of the critical anatomical structures. However, due to fetal and maternal exposure with relatively high doses of radiation, the application of this method is controversial.
The literature discusses various other sonographic features indicating a possible diagnosis of OI. In contrast to our findings, some studies recommend focusing on an increased NT thickness at the first trimester screening. In one case report the thickness of the nuchal translucency was 3.8 mm , in another case report it was 4.2 mm . Both children were diagnosed with OI type II at a later stage. The exact correlation could not be proven, but it is assumed that the different composition of the extracellular matrix leads to a seemingly increased NT thickness . However, it must be taken into consideration that the hypomineralization of the skull can falsify the results by mimicking a higher NT thickness. Nevertheless, if an increased NT thickness with a generalized hypomineralization of the bones is detected with antenatal ultrasound examinations , further procedures such as an amniocentesis could be done to enable genetic analyses for an early diagnosis of skeletal dysplasias in the first trimester.
Based on parental germline mosaicism for point mutations in OI genes, the recurrence risk is described to be up to 7% for the diagnosis of an OI in a next pregnancy [3, 7]. For this reason it should be considered to expand the first trimester screening by a transvaginal ultrasound examination or even by a chorionic villus sampling  for every woman with a positive family history. The confirmed diagnosis of OI in the early pregnancy would allow the parents to make further, possibly life-changing decisions.
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The authors stated that there are no conflicts of interest regarding the publication of this article.
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