Clinic of reproductive medicine “NADIYA”, Kyiv, Ukraine;
Andrijivskyj uzviz, 28A, Kyiv 01025, Ukraine.

Synonyms

Osteogenesis imperfecta congenita, Van der Hoeve syndrome, Eddowe syndrome, Lobstein disease, fragile bones disease, fragilitas ossium, Vrolik disease, osteopsathyrosis idiopathica, and brittle bone syndrome.

Case report

35-year-old G2P1 came to our clinic for the first trimester ultrasound scan. Her personal and family history were unremarkable. Her previous pregnancy with the same partner was uncomplicated and the child is healthy. The first trimester scan was negative, with a risk of Morbus Down 1:6402. There were no abnormalities detected on the ultrasound examination. The second trimester scan performed at 20 weeks of gestation revealed the following findings:

• Significant shortening and curvature of all long bones (0.01-0.8^th percentile)
• Long bone fractures, rib fractures
• Lack of mineralization of the skull; deformation under the probe pressure
• Clear image of both cerebral hemispheres
• High prominent forehead
• Micromandible

There were no other anomalies seen on the ultrasound examination. There was normal amount of the amniotic fluid and the umbilical artery Doppler was normal as well. Our diagnosis based on the ultrasound images was osteogenesis imperfecta, type II. Due to it's adverse prognosis, patient decided for the pregnancy termination. The postnatal findings confirmed our diagnosis. Unfortunately, there was no genetic testing performed on the fetus. Further genetic counseling is recommended, especially in case, couple plans on further pregnancy.

Images 1,2: Image 1 shows humerus and radius with fractures, note arrows. Image 2 shows femur bone and tibia.

Images 3,4: Images show a sagittal view of the thorax with detail of the ribs. Fractures of the ribs can be seen, note the arrows.

Images 5,6: Image 5 shows a transverse view of the fetal thorax, arrows indicate the rib fractures. Image 6 shows an axial view of the fetal brain, note the clear image of both brain hemispheres. The skull is deformed by the ultrasound probe pressure due to a lack of mineralization.

Images 7,8: Image 7 shows a reduced nasal bones mineralization. Image 8 shows the biometry of the fetus at 20 weeks. Femur length corresponds to 15 weeks, same as the length of the humerus, ulna and tibia.

Images 9,10: 3-D images show an abnormal curvature of the upper extremities due to fractures.

Images 11,12: 3-D images of the fetal face, arrows indicate the micromandible.

Images 13,14: Images of the fetus after pregnancy termination. Fractures of the both, upper and lower extremities are apparent.

Prevalence

Classification

Pathogenesis

Osteogenesis imperfecta is a hereditary disease of connective tissue which primarily affects bones, but has other manifestations as well. These include visual complications, dentinogenesis imperfecta, hearing loss, weakness of joints, restrictive lungs disease and short stature[4].

About 90% of individuals with types I,II,III, and IV have and identifiable mutation in either COL1A1 or COL1A2. Mutations lead to the formation of pathological amount of collagen (osteogenesis imperfecta type I) or to the production of collagen of different quality (osteogenesis imperfecta type II, III and IV) [3].

Prenatal diagnosis

Clinical symptoms of osteogenesis imperfecta depend on the type of the disease and it's manifestations.

Type I osteogenesis imperfecta is an autosomal dominant disease. Affected individuals have fragile bones, blue scleras and progressing deafness. Life expectancy is normal. Children are born with normal weight and length, multiple fractures are usually absent. It is sometimes possible during the ultrasound examination to reveal individual long bones fractures.

This type of imperfect osteogenesis is divided into A and B form according to the presence/absence of pathological dentinogenesis. Prenatal diagnosis is possible with DNA analysis.

Type II osteogenesis imperfecta is a lethal variant of the disease. Ultrasound findings include: a marked shortening of the long bones, multiple bone fractures, lack of mineralization of the skull. Affected fetuses die in the prenatal period or in an early postnatal period, usually because of respiratory failure or central nervous system injury.

Sillence et al. suggested to divide type ІІ into three variants according to the radiological criteria. Varinat (A) includes short, wide and bent tubular bones and beaded ribs. Variant (B) includes wide curved femurs and minimal or absent ribs fractures and variant (C) narrow femurs with fractures and beaded ribs [5].

Type ІІІ osteogenesis imperfecta may have both autosomal dominant and autosomal recessive character of inheritance. Long bones are shortened and curved, multiple fractures are found at birth in the majority of affected children. Skull bones are lacking ossification.

Type IV osteogenesis imperfecta is autosomal dominant disease with different degree of symptoms expression. This type belongs to the mildest form of the disease. Scleras are blue-colored in the newborn, but they become white within the years. Tubular bones are of usual length, femur may be slightly curved. Patients with heavy manifestation may have long bones deformations because of fractures. According to the presence or absence of dentinogenesis imperfecta, this type is divided into А- and B-form correspondingly.

Prenatal diagnosis of ІІІ and IV types may be carried out by chorion villi sampling and DNA analysis or by the confirmation of pathological production of collagen in fibroblasts culture [FMF].

There is a number of reports in the literature about prenatal ultrasound diagnosis of type II. Sonographic signs may be found in the whole skeletal system. Fractures, bending, shortening, local thickening because of callus formation, bow-shaped curvature and symptoms of demineralization may be found during the ultrasound examination.

In rare cases the extremities are so shortened, that they cannot be measured. Skull bones may be so thin, that the pressure of ultrasound probe easily leads to their deformation. In the severe forms of the disease the contours of a skull are wavy, cranium can be easily compressed.

Multiple ribs fractures result in the formation of bell-shaped or narrow thorax. Echogenicity of spine is rarely decreased. Fetus activity is lowered.

Ultrasound examination in the second trimester after 17-18 weeks is quite reliable method of prenatal diagnosis of type II osteogenesis imperfecta [11]. There are single reports about diagnosis in 15 weeks and even 13 weeks of pregnancy [12].

MIld forms of the disease do not have such a significant ultrasound signs and ultrasound diagnosis in this cases may be difficult [2].

Associated anomalies

Osteogenesis imperfecta is rarely accompanied by other congenital defects. Single cases of microcephaly, heart defects, anencephaly etc. are described [6]. There are some reports about the diagnosis of osteogenesis imperfecta combined with other congenital defects in the first trimester [7]. Osteogenesis imperfecta may be a part of the following hereditary syndromes: Osteogenesis imperfecta, microcephaly and cataract; Brook's syndrome - osteogenesis imperfecta with joint contractures; Lewin’s osteogenesis imperfecta.

Prognosis

Osteogenesis imperfecta is a disease with a wide spectrum of clinical symptoms. Multiple fractures and intracranial hemorrhage may cause a death in the perinatal period.

The prognosis and performance of the affected individuals varies with the type of the disease and phenotype. Multiple fractures may be a reason for repeated operative treatment and may be accompanied by significant complications.

The prognosis of type II is very unfavorable, mainly due to pulmonary insufficiency ralated to the small thorax and rib fractures.  Types І and ІІІ are compatible with life, but patients may develop significant complications connected with multiple fractures and deformations. Type ІV has the most favorable prognosis, fractures and deformations are rare.

Recurrence risk

The majority of the type II osteogenesis are results of new autosomal dominant mutations. The recurrence of such forms is reported to be very low up to 6 % [8]. The expected recurrence risk of rare autosomal recessive type ІІ osteogenesis imperfecta reaches from 10 % up to 25 % [9, 10].

Management

The management of the affected children begins prenatally. The mode and timing of delivery should be planned after counseling with neonatologists. Patient should deliver in the perinatology center equiped with the neonatal intensive care unit. Considering the lethality of type II, termination of pregnancy can be offered to the parents.

References

1. Nazario A.C.P., Tanaka C., Novo N.F. Proximal humeral ossification centre of the fetus: Time of appearance and the sensitivity and specificity of these findings. J Ultrasound Med. 1993;12:513.
2. Lehmann H.W., Herbold M., J. Von Bodman, Karbowski A., Stucker R. Osteogenesis imperfecta. Aktuelles Therapiekonzept. Monatsschr Kinderheilkd. 2000;148:1024-9.
3. Marini Joan C. Osteogenesis Imperfecta — Managing Brittle Bones. NEJM. 1998;339:986-7.
4. Martin E., Shapiro J.R. Osteogenesis imperfecta: epidemiology and pathophysiology. Curr Osteoporos Rep. 2007;5(3):91-7.
5. Ромеро Р., Пилу Дж., Дженти Ф., Гидини А., Хоббинс Дж. С. Пренатальная диагностика врожденных пороков развития плода. Пер. с англ. – М.: Медицина, 1994; 448 с.: ил.
6. Ozkur A., Kervancioglu R., Kervancioglu S. et al. Second-trimester diagnosis of osteogenesis imperfecta associated with schizencephaly by sonography. Saudi Med J. 2007;28(8):1289-90.
7. Ruano R., Picone O., Benachi A. et al. First-trimester diagnosis of osteogenesis imperfecta associated with encephalocele by conventional and three-dimensional ultrasound. Prenat Diagn. 2003;23(7):539-42.
8. Byers P.H., Tsipouras P., Bonadio J.F. et al. Perinatal lethal osteogenesis imperfecta (type II): A biochemically heterogeneous disorder usually due to new mutations in the genes for type I collagen. Am J Hum Genet. 1988;42:237.
9. Spranger J., Cremin B.J., Beighton P. Osteogenesis imperfecta congenita. Pediatr Radiol. 1982;12:21.
10. Sillence D.O., Barlow K.K., Garber A.P. et al. Osteogenesis imperfecta type II delineation of the phenotype with reference to genetic heterogeneity. Am J Med Genet. 1984;17:407.
11. Munoz C., Filly R.A., Golbus M.S. Osteogenesis imperfect type II: Prenatal sonographic diagnosis. Radiology. 1990;174:181.
12. Dhouib M., Guirat N. Lethal osteogenesis imperfecta. Prenatal diagnosis. Presse Med. 2004;33(10):658-60.