Search :     
Articles » Skeletal » Osteogenesis Imperfecta

1994-07-07-15 Osteogenesis Imperfecta © Kennon

Osteogenesis imperfecta

Julie C. Kennon, MD, Jonathan L. Vitsky, BA, George E. Tiller, MD, PhD, Philippe Jeanty, MD, PhD

Address correspondence to Julie Kennon, MD, Dept. of Radiology, Vanderbilt University, 21st and Garland, Nashville, TN 37232-5316. Ph: 615-343-0595; Fax: 615-343-4890 ¶Dept. of Genetics; §Dept. of Pathology

Synonyms: Osteogenesis imperfecta congenita, Van der Hoeve syndrome, Lobstein disease, trias fragilitas osseum, brittle bone disease, Vrolik disease.

Definition: Heterogeneous group of genetic disorders characterized by bone fragility.

Incidence: 0.4:10,000 live births and 0.19:10,000 for Type II1.

Etiology: Disorder of Type I collagen production.

Pathogenesis: The defect in Type I collagen is responsible for decreased mineralization and bone fragility.

Differential diagnosis: Hypophosphatasia (infantile form), achondrogenesis, and other short-limbed dwarfisms.

Prognosis: Type II osteogenesis imperfecta is uniformly fatal.

Management: Due to the uniformly fatal outcome, termination of pregnancy could be offered at any stage of the gestation.

MESH Osteogenesis imperfecta BDE 0777 MIM 259400, ~20, 166200,~10,~20,~40 POS 3349 ICD9 756.5 CDC 756.502


A diagnosis of short limb dysplasia probably representing Achondrogenesis and less likely Osteogenesis imperfecta Type II, was made based on a 19 week ultrasound.

Case report

A 25-year-old G1P0 patient was referred to our institution following a screening ultrasound which demonstrated structural anomalies of the fetus. The BPD measurements were consistent with the 19 week gestational age. The skull was remarkable for its decreased echogenicity, a sign associated with decreased mineralization (fig. 1,2).

Figure 1: The skull demonstrates markedly decreased echogenicity and is readily compressible even with moderate transducer pressure (left).


Figure 2: The skull in an occipital-anterior view again demonstrates abnormally low echogenicity.

The limb bones were extremely short; all measurements were markedly below the fifth percentile. The femur measured 14 mm, and the humerus was 13 mm (fig. 3,4).

Figure 3: The humerus is 13mm on the right side.
Figure 4: The femur measures 14mm.

The ulna and radius were 8mm, and the tibia and fibula were around 6mm (fig. 5,6).

Figure 5: The ulna is only 9 mm.
Figure 6: The tibia-fibula complex is only 6mm.

The ribs were short, and the chest had a bell-shaped configuration (fig. 7).

Figure 7: The ribs are soft and the chest has a bell-shape configuration.

The chest was decreased in size, suggestive of marked lung hypoplasia. The long bones were very poorly echogenic and appeared slightly bowed, but no evidence of fracture was recognized. The spine was morphologically normal (fig. 8).

Figure 8: The spine is morphologically normal, but also poorly mineralized.

Achondrogenesis and osteogenesis imperfecta Type II were the most likely diagnosis because of the marked limb shortening. The differential diagnosis included hypophosphatasia (infantile form) and other short-limbed skeletal dysplasias (thanatophoric, camptomelic, kyphomelic). Because most of these diseases are fatal in the perinatal period, the patient was offered the option of pregnancy termination. A non-viable fetus was delivered after prostin induction (fig. 9-11), and the pathologic diagnosis of osteogenesis imperfecta Type II was made.

Figure 9: Frontal and lateral X-rays of the fetus. Note the poor mineralization and the numerous fractures.

Figure 10: The fetus after delivery. Note the short limbs compared to the size of the body.

Figure 11: Close-up view of the posterior aspect of the limbs demonstrating the distortion and fractures.


The male fetus weighed 188g. All four extremities were distorted, short, and had numerous fractures visualized on radiographs (fig. 9) and evident on sectioning. The skull was soft and poorly calcified. No other gross abnormalities were noted. Histologic analysis revealed proliferation and columnization of chondrocytes. There was abundant hyaline cartilage with little endochondral ossification (fig. 12,13). Cortical bone formation was absent. These findings are consistent with osteogenesis imperfecta Type II.

Figure 12: The physeal growth zone is normal, inconsistent with achondrogenesis.

Figure 13: Bony spicules in the metaphysis exhibit poor ossification, a characteristic histologic finding in osteogenesis imperfecta Type II.



The incidence for osteogenesis is 0.4:10,000 live births, about half of which (0.19:10,000) represent Type II1.


Osteogenesis imperfecta Type II was first described in 18492. The majority of cases are inherited as new, dominant mutations. Occasional cases of autosomal recessive and germline mosaicism have been reported3-5.


Histopathologic examination of dermal connective tissue suggests disturbances of collagen formation, organization, and chemical composition6. Biochemical studies have corroborated this suspicion through the demonstration of abnormalities in the secretion of Type I procollagen. Defects in either the alpha1(I) or a2(I) chains of Type I collagen have been demonstrated in all forms of osteogenesis imperfecta.

Achondrogenesis is also due to a defect in collagen development. Abnormal production and decreased secretion of Type II collagen is also associated with spondyloepiphyseal dysplasia and hypochondrogenesis7,8,9.

Diagnosis of osteogenesis imperfecta

Ultrasound examination from 14 weeks10 gestational age can diagnose osteogenesis imperfecta Type II. The findings include: broad, short, fractured long bones with the appearance of "wrinkling" due to callus formation, underossification of the skull with clarity of intracerebral structures, small chest circumference ("champagne cork" on longitudinal section and "waisting" on transverse section11), abnormal, varying skull shape, broad irregular ribs, and abnormal face12.

Differential diagnosis

Achondrogenesis is divided into Types IA, IB and II. In Type IA, the skull is partially ossified, and only the cervical and upper thoracic pedicles are ossified. The vertebral bodies, as well as the ischial and pubic bones, are not ossified. The iliac bone is small and deformed. The long bones are short with concave ends. The thorax is short and barrel shaped, and multiple rib fractures with a "beaded" appearance are often seen. Type IB can be distinguished from Type IA by the ossification of the skull, vertebral bodies and pedicles. The long bones are shorter, and spurring of the metaphyses is demonstrated.

In Type II achondrogenesis, normal ossification of the skull is seen. The vertebral body ossification is variable. The iliac wings are small, and the ischial and pubic bones are not ossified. The long bones are short and bowed. The thorax is small, and the ribs are shortened without fractures13.

Achondrogenesis has been diagnosed by ultrasound as early as 12 weeks14. The characteristics are severe, short-limbed dwarfism, a disproportionately large head, abnormal vertebral body ossification, nuchal edema, and a narrow or short thorax. One-third of the cases of achondrogenesis are associated with hydrops fetalis14. Localized nuchal edema has been reported by Fisk15 as a diagnostic feature of achondrogenesis Type II. The upper and lower limbs were abnormally shortened and held in an abnormal, fixed position. Achondrogenesis was diagnosed after pregnancy termination.

In our particular case, the major findings were short tubular bones, short ribs, and demineralization of the skull. The bones did not appear fractured by ultrasound. The length of the tubular bones was markedly below the fifth percentile. D"Ottavio et al. comment on the rapid healing of long bone fractures in osteogenesis imperfecta Type II, with the resulting appearance of the bone as short or curved, which makes diagnosis difficult because this appearance is suggestive of many other types of bone disorders. Both osteogenesis imperfecta Type II and achondrogenesis can be diagnosed in the first trimester. The findings of fractured long bones versus shortened bones is difficult to distinguish. Follow-up scans allow one to follow the progression of the bone development. Demineralization is nonspecific and does not translate well to sonographic criteria.

Numerous gross abnormalities are characteristic of osteogenesis imperfecta Type II. The affected infant is small for gestational age. The cranial bones are small and soft, and the cranial sutures and fontanelles are wide open. The extremities are distorted because of multiple fractures (fig. 1,2). Extraskeletal manifestations may include deep blue sclerae, hyperlaxity of joints, and hernia.

Histopathologic changes of the skeletal system also provide distinction from achondrogenesis. In achondrogenesis, the physeal growth plate zone is distorted and markedly retarded. In osteogenesis imperfecta Type II, the cartilage, including the physeal growth zone, is unremarkable (fig. 12). The primary change is a severe deficiency of ossification in the metaphysis, diaphysis, and cortex. In the metaphysis, the columns of calcified cartilage matrix are narrow and covered by a thin layer of basophilic primitive woven bone (fig. 13)16.


Osteogenesis imperfecta Type II is uniformly lethal in the perinatal period. The usual cause of death is intracranial hemorrhage or respiratory insufficiency.

Recurrence risk

The majority of osteogenesis imperfecta Type II cases are due to spontaneous, dominantly acting mutations. However, rare cases of recurrence due to germinal mosaicism and autosomal recessive inheritance have been reported17. Therefore, a rough estimate of recurrence is in the range of 2-5%.


1. Romero R, Pilu GL, Jeanty P: Prenatal diagnosis of congenital anomalies. CT Appleton and Lange, Norwalk, l988.

2. Maroteaux P: Bone diseases of children. JB Lippincott, Philadelphia, 1979.

3. Lachman RS and Rappaport V: Fetal imaging in the skeletal dysplasias. Clin Perinatol 17:703-722, l990.

4. Taybi H, Lachman RS: Radiology of syndromes, metabolic disorders, and skeletal dysplasias. 3rd ed. Year Book Medical Publishers, Chicago p761-767, l990.

5. Young ID, Thompson EM, Hall CM, et al.: Osteogenesis imperfecta Type IIA: evidence for dominant inheritance. J Med Genet 24:386-9, 1987.

6. Prockop DJ: Mutations in collagen genes as a cause of connective tissue diseases. N Engl J Med 326:8, l992.

7. Knowlton S, Graves C, Tiller GE, et al.: Achondrogenesis. The Fetus 2:7564-13-16, l992.

8. Tiller GE, Rimoin DL, Murray LW, et al.: Tandem duplication within a Type II collagen gene (COL2A1) exon in an individual with spondyloepiphyseal dysplasia. Proc Natl Acad Sci USA 87:3889-93, 1990.

9. Bogaert R, Tiller GE, Weis MA, et al.: An amino acid substitution (Gly853 - Glu) in the collagen a1(II) chain produces hypochodrogenesis. J Biol Chem 267:22522-6, 1992.

10.D"Ottavio G, Tamaro LF, Mandruzzato G: Early prenatal ultrasonographic diagnosis of osteogenesis imperfecta: A case report. Am J Obst Gyn 169:384-385, l993.

11. Constantine G, McCormack J, McHugo J, et al.: Prenatal diagnosis of severe osteogenesis imperfecta. Prenatal Diagnosis 11:103-106, l991.

12. Krause M, Feige A: "Facing" - Ein Einstiegsparameter in die Diagnostik fetaler Skelettfehlbildungen. Geburt Frauen 53: 186-187, l993.

13. van der Harten JJ, Brons JT, Dijkstra MF, et al.: Achondrogenesis, hypochondrogenesis, the spectrum of chondrogenesis imperfecta: A radiologic, ultrasonographic and histopathologic study of 23 cases. In Skeletal Dysplasias: Pre- and postnatal identification. Vrije Universiteit, Amsterdam, l988.

14. Soothill PW, Vuthiwong C, Rees H: Achondrogenesis Type II diagnosed by transvaginal ultrasound at 12 weeks gestation. Prenatal Diagnosis 13:523-528, l993.

15. Fisk NM, Vaughn J, Smidt M, et al.: Case report: Transvaginal ultrasound recognition of nuchal edema in first trimester diagnosis of achondrogenesis. J Clin Ultra 19:586-590, l991.

16. Yang SS: The skeletal fetal and perinatal pathology. Blackwell Scientific Publications System Boston, p1171-1206, 1991.

17. Cohn DH, Starman BJ, Blumberg B, et al.: Recurrence of lethal osteogenesis imperfecta due to parental mosaicism for a dominant mutation in a human Type I collagen gene (COL1A1). J Hum Genet 46:591-601, 1990.

Help Support :