*University of New Mexico School of Medicine, Department of Obstetrics and Gynecology, 2211 Lomas Blvd N. E., Albuquerque, NM 87131-5286, Ph: 505-272-6386, Fax 505-272-6385.

Synonyms: Van der Hoeve syndrome, trias fragilitas osseum, Eddowe"s syndrome, osteopsathyrosis ideopathica of Lobstein, Ekman-Lobstein disease, osteogenesis imperfecta congenita, osteogenesis type III lethalis, brittle bone disease.

Definition: Inherited disorders of collagen that also include such diseases as Ehler-Danlos and Marfan syndrome.

Incidence: 0.36:10,000 live births overall and 0.19:10,000 for type II¹.

Etiology: This is a disorder of production, secretion, or function of Type I collagen, which is found in skin, ligaments, tendons, demineralized bone and dentine³.

Pathogenesis: The defect in the collagen accounts for the bone fragility and the significant phenotypic consequences.

Differential diagnosis: Congenital hypophosphatasia or achondrogenesis^I5, and other short limb dysplasias.

Diagnosis: The diagnosis is possible by ultrasound examination between 16 and 24 weeks. Type II is usually apparent at less than 20 weeks. The appearance of normal long bones at less than 20 weeks does not eliminate the diagnosis⁶, and serial measurements are recommended for diagnosis.

Prognosis: The combination of pedigree and clinical information is adequate to give a reasonable recurrence risk to most families. When diagnosed in utero, the majority of these pregnancies end in pregnancy interruption. Since there is a wide range of presentations in phenotype,  the quality of life is difficult to predict, but it may include multiple surgeries for fractures. Multiple fractures and possible intracranial bleeding can cause death in utero or neonatally.

MESH Osteogenesis imperfecta BDE 0777 ICD9 756.5 CDC 756.502 MIM 259400 POS 3349

Introduction

We present a case of lethal osteogenesis imperfecta diagnosed by prenatal ultrasound.

Case report

A 21-year-old G4P3 with three normal children was referred to our Maternal-Fetal Medicine clinic at 20 weeks estimated gestational age for follow-up evaluation of abnormalities found on routine ultrasound. The femur length was short (4 weeks behind the remainder of the dating measurements), suggesting possible achondroplasia. Our targeted ultrasound confirmed severely shortened long bones with a small chest and demineralized calvaria (fig. 1, 2). The estimated gestational age was 19 weeks, but the femur length was only 19 mm, which was consistent with only 15 weeks. The small chest was thought to be a result of the rib deformities, as would be expected in osteogenesis imperfecta. At 21 weeks, another ultrasound showed possible fractures of the femur and ulna. In addition, the calvaria was compressible and still demineralized. The patient was advised that the diagnosis was osteogenesis imperfecta, but she opted to continue the pregnancy with no intervention.

At 36 weeks, the patient presented with spontaneous rupture of membranes, the fetus in breech position, and contractions occuring irregularly. Pitocin augmentation was begun, and eventually a liveborn male neonate was delivered in breech position. The Apgars were 3 and 3 (one and five minutes). The neonate was clearly abnormal and was pronounced dead 16 minutes from the time of birth. He had a soft, pliable cranium, micromelia, a protuberant abdomen, and a bell-shaped thorax with a normal placenta and cord (fig. 3, 4). The family refused an autopsy.

Figure 1:  Axial scan of fetal head, demonstrating poor ossification

Figure 2:  Transverse scan of the fetal thorax showing multiple

Figure 3: Stillborn showing evidence of micromelia.

Figure 4:  Radiograph of the fetus showing fractured ribs and long

Discussion

Synonyms

Van der Hoeve syndrome, trias fragilitas osseum, Eddowe"s syndrome, osteopsathyrosis ideopathica of Lobstein, Ekman-Lobstein disease, osteogenesis imperfecta congenita, osteogenesis type II lethalis, and brittle bone disease.

Definition

Osteogenesis Imperfecta is one of the inherited disorders of collagen that also includes such diseases as Ehlers-Danlos and Marfan syndrome. It is a heterogeneous group of collagen disorders of different severity characterized by osteopenia and bone fragility, blue sclerae, dentinagenesis imperfecta or opalescent and brittle teeth, progressive sensorineural deafness, and laxity of the joints. There are four types² with subdivisions of the types. Each subtype can be divided due to locus and allelic heterogeneity. Type II is the most severe type with certain stillbirth or neonatal death.

Classification

There are four types defined and subdivided as follows:

Type I

This is the classic, non-lethal type with autosomal dominant inheritance. It is the most common type. The patients usually have blue sclerae, and the infants lack fractures at birth and are of normal height. Type 1_A has abnormal dentinogenesis and type 1_B does not. Vertebral malalignment and deformation of tubular bones would be unusual in this type. 96% are able to walk, and 35 % are deaf, with the usual onset in childhood or puberty. The recurrence risk is 50%.

Type II

Stillbirth or neonatal death is certain, making this a much more severe form of the disease with many fractures occurring from movement in utero and at birth. Limb shortening with crumpled long bones with bowing is usually present. Broad, beaded ribs are present except in types II_B & II_C. Type II_A is due to a new autosomal dominant inheritance, so recurrence risk is 2-5%. In the earlier literature, the risk was thought to be 25%, due to autosomal recessive inheritance, but subsequent studies have found a paucity of affected siblings^9,14,15,16 of probands and an increased paternal age effect. A small thorax is seen with poor ossification of the skull and blue sclerae. Many of the fetuses will be small for gestational age. Types II_B & II_C contain recessively inherited forms, and the recurrence risk is 10-25%.

Type III

This type is characterized by progressive deformity of the long bones and spine and often leads to an early death. These patients may show shortened and bowed long bones and decreased ossification of the skull. The blue sclerae may fade or disappear later in life. It is hard to differentiate from type II at birth when these also have multiple fractures present. Autosomal dominant and recessive inheritance is seen, with a recurrence rate quoted at 7%.

Type IV

This is the mildest form and may not be separate from Type I. Inheritance is autosomal dominant and their sclerae can fade to white over time. Fractures and deformities are rare. The recurrence risk is 50%.

In 1988¹⁷, Hobbins in examined 66 females at risk for skeletal dysplasia, and osteogenesis imperfecta was diagnosed in one with decreased long bone measurements and a femoral fracture. He found no false positives and concluded that skeletal dysplasias can be recognized by ultrasound in the second trimester if one compares the measurements of the long bones with normal dimensions.

Incidence

Approximately 0.36:10,000 live births overall and 0.19:10,000 for type II¹.

Etiology

This is a disorder of production, secretion, or function of Type I collagen which is found in skin, ligaments, tendons, demineralized bone and dentine³.  A study of several families has suggested that the defect may reside in Type I collagen. In Type I with inactivation of one allele of the a₁I gene,   only one-half of the normal amount of a1I protein is being produced, and type I collagen requires 2:1 of a₁I to a₂I protein chains to form a triple helix. In Type II, a normal amount of abnormal protein is produced by point mutations or rearrangements in a₁I or a₂I. These defective trimers (triple stranded protein) are degraded prematurely, are difficult to export out of the cells and assemble poorly, so there is a great deficiency of normal collagen available for use. It has been noted that 90% of the cases of osteogenesis imperfecta can be explained by a mutation in either the gene for pro-a₁I or pro-a₂I of Type I procollagen, and more than 70 different mutations have been identified.

Pathogenesis

The defect in the collagen accounts for the bone fragility and the significant phenotypic consequences. The conductive deafness that can occur is due to the immobilization of the middle ear bones later in life. Death is usually from intracranial hemorrhage or infection⁴.

Differential diagnosis

It may pose a dilemma deciding whether short limbs and underossification are suggestive of osteogenesis imperfecta or congenital hypophosphatasia or achondrogenesis¹⁵ dwarfism.

Diagnosis

The diagnosis is possible by ultrasound examination between 16 and 24 weeks. Type II is usually apparent at less than 20 weeks. The appearance of normal long bones at less than 20 weeks does not eliminate the diagnosis⁶, and serial measurements are recommended for diagnosis. Post-mortem radiographic studies are the most definitive. Tissue from autopsy should always be kept for future DNA/collagen studies. In addition, Type I collagen metabolism can be abnormal in fetal amniotic cells and fetal dermal fibroblasts⁷. Measuring pyrophosphate in amniotic fluid was studied by Solomons and Gottesfeld⁸, but the increased level they reported was not confirmed by others^9,10. DNA linkage analysis can be used in the prenatal diagnosis of dominantly inherited osteogenesis imperfecta¹⁰ using restriction fragment length polymorphisms associated with the COL₁A₂ gene located on chromosome ⁷.

Ultrasound diagnosis

Elejalde et al.¹¹ proposed certain criteria for diagnosis of perinatally lethal type osteogenesis imperfecta:

• An abnormally shaped skull, trapezoid, with varying shape when the mother coughed or laughed.

• Decreased echoes of the long and trabecular bones.

• Bell-shaped thorax, abnormal rib cage, and thin ribs with calluses.

• Wide metaphyses and thin diaphyses causing an angulated shape with fractures and callus formation at all levels.

• Decreased fetal movement with no flexion-extension of the upper and mostly lower limbs. No movements of the hands and feet.

• Soles face each other and the legs are bowed in the middle of the tibia and fibula. There is angulation of all long bones.

• Very decreased movement of the hips in an abnormal pattern with the lower limb moving only away/towards the midline with limited range of motion. No movement of the knee or ankle.

• Long bone length less than normal for the gestational age.

In addition, the following criteria seemed to be consistent with current diagnosis of osteogenesis imperfecta^{5-7,9,12,18-20}:

• Bowing of the long bones may be seen in normal fetuses, but campomelia or excessive bowing is more suggestive of campomelic dysplasia and osteogenesis imperfecta. Muñoz et al. found that six out of eight patients had multiple fractures, demineralization of the calvaria, and femoral length greater than three standard deviations below the mean for gestational age¹². There were no false positives with this criteria, but two patients were undiagnosed. They also felt that a normal scan after 17 weeks excluded Type II.

• BPD is normal and the abdomen is normal or small for gestational age. However, the abnormal compressibility of the vault may alter the measurements of the BPD.

• Angulation and fractures are apparent, resulting in foreshortening of the long bones. The cortex will appear wrinkled with thickening secondary to callous formation.

• Types II_B, II_C, & III need a longer observation time.

• Demineralization of the calvaria with decreased or absent brightly echogenic margins and enhancement of the brain are seen. The major sutures may also appear abnormally open.

• Increased visibility of the orbits and arterial pulsations are seen.

• Increased through transmission is seen with the spine, ribs, sphenoid, mandible, ethmoid, clavicles, iliac bones and long bones due to decreased mineralization.

• A small, bell-shaped thorax is seen due to collapse of the rib cage.

• Abnormal ventricle to hemisphere ratios and decreased fetal movement may be part of the presentation.

• Beaded ribs are possible, but are not always present.

• One may see the typically peculiar face as pictured before in this article, especially with type II.

• Range of motion of the elbow and wrist is decreased with no movement at the knee and ankle, and no extension or flexion of the limbs was seen in type II. Overall decreased movement is usually apparent.

• The soles of the feet face each other and the limbs make a square. The lower limbs are internally angulated, and all the long bones are deformed in type II.

• The placenta and amniotic fluid have been reported as normal.

• Table I describes diagnostic findings of osteogenesis imperfecta diagnosed in uterus.

Table 1:

Prognosis

The combination of pedigree and clinical information is adequate to give a reasonable recurrence risk to most families. Most studies indicate homogeneity in families so that the fetus will likely have the same type, and parents with a type I child are not at increased risk for a child with type II. When diagnosed in utero, the majority of these pregnancies end in pregnancy interruption. Because there is a wide range of presentations in phenotype, the quality of life is difficult to predict but may include multiple surgeries for fractures. Multiple fractures and possible intracranial bleeding can cause death in utero or neonatally. As noted, spinal deformities, otosclerosis, and deafness can occur.

A radiographic scoring system based on the amount of fractures, bone deformity, and under-ossification can be used to predict mortality in neonates with a score greater than 2.6 having an 88% mortality rate, and less than or equal to 2.6 having a 90% survival¹³. It is clear that the prognosis of Types I and IV is much better than for types II and III. The radiological appearance of the neonate predicts the prognosis in that better bone mineralization and morphology suggest a more favorable outcome.

Management

All patients should be referred for appropriate genetic counseling in a genetics center. There is no empiric data to prove that cesarean section will improve the outcome over vaginal birth. However, fractures in the birth canal are possible. Pregnancy interruption is an option when prenatal diagnosis is made¹. Supportive and preventive treatment is used for the non-lethal types. Early therapy with estrogen and other agents is possible for those women with osteoporosis due to Type I procollagen gene mutations.

References

1. Romero R. Prenatal Diagnosis of Congenital Anomalies. Norwalk, CT Appleton and Lange, 1988.

2. Gelehrter TD, Collins FS. Principles of Medical Genetics, Baltimore, Williams & Wilkins, 1990.

3. Prockop DJ. Mutations in collagen genes as a cause of connective tissue diseases. Seminars in Medicine of the Beth Israel Hospital, Boston. N Engl J Med 326:8,1992.

4. Merz E, Goldhofer W, et al. Sonographic diagnosis of lethal osteogenesis imperfecta in the second trimester: case report and review. JCU 14:380-383,1986.

5. Brons JTJ, van der Harten HJ, Wladimiroff JW, et al: Prenatal ultrasonographic diagnosis of osteogenesis imperfecta. Am J Obstet Gynecol 159:176-81, 1988.

6. Carpenter MW, Abuelo D, Neave C. Midtrimester diagnosis of severe deforming osteogenesis imperfecta without autosomal dominant inheritance. Am J Perinatol Vol 32, 1986.

7. Stephens JD, Filly RA, Callen PW, et al. Prenatal diagnosis of osteogenesis imperfecta Type II by real time ultrasound. Hum Genet 64:191-93,1983.

8. Solomons C, Gattesfeld K. Prenatal biochemistry of osteogenesis imperfecta. Birth Defects 15:69-73, 1979.

9. Thompson EM, Young ID, Hall CM, et al. Recurrence risks and prognosis in severe sporadic osteogenesis Imperfecta. J Med Genet 24:390-405, 1987.

10. Tsipouras P, Schwartz RC, Goldberg JD, et al. Prenatal prediction of osteogenesis imperfecta (OI Type IV): Exclusion of inheritance using a collagen gene probe. J Med Genet 24:406-9, 1987.

11. Elejalde BR, de Elejalde MM. Prenatal diagnosis of perinatally lethal osteogenesis imperfecta. Am J Med Genet 14: 353-59, 1983.

12. Munoz C, Filly RA, Golbus MS. Osteogenesis imperfecta type II prenatal sonographic diagnosis. Radiology 174:181-185, 1990.

13. Van Der Harten HJ, Brons JTJ, Dijkstra P, et al. Perinatal lethal osteogenesis imperfecta: Radiologic and pathologic evaluation of seven prenatally diagnosed cases. Pediatr Pathol 233-252, 1988.

14. Lubs HA, Travers H. Genetic counseling in osteogenesis imperfecta. Clin Orthop 159:36-41, 1981.

15. Young ID, Thompson EM, Hall CM, et al. Osteogenesis imperfecta type IIA: Evidence for dominant inheritance. J Med Genet 24:386-89, 1987.

16. Harper PS. Practical genetic counseling, 3rd ed. Butterworth & Co. Ltd., 1988.

17. Hobbins JC, Bracken MB, Mahoney MJ. Diagnosis of fetal skeletal dysplasia with ultrasound. Am J Obstet Gynecol 142:306, 1982.

18. Brown BSJ.: Prenatal ultrasound diagnosis of osteogenesis lethalis. J Can Assoc Radiol  35, 1984. 19. Woo JSK, Ghosh A, Liang ST, et al. Ultrasonic evaluation of osteogenesis imperfecta congenita in utero. JCU 11:42-44, 1983.

20. Carpenter MW, Abuelo D, Neave C, et al. Midtrimester diagnosis of severe deforming osteogenesis imperfecta with autosomal dominant inheritance. Am J Perinatol 3:2, 1986.