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Articles » Skeletal » Osteopetrosis

1994-07-08-12 Osteopetrosis © Malinger


Gustavo Malinger, MD, Asher Ornoy, MD, Raghda El Shawwa, MD, Haim Zakut, MD, Gertrude Kohn, MD

Address correspondence to Haim Zakut, MD. The Edith Wolfson Medical Center. P.O. Box 5, Holon 58100, Israel. Ph: 972-3-502-8712; Fax: 972-3-501-4111. ¶Departments of Obstetrics and Gynecology and ¢Genetics, Sackler Faculty of Medicine, Tel-Aviv University; §Laboratory of Teratology, Hebrew University, Hadassah Medical School, Jerusalem, Israel; ¤Nassr Children"s Hospital, Gaza

Synonyms: Albers-Schonberg disease, marble bones disease, infantile, malignant or lethal osteopetrosis.

Definitions: Congenital osteopetrosis is characterized by diffuse skeletal sclerosis, early blindness and deafness, cranial nerve palsies, hepatosplenomegaly and anemia.

Etymology: osteon: bone, petra: stone.

Prevalence: Less than 100 cases have been reported.

Etiology: Autosomal recessive inheritance.

Pathogenesis: Osteopetrosis is caused by the inability of osteoclasts to reabsorb primary bone and calcified cartilage.

Prenatal diagnosis: Only 2 cases in one family have been described by ultrasound1.

Differential diagnosis: At least 3 other types are known:

  • the adult type is an autosomal dominant disease characterized by delayed and mainly mild symptoms2
  • the intermediate type is similar to the adult form but is transmitted as an autosomal recessive disease
  • osteopetrosis with renal tubular acidosis and cerebral calcifications is also an autosomal recessive disease3.

Prognosis: Survival after the age of 20 years has not been reported. Death usually results from infection or anemia.

Recurrence risk: 25%, as in any autosomal recessive disease.

Management: Before viability, termination of pregnancy should be offered. Bone marrow transplantation has been reported as being successful in 8 patients4; treatment with high-dose calcitriol could result in clinical improvement in severely affected patients5. In utero interventions are a theoretical possibility in patients who want to continue the pregnancy.

MESH Osteopetrosis BDE 0780 MIM 259710-259750 POS 3374 ICD9 756.5 CDC 756.540


Lethal osteopetrosis is a rare autosomal recessive disorder characterized by fragile hyperdense bones and severe neurologic and hematological abnormalities developing after birth. Prenatal diagnosis has been reported by El Khazen et al. in two siblings1. These two cases seem to represent an unusually severe form of this disease or a different disease, developing the full picture in utero, which is associated with absent or markedly reduced osteoclasts. We present the prenatal diagnosis of one case of lethal osteopetrosis in a fetus known to be at risk after the birth of two affected siblings that died before the age of 12 months. The diagnosis was based on the appearance of hypercalcified long bones at 18 weeks of gestation.

Case report

An Arab couple without familial linkage was referred for genetic consultation after the birth of two male children affected with osteopetrosis (fig. 1).

Figure 1: Radiological appearance of osteopetrosis in a brother of the fetus.

After genetic counseling regarding recurrence risks, the woman became pregnant. She was evaluated by transvaginal ultrasound at 14 weeks. At this time, the examination was negative for any of the findings characteristic of the disease. The second examination was performed at 18 weeks. At this time, the presence of hyperechogenic long bones was noted (fig. 2).

Figure 2: Transvaginal sonography of the fetal femur showing hyperechogenic femur shaft.

Transvaginal sonography of the brain was entirely normal. Based on these findings, interruption of pregnancy was offered and accepted by the couple. A 380g male fetus was delivered after extra-amniotic instillation of Prostin E2 (Upjohn Laboratories, USA). The X-ray of the fetus depicted increased bone density and rib fractures. Histologic examination confirmed the diagnosis. Abundant "spongy" bone trabeculae were found in the metaphysis and diaphysis, partially filling out the bone marrow cavity. Osteoclasts were also observed, seemingly in a larger number than usually found at this age (figs. 3-4). There were no other malformations on the autopsy, except for the skeletal changes.

Figure 3: Photomicro- graph of a part of the upper tibial diaphysis showing numerous bone trabeculae (BT) inside the medullar cavity. Arrows point to osteoclasts. Toluidine blue x 600.

Figure 4: Photomicro- graphy of the tibial diaphysis showing bone trabeculae (BT) and somewhat fibrotic bone marrow (BM). Toluidine blue x 1000.


Prenatal diagnosis

Lethal osteopetrosis is a rare autosomal recessive disease, and its diagnosis before the age of one year is accomplished in only 50% of the cases5. The chance of diagnosing such a case during routine ultrasonographic screening is extremely low. In a known affected family, the risk of recurrence is 25%. Early diagnosis is crucial, but only in severe cases would prenatal diagnosis be possible. El Khazen et al.1 described two cases. The first case was diagnosed at 35 weeks and presented with severe hydrocephalus, a dense skeleton and a deformed humerus. In utero, radiographic examination showed the presence of multiple fractures with hypertrophic bone callus formation. There is no reference of previous ultrasonographic examinations in this pregnancy. Although diagnosed at 14 weeks because of increased bone density, the second case was aborted at 25 weeks when the fetus presented with the fully developed picture of the disease.

In our case, the findings were much more subtle. Increased bone density at 18 weeks is very difficult to determine because of the lack of standards of bone echogenicity. We compared the bone echogenicity with those of other fetuses of the same gestational age using the same ultrasound equipment and, after consultation with other ultrasonographists, recommended termination of pregnancy.

Associated anomalies

These are listed in Table 1.

Table 1: Associated anomalies


g Dense sclerotic bones

g Macrocephaly


g Hepatosplenomegaly

g Cranial nerve paralyses

g Deafness

g Blindness

g Dental caries

Biochemical anomalies

g Hypocalcemia

g Hyperphosphatasia

g Anemia

g Pancytopenia


The severe multi-systemic manifestations of the lethal form of osteopetrosis are associated with an extremely poor prognosis. Death usually occurs in infancy or early childhood. In cases treated with bone marrow transplantation4,6, a rapid improvement in hematological and biochemical parameters was observed and neurological deterioration was arrested. There are not yet reports on the long-term follow-up of those cases.


Presently, the prenatal diagnosis of osteopetrosis early in pregnancy is an indication for the termination of pregnancy. During the third trimester, the decision may be difficult due to legal, moral or religious considerations. In those cases in which termination of pregnancy is not possible, two options may be offered:

  • early postnatal bone marrow transplantation with the objective of reducing to a minimum the residual neurologic deficits incurred when the patients were treated late6
  • in utero transplantation of adult or fetal hematopoietic tissues7.


1. El Khazen N, Feverly D, Vamos E, et al.: Lethal osteopetrosis with multiple fractures in utero. Am J Med Genet 23:811-819, 1986.

2. Bollerslev J: Osteopetrosis: A genetic and epidemiological study. Clin Genet 31:86- 90, 1987.

3. Sly WS, Whyte MP, Sundaram V et al.: Carbonic anhydrase 11 deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. N Engl J Med 313:139-145, 1985.

4. Fischer A, Friedrich W, Levinsky R, et al.: Bone-marrow transplantation for immunodeficiencies and osteopetrosis: European survey, 1968-1985. Lancet ii: 1080- 1084, 1986.

5. Key LD, Carnes S, Cale M, et al.: Treatment of congenital osteopetrosis with high-done calcitriol. N Engl J Med 310:409-415, 1984.

6. Coccia PF, Krivit W, Cervenka J, et al.: Successful bone marrow transplantation for infantile malignant osteopetrosis. N Engl J Med 302:701-708, 1980.

7. Touraine JL: In utero transplantation of fetal liver stem cells in humans. Blood Cells 17:379-387, 1991.

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