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Remission of Malignant Infantile Osteopetrosis by Early Therapy with Prednisone

       Presented at the 22^nd annual ASBMR meeting in Toronto 9/22 – 9/26/2000

S. Migliaccio, M. Iacobini, B. Werner, A. Taranta, A. Panero, M. Roggini, A. Teti

Departments of Experimental Medicine and Medical Physiopatology, Univerisity LaSapienza of Rome, L’Aquila and Rome, Italy/Department of Pediatrics, University LaSapienza of Rome, Italy/Department of Histology and Medical Embryology, University LaSapienza of Rome and IDI, Rome, Italy/Department of Experimental Medicine, University of L’Aquila, Italy

Osteopetrosis is a rare genetic bone disorder, also known as Albers-Schonberg disease.  It is due to impairment of osteoclast activity and is characterized by sclerotic, fragile and dense bones, with a significant reduction in bone marrow cavity and failure in haematopoiesis.  Autosomal recessive, malignant infantile osteopetrosis also includes severe anemic, splenomegalia, growth retardation, cranial nerves compression, blindness and has an extremely poor prognosis.  In the last decades, bone marrow transplantation has become the treatment of choice.  Nevertheless, the outcome is dependent on the availability of a genotipically HLA-identical bone marrow donor.  In addition, high risk of graft failure and infections are severe complications of this therapy.  Herein, we report a case of a 27-month old female patient, diagnosed with malignant infantile osteopetrosis at birth and treated with prednisone, who had a remission of the disease.  The patient was affected by skin foci of extramedullar haematopoiesis and severe hepatosplenomegaly.  Peripheral blood analysis revealed a severe anemia (Hgb 7gr/dl), morphological alterations of erythrocytes, which appeared teardrop-like, high counts of immature erythroid and myeloid cells.  X-Rays revealed generalized increase in bone density, sclerosis of the skull, transverse wavy stripes of sclerotic bone in tubular segments, sclerosis of vertebrae and bone in bone appearance of the hand and foot phalangies, with a decrease in medullar cavities.  On the basis of these findings, the patient was diagnosed with malignant infantile osteopetrosis.  She was immediately transfused and prednisone (2 mg/kg/day) therapy was started.  Proband conditions improved over the first two months and blood cell counts returned to normal values.  Prednisone therapy was gradually decreased and maintained at a regimen of 5 mg/day.  At 1 year, bone marrow agoaspirate showed normal white and red cell lineages.  Follow-up by total body x-ray revealed normalization of bone density, medullar cavity and bone marrow.  The patient is now 27 months old.  She is not taking any medications and shows normality of all the neurological, visual and hearing scores.  In conclusion, we report a successful therapy with prednisone, which so far has apparently produced complete remission in a case of malignant infantile osteopetrosis.

Autosomal Dominant Ostopetrosis Type I is Genetically Linked to the Same Region on Human Chromosome 11 as the High Bone Mass Phenotype

             Presented at the 22^nd annual ASBMR meeting in Toronto  9/22 – 9/26/01

E. Van Hul, D. Mathysen, J. Bollerslev, J. Gram. W. Van Hul.  Medical Genetics, University of Antwerp, Antwerp, Belgium/ Endocrinology, Rikshospitalet, Oslo, Norway/ Medicine, Ribe County Hospital, Esbjerg, Denmark.

The osteopetroses are a heterogeneous group of conditions including both autosomal dominant and autosomal recessive forms.  The autosomal dominant forms of osteopetrosis can be divided into at least two radiological subgroups.  The type II, being the classical Albers-Schonberg disease, is characterized by the presence of endobones and a “Rugger-Jersey spine.”  The most important clinical complication in these patients is an increased fracture rate.  Previously, we were able to show that, for at least a proportion of these patients, the underlying genetic defect can be found in a gene on chromosome 1p21.

ADO type I is characterized by a more diffuse osteosclerosis most pronounced at the skull.  In these patients, no evidence for an increased fracture rate is found.  To identify the disease causing gene, several chromosomal regions were analysed by linkage analysis in two extended pedigrees.  The chromosome 11q12-13 region was considered because of the previous assignments of bone diseases such as the High Bone Mass phenotype, recessive osteopetrosis and osteoporosis-pseudoglioma syndrome.  In both ADO type I families evidence was obtained for linkage to this region.  Several markers resulted in a summated lodscore above +3 with a maximum of +6.3 with marker D11889.  Halotyping of the markers enabled us to delineate a candidate region of 6cM flanked by D11S1765 on proximal side and by  D11S4095 on distal side.  This region overlaps at least partially with the candidate regions for both recessive osteopetrosis and osteoporosis-pseudoglioma syndrome, but most interesting maps completely within the candidate region described for the High Bone Mass phenotype.

In conclusion, we obtained clear evidence for the presence of a gene causing autosomal dominant osteopetrosis type 1 on chromosome 11q12-13.  The localization of the genes causing this condition and the High Bone Mass phenotype can still be explained in two ways-both conditions are allelic as caused by mutations in the same gene, or, alternatively, this study provides evidence for the presence in this chromosomal region of another gene implicated in the homeostasis of bone tissue.  Further studies are currently performed to prove either possibility.

FDA Approves Actimmune For Children With Osteopetrosis

PaloAlto, CA – February 14,2000  InterMune Pharmaceuticals announced that the US Food and Drug Administration has approved Actimmune ® (Interferon Gamma Ib) Injection for delaying the time to disease progression in patients with severe , malignant osteopetrosis.  Osteopetrosis is a life-threatening, congenital disorder in which an overgrowth  of bony structures leads to blindness, deafness, and increased susceptibility to infections.  In the most serious form of the disease, most patients become blind or anemic by six months of age within the first ten years of life, frequently in the first two years.  Actimmune was previously approved in 1990 for reducing the frequency and severity of serious infections associated with Chronic Granulomatous Disease.

“Actimmune provides us with a new treatment option for osteopetrosis in that it helps to reduce the number of infections, improve bone marrow function and prolong the lives of children with this disease,” said L. Lyndon Key, Jr., M.D., Professor of Pediatric Endocrinology at the Medical University of South Carolina.

“The approval of Actimmune is a significant milestone for InterMune and for patients who suffer from osteopetrosis and makes available a much needed medication to patients in need of treatment alternatives,” said W. Scott Harkonen, M.D., President and Chief Executive Officer of InterMune Pharmaceuticals.  “Additionally, we believe that Actimmune has tremendous potential in the treatment of a variety of other diseases.  In fact, published clinical trial results have suggested that this may be useful intreating serious lung diseases and systemic infections.”