Bệnh án

Em Phan thị N. T., sanh tháng 9/95, được BV Tỉnh- chuyển đến BV Nhi Ðồng 1 TP.HCM, ngày 9 tháng 10 năm 1999 với chẩn đoán "Cốt tủy viêm xương hàm ở bé bệnh thalassemie".

Em bị thiếu máu nặng và đã được truyền máu nhiều lần. Lần bệnh này, ngoài bệnh cảnh thiếu máu, em bị viêm xương hàm, chảy mủ ra ngoài. Gan to 5cm; lách to độ 4, chắc.

Các xét nghiệm:

Máu: Hct:15%; Bạch cầu 7.700/mm3 (N:49%, L: 35%, Mono: 2%, Metamyelocyte: 12%, Band neutro-phile: 12%); Tiểu cầu 40.000/mm3; Ký sinh trùng sốt rét âm tính.

MCV: 92 fl; MCH: 27,4 pg; MCHC: 29,8%; RDW:18,6%.

Ðiện di hemoglobin: A2: 2.9%, A: 97,1%: Kết quả điện di bình thường, em không bị Thalassemie.

Siêu âm não: Não úng thủy.

Tủy đồ: Rất khó thực hiện vì vỏ xương rất cứng, không thể đâm kim tới tủy.

X quang xương sọ và X quang phổi: Hình ảnh tăng độ đậm rất rõ vì xương xâm lấn vào khoang tủy (hình trên)

Chẩn đoán: Xương đá (Osteopetrosis)

Bàn luận

Ðây là một trường hợp xương đá do sự tiêu xương bị khiếm khuyết (defect in bone resorption), tăng sự tạo xương (hyperosteosis). Bệnh có tính di truyền, thường là tính lặn (autosomal recessive), đôi khi cũng có thể là tính trội (autosomal dominant inheritance).⁽¹⁾

Bệnh hiếm gặp, al-Rasheed-SA báo cáo có 28 trẻ bị xương đá qua hơn 10 năm theo dõi tại 2 bệnh viện ở Riyadh, Saudi Arabia.⁽²⁾

Biểu hiện bệnh có thể sớm trong thời kỳ sơ sinh, tử vong nhanh. Nhưng thường là biểu hiện trễ hơn, trong tuổi thiếu nhi. (osteopetrosis tarda; Albers-Schšnberg disease). Một số trường hợp được phát hiện tình cờ do chụp X quang vì hình ảnh rất đặc trưng của bệnh (Albers-Schšnberg là tên một bác sĩ quang tuyến người Ðức).

Theo y văn, một trong những biến chứng thường gặp là viêm xương, nhất là xương hàm.⁽³⁾

Dự hậu của bệnh rất xấu, bệnh nhân thường tử vong sau vài năm vì xuất huyết và nhiễm trùng.⁽¹⁾

TÀI LIỆU THAM KHẢO

1. Bryan D. Hall. Genetic Skeletal Dysplasias. Chapter 644: Osteopetrosis, pyknodysostosis, dysosteosclerosis, and cortical hyperostosis In Nelson Textbook of Pediatrics. 1996 W.B. Saunders Company

2. al-Rasheed-SA; et al Osteopetrosis in children Int-J-Clin-Pract. 1998 Jan-Feb; 52(1): 15-8 (Medline)

3. Ozmen-Y; Klesper-B; Lenzen-J. Mund-Kiefer-Gesichtschir. Osteomyelitis of the facial skull in Albers-Schšnberg osteopetrosis. Mund-Kiefer-Gesichtschir. 1997 Mar; 1(2): 121-4 (Medline)

Osteopetrosis.

AU: Carolino-J; Perez-JA; Popa-A

AD: Saint Mary Hospital, Hoboken, New Jersey, USA.

SO: Am-Fam-Physician. 1998 Mar 15; 57(6): 1293-6

AB: Osteopetrosis is a rare hereditary bone disorder that presents in one of three forms: osteopetrosis tarda, osteopetrosis congenita and "marble bone" disease. Osteopetrosis tarda, the benign form, presents in adulthood, while the two more malignant variants, osteopetrosis congenita and marble bone disease, present in infancy and childhood, respectively. In all three forms, the main features are pathologic alteration of osteoclastic bone resorption and thickening of cortical and lamellar bones. Osteopetrosis tarda is usually discovered accidentally on routine radiographs and is often asymptomatic; however, patients may present because of related degenerative joint disease. Osteopetrosis congenita results in bone marrow failure and is almost always fatal. Marble bone disease causes short stature, cerebral calcification and mental retardation. Bone marrow transplant is the only chance for survival in patients with osteopetrosis congenita.

Osteopetrosis in children.

AU: al-Rasheed-SA; al-Mohrij-O; al-Jurayyan-N; al-Herbish-A; al-Mugeiren-M; al-Salloum-A; al-Hussain-M; el-Desouki-M

SO: Int-J-Clin-Pract. 1998 Jan-Feb; 52(1): 15-8

AD: Department of Paediatrics, King Khalid University Hospital, Riyadh, Saudi Arabia.

AB: Over a 10-year period, 28 Arab children with autosomal recessive osteopetrosis were seen in two hospitals in Riyadh, Saudi Arabia. Eighteen (64%) had osteopetrosis associated with metabolic acidosis probably due to a renal tubular defect; nine (32%) had a malignant infantile form of osteopetrosis and one had a mild form with delayed onset. Parental consanguinity was 56% and 40% among patients with and without acidosis respectively. Somatic and psychomotor retardation and recurrent bone fractures were common in both groups. Dental caries, cerebral calcification and optic atrophy were more frequent in patients with acidosis, while anaemia, hepatosplenomegaly and deafness were more common in patients without acidosis. To guarantee optimal rehabilitation, children with this progressive disease require an early multiteam approach.

-[A case of osteopetrosis with an abnormal CK-MB/T-CK ratio]

AU: Ito-K; Komiyama-Y; Mitani-K; Ogawa-N; Egawa-H; Takahashi-H

AD: Department of Clinical Laboratory, Kansai Medical University Hospital, Moriguchi.

SO: Rinsho-Byori. 1997 Dec; 45(12): 1197-200

AB: Creatine kinase (CK)-MB subunit has been recognized as a useful marker for acute myocardial infarction (AMI). However, we recently experienced one case of osteopetrosis with moderately high CK-MB and an abnormal (more than 100%) CK-MB/total (T)-CK ratio without evidence of AMI in a medical examination. We have already experienced 17 cases with an abnormal CK-MB/T-CK ratios in addition to the present case. Those cases were patients with malignant tumor with metastasis (n = 13), leukemia (2), liver cirrhosis (1), and cerebral death (1), and thereby the band of macro-CK was found in the electrophoresis. However, we detected neither the band of macro-CK nor the abnormal levels of tumor markers such as CEA, alpha-fetoprotein, CA-19-9 in the present case. Instead of the macro CK, the high level of CK-BB was detected in electrophoresis. In the medical examination, especially in screening tests, the CK-MB was generally assayed with use of the immunoinhibition method in automated analyzers. The method principle was based on the absence of CK-BB in the patient serum. Since the patient had the past history of pathological fracture in his boyhood, this patient was diagnosed as osteopetrosis. These results suggest that we must consider the possibility of osteopetrosis when an abnormal CK-MB and CK-MB/T-CK ratio without evidence of serious diseases were found. This is simply because of the assay method of immunoinhibition for CK-MB activity.

[Osteomyelitis of the facial skull in Albers-Schonberg osteopetrosis]

TO: Osteomyelitis des Gesichtsschadels bei Osteopetrosis Albers-Schonberg.

AU: Ozmen-Y; Klesper-B; Lenzen-J. Mund-Kiefer-Gesichtschir. Osteomyelitis of the facial skull in Albers-Schonberg osteopetrosis. Mund-Kiefer-Gesichtschir. 1997 Mar; 1(2): 121-4

AD: Klinik und Poliklinik fur Zahn-, Mund- und Kieferheilkunde, Universitat Koln.

SO:- CP: GERMANY

AB: Albers-Schonberg osteopetrosis, a rare heritable bone disease with autosomal dominant or recessive transmission, is generally characterised by diffuse sclerosis of the whole skeleton accompanied by pathological bone fragility and delayed physical development, profound intractable myelophthisic anaemia, neurological deficits, and osteomyelitis, especially of the jaws and the skull. The precise aetiology of the osteopetrosis is not clear. Therefore therapy is restricted to alleviation of symptoms. In this study the case of a patient suffering from the benign form of osteopetrosis is presented. Osteomyelitis of the skull was treated successfully 2 years after the removal of lower and upper jaw teeth by a combined multistage surgical and antibiotic approach.

Maxillary osteomyelitis secondary to osteopetrosis.

AU: Hanada-T; Furuta-S; Moriyama-I; Hanamure-Y; Miyanohara-T; Ohyama-M

AD: Department of Otorhinolaryngology, Faculty of Medicine, Kagoshima University, Japan.

SO: Rhinology. 1996 Dec; 34(4): 242-4

CP: NETHERLANDS

AB: A 41-year-old Japanese woman complained of a gradually enlarging swelling of her left cheek for seven months. She was diagnosed with osteopetrosis by standard skeletal radiographs, and her cheek swelling was diagnosed as maxillary osteomyelitis secondary to osteopetrosis. She underwent a left partial maxillectomy, and her post-operative course was stable with no complications. A literature review is also presented.

Cortical bone remodeling in autosomal dominant osteopetrosis: a study of two different phenotypes.

AU: Brockstedt-H; Bollerslev-J; Melsen-F; Mosekilde-L

AD: University Department of Endocrinology and Metabolism, Aarhus Amtssygehus, Denmark.

SO: Bone. 1996 Jan; 18(1): 67-72

CP: UNITED-STATES

AB: Previous analyses of cancellous bone remodeling in autosomal dominant osteopetrosis (ADO) have suggested a diminished osteoclastic resorption at the endocortical surface. Consequently, cortical width increases with age in both ADO type I and II. By means of histomorphometric methods, the remodeling cycle of the Haversian surface in the iliac crest has recently been reconstructed in normal individuals. The aim of the present investigation was to study cortical bone remodeling in ADO type I and II. Transcortical iliac crest bone biopsies obtained from 21 ADO patients were studied. Of these, 14 had ADO type I and seven had ADO type II. Twenty of the patients had received intravital double labeling with tetracycline before the biopsies were obtained. The static histomorphometric parameters for cortical bone mass and structure were compared with a control group of 21 sex- and age-matched individuals. Regarding the dynamic histomorphometric parameters for reconstruction of the cortical bone remodeling cycle, the ADO type I material was compared with control material from 14 sex- and age-matched individuals, whereas the ADO type II material was compared with control material from six sex-matched but younger individuals. Significant increases were seen in absolute as well as fractional cortical widths in both ADO types. Furthermore, an age-related increase was observed in both absolute and fractional cortical widths in ADO type I, whereas ADO type II was nonsignificant with regard to age. The fractional cancellous width was reduced in both type I and type II. However, only in ADO type I did the fractional cancellous width significantly correlate inversely with age. In the control group, neither cortical dimensions nor cancellous width correlated significantly with age. No significant differences were observed between patients and the control group in osteon dimensions; fractional resorptive, formative, or quiescent sites; resorptive or formative remodeling rates; remodeling periods; or activation frequency. An age-related increase in cortical porosity was seen in the group of normal individuals, but not in the two patient groups. The fractional remodeling space was increased in the ADO type II group. In conclusion, cortical dimensions are increased in both ADO type I and II and positively correlated to age in type I. However, cortical remodeling at the Haversian surface is essentially normal in both ADO type I and II. This could be explained by a defective endocortical bone resorption, as no periosteal accretion was observed, and because cancellous bone remodeling previously has been described to be normal.

Bone scintigraphy and densitometry in children with osteopetrosis.

AU: el-Desouki-M; al-Herbish-A; al-Rasheed-S; al-Jurayyan-N

AD: Department of Medicine, King Khalid University Hospital, Riyadh, Saudi Arabia.

SO: Clin-Nucl-Med. 1995 Dec; 20(12): 1061-4

CP: UNITED-STATES

AB: Bone scintigraphy and dual x-ray absorptiometry were performed in 18 children (8 males, 10 females) with clinical and radiologic diagnoses of osteopetrosis in order to demonstrate the scintigraphic features of this rare disorder and to measure the bone mineral density. Their mean age was 9 years (range, 3-16 years). Bone scintigraphy demonstrated characteristic features of a widened metaphysis of all long bones that showed increased tracer uptake, particularly in the distal femur and proximal tibia. Dual x-ray absorptiometry of the lumbar spine, three femoral sites, and total body showed a marked increase in bone mineral density. The mean values for bone density of the lumbar spine and greater trochanter were markedly elevated than were other sites. Compared with a normal group matched for age and gender, the increase in bone mineral density was 181% for the lumbar spine and 193% for the greater trochanter. The authors concluded that bone imaging and bone densitometry are useful in establishing the diagnosis of osteopetrosis by demonstrating increase tracer uptake in the widened metaphysis and increased bone density. Bone densitometry may be of prognostic value in follow-up, especially in monitoring the response to therapy.

Recent developments in the understanding of the pathophysiology of osteopetrosis.

AU: Felix-R; Hofstetter-W; Cecchini-MG

AD: Department of Pathophysiology, University of Berne, Switzerland.

SO: Eur-J-Endocrinol. 1996 Feb; 134(2): 143-56

CP: NORWAY

AB: Osteopetrosis is a rare metabolic bone disease characterized by a generalized increase in skeletal mass. It is inherited in a number of mammalian species, including man, and results from a congenital defect in the development or function of the osteoclasts. The consequent impairment of bone resorption prevents formation of bone marrow cavities, causes delayed or absent tooth eruption and results often in abnormally shaped bone. The pathogenetic defect may be intrinsic either to the osteoclast lineage or to the mesenchymal cells that constitute the microenvironment supporting the development and activation of the osteoclasts. In the first example, the disease can be cured by transplantation of hemopoietic cells. In some cases, bone marrow transplantation has also been successful in curing human osteopetrosis. This, together with the variability in the age of onset and severity of clinical aspects, suggests that a multiplicity of genetic mutations may cause the human disease. In recent years the genetic effects of some osteopetrotic mutations have been identified. This new information has been essential for the understanding of osteoclast biology. Colony stimulating factor 1 (CSF-1), the growth factor for cells of the mononuclear phagocytic system, is also essential for the development of osteoclasts. In the osteopetrotic (op) mouse, no biologically active CSF-1 is synthesized due to a point mutation in the coding region of its gene. This leads to an almost complete lack of osteoclast development and to impaired bone resorption. Altered CSF-1 production seems also to be involved in the toothless (tl) rat osteopetrosis. Recently, the mutation responsible for the microphthalmic (mi) mouse osteopetrosis has been identified in the gene encoding a member of the basic-helix-loop-helix-leucine zipper (bHLH-ZIP) protein family of transcription factors. The mi gene product seems to play a role in the fusion process of osteoclast precursor cells. Finally, osteopetrosis has been the result of experimental gene disruption in mice. Targeted disruption of the c-src proto-oncogene encoding a nonreceptor tyrosine kinase leads to a form of osteopetrosis where osteoclasts are present but inactive. This indicates that pp60c-src, localized primarily on ruffled border membranes and vacuoles of the osteoclasts, is important for osteoclastic function. Disruption of the c-fos proto-oncogene, a major component of the AP-1 transcription factor complex, leads to an osteopetrotic phenotype characterized by a complete absence of osteoclasts. The defect is intrinsic to hemopoietic precursors that are unable to progress beyond an early stage of osteoclast differentiation. In humans, deficiency of carbonic anhydrase II has been identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. A lack of expression of the vacuolar proton pump has been observed in osteoclasts of a patient with craniometaphyseal dysplasia. In conclusion, the disease, although rare, is of great pathophysiological relevance for our understanding of the processes that govern the development and function of osteoclasts.

Bone marrow transplantation for infantile malignant osteopetrosis.

AU: Solh-H; Da-Cunha-AM; Giri-N; Padmos-A; Spence-D; Clink-H; Ernst-P; Sakati-N

AD: Department of Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia.

SO: J-Pediatr-Hematol-Oncol. 1995 Nov; 17(4): 350-5

CP: UNITED-STATES

AB: PURPOSE: Most patients diagnosed with malignant osteopetrosis die during infancy or early childhood from hemorrhage and infection due to bone marrow failure. Allogeneic bone marrow transplantation (BMT) has been reported to provide curative therapy for this disorder. We report our experience with eight patients with malignant osteopetrosis who underwent BMT. PATIENTS AND METHODS: Between May 1987 and August 1992, eight children with malignant osteopetrosis underwent allogeneic BMT. Median age at BMT was 9 months (range, 2-36 months). Six patients received marrow from HLA-identical sibling donors, one from phenotypically matched father, and one from a one antigen mismatched father. BMT conditioning for all patients was busulfan 16 mg/kg and cyclophosphamide 200 mg/kg each administered over 4 days. Graft versus host disease (GVHD) prophylaxis included cyclosporin A in six patients or cyclosporin A and methotrexate in two patients. RESULTS: Six patients, including those who received bone marrow from their father's, engrafted as documented by bone marrow biopsy showing an increase in osteoclasts in all cases and by chromosomal analysis in four patients. Two patients died without engraftment. Three out of six patients engrafted are alive and well at the follow-up of 48, 63, and 81 months. Serum calcium, alkaline, and acid phosphatase levels normalized within 2 months. These patients have full bone marrow reconstitution. Serial radiologic studies revealed bone marrow remodelling and a new nonsclerotic bone formation. Vision improved dramatically in the youngest patient. CONCLUSION: BMT offers cure to patients with malignant osteopetrosis with reconstitution of bone marrow and correction of metabolic disturbances. In our experience, reversibility in neurosensory deficit is possible when BMT is done at an early age.

OSTEOPETROSIS, PYKNODYSOSTOSIS, DYSOSTEOSCLEROSIS, AND CORTICAL HYPEROSTOSIS

These conditions are characterized by a generalized increase in skeletal density. Individually, they are distinguished by their mode of inheritance, age of onset, and pattern of skeletal involvement. At least nine forms of osteopetrosis ("marble bone disease") have been described with overlapping spectra of clinical and roentgenographic features. A form with manifestations in the newborn and a progressive course leading to death at an early age is called osteopetrosis with precocious manifestations. A usually milder disorder with delayed manifestations is known as osteopetrosis tarda or Albers-Schư }nberg disease. Intermediate forms occur and include a type of osteopetrosis with renal tubular acidosis and cerebral calcification.

OSTEOPETROSIS WITH PRECOCIOUS MANIFESTATIONS. This form is most frequently discovered during the first months of life; it may appear as failure to thrive, malignant hypocalcemia, anemia with thrombocytopenia, or severe, perhaps overwhelming infection. Inheritance is generally autosomal recessive, but some cases may show autosomal dominant inheritance.

Rarely, fractures lead to medical attention. Hyperostosis may crowd the marrow cavity, with anemia and extramedullary hematopoiesis, hepatosplenomegaly, and thrombocytopenia. Anemia results from excessive hemolysis. A defect in macrophage killing of bacteria may account for recurrent and sometimes overwhelming infection. Bony encroachment on the optic foramina may lead to optic atrophy and blindness, in some cases detectable at birth. Hypocalcemia is not uncommon, and serum phosphorus may be low. Serum alkaline phosphatase activity is elevated. Roentgenographically, the diagnostic findings are a generalized increase in bone density, with defective metaphyseal modeling and a "bone in bone" appearance most marked in the vertebral bodies. Diffuse hyperostosis leads to loss of demarcation between the cortex and the medullary cavity. Irregular condensation of bone at the metaphyses may produce the appearance of parallel plates of dense bone at the ends of the long bones. The base of the skull is dense, having normal to increased density of the vault and markedly increased density in the orbital margins.

Treatment is aimed at decreasing or arresting progressive hyperostosis, correcting anemia and thrombocytopenia, and treating infections promptly and vigorously; a regimen of oral cellulose phosphate, prednisone, and low-calcium diet has been reported effective in some but not all patients. The prednisone arrests the progress of anemia and thrombocytopenia. Long-term treatment with recombinant human interferon gamma may also be beneficial. Neurosurgical unroofing of the optic foramina is useful in selected cases. Bone marrow transplantation with appropriately HLA-matched donor marrow has been curative in several patients. Generally, the prognosis for survival is poor, and death in the first few months or years from anemia, bleeding, or overwhelming infection is not uncommon.

OSTEOPETROSIS WITH RENAL TUBULAR ACIDOSIS. This important entity is usually recognized because of failure to thrive in the 1st yr of life. Electrolyte investigation shows a metabolic acidosis. Intracerebral calcification may be found on a roentgenogram. Inheritance is autosomal recessive, and a defect in the enzyme carbonic anhydrase II can be shown in red blood cells.

OSTEOPETROSIS TARDA (ALBERS-SCHƯ{umlaut-o}NBERG DISEASE). This condition presents in childhood, adolescence, or young adult life because of fractures (about 10% of patients), mild craniofacial disproportion, mild anemia, complications arising from neurologic involvement, or osteitis with osteonecrosis (usually of the mandible). Increased bone density may be discovered incidentally on a roentgenographic study made for some other problem. Most cases represent autosomal dominant inheritance, a few autosomal recessive.

Skeletal roentgenograms show generalized increase in density of cortical bone, with a club-shaped appearance of the long bones due to defective metaphyseal modeling. More than 50% of patients have longitudinal and transverse dense striations at the ends of the long bones. The vertebrae show alternating lucent and dense bands. The base of the skull is dense and thickened, but the face and vault are less affected.

Management should be directed at recognition and treatment of complications, with frequent testing of visual fields and acuity and periodic roentgenograms of the optic foramina. Transfusion may be required for anemia, and splenectomy may be useful in some patients.

PYKNODYSOSTOSIS. This autosomal recessive disorder is characterized by postnatal onset of short-limbed short stature and generalized hyperostosis. A disproportionately large skull, frontal and occipital bossing, and a wide anterior fontanelle may bring the patient to the physician's attention. The hands and feet are short and broad, and the nails may be deformed and brittle. The sclerae are often blue; this evidence combined with a tendency to fractures may lead to confusion with osteogenesis imperfecta.

Roentgenographically, there is a generalized increase in bone density without metaphyseal striation. The distal phalanges are characteristically hypoplastic or aplastic. The skull has wide sutures and wormian bones; the face has a small mandible with an obtuse mandibular angle.

DYSOSTEOSCLEROSIS. This rare autosomal recessive disorder is characterized by generalized increase in bone density and short stature of postnatal onset. Dysosteosclerosis differs from osteopetrosis and pyknodysostosis in showing platyspondyly with superior and inferior irregularity of vertebral ossification. Developmental defects of the teeth are common, with delayed eruption of primary dentition, severe hypodontia, and early loss of the teeth. Secondary dentition may fail to erupt. Other complications (fractures, visual and hearing loss, and recurrent infections of mandible and paranasal sinuses) are similar to those of osteopetrosis.

Osteopetrosis ('marble bone' disease).

AU: Manusov-EG; Douville-DR; Page-LV; Trivedi-DV

AD: Scott Medical Center, Scott Air Force Base, Illinois.

SO: Am-Fam-Physician. 1993 Jan; 47(1): 175-80

AB: Osteopetrosis is a hereditary disorder in which pathologic alteration of osteoclast resorption of bone results in thickening of cortical and lamellar bone. Before bone marrow transplantation, the infantile recessive form was uniformly fatal within the first two decades of life as a result of invasion of the marrow space by abnormal bone formation. The adult autosomal dominant form causes minimal morbidity and is usually diagnosed incidentally on routine radiographs. Although osteopetrosis is an extremely rare disorder, the study of this disease can provide insights into the formation of bone and the inheritance of disease.

[Recessive osteopetrosis. Identification of a form of medium severity]

TO: La forme recessive de l'osteopetrose. Individualisation d'une forme de gravite intermediaire.

AU: Bejaoui-M; Baraket-M; Lakhoua-R; Mezni-F; Hammou-Jeddi-A; Kamoun-A; Kharrat-H; Essoussi-S; Harbi-A; Ben-Dridi-MF; et-al

AD: Service de Pediatrie, Hopital Charles-Nicolle, Tunis.

SO: Arch-Fr-Pediatr. 1992 Aug-Sep; 49(7): 627-31

CP: FRANCE

AB: BACKGROUND. Several distinct forms of osteopetrosis have been identified. Some of the autosomally recessive inherited forms are benign, much like the autosomal dominant form. Others are more malignant. PATIENTS. The clinical data, skeletal radiographs, histological features and histories of 32 children with osteopetrosis were analyzed retrospectively. RESULTS. The 32 patients, belonging to 20 sibships were divided into two groups. The first group included 24 patients, aged 1 day-11 months (mean 4.5 months), suffering from hepatosplenomegaly, anemia, thrombocytopenia and optic atrophy in early infancy. They also had a generalized increase in bone density, abnormal bone remodeling, rachitic lesions and a "bone-within-bone" appearance. Biopsies showed severe bone resorption and myelofibrosis. 19 of the 20 patients whose outcomes were known died during the first year of life. The second group included 8 patients, aged 40 days-3 years (mean: 11 months). Hepatosplenomegaly appeared later, anemia was less severe and thrombocytopenia occurred in only 1 patient. However, all 8 patients suffered from optic atrophy and 3 were deaf. Radiographs showed bone growth without rachitic lesions. Biopsies from 2 patients showed bone resorption, but no myelofibrosis. The outcome was less severe: 6 patients, now aged 8 months to 8 years, have survived, 3 of them for over 5 years. Genetic investigation showed patterns compatible with autosomal recessive inheritance in both groups, with similar sets of features within each sibship. CONCLUSION: This study reveals a new type of recessively inherited osteopetrosis. It can be classified as an intermediate form, distinct from both the malignant and the benign forms, and also distinct from osteopetrosis with carbonic anhydrase II deficiency.

Osteopetrosis. Current clinical considerations.

AU: Shapiro-F

AD: Department of Orthopaedic Surgery, Children's Hospital, Boston, MA 02115.

SO: Clin-Orthop. 1993 Sep(294): 34-44

CP: UNITED-STATES

AB: Osteopetrosis is an inherited skeletal condition characterized by increased bone radiodensity. There are three clinical groups: infantile-malignant autosomal recessive, fatal within the first few years of life (in the absence of effective therapy); intermediate autosomal recessive, appears during the first decade of life but does not follow a malignant course; and autosomal dominant, with full-life expectancy but many orthopaedic problems. The infantile variant shows a myelophthisic anemia, granulocytopenia, and thrombocytopenia, and patients eventually die from infection or bleeding or both. Neurologic sequelae include cranial nerve compression (optic nerve, blindness; auditory nerve, deafness; facial nerve, paresis), hydrocephalus, convulsions, and mental retardation. Radiographs show uniform bone density without corticomedulary demarcation, broadened metaphyses, "bone within a bone" or endobone phenomena (tarsals, carpals, phalanges, vertebra, ilium), and thickened growth plates if there is superimposed rickets. Transverse pathologic fractures occur, often followed by massive periosteal bone formation. Computed tomographic scans, magnetic resonance imaging, and bone scans provide specific information. Iliac crest bone biopsy is valuable to quantitate osteoclast and marrow changes by light and electron microscopy. Medical treatments involve high-dose calcitriol to stimulate osteoclast differentiation and bone marrow transplantation to provide monocytic osteoclast precursors. Orthopaedic problems in the intermediate and autosomal dominant forms include increased fractures, coxa vara, long-bone bowing, hip and knee degenerative arthritis, and mandibular and long-bone osteomyelitis. Cranial nerve compression also occurs. Osteotomy, plating, intramedullary rodding, and joint arthroplasty can be done, but are difficult because of bone hardness.

Autosomal dominant osteopetrosis.

AU: Bollerslev-J; Mosekilde-L

AD: Department of Medical Endocrinology M, Odense University Hospital, Denmark.

SO: Clin-Orthop. 1993 Sep(294): 45-51

AB: Autosomal dominant osteopetrosis is radiographically characterized by universal osteosclerosis, primarily involving the axial skeleton, and by symmetrical affections of the long bones without modeling defects. Based on standard radiographs, it is possible to describe two different subtypes with different clinical, biochemical, and histologic manifestations. Type I is radiographically characterized by pronounced osteosclerosis of the cranial vault, whereas Type II has end-plate thickening of the vertebrae (Rugger-Jersey spine) and endobones in the pelvis. Both types are strictly family related and seen in childhood. Combined radiogrammetric, biochemical, and histologic investigations indicate states of defective bone resorption, whereas bone formation seems to be normal in both types of patients. Patients with autosomal dominant osteopetrosis are often asymptomatic, and the diagnosis may be reached by chance. However, by systematic investigations, nearly all patients have manifestations related to the disorder. Symptoms are progressive with age, and correlated with osteosclerosis. The fracture frequency is increased in Type II patients, and normal in Type I, where biomechanical investigations have shown normal, or even increased trabecular bone strength. Treatment has been symptomatic. A rational treatment consists of stimulation of bone resorption, in combination with inhibition of bone formation if possible.

Osteopetrosis. The pharmaco-physiologic basis of therapy.

AU: Key-LL Jr; Ries-WL

AD: Department of Pediatrics, Brenner Children's Hospital, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina.

SO: Clin-Orthop. 1993 Sep(294): 85-9

ISSN: 0009-921X

PY: 1993

LA: ENGLISH

CP: UNITED-STATES

AB: Medical treatments of osteopetrosis have attempted to improve hematologic function, reduce the osteosclerotic condition, and/or improve immune function. Prednisone therapy has improved hematologic function in some patients, but has not resulted in a reduction in bone mass. Calcium deficient diets have limited further sclerosis in some patients. High-dose calcitriol and parathormone infusions have stimulated osteoclastic activity. In some patients, high-dose calcitriol has resulted in clinical improvement. Newer treatments, such as interferon gamma and macrophage colony stimulating factor, may alter the osteoclastic and immune defects by stimulating cellular formation and function. These therapies, alone or in combination, ameliorate but do not cure the osteopetrotic condition.