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Year : 2009  |  Volume : 52  |  Issue : 3  |  Page : 363-367
Osteopetrosis: A rare cause of anemia - Review of literature

1 Department of Hematology, VM Medical College and Safdarjung Hospital, New Delhi, India
2 Department of Radiology, VM Medical College and Safdarjung Hospital, New Delhi, India
3 Department of Medicine, VM Medical College and Safdarjung Hospital, New Delhi, India
4 Institute of Pathology (ICMR), Safdarjungg Hospital Campus, New Delhi, India

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Date of Web Publication12-Aug-2009


Normocytic anaemia is caused either by hypoproliferation of haemopoietic tissue or increased destruction of red cell. Osteopetrosis is a rare cause of anaemia. The leading clinical features are pallor, growth failure, hepatosplenomegaly.On hematological examination, anemia, thrombocytopenia, leucocytosis and myelophthisic anemia are commonly observed in this disease. We are highlighting osteopetrosis as a rare cause of anemia presenting to us for evaluation of anemia

Keywords: Hemoglobin, total lukocyte count, nucleated red blood cell, bone marrow aspirate

How to cite this article:
Saluja S, Bhandari S, Aggarwal S, Kapoor S. Osteopetrosis: A rare cause of anemia - Review of literature. Indian J Pathol Microbiol 2009;52:363-7

How to cite this URL:
Saluja S, Bhandari S, Aggarwal S, Kapoor S. Osteopetrosis: A rare cause of anemia - Review of literature. Indian J Pathol Microbiol [serial online] 2009 [cited 2022 Jun 25];52:363-7. Available from: https://www.ijpmonline.org/text.asp?2009/52/3/363/54995

   Introduction Top

Anemia is caused by marrow production defects (hypoproliferation), red cell maturation defects (ineffective erythropoiesis), and decreased red cell syrvival (blood loss/hemolysis). Osteopetrosis (OP) is a rare, inherited disorder in which failure of osteoclastic bone resorption leads to increased bone mass with decreased haemopoietic tissue leading to normocytic anaemia. [1] Based on the age, clinical, hematological and radiological features three distinct forms namely the infantile or AR, adult (AD) form, and intermediate OP are known. Other rare forms like lethal, transient, post infectious and a distinct form due to carbonic anhydrase deficiency have also been described. [2]

Although large series of OP have been described by authors from France, Saudi Arabia and Costa Rica, isolated case reports are available from other countries like USA and Taiwan. [3],[4],[5],[6],[7] There are few short reports on the experience in Indian patients. [8],[9],[10],[11] We retrospectively analysed the data for this disease as a cause of anaemia from 1998 to 2006. The paucity of cases seen even at our institution which is a tertiary care centre, highlights the rarity of the disease in this part of the world.

   Materials and Methods Top

It is a retrospective analysis of cases of normocytic amaemia over eight years. Total number of cases were 498. Main causes of anaemia were haemolytic anaemia, blood loss, chronic renal failure. Osteopetrosis was observed in only eight cases. We retrospectively reviewed the clinical, hematological and radiological features of these patients of osteopetrosis. The records were analyzed with respect to the age, presenting symptoms, physical signs, hematological, biochemical and radiological parameters and cranial CT findings. Bone marrow aspiration and biopsy was analyzed in all the cases. Heamatological investigations were Haemogram, red cell indices, iron profile, reticulocyte count, bone marrow aspiration and biopsy. Biochemical parameters were liver function test, kidney fuction test, serum calcium, serum phosphate, serum alkaline phosphatase. Malaria, Kala-azar and chronic hemolytic anemia were excluded by relevant tests. Genetic studies could not be performed.

   Results Top

The results of our analysis are tabulated in [Table 1],[Table 2],[Table 3],[Table 4]. The origin, age, sex distribution and parental consanguinity are shown in [Table 1]. Of the eight cases, seven cases came from North India, while one case was a migrant from Afghanistan. There were six boys and two girls. Their age at presentation was variable ranging from 3 months to 12 years. Parental consanguinity was not found in any of these cases. History of affected sibling was found in one case only [Table 1].

The leading clinical complaints were pallor, abdominal distension, growth failure and diminution of vision [Table 2]. Frequent clinical signs were anemia, hepatosplenomegaly and optic atrophy as shown in [Table 3]. Results of the hematological and biochemical investigations are shown in [Table 4]. Severe degree of anaemia, thrombocytopenia and leucocytosis was encountered in majority of the cases. Feature of myelopthisic anemia was universally present. Red cell indices and iron profile were normal in all caases. The results of bone marrow studies are shown in [Table 4]. Bone marrow aspirate was dry tap in all seven cases. In three patients bone marrow biopsy revealed aberrant bone formation with marked disorganization of the bony trabaculae, most of which contained a core of calcified cartilage and severe effacement of hemopoeitic space by fibrous tissue [Figure 1]a. In four cases the bone marrow biopsy showed mild compromise of bone marrow as there was lesser degree of disorganization of bony trabeculae accompanied by mild fibrosis of bone marrow spaces [Figure 1]b.

Serum Calcium, phosphorus and alkaline phosphatase were normal in all the cases. Skeletal survey revealed characteristic roentgenographic appearances of OP in all patients.

Generalized scleerosis of skull and narrowing of optic foramina was present in all cases [Figure 2]a. Three cases revealed the vertebral end plate thickening with the typical "Rugger-jersy" appearance of the vertebrae [Figure 2]b. Defective modelling with clubbed ends of long bones was a feature seen in 5 cases [Figure 2]c. Horizontal striations were seen in 2 cases, which occurred in various sites namely radius, ulna, femur, scapula and iliac bones [Figure 2]d. "Bone within bone" appearance and pathological fracture were unusual features in our series and was seen only in one case each [Figure 3]a,b. CT brain confirmed bilateral optic canal stenosis in all patients whereas acqueductal stenosis with secondary hydrocephalus was an additional finding in one patient [Figure 3]c,d. Based on the clinical, hematological, radiological and BMB findings the final diagnosis was made.

   Discussion Top

Osteopetrosis is a disease of unknown etiology. [8] It is a genetically heterogenous disorder classified as autosomal recessive and autosomal dominant type OP. The AR variety is also known as congenital or infantile or malignant OP occurs in infancy and has a rapid downhill course due to severe bone marrow failure. [2] AD variety also known as benign or tarda variety is detected in older children, adolescents and adults and has a benign course due to normal bone marrow function. [2] Cases that do not fit characteristically into the above two types on either clinical, hematological or radiological grounds have been classified as intermediate OP. The underlying pathophysiological mechanism in all types of OP is failure of the osteoclasts to reabsorb bone, leading to thickened sclerotic bone with poor mechanical properties. Recently mutations have been identified in the ATP 6 (ICIR GI gene) encoding the a3 subunit of the vascular proton pump, which mediate acidification of the bone osteoclast interface. This defect is estimated to occur in half of the case of AR OP. A defect in the CIC-7 chloride channel has been demonstrated in minority of both AR and AD OP.

The age of presentation in our series was 5-6 years, while it was 2 years and 4 years as described by authors from Saudi-Arabia. [5] No sex preponderance for the disease has been described by earlier workers and none existed in our series. Parental consanguinity has been frequently observed by investigators from Saudi Arabia [5] while it was conspicuous by its absence in our series.

In our patients pallor, hepatosplenomegaly, and visual disturbance were the commonest clinical manifestation. This is different from the leading presentation of pathological fracture, dental caries and nasal obstruction as described by workers from other countries. [7] Anemia and thrombocytopenia were the universal hematological manifestation found in our patients. A similar experience has been reported by investigations from Costa Rica. [7]

Myelopthisic anaemia with a shift to left and presence of normoblasts in the peripheral smear is a feature seen consistently in all our patients and has also been described in other sporadic reports from India. [8],[9] Authors from Costa Rica have also described normoblasts in the peripheral smear in several of their patients while it has not been described by other investigators. [7] Hence it appears that myelophthisic anemia is a feature characteristically observed in Indian and Saudi Arabian patients. Bone marrow aspirate was performed in all our patients and was a dry tap. This can be explained on the basis of fibrosis. Subsequent bone marrow biopsy revealed the histopathological features consistent with osteopetrosis. On the basis of the degree of disorganization of bony trabeculae and effacement of hemopoeitic space by fibrous tissue cases were classified as AD OP and AR OP. Hence BMB is essential for the final diagnosis of OP and its variety. Investigators from SA performed BMA and BMB in very few of their patients.

On radiological examination patients from all reports fulfilled the criteria for diagnosis of OP due to manifestation of generalized dense sclerosis of skull, vertebra and long bones. "Bone within bone" and pathological fracture were rarely observed in our patients. "Rugger Jersey" or sandwich vertebra was seen in 42% of our cases while it has been described in 50% of cases from Costa Rica. [7] Rachitic changes and striations were infrequent radiological finding in our series. CT brain revealed optic canal narrowing with normal brain parenchyma in all our patients. Hydrocephalus with acqueductal stenosis was seen in one of these patients.

The current recommended treatment of OP is based on its variety. In AR OP BMT is recommended along with high dose calcitriol, recombinant human gamma interferon. However in adult OP which has relatively normal bone marrow function no specific medical treatment exists. Therefore since BMB results have a bearing on deciding the treatment strategies. The importance of this investigation in the complete work up does not need further emphasis.

   Conclusion Top

We conclude that OP is a rare cause of anaemia due to effacement of heamopoitic tissue by fibrous tissue dignosed during evaluation of anaemia. In our study, the clinical, hematological, and radiological spectrum of OP seen in Indian patients is far different from that characteristically described by workers from other countries. Hence increased awareness of the myriad manifestations of the disease can lead to early diagnosis of this potentially fatal condition. In addition we recommend that BMB should be included in the diagnostic protocol of OP so that definite treatment strategies can be planned.

   References Top

1.Bhargava A, Blank R. Instant access to the minds of medicine: Osteopetrosis.  Back to cited text no. 1    
2.Bodamer OA, Braverman RM, Craigen WJ. Multiple fractures in a 3-month-old infant with severe infantile osteopetrosis J Pediatr Child Health 2001;37:520-2.  Back to cited text no. 2    
3.Bernichow OD, Laredo JO, de Veinejoul MC. Type II Autonomic dominant osteopetrosis; clinical and radiological manifestations in 42 patients. Bone 2000;26:87-93.  Back to cited text no. 3    
4.Chen CJ, Lee MY, Hsu ML, Lien SH, Cheng SN. Malignant infantile OP initially presenting with neonatal hypocalcaemia: Case report. Ann Hematol 2003;82:64-7.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.Mahdi AH. Osteopetrosis in Saudi children: A report of 10 cases. Ann Trop Pediatr 1988;8:112-5.  Back to cited text no. 5    
6.Abdel-AL YK, Shabani IS, Lubani MM, AI Ghawaibi MA, Ibrahim MD, Montaseb AL, et al . Autosomal recessive osteopetrosis in Arab children. Ann Trop Pediatr 1994;14:59-64.   Back to cited text no. 6    
7.Loria - Cortes R, Quesada-Calvo E, Cordero-Chaverri C: Osteopetrosis in children: A report of 26 cases. J Pediatr 1977;91:43-7.  Back to cited text no. 7    
8.Tripathi AK, Tandon V, Kumar A, Sarkari M, Chaturvedi R. A rare cause of Leuco-erythroblastic anemia. Indian J Hematol Blood Transfusion 1998;16:62-4.  Back to cited text no. 8    
9.Kumar P, Shashi Kala P, Chandrashekhar HR, Basavargin Band Ajay Shesh. Osteopetrosis presenting as leuko-erythroblastic anemia: A case report. Indian J Haemat Blood Transfusion 1998;116:260-1.  Back to cited text no. 9    
10.Sharma A, Kumar S. Ostepetrosis tarda: A case report. J Indian Med Assoc 1999;97:22-4.  Back to cited text no. 10  [PUBMED]  
11.Kumar VV, Narasimha Raju PA, Rao lV. Ostepetrosis: Report of four cases. Indian Pediatr 1989;26:938-42.  Back to cited text no. 11    

Correspondence Address:
S Saluja
251 Type III AV Nagar, AIIMS Extension, New Delhi - 110 049.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.54995

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3], [Table 4]

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