Increasing pallor and listlessness was the most common initial symptom (n=4), other symptoms being distension of abdomen, fever, increasing head size and nasal block. Five patients had more than one symptom.

On examination, all patients had anemia and hepatosplenomegaly. Nasal obstruction was seen in four patients one of whom also had epistaxis. Ophthalmological examination revealed optic atrophy in three. Cranial CT scan done in these three patients revealed normal anatomy in one, hydrocephalus with aqueductal stenosis in one and subdural hematoma in one. The latter patient (Case 4) had presented to the Department of Neurosurgery at the age of six months with complaints of increasing head size and delayed milestones. She was found to be pale, had hepatosplenomegaly, macrocephaly and optic atrophy. The subdural hematoma was evacuated surgically. Skeletal X-rays clinch- ed the diagnosis of osteopetrosis.

The hemoglobin values were low in all the patients (6.8±1.22 g/dl). Thrombocytopenia and leukocytosis were seen in five patients each. Peripheral smear showed the presence of immature leukocytes (myelocytes and metamyelocytes 6-32%) and normoblasts (2-45/100 WBC) in all the patients. Serum calcium and inorganic phosphorus were normal in all. Serum alkaline phospha1ase was elevated in two.

The skeletal X-rays (Figs. 1-3) showed generalized increase in bone density, widening and modelling deformity of metaphyses of long bones and "bone in bone" appearance in the phalanges, long bones and pelvic bones of all the patients and confirmed the diagnosis of osteopetrosis.

Discussion

Autosomal recessive osteopetrosis is a rare disorder and reports of large groups of patients are scarce. Loria-Cortes' detailed a cr9ss-sectional study of 26 patients from Costa Rica(3) and Gerritsen's retrospective longitudinal study of 33 patients(4) have summarized the clinical picture and natural course of the disease.


 

Fig. 1. Radiograph of hands showing increased. bone density and bone in bone appearance.

The commonest presenting symptom in our patients was pallor and listlessness. Other authors have reported nasal obstruction(3) and visual impairment(4) as the initial symptoms. Nasal obstruction was present in four of our patients although it was the primary complaint in only one.
Our findings are in agreement with those -reported in the above studies: Most of the children present before 6 months of age with anemia, hepatosplenomegaly and loss of vision either alone or in combination. The hematological. manifestations are due to obliteration of marrow cavity leading to myelophthisic anemia with reticulocytosis, normoblastosis, and leukocytosis of immature myeloid series. Hepatosplenomegaly develops because of extramedullary hematopoiesis. Ensuing hypersplenism leads to thrombocytopenia, leukopenia and hemolytic anemia(5). The risk of developing hematological impairment in the first year of life is about 75% and its onset within 3 months of life is indicative of a poor outcome(4).


 

Fig. 2. Increased density of bones of the base of the skull.

Fig. 3. Dense bones and modelling deformity of metaphyses of humori.

Visual impairment due to optic nerve encroachment is a common feature at presentation. Surgical decompression of optic nerve may restore sight in some cases{6,7). Cumulative risk of developing a visual defect in the first year of life is about 75%. Combined early visual and hematological impairment is very significantly associated with a poor outcome(4).

Other features like macrocephaly, nystagmus, exophthalmos, strabismus, petechiae, nasal block, psychomotor retardation, failure to thrive and convulsions may be present(3). One of our patients had hydrocephalus due to aqueductal stenosis.

The characteristic radiological feature of osteopetrosis is generalized sclerosis of bone. Other radiological changes observed are splaying of metaphyses and rib ends, vertical or transverse metaphyseal lines, bone in bone appearance, sandwich appearance of vertebral bodies (rugger jersey spine), non-visualization of marrow cavity, pathological fractures, curvature of bones, osteomyelitis and sun burst appearance of skull vault(8). AR osteopetrosis can manifest in utero with multiple fractures(9) and may cause non- immune hydrops fetalis(10).

The natural course of the disease results in survival of about 30% of patients at six years of age. Some may live till 2nd or 3rd decade but the quality of life is mostly poor(4).

Bone marrow transplantation (BMT) pro- vides the only curative treatment for AR osteopetrosis. Recipients of HLA identical BMT have been reported to have 5 year survival of 79% while survival falls to 38% with one HLA mismatch and to 13% with a com- plete HLA mismatch(11).

Clinical outcome with paratharmone, calcitrol and prednisone therapy has been found to be inconsistent and variable(12-14). Recently, use of interferon gamma has been found to decrease the rate of infection and transfusion requirements after 24 months of therapy(15).

Though rare, AR osteopetrosis should be considered in the differential diagnosis of an infant or young child presenting with anemia and hepatosplenomegaly otherwise he/she may be wrongly diagnosed as leukemia or other hemolytic anaemia. The diagnostic test, i.e., skeletal radiography is simple and readily available. An accurate diagnosis is essential in view of availability of curative treatment (BMT) and for genetic counselling as the risk of recurrence in siblings is 25%.