Osteopetrosis masquerading as hereditary hemolytic anemia: A case report of a 13-year-old girl with massive splenomegaly

Introduction

Osteopetrosis is an exceedingly rare inherited condition that causes bones to harden and become denser. Pathologic fractures, cranial nerve palsies, and hematologic abnormalities are among the clinical symptoms of osteopetrosis, as well as a higher risk of osteomyelitis and infections [1,2].

Radiologic assessment is critical for early diagnosis, frequently revealing hallmark features like diffuse skeletal sclerosis, ``bone-in-bone'' look, ``Harlequin mask'' appearance, and ``sandwich'' vertebrae [3]. Additionally, imaging is essential for evaluating conditions such as fractures and cranial nerve compression.

Anemia and cytopenia are typical findings in individuals with osteopetrosis. Patients often have no symptoms, and routine blood tests find hematologic abnormalities. These abnormalities mainly result from the replacement of the medullary bone space by sclerotic bone [2]. This case describes the presentation and clinical progression of a 13-year-old girl with osteopetrosis, who was first worked up for a potential hereditary hemolytic anemia, despite no known family history of the disease.

Case presentation

This is the case of a 13-year-old girl who presented to the hospital with a 7-month history of a slowly increasing, non-tender lump on the left side of her abdomen. She also had generalized weakness and a decline in school performance during this same period. She demonstrated no history of fever, jaundice, epistaxis, hematemesis, or melena, as well as travel to the hill tract or other kala-azar-endemic locations.

Her prior medical history included a low-trauma fracture of the left femur's neck 4 years prior, which was fixed internally with cannulated hip screws. Her parents had a consanguineous marriage, and her 2 siblings were healthy, with no history of similar disease or unexplained sibling deaths.

Clinical examination revealed a thalassemic appearance, moderate pallor, slight jaundice, and a solitary mobile, non-tender lymph node in the left anterior cervical chain. Abdominal examination showed massive splenomegaly, palpable 20 cm below the left costal border, firm in consistency, with a palpable splenic notch and mild hepatomegaly. Splenomegaly, anemia, and hepatomegaly in an adolescent from a consanguineous family initially indicated hereditary hemolytic anemia as the leading diagnosis.

A complete blood count revealed severe microcytic hypochromic anemia (Hb: 6.9 g/dL) [reference range, 12-16 g/dL] with thrombocytopenia, whereas hemoglobin capillary electrophoresis was largely normal (HbA: 96.7%; reference range: 96-98%; HbF: 0.9%; reference range: <1%; HbA2: 2.4%; reference range: 2-3.5%) and direct and indirect Coombs tests were negative. Wilson's disease was ruled out by serum ceruloplasmin, 24-hour urinary copper, and slit-lamp examination, although the latter also indicated primary optic nerve atrophy on the left side. A Doppler assessment of the portal, hepatic, and splenic veins ruled out portal hypertension, and investigations for kala-azar, malaria, and viral hepatitis turned out negative.

Skeletal imaging was ordered after no hepatic or hematologic etiology was found. X-rays of the spine and pelvis revealed diffuse vertebral sclerosis with a "bone-within-bone" appearance (Fig. 1), L5-S1 spondylolisthesis, and diffusely dense sclerotic pelvic/femoral bone with past fixation hardware (Fig. 2), results indicative of osteopetrosis. MRI of the orbits further confirmed this, revealing bilateral optic canal narrowing, which coincided with clinical optic atrophy.

Bone marrow aspiration yielded a dry tap, prompting a trephine biopsy. Histopathology demonstrated fragmented bony trabeculae with focal thick sclerotic bone and calcified cartilaginous tissue, with intertrabecular spaces replaced by fibrovascular tissue and scanty marrow cellularity—findings confirming her diagnosis of osteopetrosis and clarifying her massive splenomegaly because of compensatory extramedullary hematopoiesis rather than a primary hematologic disorder.

To rule out secondary causes of osteosclerosis, more laboratory tests were conducted. The findings revealed a borderline-low 25-hydroxy vitamin D level and normal serum levels of calcium, phosphate, and parathyroid hormone.

Due to financial and technological constraints, genetic testing could not be done. Following the diagnosis, a treatment plan was developed that included supportive care, hematinic, calcium, and vitamin D supplementation, as well as referrals to pediatric hematology and endocrinology for additional management.

Discussion

Osteopetrosis is a group of related rare bone diseases characterized by high bone mass due to impaired osteoclast-mediated bone resorption. Although there is high bone mass, skeletal strength is impaired, and the risk of fracture is substantial, particularly in the long bones [4]. Heinrich Albers Schönberg first defined this condition in 1904, and Karshner coined the name in 1926, derived from the Greek words "osteo" (bone) and "petros" (stone) [3]. It is noteworthy that this condition has clinical and genetic variability, ranging in severity from mild forms to those that are fatal in early childhood [5].

Osteopetrosis is classed as autosomal dominant, autosomal recessive, and X-linked according to its inheritance pattern [6,7]. The most prevalent type of osteopetrosis is autosomal dominant (ADO). It often results from defects in osteoclast function, most commonly caused by mutations in the chloride channel 7 (CLCN7) gene [8]. On the contrary, the autosomal recessive type of osteopetrosis is an extremely rare and severe form of this illness, with an estimated incidence of only 1 in every 250,000 live births, making it substantially less prevalent than the autosomal dominant form [9].

Most clinical symptoms of osteopetrosis are the result of a failure to remodel growing bones. This causes the cranial nerve foramina to constrict and encroach on marrow spaces, leading to secondary symptoms like anemia and optic and auditory nerve dysfunction. Hepatosplenomegaly results from compensatory extramedullary hematopoiesis in the liver and spleen in conjunction with anemia, as observed in our patient. A crucial characteristic of this case is the diagnostic overlap between osteopetrosis and hereditary hemolytic anemia. Both disorders can cause splenomegaly, anemia, and hepatomegaly, especially in children from consanguineous families, where hemoglobinopathies are also common. However, with osteopetrosis, the underlying cause is not increased red cell destruction, which is why our patient's hemoglobin electrophoresis and Coombs testing were unrevealing, despite a hematologic picture that initially mimicked a hematologic disorder.

The radiologist plays a vital role in diagnosing osteopetrosis, especially given its complex and diverse appearance across imaging modalities. In our case, diffusely increased bone density in the lower dorsal and lumbosacral vertebral bodies can be seen. It is the best-known imaging feature of osteopetrosis, and the cause for the name 'marble bone disease' for this disorder. Our patient also had the 'bone-within-a-bone' or 'bone-in-bone' appearance, defined by the presence of distinct foci of sclerosis within a skeletal segment mimicking another bone within the affected bone [10].

Genetic testing is important for accurate diagnosis and treatment planning, but it is not always possible in resource-limited settings. When genetic testing is inconclusive, a bone biopsy may be used to differentiate between osteoclast-rich and osteoclast-poor variants of the disease. However, radiology remains an important tool for early diagnosis and for monitoring disease progression [9].

Currently, treatment options for osteopetrosis include vitamin D and calcium supplements, IFN-γ therapy, and hematopoietic stem cell transplantation (HSCT). HSCT is preferred in most cases of osteopetrosis. Two gene therapy- and induced pluripotent stem cells (iPSCs)- derived techniques, centered on reconstituting the function of osteoclasts, were recently developed for the management of this hereditary bone disease [11].

Conclusion

This case illustrates osteopetrosis as an important but often overlooked mimicker of hereditary hemolytic anemia. It emphasizes the significance of a multidisciplinary approach if clinical and laboratory findings do not correspond to an initial provisional diagnosis. For the diagnosis of osteopetrosis and the tracking of the disease's course, radiographic assessment is still a primary diagnostic method. In order to improve patient outcomes, prompt intervention and multidisciplinary care are essential due to the serious implications of this disease, especially in its autosomal recessive form.

Author contribution

Dr. A.K.M. Munim Khan and Dr. Tushar Kanti Bhadra contributed to the conception and design of the case report and drafted the manuscript. Dr. Mohammad Abdus Sattar Sarker and Dr. Muntasir Hasan Ain contributed to data acquisition and critically revised the manuscript for important intellectual content. All authors approved the final version submitted for publication.

Patient consent

A written informed consent was obtained from the patient for the publication of this case report.