My Strangest Case: An Infant With Lumps in Her Belly

Vikramjit S. Kanwar, MBA, MRCP(UK)


June 10, 2020

The laboratory had correctly reported that there were no leukemic blasts. However, the technician had failed to recognize the significance of the scattered immature precursors of red cell and white cell lineage, with occasional giant platelets and red cell anisocytosis that were seen. It was a "leukoerythroblastic" blood picture, which is the hallmark of extramedullary hematopoiesis.[10]

In adults, this is seen in primary myelofibrosis, in which the marrow is obliterated and the liver and spleen become the sites for blood cell production. This is extremely rare in childhood, and nystagmus is not a reported finding.[11] Nevertheless, we felt confident that the hepatosplenomegaly and deranged blood counts represented extramedullary hematopoiesis. We had excluded all other differential diagnoses.

The next step was a bone marrow biopsy. However, before calling the family to schedule such an invasive procedure, it seemed prudent for me to "phone a friend" at a large hematology-oncology center and seek her opinion.

"Failure to thrive, hepatosplenomegaly, abnormal eye movements, and leukoerythroblastic peripheral blood smear? That sounds like a case of malignant infantile osteopetrosis," was her response. She told me not to bother with a bone marrow biopsy and that the constellation of findings was pathognomonic.[12] She recommended plain skull or chest radiography for "insurance purposes." An example of such imaging is shown below.

She also told me that early hematopoietic stem cell treatment (HSCT) is the treatment of choice, and the 5-year survival is almost 80%.[13] As soon as I got off the phone with my colleague, we brought the family back in for counseling and discussion about the child's diagnosis and treatment. They were tearful but grateful that they now had a diagnosis and course of action.

The child later underwent an alternate-donor allogeneic HSCT under the care of my colleague. She recovered some of her vision and all of her growth, hearing, and speech with the help of intensive rehabilitation. Today, she is a confident and healthy young woman.

Osteopetrosis—from the Greek osteo, meaning "bone," and petros, meaning "stone"—is a rare genetic disorder that is characterized by increased bone density on plain radiography, which is diagnostic.[14] The autosomal dominant variant is 10 times more common and is usually mild or asymptomatic. In contrast, the autosomal recessive variant, known as "malignant infantile osteopetrosis," is extremely rare. It has an incidence of 1 in 250,000 population and presents in the first few months of life. Sometimes, it is diagnosed in utero, and it is universally fatal by school age if undiagnosed and untreated.[15]

Impairment of osteoclast function, failure of bone remodeling, and disordered bone growth are the key underlying causes. At a molecular level, mutations in TCIRG1 and CLCN7 account for 70% of cases, impairing the ion pump mechanisms that osteoclasts need to create the acidic environment needed for bone resorption[16]; however, in more than 20% of cases, the gene defect remains unidentified. This leads to numerous symptoms, including narrowing of the intramedullary space that impinges on the bone marrow, with compensatory extramedullary hematopoiesis that manifests as hepatosplenomegaly and leukoerythroblastic anemia.

Narrowing of skull foramina impinges on the optic nerves and leads to visual impairment, which is a frequent early finding, as well as hearing loss, cranial neuropathies, and obstructive hydrocephalus.[16] Failure to thrive, dental problems, pathologic fractures, osteomyelitis of the mandible, and ear infections are all reported.[17] Patients whose disease goes undiagnosed develop macrocephaly and frontal bossing in the first year of life. Some newborns develop hypocalcemia, with attendant tetanic seizures and secondary hyperparathyroidism.[17]

The diagnosis is easily confirmed with skeletal radiography that show diffuse bone sclerosis.[15] CT can also document the narrowing of the optic and auditory canals. Genetic testing does not play a significant role in diagnosis.[16] Osteoclasts are derived from hematopoietic cells, and HSCT is curative for malignant infantile osteopetrosis; however, some complications are common, such as graft failure, pulmonary hypertension, and interstitial fibrosis.[13] Although medical therapies, such as calcitriol and gamma interferon, may palliate the patient for a prolonged duration, they are not curative.[14]

In summary, the old adage held true: A careful history, physical examination, and review of tests yielded an accurate diagnosis. For hematologists, review includes the peripheral blood smear, which should always be part of the routine. When confronted with a confusing case, going back to first principles and using the information you have to map out the disease process can help move you forward. Complex or invasive testing should only be used to confirm a diagnosis that is suspected, rather than as a screen. Also, because "rare things occur rarely," you may reduce unnecessary anxiety, tests, and referrals by reaching out to a more experienced colleague, as I did in this case.

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