The Quarterly Consult is a quarterly supplement to the Bulletin highlighting pediatric clinical expertise. If you have an item of interest to include in the Quarterly Consult, contact Dr. Steve Dassel at 206-625-7373, mailbox 8588.

By Steve Dassel, MD

In 30-some years of doing the Consult, it occurred to me that I had never talked to Hematology. I sought out Akiko Shimamura, MD, PhD, the principal physician in the Bone Marrow Failure Program at Seattle Children's Hospital. Dr. Shimamura did her undergraduate studies at Princeton University and medical school at Johns Hopkins, finishing up at the University of Rochester. This was followed by a residency at Johns Hopkins and a pediatric hematology/oncology fellowship at Children's Hospital Boston and Dana-Farber Cancer Institute. She was on faculty at Boston Children's as director of the Bone Marrow Failure Program until July 2007, when she and her husband moved to Seattle. Here, she resumed a similar position. She holds the academic title of associate professor at the University of Washington School of Medicine.

Q: Dr. Shimamura, what is the primary referral source for the Bone Marrow Failure Program?

A: Primarily from subspecialists at Seattle Children's or hematologists in the community. I received more direct referrals from community physicians in Boston. That is possibly because our program is not as well known in this community.

Q: What is the incidence of bone marrow failure in the Pacific Northwest and is that different from the United States as a whole?

A: I am not aware of data on the incidence of bone marrow failure in the Pacific Northwest. The incidence of marrow failure for the general population is estimated at two per million per year. So far, I am currently seeing between two to four new patients with marrow failure every month. I work closely with my colleagues in the hematopoietic stem cell transplant service to coordinate the diagnostic workup and management of patients referred for marrow failure.

Q: What are the usual causes of bone marrow failure?

A: There is both primary and secondary bone marrow failure. Etiologies of primary bone marrow failure are idiopathic aplastic anemia and inherited bone marrow failure syndromes such as Fanconi anemia (different from Fanconi syndrome), Diamond-Blackfan anemia, Shwachman-Diamond syndrome and dyskeratosis congenita. The secondary bone marrow failure problems are commonly due to drug suppression, infections, systemic illnesses, and malignancies, both leukemias and metastatic solid tumors.

Q: How do bone marrow failure problems present, i.e., what is the chief complaint?

A: More common are the presentations due to deficiency of platelets, which are important for proper coagulation, and of red blood cells, which are important for oxygenation. Petechiae, bruising, or even bleeding are common manifestations of low numbers of platelets. Anemia often presents with pallor, fatigue, exercise intolerance or even syncope if severe. Neutrophils are important to fight infection so neutropenic patients may present with infections or fever. The infections are typically bacterial, often presenting as recurrent skin infections, oral lesions, perianal infections, bacteremias, etc. With the inherited marrow failure syndromes, cytopenias often develop over time and are not always present at birth.

It is important to point out that with marrow failure, the cytopenias arise from decreased blood cell production by the bone marrow. It is essential to rule out other causes of cytopenias, such as blood loss, hemolysis, antibody-mediated processes, consumptive processes, infection, malignancy, etc.

Q: To compulsively round it out, how about family history and social history?

A: A really good, compulsive family history is extremely helpful to us. Genetics here play a very significant role. In a patient with inherited marrow failure syndromes, the siblings should be evaluated. A problem we run into much too often is the time it takes to come to a diagnosis after initially starting the workup of the inherited anemias. This can take months and may lead to delay in initiating the correct treatment.

There is an increased risk of malignancies in the inherited anemias. The resulting problem is that malignancy will require immediate treatment, yet usual chemotherapy and radiation dosages can be extremely toxic to the individual with inherited marrow failure syndromes. Thus, for a patient whose malignancy is due to an as yet undiagnosed inherited marrow failure syndrome, being treated in the usual way can have disastrous results. The key here is early diagnosis requiring a high index of suspicion in patients with bone marrow failure and either a suspicious family history or associated clinical stigmata.

Q: What else should be sought in terms of family or social history?

A: With respect to family history, look for an increased incidence of cancers, particularly with onset at an early age, anything suggestive of cytopenias, and congenital anomalies. The inherited bone marrow failure problems can be associated with congenital anomalies. Rarely, hobbies or occupations may give some clues as to a source of toxins to the bone marrow; for example, some organic solvents may cause marrow failure.

Q: What, on physical examination, along with evidence of cytopenia, should raise our suspicion of the inherited bone marrow failure syndrome?

A: Look for cytopenias arising in association with dysmorphic features and congenital anomalies, short stature/failure to thrive, cafe au lait spots, and anything unusual about the thumbs. A common dysmorphic feature with the inherited bone marrow failure syndrome is joint anomalies of the thumbs.

Q: What laboratory evaluations might the primary physician be expected to do in evaluating these patients?

A: A complete blood count (CBC) and smear indices and platelet count. The primary care physician should be interested in red cell count, hematocrit or hemoglobin and a mean cell volume (MCV) with a reticulocyte count, a platelet count and a look at platelet morphology and finally, a white count and differential. An unexplained elevated MCV may be the only hematologic manifestation of an underlying marrow failure syndrome. Any laboratory evaluations beyond that would be an evaluation of complications, such as chest X-ray for pneumonia, etc. Referral to a hematologist for an examination of the bone marrow is warranted.

Q: Let's talk a little bit about the complications of these bone marrow failure problems.

A: The problem with idiopathic aplastic anemia is just the problem with the bone marrow. However, in inherited bone marrow failure, there is a predilection for malignancy, both solid tumors and leukemia. There are also other organ system problems. For example, with dyskeratosis congenita, such as pulmonary problems, liver problems, and GI problems, and, as we discussed, short stature Shwachman-Diamond syndrome, patients have exocrine pancreatic insufficiency presenting with steatorrhea and neutropenia, osteopenia, short stature, and other problems. I already alluded to congenital anomalies.

Q: Let's turn to treatment - how is the condition managed?

A: The treatment for idiopathic aplastic anemia where there is a matched sibling is bone marrow transplant alone. If there is not a matched sibling available, then medical therapy with cyclosporin and ATG, anti-thymocyte globulin, is typically the recommended treatment. The treatment for inherited marrow failure syndromes is more complicated since multi-organ system disease may be present, but bone marrow transplant can cure the hematologic abnormalities in those disorders. Reducing doses of the chemotherapy and radiation used in the transplant regimens is essential for many of the inherited marrow failure syndromes since these patients may experience undue toxicity from standard doses. Thus, recognition of the diagnosis prior to the transplant is critical.

Q: What are the respective success rates?

A: It depends upon how you measure success. There is an 85% to 95% cure in well-established bone marrow transplant centers for matched sibling bone marrow transplants performed early in the course of the disease. You don't get a cure with medication therapy, in that blood counts and/or MCV often do not normalize, but there is a 66% success rate using the criteria of transfusion independence and good neutrophil counts. For the inherited marrow failure syndromes, bone marrow transplant can cure bone marrow failure, but that does not eliminate the problems of solid tumor risk or other organ system problems.

Q: Finally, I like to close these consults with the question, "What kind of mistakes do you see primary care physicians making?"

A: Let me answer that question by first saying I really appreciate the difficult task you have. Almost everything that comes to me is serious stuff, because you have to maintain such a high index of suspicion. You have the unenviable task of picking out the few hematologic problems with serious pathology from the many who do not need a referral.

But to answer your question, the most common difficulty I run into is the failure to make an early diagnosis, with subsequent delay in initiation of the correct treatment. Some red flags are unexplained cytopenias arising in the context of short stature, dysmorphology, steatorrhea, cafe au lait spots, macrocytosis (elevated red cell MCV), etc. The diagnostic workup may require several months, so referral well before the cytopenias are severe or before a malignancy develops would prevent costly delays in the initiation of urgently needed therapy. All siblings of a patient with an inherited marrow failure syndrome should be tested regardless of clinical stigmata or blood counts. Another benefit of early diagnosis is in the area of family planning.

Q: So, it is a good idea to get a CBC in a patient with very short stature, congenital anomalies or suspicious family history?

A: Yes!

Q: What are some common misconceptions about the inherited marrow failure syndromes?

A: Prior to the development of recent laboratory tests, the diagnosis of an inherited marrow failure syndrome was recognized in only the most severely affected patients. These patients were classically believed to present with severe failure to thrive, dysmorphic features, and severe marrow failure. With the advent of genetic and functional tests, it is clear that the clinical spectrum of these disorders is much broader than previously recognized. Patients of normal stature and lacking any apparent clinical stigmata may have an inherited marrow failure syndrome. It has recently been estimated that up to 10% to 25% of patients with seemingly idiopathic aplastic anemia actually have an underlying inherited marrow failure syndrome. Since conventional treatments for aplastic anemia or malignancy can be toxic for the inherited marrow failure patients, correct diagnosis is essential. Early referral to allow time for a full diagnostic workup is essential. The other misconception is that these syndromes are too rare to consider.