Transcript C-02_Muhammad - Advocatehealth.com

A Case Report: Juvenile Myelomonocytic Leukemia
Nina Muhammad, DO
Department of Pediatrics, Advocate Hope Children’s Hospital
Introduction:
An 18-month-old boy presents with increasing abdominal distension over the last 3
months. He had no abdominal pain, fever, nausea or vomiting. He has had a
decrease in appetite over the last 3 weeks and occasionally sweats at night. He has
had no noticeable weight loss, fatigue, bleeding or bruising.
Physical examination revealed a quiet, pale appearing boy with a temperature of
36.5C, heart rate of 130 beats/min, respiratory rate of 28 breaths/min and blood
pressure of 116/65 mmHg. His weight was 11.7kg (50th percentile) and his height
was 84.5cm (75th percentile). His skin exam demonstrated a faint macular rash on
his chest. His abdomen was nontender with bowel sounds present throughout but
shows marked distension with the liver edge palpable 2 cm below the costal margin
and the spleen 20 cm below the costal margin. The remainder of his physical
examination was unremarkable.
The patient was hospitalized, underwent blood testing and imaging was done.
Results led to a diagnosis of Juvenile Myelomonocytic Leukemia (JMML).
JMML is a chronic leukemia that is characterized by clonal proliferation of the
monocytic cell line of myeloid progenitor cells. The median age of diagnosis is 2
years with predominance towards males (2:1 male to female ratio). Up to 15% of
patients have an underlying disorder such as Neurofibromatosis-1 or Noonan
syndrome.
JMML is believed to be caused by a variety of genetic mutations all leading to
hypersensitivity of macrophage colonies to the cytokine, GM-CSF. The RAS signal
transduction pathway is responsible for transmission of GM-CSF signals from its
receptor to the nucleus. Therefore, the initiating factor is believed to be a
hyperactive RAS-mitogen activated protein kinase pathway. RAS is a family of
proteins involved in cellular signal transduction. RAS proteins bind to GTP in their
active form and GDP when inactive. Extracellular stimulation by molecules such as
GM-CSF allows GTP to bind, thereby activating the RAS cascade. RAS also has
GTPase activity to allow hydrolysis of RAS-GTP to RAS-GDP to permit selfregulation. Mutations in any of the 3 RAS proto-oncogenes (HRAS, KRAS,
NRAS) cause a reduction in this hydrolysis capability leading to inappropriate overstimulation of cells. GAP, which is a product of the NF-1 gene, normally speeds up
the process of hydrolysis of RAS-GTP to inactivate it. Therefore in patients with
the NF-1 mutation there may also be an inappropriate activation of the RAS
pathway.
Significance of Case:
Differential Diagnosis:
JMML is unique in its rarity. It is a chronic leukemia that accounts for less than 2%
of all childhood leukemias, with less than 25-50 new cases reported each year.
Method:
Literature review using PubMed/Ovid MEDLINE with searches “juvenile
myelomonocytic leukemia,” “splenomegaly AND children,” limited to English
language and “all child (0-18years).”
Patient Description:
The patient past medical history is significant for iron deficiency anemia for which
he completed iron supplementation > 4 months prior to presentation. He was on no
medications, had no known drug allergies. The patient lives in a house with his
parents and younger brother, had no new exposures to pets, ill contacts or travel.
When evaluating splenomegaly in children there are numerous etiologies to
consider. Splenomegaly can be infectious, hematologic, infiltrative, rheumatologic
or immunologic in origin to name just a few. With infectious causes viral is the
most common and is a result of hyperplasia of the reticuloendothelial system which
has phagocytic properties. Infiltrative causes in children can result from leukemia
or lymphoma secondary to extramedullary hematopoiesis from the increased
demand on the bone marrow. Hematologic causes may also be secondary to
extramedullary hematopoiesis or from the entrapment of abnormally shaped cells in
cases of sickle cell sequestration.
One must narrow their differential by history and physical exam. In this case
splenomegaly was first confirmed with an ultrasound; which is important to rule out
other abdominal masses, such as Wilms tumor. In view of an abnormal CBC,
affecting all 3 cell lines, with some systemic symptoms by report, a bone marrow
biopsy is required to rule out an acute leukemic process. With myeloid precursors
on peripheral smear, one must also rule out chronic myeloid leukemia (CML). To
differentiate JMML from CML, BCR-ABL gene rearrangement must be negative.
Infectious processes should be ruled out as well, especially Epstein - Barr virus
(EBV) infections, as it may present in a very similar fashion, including abnormal
peripheral smear findings.
Initial laboratory results showed a WBC count of 14.7x103/mcL with 24%
neutrophils, 8 bands, 44% lymphocytes and 12% monocytes. Myelocytes,
metamyelocytes and nucleated red cells are noted on peripheral smear. His Hgb is
6.7 g/dL and platelet count is 82 x 103/mcL. Serum electrolytes, liver enzyme and
coagulation studies were all normal. His lactic dehydrogenase level was elevated at
319 IU/L. Abdominal ultrasonography confirmed splenomegaly.
Diagnosis:
The patient underwent a bone marrow biopsy which was inconclusive, showing
nonspecific fibrosis. Flow cytometry was negative for breakpoint cluster regionAbelson (BCR-ABL) gene rearrangement. Absolute monocyte count was elevated at
1764/mcL. Hgb electrophoresis showed elevated Hgb F of 9.7%. In vitro study
showed hypersensitivity of myeloid progenitor cells to granulocyte macrophage colony
stimulating factor (GM-CSF). Remainder of laboratory testing, including serology for
multiple microorganisms and immunoglobulin levels were normal. All of these
laboratory test results establish a diagnosis of JMML.
Diagnosis of JMML is made when the following criteria are met:
ALL of the following
AT LEAST 2 of the following
Absence of the t(9;22)
BCR/ABL fusion gene
Circulating myeloid
precursors
Absolute monocyte count >
1000/μL
White blood count
>10,000/μL
< 20% blasts in the bone
marrow
Increased fetal hemoglobin
(HgF) for age
GM-CSF hypersensitivity of
myeloid progenitors in vitro
Intervention:
The patient received a packed red blood cell transfusion and was started on oral iron
supplementation. Following HLA typing of his family the boy was referred to another
hospital for bone marrow transplant. He has since undergone chemotherapy and a
splenectomy followed by a matched unrelated cord blood transplant and is currently
doing well.
Conclusion/Implications:
JMML is a chronic myel oid leukemia accounting for less than 2% of childhood
leukemias. Clinical presentation most commonly includes fever, rash,
Figure 3. Extent of Splenomegaly
lymphadenopathy, splenomegaly, leukocytosis with monocytosis and
thrombocytopenia. Diagnosis includes excluding other causes of splenomegaly and
excluding CML. Diagnosis can then be made if clinical criteria is met. Prognosis is
poor; the only chance for cure being a hematopoeitic stem cell transplant (HSCT)
which still leaves a 50% relapse rate. Chemotherapy alone has not shown any
efficacy but is used in conjunction with HSCT as a part of the Children’s Oncology
Group (COG) protocol.
References:
Figure 2 Extent of Splenomegaly
Figure 1.
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=hmg&part=A127
George, et al, "Pathology of Myeloproliferative Diseases." Hematology Oncology Clinics of North America 17, no.
(2003): 1101-1127.
Locatelli et al, "HSCT in children with JMML, results of the EWOG-MDS/EBMT trial." Blood 105, no. 1 (2005):
410-419.
Acknowledgements:
Dr. Hayani