Unmistakable Morphology? Infantile Malignant Osteopetrosis Resembling Juvenile Myelomonocytic Leukemia in Infants Anne Strauss, MD1, Ingrid Furlan, MD2, Sandra Steinmann2, Bernd Buchholz, PhD3, Bernhard Kremens, MD4, Claudia Rossig, MD5, Selim Corbacioglu, MD6, Revathi Rajagopal, MD7, Georgia Lahr, PhD2, Ayami Yoshimi1, Brigitte Strahm, MD1, Charlotte M. Niemeyer, PhD1, and Ansgar Schulz, MD, PhD2 The initial clinical and hematologic presentation of infantile malignant osteopetrosis may be indistinguishable from that of juvenile myelomonocytic leukemia in infants. Timely radiographic imaging, however, allows straightforward delineation of these 2 severe diseases and facilitates immediate initiation of appropriate therapy. (J Pediatr 2015;-:---).
T
he diagnosis of acute leukemia in children presenting with sudden onset of classical symptoms is generally straightforward and can be confirmed without delay by widely used diagnostic tools. It appears to be just as straightforward to diagnose a trivial viral syndrome in an infant with persisting general symptoms and leukocytosis. However, even though common syndromes are widespread, the latter, nonspecific clinical picture may have a less common cause and require the consideration of differential diagnoses. The combination of leukocytosis, monocytosis, organomegaly, and such symptoms as fever, recurrent infections, malaise, exanthema, or bleeding are frequent findings in cases of leukocyte adhesion deficiency (LAD), Wiskott-Aldrich syndrome (WAS), juvenile myelomonocytic leukemia (JMML), and infantile malignant osteopetrosis (IMO).1-3 Patients with LAD or WAS are usually diagnosed readily on the basis of distinct clinical symptoms, such as umbilical infection or severe eczema, but additional diagnostic measures might be needed to distinguish JMML from IMO. JMML is a malignant hematopoietic disorder of early childhood. Pivotal diagnostic criteria are a leukoerythroblastic blood morphology with left-shifted myelopoiesis, presence of myeloblasts and nucleated erythroblasts, and increased monocyte count (>1.0 G/L) in the peripheral blood (PB) in combination with thrombocytopenia, anemia, and splenomegaly.4 Liver enlargement, elevated fetal hemoglobin, and variable skin infiltrations are commonly observed. A milestone in understanding the pathogenesis of the disease was the description of a hypersensitivity of JMML myeloid progenitors to granulocyte macrophage colony-stimulating factor, as well as the association of neurofibromatosis 1 and JMML, which led to the discovery of a defective Ras signaling pathway and subsequently to the
IMO JMML LAD PB SCT WAS
Infantile malignant osteopetrosis Juvenile myelomonocytic leukemia Leukocyte adhesion deficiency Peripheral blood Stem cell transplantation Wiskott-Aldrich syndrome
identification of pathogenic mutations in NRAS, KRAS, PTPN11, CBL, and NF1.5 At present, the diagnosis of JMML can be confirmed by molecular genetic analysis in close to 90% of affected patients.6-8 IMO is a rare genetic disorder of bone resorption. Its early presentation strongly resembles and may be mistaken for JMML.9 Autosomal recessive IMO, the most severe form of osteopetrosis, has an estimated incidence of 1:200 000300 000 births, with symptoms manifesting in the first months of life.10,11 Underlying mutations in TCIRG1, CLCN, SNX210, and OSTM1 cause dysfunction of osteoclasts, and the rarer mutations in RANK and RANKL lead to a marked decrease in the number of osteoclasts.9,11,12 All mutations result in severe suppression of bone marrow function and subsequent extramedullary hematopoiesis with concomitant hepatosplenomegaly.2,13,14 IMO is not recognized immediately in a considerable number of children. Indicative signs, such as visible fractures, neurologic impairment, blindness secondary to optic nerve compression, and hydrocephalus, may be absent initially. Early diagnosis and stem cell transplantation (SCT) is the only curative therapy in this otherwise fatal disease. Patients with neuronopathic forms of IMO do not qualify for SCT. Of note, preparative regimens for SCT differ between IMO and JMML.
Methods This study has been approved by the University of Freiburg and the University of Ulm. We identified 6 infants presenting
From the 1Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany; 2Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany; 3 Department of Pediatrics, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; 4Department of Pediatric Hematology and Oncology, University of Duisburg-Essen, Essen, Germany; 5Department of Pediatric Hematology and Oncology, University Children’s Hospital Muenster, Muenster, Germany; 6Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Regensburg, Children’s Hospital Regensburg, Regensburg, Germany; and 7Pediatric Hematology-Oncology Unit, University of Malaya Medical Center, Kuala Lumpur, Malaysia The authors declare no conflict of interest. 0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.04.064
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Table I. Characteristics of patients with IMO Characteristics
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
Age at symptom onset, mo Age at diagnosis, mo Sex Hb, g/dL PLT, G/L WBC, G/L Monocytes, G/L IMC, % Blasts, % Normoblasts, % HbF, % Transfusions Splenomegaly Hepatomegaly Mutation
Unknown 10 Female 7 43 13.6 0.5 12 2 7 NA RBC + + CLCN7
3 5 Female 7.5 49 67.7 6.1 9 1 11 5.1 + + TCIRG1
Birth 6 Male 6.8 45 15.1 1.5 11 2 14 NA + + OSTM1
2.5 4 Male 9.5 51 15.7 2.2 11 2 8 26.9 RBC, PLT + + CLCN7
36 36 Female 6.1 71 11.7 0.47 16 0 12 NA + NA TCIRG1
3 4 Male 9.3 55 27.4 3.8 8 2 22 NA + + None*
Hb, hemoglobin; HbF, fetal hemoglobin; IMC, immature myeloid cells in PB (promyelocytes, myelocytes, metamyelocytes, bands); NA, not available; PLT, platelets; RBC, red blood cells; WBC, white blood cells. *No mutation in CLCN7 or TCIRG; other genes were not analyzed.
with the clinical and laboratory picture of JMML who were referred for molecular confirmation of this diagnosis, but eventually turned out to have IMO. To illustrate the overlapping features of both conditions of JMML and IMO in infants, we compared hematologic variables in 130 patients with JMML (date of diagnosis, September 1975 to October 2013) and 45 patients with IMO (date of diagnosis, August 1990 to August 2013) with data derived from German patients in European Working Group of Myelodysplastic Syndromes in Childhood study and the International Osteopetrosis Registry of the European Society for Immunodeficiencies and European Society for Blood and Marrow Transplantation Inborn Errors Working Party, respectively. Inclusion of patients had been restricted to children up to age 3 years to focus on the age group in which the majority of cases with JMML and IMO are diagnosed and the clinical picture may be similar.
Results The 6 children diagnosed with IMO included 2 of Turkish origin, 1 of Arabic origin, 1 of Malaysian origin, and 2 of German origin. Consanguineous background was confirmed in 2 patients (patient 3 and patient 6; Table I). Onset of symptoms occurred between birth and age 3 months in 5 of the 6 patients. Patient 5 had initially been suspected of having Russell-Silver syndrome and was diagnosed with IMO at age 3 years only when hematologic symptoms became evident. Total white blood cell count was increased in all cases (11.7-67.7 G/L). Monocyte count exceeded 1.0 G/L in 4/6 cases. All patients presented with thrombocytopenia (43-71 G/L) and anemia (6.1-9.5 g/dL). The percentage of immature myeloid cells in the PB ranged from 8% to 16%, and the blast differential ranged from to 0% to 2%. Hepatosplenomegaly was present in all 5 patients with available data (Table I). The diagnosis was confirmed by molecular genetics in 5 of 6 patients and by clinical and radiologic findings with increased bone density and 2
defective metaphyseal remodeling with bone-in-bone appearance in 1 patient (patient 6). There is a notable resemblance in complete and differential blood counts in patients with JMML and those with IMO (Table II). Both diseases show values above-age specific normative values for white blood cells and monocytes, as well as anemia, thrombocytopenia, and immature myeloid cells, blasts, and normoblasts in PB. Leukocytosis, monocytosis, elevated blast count, and presence of normoblasts in PB are significantly more pronounced in JMML, whereas the range of anemia, thrombocytopenia, and left-shifted myelopoiesis are similar in the 2 conditions.
Discussion There is a noteworthy overlap in the phenotypic presentation of autosomal recessive IMO and JMML in infants. Both JMML and IMO can manifest with leukocytosis, monocytosis, anemia, thrombocytopenia, a leukoerythroblastic blood count, and organomegaly. Radiologic imaging displaying increased bone density is the key diagnostic method for an unequivocal distinction of the 2 diseases.11,15,16 Additional laboratory variables, such as calcium and alkalkine phosphatase, provide further indication to the correct diagnosis.1 Other differential diagnoses, such as LAD, WAS, or viral infections, usually can be excluded quickly. IMO is the most Table II. Hematologic findings in patients diagnosed with JMML and IMO up to age 3 years Variables
JMML (n = 130)
IMO (n = 45)
P value
WBC, G/L, median (range) Hb, g/dL, median (range) PLT, G/L, median (range) Monocytes, G/L, median (range) IMC, %, median (range) Blasts, %, median (range) Normoblasts, %, median (range)
31.6 (2.2-167) 9.4 (4.1-21.3) 88 (9-938) 5.8 (0.5-50.1) 9 (0-52) 2 (0-16) 0.5 (0-78)
14.6 (4.2-45.7) 9.2 (5-16.8) 137 (6-372) 1.15 (0-6.4) 10 (0-26) 0 (0-10) 4 (0-53)
T
he diagnosis of acute leukemia in children presenting with sudden onset of classical symptoms is generally straightforward and can be confirmed without delay by widely used diagnostic tools. It appears to be just as straightforward to diagnose a trivial viral syndrome in an infant with persisting general symptoms and leukocytosis. However, even though common syndromes are widespread, the latter, nonspecific clinical picture may have a less common cause and require the consideration of differential diagnoses. The combination of leukocytosis, monocytosis, organomegaly, and such symptoms as fever, recurrent infections, malaise, exanthema, or bleeding are frequent findings in cases of leukocyte adhesion deficiency (LAD), Wiskott-Aldrich syndrome (WAS), juvenile myelomonocytic leukemia (JMML), and infantile malignant osteopetrosis (IMO).1-3 Patients with LAD or WAS are usually diagnosed readily on the basis of distinct clinical symptoms, such as umbilical infection or severe eczema, but additional diagnostic measures might be needed to distinguish JMML from IMO. JMML is a malignant hematopoietic disorder of early childhood. Pivotal diagnostic criteria are a leukoerythroblastic blood morphology with left-shifted myelopoiesis, presence of myeloblasts and nucleated erythroblasts, and increased monocyte count (>1.0 G/L) in the peripheral blood (PB) in combination with thrombocytopenia, anemia, and splenomegaly.4 Liver enlargement, elevated fetal hemoglobin, and variable skin infiltrations are commonly observed. A milestone in understanding the pathogenesis of the disease was the description of a hypersensitivity of JMML myeloid progenitors to granulocyte macrophage colony-stimulating factor, as well as the association of neurofibromatosis 1 and JMML, which led to the discovery of a defective Ras signaling pathway and subsequently to the
IMO JMML LAD PB SCT WAS
Infantile malignant osteopetrosis Juvenile myelomonocytic leukemia Leukocyte adhesion deficiency Peripheral blood Stem cell transplantation Wiskott-Aldrich syndrome
identification of pathogenic mutations in NRAS, KRAS, PTPN11, CBL, and NF1.5 At present, the diagnosis of JMML can be confirmed by molecular genetic analysis in close to 90% of affected patients.6-8 IMO is a rare genetic disorder of bone resorption. Its early presentation strongly resembles and may be mistaken for JMML.9 Autosomal recessive IMO, the most severe form of osteopetrosis, has an estimated incidence of 1:200 000300 000 births, with symptoms manifesting in the first months of life.10,11 Underlying mutations in TCIRG1, CLCN, SNX210, and OSTM1 cause dysfunction of osteoclasts, and the rarer mutations in RANK and RANKL lead to a marked decrease in the number of osteoclasts.9,11,12 All mutations result in severe suppression of bone marrow function and subsequent extramedullary hematopoiesis with concomitant hepatosplenomegaly.2,13,14 IMO is not recognized immediately in a considerable number of children. Indicative signs, such as visible fractures, neurologic impairment, blindness secondary to optic nerve compression, and hydrocephalus, may be absent initially. Early diagnosis and stem cell transplantation (SCT) is the only curative therapy in this otherwise fatal disease. Patients with neuronopathic forms of IMO do not qualify for SCT. Of note, preparative regimens for SCT differ between IMO and JMML.
Methods This study has been approved by the University of Freiburg and the University of Ulm. We identified 6 infants presenting
From the 1Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany; 2Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany; 3 Department of Pediatrics, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; 4Department of Pediatric Hematology and Oncology, University of Duisburg-Essen, Essen, Germany; 5Department of Pediatric Hematology and Oncology, University Children’s Hospital Muenster, Muenster, Germany; 6Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Regensburg, Children’s Hospital Regensburg, Regensburg, Germany; and 7Pediatric Hematology-Oncology Unit, University of Malaya Medical Center, Kuala Lumpur, Malaysia The authors declare no conflict of interest. 0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.04.064
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Table I. Characteristics of patients with IMO Characteristics
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
Age at symptom onset, mo Age at diagnosis, mo Sex Hb, g/dL PLT, G/L WBC, G/L Monocytes, G/L IMC, % Blasts, % Normoblasts, % HbF, % Transfusions Splenomegaly Hepatomegaly Mutation
Unknown 10 Female 7 43 13.6 0.5 12 2 7 NA RBC + + CLCN7
3 5 Female 7.5 49 67.7 6.1 9 1 11 5.1 + + TCIRG1
Birth 6 Male 6.8 45 15.1 1.5 11 2 14 NA + + OSTM1
2.5 4 Male 9.5 51 15.7 2.2 11 2 8 26.9 RBC, PLT + + CLCN7
36 36 Female 6.1 71 11.7 0.47 16 0 12 NA + NA TCIRG1
3 4 Male 9.3 55 27.4 3.8 8 2 22 NA + + None*
Hb, hemoglobin; HbF, fetal hemoglobin; IMC, immature myeloid cells in PB (promyelocytes, myelocytes, metamyelocytes, bands); NA, not available; PLT, platelets; RBC, red blood cells; WBC, white blood cells. *No mutation in CLCN7 or TCIRG; other genes were not analyzed.
with the clinical and laboratory picture of JMML who were referred for molecular confirmation of this diagnosis, but eventually turned out to have IMO. To illustrate the overlapping features of both conditions of JMML and IMO in infants, we compared hematologic variables in 130 patients with JMML (date of diagnosis, September 1975 to October 2013) and 45 patients with IMO (date of diagnosis, August 1990 to August 2013) with data derived from German patients in European Working Group of Myelodysplastic Syndromes in Childhood study and the International Osteopetrosis Registry of the European Society for Immunodeficiencies and European Society for Blood and Marrow Transplantation Inborn Errors Working Party, respectively. Inclusion of patients had been restricted to children up to age 3 years to focus on the age group in which the majority of cases with JMML and IMO are diagnosed and the clinical picture may be similar.
Results The 6 children diagnosed with IMO included 2 of Turkish origin, 1 of Arabic origin, 1 of Malaysian origin, and 2 of German origin. Consanguineous background was confirmed in 2 patients (patient 3 and patient 6; Table I). Onset of symptoms occurred between birth and age 3 months in 5 of the 6 patients. Patient 5 had initially been suspected of having Russell-Silver syndrome and was diagnosed with IMO at age 3 years only when hematologic symptoms became evident. Total white blood cell count was increased in all cases (11.7-67.7 G/L). Monocyte count exceeded 1.0 G/L in 4/6 cases. All patients presented with thrombocytopenia (43-71 G/L) and anemia (6.1-9.5 g/dL). The percentage of immature myeloid cells in the PB ranged from 8% to 16%, and the blast differential ranged from to 0% to 2%. Hepatosplenomegaly was present in all 5 patients with available data (Table I). The diagnosis was confirmed by molecular genetics in 5 of 6 patients and by clinical and radiologic findings with increased bone density and 2
defective metaphyseal remodeling with bone-in-bone appearance in 1 patient (patient 6). There is a notable resemblance in complete and differential blood counts in patients with JMML and those with IMO (Table II). Both diseases show values above-age specific normative values for white blood cells and monocytes, as well as anemia, thrombocytopenia, and immature myeloid cells, blasts, and normoblasts in PB. Leukocytosis, monocytosis, elevated blast count, and presence of normoblasts in PB are significantly more pronounced in JMML, whereas the range of anemia, thrombocytopenia, and left-shifted myelopoiesis are similar in the 2 conditions.
Discussion There is a noteworthy overlap in the phenotypic presentation of autosomal recessive IMO and JMML in infants. Both JMML and IMO can manifest with leukocytosis, monocytosis, anemia, thrombocytopenia, a leukoerythroblastic blood count, and organomegaly. Radiologic imaging displaying increased bone density is the key diagnostic method for an unequivocal distinction of the 2 diseases.11,15,16 Additional laboratory variables, such as calcium and alkalkine phosphatase, provide further indication to the correct diagnosis.1 Other differential diagnoses, such as LAD, WAS, or viral infections, usually can be excluded quickly. IMO is the most Table II. Hematologic findings in patients diagnosed with JMML and IMO up to age 3 years Variables
JMML (n = 130)
IMO (n = 45)
P value
WBC, G/L, median (range) Hb, g/dL, median (range) PLT, G/L, median (range) Monocytes, G/L, median (range) IMC, %, median (range) Blasts, %, median (range) Normoblasts, %, median (range)
31.6 (2.2-167) 9.4 (4.1-21.3) 88 (9-938) 5.8 (0.5-50.1) 9 (0-52) 2 (0-16) 0.5 (0-78)
14.6 (4.2-45.7) 9.2 (5-16.8) 137 (6-372) 1.15 (0-6.4) 10 (0-26) 0 (0-10) 4 (0-53)
