Isolated thrombocytopenia in childhood is a common phenomenon and mostly occurs due
to immune destruction of platelet (immune thrombocytopenic purpura [ITP]). But sometimes,
the patient is diagnosed with congenital amegakaryocytic thrombocytopenia (CAMT),
a rare inherited bone marrow failure syndrome (IBMFS) affecting a single cell line.
The diagnosis and treatment of such a condition is very difficult and long-term follow-up
is very important, as these patients may transform into some hematological malignancy.
Here, we report one such patient, who was diagnosed with CAMT and on follow-up developed
juvenile myelo-monocytic leukemia (JMML), another rare myelodysplastic/myeloproliferative
syndrome (MDS/MPN) syndrome.
A 5-year, 9-month-old female child presented to the hematology outpatient department
(OPD) in September 2018 with a history of purpuric rash all over the body with gum
bleeding for 3 days. There was no history of antecedent fever, jaundice, pain abdomen,
shortness of breath, or rash. There was no history of recent exposure to any drug
or vaccine. The child was born at full-term normal delivery out of nonconsanguineous
marriage. There was no congenital structural abnormality at birth, and no developmental
delay was noted. She had one elder sister. On examination, there was no organomegaly,
lymphadenopathy, sternal tenderness, or arthropathy. Blood investigations revealed
isolated thrombocytopenia with a platelet count of 6000/mm3 on admission. Peripheral blood smear revealed no atypical cells. Lactate dehydrogenase
was 420 μ/dl; direct Coombs' test was negative. Other biochemical parameters were
normal, and antinuclear antibody was negative. Ultrasonography of the abdomen did
not reveal any abnormalities.
The patient was clinically diagnosed as ITP, and was started on prednisolone at 1
mg/kg and intravenous immunoglobulin 1 g/kg for 2 days, along with tranexamic acid.
The bleeding manifestation subsided, and platelet count rose to 30,000/mm3 on day 5. The child was discharged with oral medication and followed up in the OPD.
However, even after 2 months of steroid therapy, the platelet count did not improve
beyond 50,000/mm3.
The patient was planned to be started on 2nd-line therapy, and a bone marrow (BM) study was done in November 2018. BM aspiration
revealed cellular trail with normal maturation of erythroid and myeloid lineage without
dysplasia [Figure 1a]. However, megakaryocytes were conspicuously absent. No increase in blast percentage
was seen. The BM biopsy was normocellular for age, but megakaryocyte was absent [Figure 1b]. No granuloma, infiltration, or fibrosis was seen on biopsy. The features were suggestive
of amegakaryocytic thrombocytopenia. The peripheral blood stress cytogenetics did
not reveal any chromosomal breakage. The other mutation for IBMFS including thrombopoietin
receptor (c-MPL) mutation was not done as the tests were not available in our setup.
Figure 1 Initial bone marrow aspiration (a) and biopsy (b) of the patient showing cellular
marrow with absent megakaryocyte. The erythroid and myeloid lineage are showing normal
maturation without any dysplasia. There was no granuloma, infiltration, or fibrosis.
The bone marrow morphology is suggestive of amegakaryocytic thrombocytopenia
The patient's parents were counseled regarding allogeneic BM transplant (BMT). However,
no matched sibling donor was available. The parents were not willing for haploidentical
transplant, so a matched unrelated donor (MUD) search was initiated. In the meantime,
she was started on anti thymocyte globulin + cyclosporin and eltrombopag in January
2019. However, she continued to have persistent thrombocytopenia in the range of 15,000/mm3 to 65,000/mm3, with occasional purpuric spots and gum bleeding and occasional platelet
transfusion support. Due to financial issues, she stopped eltrombopag after 5 months
of treatment and continued only oral cyclosporine.
In October 2019, after 1 year, 1 month of diagnosis, she was again admitted with fever
for 5 days, gum bleeding, and excessive weakness. There was also pain in the bilateral
ankle joints. On examination, there was pallor; bilateral cervical lymph nodes were
measuring 0.5 cm × 0.5 cm; there was mobile, nontender, per abdomen; liver was of
2 cm; spleen was of 4 cm; there was no ascites; and chest revealed bilateral crepitation.
The blood report showed hemoglobin of 3.7 g/dl, total leukocyte count of 45,000/mm3, and platelet count of 10,000/mm3. The differential count showed neutrophil of 70%, lymphocyte of 6%, monocyte of 5%,
eosinophil of 1%, myelocyte of 14%, metamyelocyte of 4%, and nucleated RBC of 4 per
100 WBC counted. Peripheral smear showed the presence of microcytic hypochromic anemia
and polychromasia with occasional nRBCs. The WBC showed dysplastic hypogranular neutrophils,
pseudo Pelger–Huet anomaly, and bilobed neutrophils [Figure 2a]. The repeat BM aspiration and biopsy revealed cellular marrow with dysplasia noted
in all cell lineages and increased blast of 14% [Figure 2b]. Flow cytometry confirmed the presence of 16% myeloblasts, with increase in monocytic
population. The cytogenetic study revealed normal female karyotype. The patient was
diagnosed as amegakaryocytic thrombocytopenia transformed into JMML. The patient is
planned to be treated with intensive chemotherapy using Fludarabine, Arabinoside C,
GCSF- Idarubicine regimen followed by an immediate Haplo transplant from her sister
who is 6/10 matched.
Figure 2 Repeat peripheral smear (a) and bone marrow aspiration (b) suggestive of juvenile
myelo monocytic leukemia. The peripheral smear (a) showing the presence of dysplastic
hypogranular hypolobated neutrophils with pseudo Pelger–Huet anomaly (red arrow),
monocyte (black arrow), and myeloblast (white arrow). The bone marrow aspiration (b)
smear is showing the presence of myeloblast (white arrow) and dysplasia in myeloid
lineage (red arrow). The features are suggestive of juvenile myelo monocytic leukemia
CAMT is an autosomal recessive IBMFS which occurs due to congenital absence or deficiency
of cMPL, the receptor of thrombopoietin, resulting in reduced or absent megakaryocyte
proliferation and maturation. The suspicion arises when children with isolated thrombocytopenia
present with excessive bleeding manifestation and do not respond well with conventional
treatment for ITP.[1] The diagnosis is confirmed by documenting the absence or reduced number of megakaryocytes
in the BM.[2] A germline cMPL mutation can conclusively prove the diagnosis, but most centers
do not have such facilities.[3],[4] Inherited thrombocytopenia in children may be found in other IBMFS also. Hence,
thorough clinical examination, for characteristic phenotypic abnormalities (e.g. thrombocytopenia-absent
radius syndrome) and stress cytogenetics to test chromosomal hypersensitivity to DNA
cross-linking agents (to rule out early Fanconi's anemia), should be done before confirming
CAMT.[2]
Currently, there are only limited data available on the clinical course and the outcome
of patients with CAMT. The only curative treatment is allogeneic BMT from a matched
sibling or unrelated donor, if available.[5] The other therapies including immunosuppressor therapies or thrombopoietin mimetic
have been tried in different inherited thrombocytopenias with limited success.[6],[7] Because our patient did not have human leucocyte antigen-matched donor, a possible
MUD search was started.
The increased propensity to develop different malignancies, including hematological
malignancies, is a well-known phenomenon for different IBMFS conditions. The alteration
of genetic landscape with acquiring new mutations and defect in DNA repair mechanism
leads to development of myelodysplasia and leukemia in such patients. Little is known
about long changes in CAMT patients. Although the risk for malignant transformation
seems to be very low in contrast to that observed in other BM failure syndromes, the
scarcity of literature and rarity of the disease make it difficult to study the long-term
outcome of CAMT patients.[8] Alter described two CAMT patients: one developed acute myeloid leukemia (AML) at
the age of 16 years and another developed myelodysplasia with abnormalities of chromosome
19.[9] Another study of long-term follow-up of CAMT patients showed the development of
myelodysplasia in one out of twenty patients, who progressed to develop AML in spite
of undergoing allogeneic BMT.[1] Our patient also developed JMML, a rare MDS/MPN overlap syndrome, hitherto not mentioned
in previous literature. The diagnosis was confirmed by morphological and flow cytometry
analysis, though conventional karyotyping did not reveal any chromosomal alteration.
CAMT is always a difficult-to-diagnose and difficult-to-treat disorder. Although allogeneic
BMT is the only curative option, it cannot prevent further genetic alteration and
possible development of second malignancy. Increased vigilance and long-term follow-up
is required for such patients.
