Myelofibrosis is an uncommon hematological condition
characterized by progressive fibrous tissue replacement of the bone
marrow. Fewer than 100 cases of pediatric myelofibrosis have been
reported worldwide(1) and in young children it may be primary or
secondary. One of the rare causes for secondary myelofibrosis is vitamin
D deficient rickets(2). We report a 6-month-old male infant, who was
diagnosed to have myelofibrosis due to vitamin D deficient rickets and
succumbed to the same.
Case Report
A 6-month-old, exclusively breast fed male infant,
born after a full term normal delivery to parents of non consanguineous
marriage was hospitalized for seizures with fever. His birth weight was
2.5 kg and his developmental milestones were appropriate for age. He
weighed 6.5 kg (86% of expected) and his head circumference was normal
(39 cm). His elder sibling aged 4 years was normal. On examination he
had severe pallor with massive splenohepatomegaly (spleen 7cm below left
costal margin and liver 6cm below right costal margin). He also had
classic features of rickets with craniotabes, wide open anterior
fontanel and rachitic rosary.
His hemoglobin was 3.9 g/dL while peripheral smear
suggested pancytopenia with atypical lymphocytes (TC 3,700/mm3, DC:
lymphocyte 79%, neutrophils 21%, platelets 65,000/mm3). He also had
hypocalcemia (serum calcium-7.9 mg/dL and ionized calcium-0.9 mmol/L),
hypophosphatemia (serum inorganic phosphorous 2.9 mg/dL) with normal
magnesium levels. Renal function tests were normal and liver function
tests revealed markedly elevated alkaline phosphatase levels (2697 IU/L).
His bone marrow aspiration turned out to be a dry tap and bone marrow
trephine biopsy showed normocellular to hypocellular marrow with serial
sections showing few megakaryocytes. There was a mild to moderate
reduction in erythroid and granulocytic series of cells. The
interstitium showed moderate infiltration of lymphocytes, histiocytes
and scattered osteoclastic giant cells and there were also occasional
large histiocytes with eosinophilic cytoplasm. There was mild to
moderate increase in interstitial reticulin with an occasional
intertrabecular space showing significant mineralisation. The cortical
fibroblastic reaction was suggestive of defective mineralisation and
urine-screening tests for metabolic disorders were negative.
Ultrasonogram of the abdomen revealed massive spleno-hepatomegaly with
normal kidneys. Skeletal survey suggested active rickets. Blood, urine
and CSF cultures were sterile. Serological tests for HIV, TORCH and VDRL
were negative. Serum 25-hydroxy-cholecalciferol was 5 ng/mL (9-37.6 ng/mL)
and parathyroid hormone level was 180 pg/mL (12-65 pg/mL), thus
confirming the diagnosis of vitamin D deficient rickets. Since the
infant was exclusively breast-fed, maternal 25 hydroxycholicalciferol
and parathyroid hormone assay were done which showed low 25
hydroxycholecalciferol –8.9 ng /mL and increased parathyroid hormone
-130 pg/mL.
The infant was managed with intravenous antibiotics,
antimalarials (in view of persisting fever spikes) and oral calcium. A
single dose of vitamin D3 6,00,000 IU was given intramuscularly.
Multiple transfusions were required to maintain his hemoglobin levels.
Within 4 weeks of therapy following a single dose of
vitamin D3 and oral calcium, his calcium, phosphorous, ALP levels became
normal. His repeat serum calcium was 8.9mg/dL, inorganic phosphorus –3.7
mg/dL and ALP- 543 IU/L thus confirming that vitamin D deficiency
rickets had responded to treatment. However, pancytopenia and
spleno-hepatomegaly persisted. Within 2 months, he needed 240mL/kg of
packed cells to maintain his hemoglobin level and by 8 months of life,
he died due to sepsis and ARDS.
Discussion
Myelofibrosis is the descriptive term referring to
excessive reticulin deposition in the bone marrow. Primary (idiopathic)
myelofibrosis is characterized by bone marrow fibrosis with no apparent
cause and is very rare in children. Secondary myelofibrosis due to
neoplastic causes includes acute lymphoblastic leukemia, acute myeloid
leukemia, acute megakaryocytic leukemia, non Hodgkin’s lymphoma etc.
and due to non neoplastic causes includes vitamin D deficient rickets,
hyperparathyroidism, renal osteo-dystrophy, SLE, Fanconi’s anemia,
etc.(1). Vitamin D deficient rickets is an important cause for
secondary myelofibrosis, as an active metabolite of this vitamin
normally inhibits the proliferation of megakaryocytes and promotes the
maturation of monocytes and macrophages that degrades collagen(1,3). In
vitamin D deficient rickets there is secondary hyperparathyroidism,
which is the cause for myelofibrosis(4). In our case, the diagnosis of
vitamin D deficient rickets was confirmed by clinical findings,
investigations and by its prompt response to vitamin D therapy. The
other neoplastic and non-neoplastic causes of myelofibrosis were also
considered and excluded with the detailed clinical work up and
investigations. Myelo-fibrosis associated with rickets has been reported
almost exclusively in Turkish children(2,5). Stephen, et al.(4)
have reported myelofibrosis due to vitamin D deficiency and its prompt
response to vitamin D therapy in 1999. Exclusive breast-feeding and lack
of exposure to sunlight are the risk factors for vitamin D deficiency,
which can easily be prevented with vitamin D supplementation and with
adequate exposure to sunlight(6,7). In our patient, though the rickets
resolved with vitamin D therapy, the hematological problems persisted
and the infant became transfusion dependant and finally succumbed to
septic shock due to pancytopenia that was secondary to intense
myelofibrosis. Therapy for secondary myelofibrosis consists of treating
the underlying disease and it has been reversed concomitantly with
therapeutic control of primary condition(3). In contrast primary
myelofibrosis has a poor prognosis in spite of treatment with various
modalities like androgens, corticosteroids, chemotherapeutic agents,
irradiation and splenectomy.
Contributors: SBS conception of design, critical
evaluation of the manuscript and final approval of the manuscript. He
shall act as the guarantor; RV: interpretation of data, critical
evaluation of the manuscript and final approval of the manuscript. SOS
and RG: Acquisition of data, drafting the manuscript and final approval
of the manuscript.
Funding: None.
Competing interests: Nil.