Dr.Terencia, Dr Neeraj /Dr.Manoj Unni/Dr. Rema(Dept of Clinical Hematology), Dr. C Jayakumar
One year old child the first born of non-consanguinous parentagewith mild motor delay presented with history of recurrent infections from 7months of age.
History of treatment for acute febrile illness with complementary and alternative system of medicine (CAM) is also available
Child had three episodes of ASOM
Since he had associated significant failure to thrive, cervical lymphadenopathy with progressive pallor and abdominal distension
Bone marrow study was done at regional cancer centre showed no evidence of malignancy.
Cervical Lymph node biopsy was deferred since cervical lymph node size was decreasing
Next generation sequencing (NSG) in suspicion of storage disorders was sent due to the massive hepatosplenomegaly and was positive for KRAS mutation, hence was referred toAIMS for further evaluation and management.
Differentials considered were:-
1.JMML- Juvenile Myelomonocytic leukemia
2.Ras-associated autoimmune leukoproliferative disorder (RALD)
3.Storage disorder
4.Autoimmune lymphoproliferative syndrome
On examination-
Ba was irritable and afebrile
Pallor+ mild icterus+ No cyanosis/No pedal edema
Cervical and axillary adenopathy+
Abdomen was distended. Umbilicus everted. Dilated veins + Hepatomegaly+,massive splenomegaly+(tip in left iliac fossa)
Other S/E-WNL
Labs showed normal counts (TC-9.08K) with monocytosis with absolute monocyte count more than 1000 with severe Anemia(Hb-5.2g/dl) and thrombocytopenia(PLT-25Ku/ml).
DCT was positive and Cold antibodies Serum was Positive(Titre:4).
USG Abdomen showed Splenomegaly with mild fatty infiltration. Bone marrow biopsy showed only 2-3 subcortical cellular marrow spaces with trilineage maturation, erythroid preponderance, mild left-shifted myeloid maturation and scattered megakaryocytes with normal morphology.
Bone marrow aspiration showed dilute yet cellular marrow aspirate smears and fairly cellular imprint showing trilineage maturation with mild dyserythropoiesis and reduced megakaryocytes. Peripheral smear showed Leuko erythro blastic blood picture with leucocytosis , monocytosis , anaemia , thrombocytopenia and dyspoiesis in myeloid series and agglutination.
ANA 4 + with low levels of serum complements.
In view of DCT positive severe Autoimmune Hemolytic Anemia, the infant was started on Inj Dexamethasone.2 units of Leukoreduced and irradiated PRBC transfusion was given.
As per Rheumatologist opine was sought in view of the autoimmunity(DCT 4+, ANA 4+, low C3, Low C4) with e/o lymphoproliferation and he was started on Tab Sirolimus
Follow up blood investigation showed evidence of significant ongoing hemolysis , hence Inj Methyl Prednisolone was given for 5 days followed tapering doses of oral Prednisolone.
Post Inj Methylprednisolone his hemolysis was under control,(LDH decreased no further drop in hemoglobin). His blood culture, EBV PCR, CMV IgM, Parvo IgM were negative.
Child had Transient Cholestasis and transaminitis with direct hyperbilirubinemia.
But USG abdomen showed no evidence of obstruction.The direct hyperbilirubinemia settled spontaneously while child was on Pulse methyl Prednisolone and Sirolimus. Transaminitis had transiently improved when the direct hyperbilirubinemia settled. However since the other blood parameters were improving, plan was made to follow up on OPD basis.
Systemic hypertension after starting steroid was manned with Oral Amlodipine in 2 divided doses.
However since the the BP remained above 95thcentile, Metoprolol was added on.
As JMML and RALD shared several overlapping features, an NGS to look for JMML mutations was planned along with parental segregation and Sanger sequencing for K-RAS mutation. The parents were counseled in detail regarding the nature of the child’s illness currently favouring RALD over JMML and regarding the 25 % possibility of progression to JMML in future.
His counts, Hb and platelet showed a gradual rise without transfusion support and continued to be stable. Hence he was discharged with stable vitals.
1. JMML- Juvenile Myelomonocytic leukemia
Points favoring-a. Absolute monocyte count > 1000 b. blast cells < 20 % c. KRAS mutation positive d. Splenomegaly e. Absence of BCR-ABL mutation f. WBC >10000
Points against-Absence of monosomy 7
2. Ras-associated autoimmune leukoproliferative disorder (RALD)
Points favouring a. Splenomegaly b. Autoimmunity (DCT 4+, ANA 4+, low complements) c. KRAS mutation
3. Storage disorder: No evidence of gaucher cells in the marrow, no evidence of GBA gene mutation on WES
4. ALPS: Double negative T cells were normal; hence did not satisfy the essential criteria.
Ras-associated autoimmune leukoproliferative disorder (RALD) is a non malignant clinical syndrome initially identified in a subset of putative autoimmune lymphoproliferative syndrome (ALPS) patients. Similar to patients with ALPS, RALD patients present with lymphadenopathy, massive splenomegaly, increased circulating B cells, hypergammaglobulinemia, and autoimmunity. In contrast to ALPS, in RALD biomarkers such as CD4–/CD8– double negative T-cell receptor αβ (TCRαβ+) T cells and serum vitamin B12 levels are not always increased, and germline or somatic mutations in FAS, FASL, or CASP10 are absent in RALD. Persistent absolute or relative monocytosis is a cardinal feature of RALD. Bone marrow and peripheral blood smear findings overlap with those of juvenile myelomonocytic leukemia (JMML) in children.
TAKE HOME MESSAGE-
Ras-associated autoimmune leukoproliferative disorder (RALD) is a chronic, nonmalignant condition that presents with persistent monocytosis and is often associated with leukocytosis, lymphoproliferation, and autoimmune phenomena. RALD has clinical and laboratory features that overlap with those of juvenile myelomonocytic leukemia (JMML) and chronic myelomonocytic leukemia (CMML), including identical somatic mutations in KRAS or NRAS genes noted in peripheral blood mononuclear cells. Long-term follow-up of these patients suggests that RALD has an indolent clinical course whereas JMML is fatal if left untreated.
Indian Academy of Pediatrics Kerala
Case Reports Pediatrics