is the paptient still w/o therapy?  
was the SNP probe indeed from the patient?  
does the patient have a mosaicism 46XY/47XY,+21?  
how does the PB look like? WBC? HB? etc.?  
is there any other evidence for consitutional problems?

is the paptient still w/o therapy? YES  
was the SNP probe indeed from the patient? YES  
does the patient have a mosaicism 46XY/47XY,+21? NO.  
 
Further ledt questions readressed- I will inform you soon.  
(how does the PB look like? WBC? HB? etc.?  
is there any other evidence for consitutional problems)

Comment of responsible haematologist: "The patient is transfusion dependent, periodically needs E or PLT concentrate transfusion. Neutropenia around 0,5-0.7. But total leukocyte count is normal. I. E. Relative lymphocytosis. Sometimes 1% of blast appear in peripheral smear. No constitutional abnormalities except failure to thrive. His weight is always below 3%. The height is normal. No Down phenotype. Splemegaly appears when tranafusion dependecy becomes more prominent. In summary, clinically looks as MDS. He has never received chemotherapy.

the case is not banal:  
 
failure to thrieve + transfulion-dep. anemia + thrombopenia + blast - it is too much to simply classify it as MDS (not yet at least)  
 
what about the reticulocyte counts?  
cutaneous status?  
nails?  
pancreatic insufficiency?  
lungs?  
are the PLT in the PB abnormal?  
family?

Hematologist comment on previous:  
- what about the reticulocyte counts?  
Low, no evidence of hemolytic anemia, checked several times  
- cutaneous status?  
normal  
- nails?  
normal  
- pancreatic insufficiency?  
no evidence  
-lungs?  
no complains on any pulmonary disfuncion  
-are the PLT in the PB abnormal?  
normal  
-family?  
any special anamnesis.  
 
Taiking into account failure to thrive we are waiting for the results of chromosomal brekage analysis to rule out Fanconi anemia that can manifest as SAA/MDS/AML in BM.  

Anyway, facing with blastic and "voluminous" and expansive process, affecting BM architecture, I cannot thing this "reactive"...  
SNP array cannot see Fanconi and Co?

Dont understand me false, I also do not think that this is a reactive process, it is "pre-neoplastic", either congenital abnormality of (T)MPD etc. lets wait for the complete analysis. I still do not exclude a mosaicism for +21!

Agree: but which morphological/"pattern" diagnosis you would prefere at the moment? MPD? Because clinical picture is swampy due to "unknown" reasons...

I would state:  
"(transient) immature myeloid disorder in the background of possible (still unproven) congenital/inherited cytopenic disease"

Thanx. One more note: how 2013 "blastic" infiltration in the skin must be interpreted in other way, than AML?

are we sure that transient MPD (like in Down) do not make organ infiltrations? obviosuly these cutaneous manifestations resolved, which is rather very unexpected for AML. we are sure, this proces is (at least pre-) neoplastic... let's wait for the additional molecular studies. the case must be discussed in a multilateral board, eventually you can ask Marija Projtcheva from Arizona (a very competant pediatric Hematopatholoogist) for her opininon.

Thanx, Alex and excusse me of such insistance.

This is a very interesting case. To summarize, this is one year old boy with peripheral cytopenias since birth who has hypercellular marrow with marked megakaryocytic proliferation with fibrosis and markedly reduced erythropoiesis and megakaryopoiesis. Flow and IHC on trephine biopsies showed various number of blasts positive for CD4+, CD7+, CD13+/-, CD33+, CD34+, and CD117+ and negative for CD13 and HLA-DR. No information on MPO is provided. One of the trephine biopsies showed also CD56+ and CD61+ cells and cytogenetic studies showed trisomy 21. In addition, all samples have variable amount of hematogones (up to 41%). The patient also had erythematous skin eruption that show focal infiltration by CD117 and MPO positive cells/CD34 is negative.  
 
Clinically, the child has growth retardation but no skeletal or other abnormalities are reported. There was no chemotherapy given but the bone marrow findings and the skin lesions did not progress. However the peripheral cytopenias worsen and now the anemia and thrombocytopenia are now transfusion dependent. He develop splenomegaly.  
 
I think that careful review of peripheral blood film (pre-transfusion) and bone marrow aspirate smears is necessary to assess the presence of blasts, the degree of dyspoiesis or presence of other abnormalities. Also,the type of anemia, degree of leukopenia and thrombocytopenia are important to know.  
 
I agree with your differential diagnosis, transient abnormal myelopoiesis (TAM) and acute megakaryocytic leukemia (AML) of Down Syndrome (DS) are high on the differential diagnosis. But some of the features are not characteristic for these disorders. TAM usually presents shortly after birth (<3 mo) and is transient, it won't persist for a year. Also, while there are circulating megakaryoblasts in the peripheral blood of such infants, the bone marrow show shows marked myeloid hyperplasia and lower number of blasts than the peripheral blood. Regarding AML of DS, while it can present with megakaryocytic hyperplasia and megakaryoblasts, it won't present at birth or be stable if the patient is untreated. Both can be seen in DS but also in the settings of trisomy 21 mosaicism that can be restricted to the BM. Was constitutional cytogenetics on PHA stimulated T lymphocytes done or just on bone marrow? Since trisomy 21 is not uncommon in acute leukemias, GATA1 mutational analysis can be helpful to determine whether those are DS related or not. Of note, the non-DS related leukemias are GATA1 negative.  
 
Another finding that does not fit with DS related myeloid proliferations is the presence of hematogones. Those are usually seen (up to 50% in the first year of life) in normal children and persist longer or are increased in number in inherited bone marrow failure syndromes. Hematogones are not usually seen in leukemias, but in recovering or regenerating marrow.  
 
Inherited bone marrow failure syndromes should also be considered, but the morphologic features are not quite characteristic of any of the most common.  
 
I think MDS is less likely since the blast count is more than 20% at one point. Also this patient's clinical course and splenomegaly are not characteristic for MDS. Other entity to consider is juvenile myelomonocytic leukemia (JMML). It presents with splenomegaly, slowly progressive course, absolute monocytosis, and skin lesion. However, presentation at birth would be unlikely. Patients with Noonan syndrome can present with transient JMML-like picture, but such BM abnormalities are not really characteristic.  
 
It is a difficult case and will require more clinical information and careful examination of peripheral blood smears and BM aspirates for making the diagnosis.  
 
Thank you for sharing this fascinating case.

Thank you Maria for this very comprehensive comment.

Than you very much. Of note (from my histo-side): dermal blastic infiltrate was MPO+. In all my BMs I cannot really visualize "blastic component" nor visually, nor in IH.  
I aggree on your proposal and repeating all tests: maybe some populations was missed in dilluted aspirates, as usually happens (they do not see/characterize predominating in this case Megas...). Dissapearing trisomy is mysterious enough too...

The last point of responsible haematologist (structured/shortened by myself):  
- Maybe trisomy "dissapear" due to small amout of blasts and sensitivity of method?  
- Additional trisomy21 evaluation will be applied (in fibroblasts (?)).  
- Molecular tests for Fankoni and GATA1 are in progress (I hope outside LT (?))  
- We have no criteria for JMML (neither clinically, neither histo).  
Splenomegaly became more prominent in transfuion dependent eposodes. Is Extramedullary haematopoiesis possible?  
 
I will keep you in line if any news appear. Thank you once more time for your donated time and ideas.

Dear Ugnius,  
 
any progress in that case?  
 
Best wishes  
 
Alex  

Comment from responsible hematologist:  
"GATA1 awaiting: 3-4 weeks... (?)  
Additional cytogenetics (due to trisomy mistery) taken 09 22. Blasts undulating about 4%.  
Megas on flow was not visualized (markers were not applied).  
 
Finals in the middle of October."  
I have no comments from my side to add. The last report not issued yet- we will see...  

"Breaking" news/ haematologist note: "From the clinical side - there is no big changes the patient is transfusion dependent (needs both platelet and erhy concentrates), has grade IV neutropenia, no organomegaly, blast count in PB and BM does not exceed 4%. We defined this situation as MDS, status post congenital AML. We have also initiated a MUD search in order to proceed to HSCT".

From correspondence with clinical consultants (dr.H.Hasle, DK):  
"Your patient had a duplication in the RUNX1 area of chromosome 21. I wonder whether it could indicate a familial platelet disorder with propensity to acute myeloid leukaemia (FPD⁄AML), one paper attached as example.  
Did you test the family for thrombocytopenia?"  
 
GATA is still not ready (I will append when get it).  

Comment from new aspirate field (clin lab): "blasts are changing its appearance: more similar to M7".

Dear all, my name is Vaidas Dirse, I am the cytogeneticist. I performed SNP array analysis of this case. The last SNP array analysis detected 21q duplication 6 Mb in size and 21q terminal deletion 0.5 Mb in size. 21q duplication encompass RUNX1 gene.  
I should remind that SNP array results were:  
 
2013-03-19 - trisomy 21.  
 
2014-07-30 - no aberations  
 
2014-09-22 - 21q duplication + 21q deletion.  
 
I have experience in SNP array analysis for 5 years (in both fields: classical genetics and hematology), but first time seen the case like that. Of course everybody knows that the the detectable clone of SNP array is approximately above 10%. Maybe we miss it?