EHA Library - The official digital education library of European Hematology Association (EHA)

GENETIC SCREENING OF CHILDREN WITH BONE MARROW FAILURE: THE ROLE OF PRIMARY IMMUNE-DEFICIENCIES
Author(s): ,
Maurizio Miano
Affiliations:
Haematology Unit,Istituto Giannina Gaslini ,Genoa,Italy
,
Gianluca Dell'orso
Affiliations:
Haematology Unit,Istituto Giannina Gaslini ,Genoa,Italy
,
Marina Lanciotti
Affiliations:
Haematology Unit,Istituto Giannina Gaslini ,Genoa,Italy
,
Francesca Fioredda
Affiliations:
Haematology Unit,Istituto Giannina Gaslini ,Genoa,Italy
,
Elena Palmisani
Affiliations:
Haematology Unit,Istituto Giannina Gaslini ,Genoa,Italy
,
Filomena Pierri
Affiliations:
Stem Cell Transplantation Unit,Istituto Giannina Gaslini,Genoa,Italy
,
Daniela Guardo
Affiliations:
Haematology Unit,Istituto Giannina Gaslini ,Genoa,Italy
,
Erika Massacesi
Affiliations:
Haematology Unit,Istituto Giannina Gaslini ,Genoa,Italy
,
Andrea Beccaria
Affiliations:
Haematology Unit,Istituto Giannina Gaslini ,Genoa,Italy
,
Eleonora Rotondo
Affiliations:
Haematology Unit,Istituto Giannina Gaslini ,Genoa,Italy
,
Enrico Cappelli
Affiliations:
Haematology Unit,Istituto Giannina Gaslini ,Genoa,Italy
,
Paola Terranova
Affiliations:
Haematology Unit,Istituto Giannina Gaslini ,Genoa,Italy
,
Michaela Calvillo
Affiliations:
Haematology Unit,Istituto Giannina Gaslini ,Genoa,Italy
,
Concetta Micalizzi
Affiliations:
Haematology Unit,Istituto Giannina Gaslini ,Genoa,Italy
,
Isabella Ceccherini
Affiliations:
Medical Genetic Unit,Istituto Giannina Gaslini ,Genoa,Italy
,
Chiara Vernarecci
Affiliations:
Haematology Unit,Istituto Giannina Gaslini ,Genoa,Italy
,
Alice Grossi
Affiliations:
Medical Genetic Unit,Istituto Giannina Gaslini ,Genoa,Italy
Carlo Dufour
Affiliations:
Haematology Unit,Istituto Giannina Gaslini ,Genoa,Italy
(Abstract release date: 05/14/20) EHA Library. Miano M. 06/12/20; 295014; S194
Dr. Maurizio Miano
Dr. Maurizio Miano
Contributions
Abstract

Abstract: S194

Type: Oral Presentation

Session title: BMF and PNH biological and clinical

Background

Patients with Marrow Failure (MF) need to undergo an accurate diagnostic work-up to identify congenital forms which require a different therapeutic approach. Due to an impaired lymphocytes production, patients with congenital MF may also show signs of immunodeficiency that, in some cases, can represent the first/prevalent sign of the disease and therefore can be misinterpreted as sign of a Primary Immunodeficiency (PID). On the other hand, patients with PIDs may also show MF as a result of an immune-mediated attack of marrow precursors, thus generating a phenotypic overlap that can impair the correct diagnosis. 

Aims
In this report we analyze all patients with MF evaluated in our Unit with the aim to identify the type and incidence of underlying molecular defects, in particular those related to PIDs.

Methods
We retrospectively evaluated all patients with single/multi-lineage MF followed in our Unit. DEB test was used to screen Fanconi Anemia (FA). Other congenital MFs have been searched by Sanger and/or NGS molecular analysis depending on the available tools over the years.

Results

Between 2009-2019, 97 patients have been studied for single-lineage (29, 30%) or multilineage (68, 70%) MF. 53 (54%) were classified as having an acquired MF, 28 (29%) were diagnosed with a cBMF (Fanconi Anemia 12, Diskeratosis Congenita 5, Severe Congenital Neutropenia 6, Blackfan-Diamond Anemia 3, Congenital Amegakaryiocitic Thrombocytopenia 2), and the remaining  16 patients (17%) were found to have an underlying PID. Table 1 shows clinical characteristics and mutations of patients with PIDs.

 

Marrow Failure

Other clinical signs

Molecular analysis method

Gene

TREATMENT

SCT

status

1

Severe PWCA

Lymphoproliferation, autoimmunity

(APDS)

NGS

PI3KCD

 

MMF, GCSF

Sirolimus

2 haplo-identical

αβ T-depleted SCTs

Alive

2

Severe PRCA

Lymphoproliferation, autoimmunity

(APDS)

SANGER 

PI3KCD

 

Rituximab, Sirolimus/IVIG

-

Alive

3

Severe PRCA

Lymphoproliferation, autoimmunity

NGS

CECR1

 

 

Rituximab,

Sirolimus/IVIG

-

Alive

4

AA

Viral infections

SANGER

GATA2

 

-

MSD-SCT

Alive

5

AA

no

NGS

GATA2

 

ATG, CsA, Steroid 

-

Dead

6

AA

no

NGS

LIG4

 

 

-

2 MSD-SCTs

Alive

7

AA

Short stature, infections

SANGER

XLF

 

-

MUD-SCT

Alive

8

AA

Physical abnormalities

SANGER

XLF

 

-

MUD-SCT

Alive

9

AA 

Physical abnormalities

SANGER 

XLF

 

-

-

Alive

10

AA

Physical abnormalities Immunodeficiency

Ohdo Syndrome

SANGER 

KAT6B

 

transfusions

-

Alive

11

PWCA

no

NGS

TACI

 

-

-

Alive

12

PWCA

Lymphoproliferation

NGS

CARD11

 

MMF

-

Alive

13

PWCA

Enteropathy

NGS

CD40L

G-CSF/IVIG

-

Alive

14

AA

Post-infectious hyperinflammatory syndrome, hypogammaglobulinemia

SANGER

GATA2

Prednisone, IVIG 

 

MSD- αβT-depleted SCTs

Alive

15

AA

Lymphoproliferation, bacterial infections, autoimmunity

NGS

IKBKG

SIROLIMUS

-

Alive

16

AA

no

NGS

TACI

Transfusions, EPO

-

Alive

Conclusion

This report shows that patients presenting with single/multi-lineage MF may have an underlying PID in a considerable number of cases.  We conclude that an accurate immunological work-up should be performed in all patients with MF and that PIDs-related genes should be included in the molecular screening of MF in order to identify specific disorders that may potentially receive targeted treatment and/or the appropriate conditioning regimen for SCT. 

Session topic: 12. Bone marrow failure syndromes incl. PNH - Clinical

Keyword(s): Immune deficiency, Pancytopenia

Abstract: S194

Type: Oral Presentation

Session title: BMF and PNH biological and clinical

Background

Patients with Marrow Failure (MF) need to undergo an accurate diagnostic work-up to identify congenital forms which require a different therapeutic approach. Due to an impaired lymphocytes production, patients with congenital MF may also show signs of immunodeficiency that, in some cases, can represent the first/prevalent sign of the disease and therefore can be misinterpreted as sign of a Primary Immunodeficiency (PID). On the other hand, patients with PIDs may also show MF as a result of an immune-mediated attack of marrow precursors, thus generating a phenotypic overlap that can impair the correct diagnosis. 

Aims
In this report we analyze all patients with MF evaluated in our Unit with the aim to identify the type and incidence of underlying molecular defects, in particular those related to PIDs.

Methods
We retrospectively evaluated all patients with single/multi-lineage MF followed in our Unit. DEB test was used to screen Fanconi Anemia (FA). Other congenital MFs have been searched by Sanger and/or NGS molecular analysis depending on the available tools over the years.

Results

Between 2009-2019, 97 patients have been studied for single-lineage (29, 30%) or multilineage (68, 70%) MF. 53 (54%) were classified as having an acquired MF, 28 (29%) were diagnosed with a cBMF (Fanconi Anemia 12, Diskeratosis Congenita 5, Severe Congenital Neutropenia 6, Blackfan-Diamond Anemia 3, Congenital Amegakaryiocitic Thrombocytopenia 2), and the remaining  16 patients (17%) were found to have an underlying PID. Table 1 shows clinical characteristics and mutations of patients with PIDs.

 

Marrow Failure

Other clinical signs

Molecular analysis method

Gene

TREATMENT

SCT

status

1

Severe PWCA

Lymphoproliferation, autoimmunity

(APDS)

NGS

PI3KCD

 

MMF, GCSF

Sirolimus

2 haplo-identical

αβ T-depleted SCTs

Alive

2

Severe PRCA

Lymphoproliferation, autoimmunity

(APDS)

SANGER 

PI3KCD

 

Rituximab, Sirolimus/IVIG

-

Alive

3

Severe PRCA

Lymphoproliferation, autoimmunity

NGS

CECR1

 

 

Rituximab,

Sirolimus/IVIG

-

Alive

4

AA

Viral infections

SANGER

GATA2

 

-

MSD-SCT

Alive

5

AA

no

NGS

GATA2

 

ATG, CsA, Steroid 

-

Dead

6

AA

no

NGS

LIG4

 

 

-

2 MSD-SCTs

Alive

7

AA

Short stature, infections

SANGER

XLF

 

-

MUD-SCT

Alive

8

AA

Physical abnormalities

SANGER

XLF

 

-

MUD-SCT

Alive

9

AA 

Physical abnormalities

SANGER 

XLF

 

-

-

Alive

10

AA

Physical abnormalities Immunodeficiency

Ohdo Syndrome

SANGER 

KAT6B

 

transfusions

-

Alive

11

PWCA

no

NGS

TACI

 

-

-

Alive

12

PWCA

Lymphoproliferation

NGS

CARD11

 

MMF

-

Alive

13

PWCA

Enteropathy

NGS

CD40L

G-CSF/IVIG

-

Alive

14

AA

Post-infectious hyperinflammatory syndrome, hypogammaglobulinemia

SANGER

GATA2

Prednisone, IVIG 

 

MSD- αβT-depleted SCTs

Alive

15

AA

Lymphoproliferation, bacterial infections, autoimmunity

NGS

IKBKG

SIROLIMUS

-

Alive

16

AA

no

NGS

TACI

Transfusions, EPO

-

Alive

Conclusion

This report shows that patients presenting with single/multi-lineage MF may have an underlying PID in a considerable number of cases.  We conclude that an accurate immunological work-up should be performed in all patients with MF and that PIDs-related genes should be included in the molecular screening of MF in order to identify specific disorders that may potentially receive targeted treatment and/or the appropriate conditioning regimen for SCT. 

Session topic: 12. Bone marrow failure syndromes incl. PNH - Clinical

Keyword(s): Immune deficiency, Pancytopenia

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