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The Congenital Dyserythropoietic Anemias: Current situation in Europe

Prof. emerit. Dr. med. H. Heimpel, FRCPath

The German Registr on CDAThe German Registry on CDA Medizinische Klinik der Universität Ulm

ENERCA-Symposium Sofia 2011

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Deutsches Register für Congenitale Deutsches Register für Congenitale Dyserythropoietische Anämien (CDA)

Hermann Heimpel, Elisabeth Kohne, Hubert Schrezenmeier Ulm

German Registry of Congenital Dyserythopoietic Anemia (CDA)

European Network on Rare Congenital Anemias:ENERCA

The German Registry of CDAs: Number of cases of all types

740800

200

401 429489

200

400

600

0

200

1997 2000 2003 2007 2009

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CDA type I IIHEMPAS

III familial IIIsporadic

Variants

Inheritance Autosomal Autosomal Autosomal Variable Autosomal

Congenital dyserythropoietic anemias: overview 2010

Inheritance Autosomal-recessive

Autosomal-recessive

Autosomal-dominant

Variable Autosomal-recessiveor x-linked

Casesreported

~150 > 500 3 families < 20 ~70

Morpho-logy

GeneLocus

CDAN115q (15.1.3)

SEC23B20p11.23-20p12.1

Unknown15q (21-25)

UnknownUnknown

UnknownUnknown

Dysmorpho-logies

Skeleton,Others

Variable,rare

B-CellsRetina

Variable CNSOthers

Frequency of CDA I and II in Europe, 2009

Heimpel et al European Journal of Haematology 2010,85,20-24

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Population size

Expected Hetero-zygotes Cases

CDA IIInciden

ce

Expected Hetero-zygotes

Cases CDA I

Incidence

Germany/ Switzerland/ Austria 98.156 26 0.26 946 70 0.71 1575

Scandinavia 24 938 1 0.04 400 1 0 04 400Scandinavia 24.938 1 0.04 400 1 0.04 400

Spain/ Portugal 53.947 17 0.32 1122 25 0.46 1276

Italy 58.607 5 0.09 584 146 2.49 3008

France 60.996 32 0.52 1254 40 0.66 1514

Netherlands/ Belgium 27.256 3 0.11 663 13 0.48 1013

Czech Republic/ Slovakia 36.629 0 0 0 8 0.22 739

Romania/ Bulgaria/ Hungary 29.364 0 0 0 18 0.61 1380

Greece/ Albania/ Macedonia 16.283 1 0.06 496 9 0.55 1486

Ireland/ Great Britain 64.340 36 0.56 1431 31 0.48 1295

Poland 38.161 1 0.03 324 6 0.16 724

Europe 518.319 122 0.24 918 367 0.71 1560

Table 2. Estimated cumulative incidence of cases and expected number of healthy heterozygotes of CDA I and CDA II in Europe. Population size is given in millions, cumulated incidence (= number of cases / population size) and expected number of heterozygotes are given per million

Congenital Dyserythropoietic Anemias (CDAs):Definition

Evidence of a congenital and/or hereditary disorder- history, family studies

Evidence of ineffective erythropoiesis- blood count, bilirubin, haptoglobin, serum transferrin receptor, reticulocytes inadequate, bone marrow

Characteristic morphological abnormalities of erythrocytes and erythroblasts- light and electron microscopyg py

Exclusion of hemolytic anemias, disorders of hemoglobin synthesis and megaloblastic anemias

Hei/cda.PPT_00109

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CDA type I IIHEMPAS

III familial IIIsporadic

Variants

Inheritance Autosomal Autosomal Autosomal Variable Autosomal

Congenital dyserythropoietic anemias: overview 2009

Inheritance Autosomal-recessive

Autosomal-recessive

Autosomal-dominant

Variable Autosomal-recessiveor x-linked

Casesreported

~150 > 400 3 families < 20 ~70

Morpho-logy

GeneLocus

CDAN115q (15.1.3)

SEC23B20p11.23-20p12.1

Unknown15q (21-25)

UnknownUnknown

UnknownUnknown

Dysmorpho-logies

Skeleton,Others

Variable,rare

B-CellsRetina

Variable CNSOthers

Grade 3 aniso-poikilozytosis in a case of CDA I

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Grade 3 aniso-poikilozytosis and gross basophilic stippling in a case of CDA I

303/01_20050319_017.jpg

CDAI, KM-Aspirate

406/01_km_005.jpg

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CDA I, KM-Aspirate

406/01_km_006.jpg

Elektronenmikroskopische Aufnahme von Erythroblasten bei CDA I

P

P

P

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CDA type I IIHEMPAS

III familial IIIsporadic

Variants

Inheritance Autosomal Autosomal Autosomal Variable Autosomal

Congenital dyserythropoietic anemias: overview 2010

Inheritance Autosomal-recessive

Autosomal-recessive

Autosomal-dominant

Variable Autosomal-recessiveor x-linked

Casesreported

~150 > 500 3 families < 20 ~70

Morpho-logy

GeneLocus

CDAN115q (15.1.3)

SEC23B20p11.23-20p12.1

Unknown15q (21-25)

UnknownUnknown

UnknownUnknown

Dysmorpho-logies

Skeleton,Others

Variable,rare

B-CellsRetina

Variable CNSOthers

CDA II: Anisopoikilocytosis, binucleated erythroblast

415/02_honig_000001.jpg

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CDA II: Nuclei of binucleated normoblasts have identical shape and DNA-content

UPN_ 478/01

CDA II: a typical binucleated mature erythroblast. Both nuclei have the same DNA-content

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CDA II: Pseudo-Gaucher-cells containing birefringent membrane remnants

Congenital Dyserythropoietic Anemia type IIAcid serum lysis („Hams Test“)

Serum 1 Serum 2

Left tubes: PNH right tubes: CDA II

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SDS-PAGE ( left) and Tomato-Lectin-Binding in cda II ( 252/01/02/03) and normal control

Band 3

CDA II: The mutated gene

• Mutations in the human secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II (CDA II)

• Klaus Schwarz1,2*, Achille Iolascon3*, Fatima Verissimo4, Nikolaus S. Trede5, Wyatt Horsley5, Wen Chen6, Barry H. Paw6, Karl-Peter Hopfner7, Karlheinz Holzmann8, Roberta Russo3, Maria Rosaria Esposito3, Katja Heinrich1, Brigitte Joggerst4, Markus T. Rojewski1,2, Silverio Perrotta9, Jonas Denecke10, Ulrich Pannicke1, Jean Delaunay11, Rainer Pepperkok4, Hermann Heimpel

• Nature genetics 2009, 41, (8), 936 – 40

• Congenital dyserythropoietic anemia type II (CDAII) is caused by mutations in the SEC23B genethe SEC23B gene

• Bianchi,P.; Fermo,E.; Vercellati,C.; Boschetti,C.; Barcellini,W.; Iurlo,A.; Marcello,A.P.; Righetti,P.G.; Zanella,A.

• Human mutations 2009, 30 (9), 1292 -8

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Mutations in CDA II 2009, own data

Mutationen des SEC23B - Gens bei Familien mit KongenitalerDyserythropoietischer Anämie Typ IIy y p yp

4

6

8

10

Beo

bach

tung

en

2 4 5 6 7 8 9 10 11 13 14 15 16 17 18 19 200

2

Exon

Zahl

der

A severe case of CDA II. Scinti 495/01, 4 7/12

years

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Two sisters with CDA II

41501 01;02.JPG

CDA: consequences and complications

• Severe anemia, regular transfusions ~ 10 %

• Skeleton abnormalities marrow expansion ~10 %

• Skeleton malformations ~10 %• Skeleton malformations ~10 %

• Splenomegaly: > 90%

• Gall stones: >70%

• Aplastic crisis: < 10%

• Leg ulcers: < 10%• Leg ulcers: < 10%

• Bulky extramedullary erythropoiesis ~ 5%

• Iron overload, if not timely treated: > 80 %

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66 year old female with CDA II, 17 years after thoracotomy. Radiographic changes were first noted at

the age of 46 years

065/01

Iron overloading in CDA I and II

CDA.PPt 01/2006

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Diagnosis of CDAs: Often delayed! Age at diagnosis before 1990

8

10

12

14

16

18

umbe

r of c

ases

CDA ICDA II

0

2

4

6

<5 <10 <15 <20 <25 <30 <35 <40 <45 >50

Age (years)

nu

Age at diagnosis after 1990

14

16

18

es CDA I

0

2

4

6

8

10

12

<5 <10 <15 <20 <25 <30 <35 <40 <45 >50

age (years)

num

ber

of c

ase CDA I

CDA II

CDA: different grades of severity and therapy

• 1. Regular transfusions needed: Type II ~ 5%Type I ~10%Variants: Less than 50%

Tx: Type I Interferon-alpha Type II splenectomy Oth All i t ll t l t ti (?)• Others Allogenic stem cell transplantation (?)All types Iron chelation according to thalassemia protocols

• 2. Regular Transfusions in infancy and early childhood, but not thereafter

Tx: Type I Interferon-alpha• Type II Selective splenectomy

All types Phlebotomy or iron chelation if needed

• 3. No regular transfusions, Hb > 10 g/dlTX: Type I Interferon-alpha

• Tx: All types: Phlebotomy or iron chelation if needed

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CDA type I IIHEMPAS

III familial IIIsporadic

Variants

Inheritance Autosomal Autosomal Autosomal Variable Autosomal

Congenital dyserythropoietic anemias: overview 2010

Inheritance Autosomal-recessive

Autosomal-recessive

Autosomal-dominant

Variable Autosomal-recessiveor x-linked

Casesreported

~150 > 400 3 families < 20 ~70

Morpho-logy

GeneLocus

CDAN115q (15.1.3)

SEC23B20p11.23-20p12.1

Unknown15q (21-25)

UnknownUnknown

UnknownUnknown

Dysmorpho-logies

Skeleton,Others

Variable,rare

B-CellsRetina

Variable CNSOthers

CDA Variant, GATA-I mutation

20301_Grill,martin_cda-VAR_20100419_007.jpg

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A variant of CDA: Bone marrow aspirate

48401_degenhardt_140502_003.jpg

A variant of CDA: Bone marrow aspirate

48401_degenhardt_140502_005.jpg

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German Registry on CDAs, ENERCA WP6: Coworkers and Cooperations

• Ulm:

• Elisabeth Kohne (Pediatrics)

• Other centers:

• A. Zanella, P. Bianchi Milan• Elisabeth Kohne (Pediatrics)• K. Schwartz, Katja Heinrich,

Tatjana Kersten ( Molecular genetics)

• Rosi Leichtle (Documentation) • Helga Dietrich (Serology) • A.Högell ( Biostatistics) • MD Students:

K ti G ll K ti

A. Zanella, P. Bianchi Milan• J.Denecke , Muenster• A.Iolascon, Napoli • H. Tamary, Tel Aviv

• J.Goede, Zuerich• S. Wickramasinghe +, London• J.Delaunay, Brigitte Bader –

Meunier.Paris• Florinda Gilsanz, Madrid

L Ch b k P• Kerstin Gallmeyer, Kerstin Kellermann, Nadine Neuschwander, Andreas Matuschek, Judith Wissmann, Christina Hepperle

•

• L. Chroback, Prague • Gabriela Smolenska, Jerzy.

Koszielak, Eva Zdebska (+), Warzawa

And many patiens, parents and physicians providing data

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Inreased cellularity and erythropoitic hyperplasia in CDA II, histology

Hei0905/cda.ppt 06501_007

(CDA II vs. controls means in % of all

CDA IIHighly significant differences for these

morphological aberrations:

erythroblasts)

• mature binucleated cells (11,68 (CI10,42 - 12,93) vs. 1,31 (0,35- 2,27))

• multinucleated cells (1,12 (0,79 - 1,45) vs. 0,04 (-0,01- 0,09))

Mann-Whitney- test with p< 0.0001

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CDA II: EM, C ,polychromatic erythroblast

496/01_1882

Mutations of exons of the CDANI-gene

• Mutations cases

• Homocygotes 4

• Compound Heterocygotes 26

• One allele only 7One allele only 7

• Wild type 2

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DNA –content andH3_thymidine uptake (hatched) in a case of CDA I

Queisser at . Al, Acta haematologica 1971, 45. 65 -76

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VIII:1Josef

Stadler

1890.1.26 - 1944.1.16

VIII:2Maria

Stadler(Bold)

1889.3.13 - 1967.6.15

VII:1BrunoStadler

1861.5.26

VII:2TheresiaStadler

(Ott)1863.10.15

VI:2MartinStadler

1811.11.8

VI:1Maria Rosa

Stadler(Hahn)

1820.3.11

VI:3Maria AnnaSchellinger

(Schellinger)1812.6.26 - 1880.10.8

VI:4??

? - ?

VII:3SophiaBold

(Schellinger)1849.5.2 - 1895.5.6

VII:4AntonBold

1842.11.12 - 1917.11.14

VIII:3Georg

Schellinger

1902.5.13

VIII:4Theresia

Schellinger(Schwägele)

1899.4.9

VI:5Johann

Ott

VI:6MariaOtt

(Riegger)

VIII:5Adolf

Stadler

VIII:6Anna

Stadler(?)

Famile 312

XI:5Mathias

X:5Kurt

Stadler

1953.9.16

X:6Luise

Stadler(Ott-Stadler)1955.4.16

?XI:1

Sandra

?XI:4

Heiko

?XI:3

Armin

IX:1Josef

Stadler

1924.8.8 - 1975.8.29

IX:2Rosa Theresia

Stadler(Schellinger)

1924.8.3

X:4GüntherStadler

1947.10.2

X:2Erwin Josef

Stadler

1958.6.16

X:3MarliesStadler

1958.4.9

X:1ChristaStadler

(Langenbacher)1960.7.1

IX:3Luise

Stadler

1922.11.23

IX:4Paul

Schellinger

1926.6.7

IX:5Lydia

Schellinger

1924.6.19

XI:6Sabrina

X:7GiselaStadler(Braun)

XI:7Rainer

XI:8Christoph

XI:9Sonja

IX:6Viktoria

Ott-Stadler(Häuptle)1919.11.1

X:8Adolf

Ott-Stadler

1957.4.2

X:9Theodor

Ott-Stadler

1959.6.12

X:10Rita

Ott-Stadler(Baumann)1919.9.20

XI:10Marion

XI:11Tanja

XI:12Walter

IX:7Alfred

Ott-Stadler

1929.12.19 - 1991.5.30

XI:2Nicole

XI:13MathiasStadler

1988.6.30

XII:1MarcelRech

2002.4.2

SandraRech

(Stadler)1974.11.24

HeikoStadler

1983.1.9

ArminStadler

1979.10.16

SabrinaStadler

(Stadler)1986.7.8

RainerStadler

1968.9.16

ChristophStadler

1971.7.24

SonjaStadler

(Stadler)1978.12.24

MarionOtt-Stadler

(Ott-Stadler)1989.2.15

TanjaOtt-Stadler

1987.7.3

WalterRech

1972.3.14

NicoleStadler

1977.7.27

Stadler

XII:2

Stadler

Pedigree of the family 412; Stadler; CDA II

Familie aus SchwabenGemeinsamer Stamm-Vater gest.1714