Mattiello V., Congresso annuale SSP- 07.06.2019

Caring for children with hemoglobinopathies: an

uptade for the pediatrician

Hemoglobinopathies

Inherited hemoglobin disorders constitute the commonest monogenic disorders worldwide.

Thalassemia syndromes : group of inherited disorders of hemoglobin synthesis, characterized by

reduced or absent synthesis of one or more of the globin chains of hemoglobin.

Structural hemoglobin variants (abnormal hemoglobin).

Epidemiology of thalassemia syndromes : some numbers

Approximately 68,000 children are born with various thalassemia syndromes each year.

β-thalassemia :

80 to 90 million people carriers across the world (1.5% of the global population).

Some 23,000 children are born with transfusion-dependent β-thalassemia major each year

α-Thalassaemia :

Approximately 5% of the world’s population are carriers

An approximate of 1,000,000 patients are affected with the various α-thalassaemia syndromes worldwide.

Taher et al., 2017

Normal Hb A (adult)

DIU Immuno-hématologie Pédiatrique,Lyon 2014

Hemoglobin switching

Cappellini et al. Guidelines for the management of transfusion dependent thalassaemia (TDT), 2014

Thalassemia: worldwide distribution

Modell et al., Scand J Clin Lab Invest 2007

Europe: burden of hemoglobin disorders

Ineffective erythropoiesis

Β0-Thalassémie Β+-Thalassémie

Intramedullary abortion of erythroid precursors in which excess free α/β chains precipitate.

Pathophysiology

Cappellini et al. Guidelines for the management of transfusion dependent thalassaemia (TDT), 2014

LIC = liver iron concentration. Adapted form Taher et al. Br J Haematol. 2011

↑ Duodenal iron

absorption

↑ Release of

recycled iron from

RES macrophages ↓ Hepcidin

↑ LIC

↓ Serum

ferritin

Ineffective erythropoiesis

Chronic anaemia

Hypoxia

Mechanism of iron overload in non-transfused patients

Clinical phenotype of thalassemia syndromes

β-thalassemia intermedia

HbC/β-thalassemia

HbE/β-thalassemia

HbH disease

B-thalassemia major

α-thalassemia

trait/minor

β-thalassemia

minor

TDTs Transfusion dependent thalassemia

NTDTs Non transfusion dependent thalassemias

β-thalassemia α-thalassemia

Primary modifiers Type of mutation Type mutation /number of

genes mutated

Secondary modifiers Co-heritance of α-

thalassemia/

Percentage of HbF

Hb variants associated HbE/ Hb Lepore HbCS

Others polymorphisms e.g. Gilbert disease,

hemochromatosis....

Clinical phenotype :genetic modifiers

β-thalassemia-phenotype

Severe and precocious anemia requiring a lifelong

transfusion regimen

Thalassemia

Major

Moderate anemia, TF absent or occasional. But, age

at presentation, degree of anemia, clinical course

extremely variable

Thalassemia

intermedia

Microcytosis +/- mild anemia

Thalassemia

minor

Seve

rity

DIU Immuno-hématologie Pédiatrique,Lyon 2014

α-thalassemia: genotype/phenotype

Piel and Weatherall N Engl J Med 2014

Taher et al. Guidelines for the management of non transfusion dependent thalassaemia (NTDT) 2017

TDT and NTDT

Viprakasit et al. Orphanet J Rare Dis 2014

β-thalassemia complications

Weidlich et al. Transfusion 2016

Iron overload

Clinical sequelae of iron overload

Pituitary impaired growth, infertility

Thyroid hypoparathyroidism

Heart cardiomyopathy, cardiac dysfunction

Liver hepatic cirrhosis

Pancreas diabetes mellitus

Gonads hypogonadism

Iron overload end-

organ iron toxicities

in the absence of

intervention therapy

Cappellini , Global Iron Summit 2011

β-thalassemia major long term outcome

Su

rviv

al p

rob

ab

ilit

y

p < 0.00005

0

1.00

0.75

0.50

0.25

0 5 10 15 20 25 30Age (years)

Birth cohort

1960–19641965–19691970–19741975–19791980–19841985–1997

Borgna-Pignatti C, et al. Haematologica. 2004

Diagnosis of thalassemia syndromes: screening

Blood count

Microcytic hypochromic anemia

Reticulocytes

Increased in intermediate and severe forms

Blood smear:

Anisocytosis , poikilocytosis, target cells, schistocytes

erytroblasts, inclusion bodies (HbH)

Normal iron and ferritin level

Diagnosis of thalassemia syndromes : specific tests

Hb electrophoresis

Migration of Hb in an electric charged field

Cellulose acetate electrophoresis or capillary electrophoresis

¨Detection of pathological Hb

High performance liquid chromatography (HPLC)

Identification and quantification of variants (HbA2,HbF,HbS,HbC,HbE)

N.B. HPLC is usually normal in α-thalassemia but severe forms can be detected

Bart’s Hb (γ4 ) at birth

HbH (β4)

HPLC

Normal profile Β-thalassemia minor Β-thalassemia major

Diagnosis of thalassemia syndromes : genetic tests

DNA analysis

PCR amplification

β-thal: detection of most common mutations

α-thal commonest deletions

Direct sequencing or array analysis

α and β thal uncommon or unknown mutations

When to suspect thalassemia? ..the role of pediatrician

Positive family history for thalassemia or abnormal Hb

Chronic microcytosis with or without anemia often refractory to iron treatment

Ethnic origin of the so-called thalassemic area and/or abnormal Hb (Mediterranean, Africa, India,

South-East Asia, etc.)

Diagnosis to be considered in presence of microcytic and hypochromic anemia without

iron deficiency at any age.

No specific treatment to be proposed in case of minor thalassemia

Importance of genetic counseling in case of further pregnancy

Maternal screening currently performed during pregnancy in presence of anemia

Fathers in most case not investigated

Management of NTDT

Transfusion

Monitor Hb

If increased symptoms of anaemia, transfusion if required

Iron Chelation

Iron overload related to hepcidine suppression

Splenectomy

To consider in transfused patients or if hypersplenism

Thrombotic and overwhelming sepsis risk increased

Hb F inducers

Treatment of TDTS

Conventional treatment:

RBC transfusion

Iron chelation

Management of complications(endocrine system, cardiology..)

Curative therapies: BMT

Matched sibling donors TFS >80%, TRM very low

Haplo indentical : EFS 90%, GVH 20%

Cord blood: EFS 50% GVH 20%

Unrelated: EFS 65 - 92% GVH up to 30%

Caocci et al. Am J Hematol. 2017

Treatment of TDTS: experimental options

Gene therapy

Interesting results in patients with β-thalassemia major

Clinical trials ongoing including pediatric patients

Other options:

Stimulation of γ chain production

Improvement of ineffective erythropoiesis

Diminution of iron absorption

ζ α1 α2

ε Gγ Aγ β δ

ε

εζ

ζ γ

γα

α β

βα

α δ

δα

α

Embryonic life Foetal life Adult life

Embryonic Hb Foetal Hb Hb A Hb A2

Chromosome 16

Chromosome 11

Haemoglobin switching

HbH disease

α-/-- deletions of 3 of the 4 α-globin genes

Excess beta globin chains form β4 tetramers called HbH

Diagnosis – Alpha gene testing

Variable phenotype

Newborns: Jaundice and anaemic

Older children/adults : chronic haemolytic anaemia,

hepatosplenomegaly,

↑indirect hyperbilirubinemia,

↑ LDH,

↓ haptoglobin

leg ulcers,

osteopenia

premature biliary tract disease (pigmented gall stones)

Usually not transfusion dependent

May require transfusions during times of increased stress (inter-current illness, pregnancy, oxidative medications)

α and β thalassemia inheritance pattern

α-thalassemia

β- thalassemia