By

Prof. Dr. Asmaa AbdulAziz

Definition:The haemoglobinopathies are inherited disorders of

haemoglobin synthesis (thalassaemias) or structure (sickle

cell disorders) that are responsible for significant morbidity

and mortality allover the world.

They are seen mainly in individuals who originate from

Africa, the Middle East,, the Mediterranean, Asia and the Far

East. However, the increased mobility of the world’s

population and inter-ethnic mixing lead to prevailing of

these conditions within any region of the world.

These disorders result in errors in oxygen-carrying

capacity of haemoglobin . Diseases linked to genetic

predisposition are not only kill prematurely, but result

in long years of ill health and disability, loss of work

and income, possible poverty, loneliness and

depression.

Sickle cell and thalassaemia are inherited disorders that are

passed on from parents to children through unusual

haemoglobin genes.

People only have these disorders if they inherit two unusual

haemoglobin genes – one from their mother, and one from

their father.

People who inherit just one unusual gene are known as

‘carriers’. (Some people call this having a ‘trait’.) Carriers are

healthy and do not have the disorders.

Individuals with Haemoglobinopathy are:

either healthy carriers (trait ) i.e. unaware of their

carrier status unless specifically screened. If a couple

both carry a haemoglobinopathy trait there is a 1 in 4

chance with each pregnancy that their child will inherit

a clinically manifested haemoglobinopathy.

or having clinically manifested haemoglobinopathy

Who can be a carrier?Anyone can be a healthy carrier. This means you are more likely to be a carrier if your ancestors came from the Mediterranean (for example Cyprus, Italy, Portugal, Spain), Africa, the Middle East, India, Pakistan, South America or south and south-east Asia.Is it important to know if you are a carrier?

1- Healthy sickle cell carry may have some problems in rare situations (Lack of oxygen ,for example), when having an anesthetic or during deep-sea diving. Knowing that you carry sickle cell can help you manage these situations. However, people who carry thalassaemia or other unusual haemoglobin genes do not experience these problems.2-If a carrier gets married from another carrier (Consanguinity) they will have one in four baby with clinically manifested disorders

The diagram below shows the chances (for each pregnancy) of two carrierparents having a child with a sickle cell or thalassaemia disorder.

If the mother is anemic & the father is healthy carrier 50% of the off springs are carriers and 50% is anaemic

Sickle Cell is a condition that affects the normal oxygen

carrying capacity of red blood cells. When the cells are de-

oxygenated and under stress in sickle cell conditions, they

can change from round flexible disc-like cells to elongated

sickle or crescent moon shape. The effect of these changes

is that the cells do not pass freely through small capillaries

and form clusters, which block the blood vessels. This

blockage prevents oxygenation of the tissues in the affected

areas resulting in tissue hypoxia and consequent pain

(known as sickle cell crisis pain) other symptoms of sickle

cell disorders include severe anaemia, susceptibility to

infections and damage to major organs.

The term sickle-cell disease is preferred because it is more comprehensive than sickle-cell anaemia.

2-The clinically significant haemoglobinopathies are listed in following Table

In children, sickle-shaped red blood cells often become

trapped in the spleen, leading to a serious risk of death

before the age of seven years from a sudden profound

anaemia associated with rapid splenic enlargement or

because lack of splenic function permits an infection.

Affected children may present with painful swelling of the

hands and/or feet (hand-foot syndrome).

Survivors may suffer recurrent & severe painful crises, as

well as “acute chest syndrome” (pneumonia or pulmonary

infarction), bone or joint necrosis, or renal failure.

Thalassaemia Major : It is the most severe form of

thalassaemia, results in the inability of the body to produce

haemoglobin, resulting in life threatening anaemia.

Those with the condition require regular therapeutic

treatment and blood transfusion .

Bone marrow transplantation is a treatment option

The impacts of genetic disorders on infectious

diseases

)Malaria & Sickle cell disorders(Many studies showed reduced morbidity and mortality from

malaria ( Falciparum) patients with thalassemia major and

minor (the carriers) (up to 50%), and decreased numbers of

circulating parasites (by 80%) The mechanism of resistance

may consist of decreased parasite replication within the

erythrocyte or enhanced splenic clearance of parasitized

erythrocytes.

A person who carries the sickle cell gene has a survival

advantage against malaria

The sickle cell trait confers a selective advantage: resistance

to severe malaria. The mechanism of this protection however,

remains incompletely understood. Proposed mechanisms

include

decreased parasite growth in the red cells and

enhanced removal of parasitized cells by the spleen.

In patients with sickle cell trait, although some protection

against malaria and its complications is present, severe or

complicated malaria can occur.

However , severe hemolytic & infarctive crises are anticipated

if patients with sickle cell diseases get Malaria

Prevalence of haemoglobinopathies 

The World Health Organization (WHO) estimates that

globally at least : approximately 5% of adults are carriers

for a haemoglobin condition 2.9% for thalassaemia and

2.3% for sickle cell diseases

Carriers are found allover the word because as a result of

migration the populations of different ethnic groups to

different regions of the world.

Prevalence of Sickle cell disorders

SITUATION in Africa

The highest prevalence of sickle-cell trait is in parts of

Africa & among people with origins in equatorial Africa, the

Mediterranean basin and Saudi Arabia. In Africa, the highest

prevalence of sickle-cell trait occurs between latitudes 15° North

and 20° South

Over 300 000 children are born each year with a severe

haemoglobinopathy. 30% are born with thalassaemia

syndromes while 70% have sickle-cell anaemia

With worldwide migration, these diseases are as much a

feature of Europe, the United States and Australia as of the

countries where they originated.

Prevalence varies from under 0.1 births per 1,000 in some

parts of the world to more than 20 per 1,000 in parts of Africa.

In America, approximately 70,000- 80,000 people suffer

from sickle cell disease . They are mainly of African Origin

      

The situation in KSA: In a study carried in KSA ,the incidence of hemoglobulin S

for the studied neonates was 14.4% and ranged from 0.8%

in Najran to 26.4% in Al-Qurayyat, KSA.

In the eastern provinces the disease is generally milder

whereas in the western provinces the disease is severe and

similar to that reported in African populations

In Bahrain Genetic disorders of haemoglobin are prevalent.

In a study of the hospital population covering

56, 198 Bahrainis, it was found that

•Sickle-cell disease was 2% of newborns

•Sickle-cell trait was 18% of newborns

•Carriers of the thalassaemia gene was 24% of newborns .

From this study it was concluded that

•The mild form of SCD predominates.

•Hematological values are similar to those of patients from

Eastern Province, Saudi Arabia, where the mild form of the

disease predominates

Sickle-cell disease in Bahrain and Saudi Arabia presents special features. SCD in this area is clinically mild, and

mortality is low in both children and adults. However, some cases died from septicemias &

Pneumococcal diseases.

In this study the most precipitating factors for crisis were:

Exposure to cold (45% of cases).

Fever or elevated body temperature (35%),

Exhaustion & severe physical activity (35%),

Hot humid weather (10%)

Crowded places (10%)

National Control program for haemoglobinopathies:

The development of appropriate national control programme

is now accepted and introduced in many parts of Asia such

as in Bahrain, the Islamic Republic of Iran and Saudi Arabia.

China, India, Indonesia, Malaysia, Maldives, Singapore and

Thailand.

The control program depends on the characteristics & the requirements of individuals with haemoglobinopathies.Sickle cell disorders :People with sickle cell disorders:

• can have attacks of very severe pain• can get serious, life-threatening infections• are usually anaemic• need medicines (antibiotics & Pneumococcal vaccine) throughout their lives to prevent infections.

Thalassaemia major People with thalassaemia major:• are very anaemic• need blood transfusions every four to six weeks, • need injections and medicines throughout their lives.

There are also other, less common, haemoglobin disorders. Many of these are not serious.

National Control program for sickle cell diseases1- setting up sickle-cell screening and genetic counseling

programmes in high prevalence countries. The disease should be identified during the prenatal period or at birth as part of a routine screening programme. Genetic counseling and screening can lead to reduction in the number of children born with the trait. The programme should be developed at the primary care level with appropriate referral system.

3-Parents must be counseled to seek medical care for all febrile events in children with sickle cell diseases.

2-Supplementation of antibiotics, rest, good nutrition, folic acid

3-Training of health personnel in prevention, diagnosis and case management should be an integral part of the national programme.

4-Integration of national control program for sickle-cell disease within the national programmes for prevention & control of non-communicable diseases (Cancer , Diabetes)

The antenatal screening programmeParent screening for sickle cell and thalassaemia aims to

• identify women/couples at risk of a pregnancy with sickle cell or thalassaemia disorders and• provide appropriate referral & care for prenatal diagnosis with continuation or termination of pregnancy according to women’s choices.

In most of the countries where sickle-cell disease is a major public health concern :

•National programmes for its control do not exist. •Basic facilities to manage patients are absent, •Screening for sickle-cell disease is not common practice The diagnosis of the disease is made when severe complication occurs.

As a result, more than 50% of the children with the severe form of the disease die before the age of five from infection or severe anaemia

ANTENATAL SCREENING Pregnancy

Offer screeningBlood sent to laboratory for haemoglobinopathy Screen

Positive resultsInformation & counseling-Offer partner screening

Partner screeningBlood sent to laboratory for haemoglobinopathy Screen

Positive results: At risk coupleInformation & counseling-Offer prenatal diagnosis

Affected fetus- Information &counseling

Parents Make- Informed Choice

Termination of Pregnancy

Prenatal diagnosisFetal blood Sampling/ Chorionic Villus sampling

Negative ResultInformation: No further action

Unaffected FetusInformation- No further action

Negative ResultInformation: No further action

Continue with Pregnancy

Premarital diagnosis :

In the Saudi society, consanguineous marriages are high

(60%).

Recently, the Saudi government introduced a new

legislation regarding premarital testing for the 2 common

genetic disorders; namely, sickle cell trait and thalassemia.

The advantage of premarital diagnosis is that : affected

births could be prevented if couples at risk were identified.

NEONATAL SCREENING

The newborn sickle cell screening is part of the existing

bloodspot programme for Phenylketonurea (PKU) and

congenital hypothyroidism (CHT).

Neonatal haemoglobinopathy screening primarily aims to

identify infants with SCDs , in order to start prophylactic

antibiotic therapy and vaccination ( Pneumococcal

vaccine) as early as possible.

detects carriers. For each baby detected with SCDs,

neonatal screening detects between 17 and 100 sickle cell

carrier babies. Parents of a carrier child should be

informed about the carrier result

In UAE, a standard form for neonatal screening is issued to every baby born hospital, where 99% of deliveries occur, and mothers are informed about the procedures &importance of neonatal screening.in January 1995 by screening for Phenylketonurea .

in January 1998. Screening for congenital hypothyroidism In January 2002, the Ministry of Health decided to launch a

pilot study for neonatal screening of sickle cell disease before expanding it at the national level.Newborn infants are brought to MCH centre on the fifth day for collection of blood samples by heel prick onto filter paperThe aim of the Screening program for haemoglobinopathy is to:

•To detect infants with haemoglobin traits, •To identify children with clinical disease and •To counsel couples at risk for having future baby with sickle cell disorders.

All infants confirmed with sickle cell disease started prophylactic penicillin by the age of 2 months and follow-up was arranged with the cooperation of haematologist.

Genetic counselingIt is the process through which knowledge about the genetic aspects of illnesses is shared by trained professionals with those who are at an increased risk or either having a genetic disorders or having them to be passed to their unborn offspring.

Genetic counseling is aiming to

•replace misunderstandings of the causes of genetic

disease with correct information

• informing parents about the resources available for

diagnosis, treatment and prevention.

•helping the families in decision making, which have life

long consequences

The family physician usually handles most of the genetic

counseling during routine clinical visits

A survey of 500 parents, with children who have a genetic

diseases was carried, to find their knowledge about genetic

diseases indicated that the majorities were unaware of

etiologies, symptoms, inheritance and therapies.

This was particularly true for parents with lower education.

Until recently a genetic counselor only advised of

possibilities of recurrence of such a disease in the family.

The new policy of genetic counseling is to help the family in

making the correct decision for preventing the disease in

the extended family and the prevention of a similar

condition in future pregnancies.

Pneumococcal diseases in children with Sickle cell disorders :•Children with sickle cell anaemia have an increased

susceptibility to severe bacteria infection, particularly from

Streptococcus pneumoniae. The risk of infection is greater in

the first 3 years of life specially at4 months.

•The incidence of Pneumococcal diseases for children with

sickle cell disease is 18.4cases per 100 patients/year

compared with 0.02 to 0.06 patientss per 100 healthy children

/year

•This infection may be the first clinical manifestation of

disease and carries .

•The case fatality rate of Pneumococcal diseases in these

children is 30%

Age distribution of pneumococcal bacteremia in children with sickle cell disease or HIV and healthy children at Boston Medical Center, 1981–1998.9

Pneumococcal diseases in sickle cell children

include

• Pneumonia & bronchitis

• Pneumococcal meningitis

• Septicemias

• Ear infections

• Peritonitis

The Risk Factors for Recurrent Pneumonia in Children

which include:

•Sickle-cell diseases

•Impaired immune system) HIV, cancer, leukemia (

•Viral respiratory Infections

•Gastroesophageal reflux disorder

•Inborn lung or heart defects

•Asthma

•The causative agents : Streptococcus pneumonia

• Children under 2 years old are at highest risk for

serious disease.

•The organisms spread from person to person through

close contact.

•Pneumococcal infections can be hard to treat because

the bacteria have become resistant to some of the drugs

that have been used to treat them. This makes

prevention of Pneumococcal infections is more

important.

Pneumococcal vaccine can help prevent serious

Pneumococcal disease, such as pneumonia, bronchitis

meningitis and septicemia & ear infections.

There are two types of Pneumococcal vaccine:

1 -Pneumococcal polysaccharide vaccine (PPV) contains

purified capsular polysaccharide from each of 23 serotypes

of Pneumococcal bacteria

2-Pneumococcal conjugate vaccine (PCV) contains capsular

polysaccharide from seven serotypes of Pneumococcal

bacteria conjugated to protein

The vaccines are inactivated, do not contain live

organisms and cannot cause the diseases against which they

protect.

Pneumococcal polysaccharide vaccine (PPV) Adults develop a good antibody response to a single dose of

PPV by the third week following immunization.

Not used in children < two years of age because of poor

antibody responses .

The overall efficacy in preventing Pneumococcal bacteraemia is

50 to 70%

Post-immunization antibody levels begin to wane after five years

Pneumococcal conjugate vaccine (PCV)The antibody response in young children can be improved by conjugating the polysaccharide to proteins. The conjugated

vaccine is immunogenic in children. The efficacy is 97% after giving the fourth doseThe vaccine protects against Pneumococcal meningitis, bacteraemia, pneumonia and otitis media.

For children under one year of age:) First dose of 0.5ml of PCV at 2nd monthSecond dose of 0.5ml, at 4th monthA third dose of 0.5ml at 6th monthThe fourth dose of 0.5ml at 13th monthSubcutaneous at anterolateral thigh

Children over one year of age and under five years of age: A single dose of 0.5ml of PCV (subcutaneous upper arm)

In general the Pneumococcal vaccine should be

given to Children having•heart condition

•chronic lung ,liver disease

•diabetes mellitus

•weakened immune system

• Children with damaged spleen or no spleen Or Sickle

cell anaemia & thalassaemias .

These children should be managed as follow:

Infants under one year of age: Give PCV vaccine as routinely recommended at two and fourmonths of age with a booster dose at around 13 months of age.

Children aged 12 months to < five yearsIf they have a single dose of PCV before ,they should receive a second dose of PCV ( Separated by two months) because they may have a reduced immune response for the first dose of the vaccine.

At-risk children aged five years and over PCV is not recommended .

Don’t give the PCV vaccine to Children had a serious

(life-threatening) allergic reaction to a previous dose of

this vaccine ( as it contains protein)

Give the PCV vaccine to Children even with minor

illnesses, such as mild fever or diarrhea

Postponed the PCV vaccine for children who are

moderately or severely ill .Wait until they recover before

getting the vaccine

Adverse effects following PCV

•25% had local redness, tenderness, or swelling

• Up to about 1 out of 3 had a fever

• Some children become drowsy, or had anorexia

So far, no serious reactions have been associated with this

vaccine.