Thalassemia

Inherited

1

You put down the last of the journals for the month. Your colleagues tease you for reading them the old fashioned way, but the online version just doesn't cut it for you somehow.


2

"Doctor, there's a family who'd like to meet you". You request the nurse to send them in.


3

A woman and her husband enter with their 2-year-old son, Jacob; they migrated from Nigeria a year ago, and Mrs. Okoye is currently eight weeks pregnant with her second child. She tells you that Jacob has been falling ill very frequently since early childhood. He always seems tired and weak, and is not as active as other children his age.


4

You gesture for them to have a seat and begin examining Jacob, who seems enchanted with the little monkey hanging off your stethoscope. He is running a mild fever, and the abdominal examination reveals a palpable spleen. His height and weight are below the 50th percentile for his age. You request his parents to distract him as you draw some blood for a complete count and peripheral smear. Jacob barely notices the prick and Mrs. and Mr. Okoye beam at you.


5

His reports arrive the following day: WBC: 10,000/mm3 (6,000 - 17,000) Hemoglobin: 7 g/dL (10.5 - 13.5) RBC: 2.3 million/mm3 (3.7 - 5.3) RDW: 23% (11.5 - 14.5) MCV: 55 fL (70 - 86) MCH: 21.5 pg (23 - 31) MCHC: 33 g/dL (30 - 36) Platelets: 150,000 /mm3 (150,000 - 400,000)


6

Reticulocyte count: 1.8% (0.5-1.5) The smear shows microcytic normochromic anemia, with tear drop cells and target cells.


7

You believe that Jacob may have beta thalassemia major or Hb H disease, but decide to confirm your suspicions before breaking this to his parents.


9

You order a direct Coombs test, but the nurse looks surprised. "Are you suspecting an autoimmune hemolytic anemia, doctor?", she asks.


10

You thank her for tipping you off and request hemoglobin electrophoresis instead.


11

Hemoglobin electrophoresis shows no synthesis of HbA, with increased synthesis of HbA2 and HbF, suggesting at beta thalassemia major.


12

You decided to use HPLC for identification of Hb variants. This shows increased synthesis of HbA2, suggesting at beta thalassemia major.


13

At Mr. and Mrs. Okoye's next visit, you talk to them about Jacob's diagnosis. They are understandably distressed and ask if anything can be done to help their son.


15

You gently tell the family that a blood transfusion, although not curative, is the best treatment for prolonging life until a bone marrow match can be obtained. Jacob will require periodic transfusions with the frequency depending on the severity of his illness, and his response to treatment.


16

Jacob's parents seem unsettled but agree to start therapy nonetheless.


17

You explain that the only curative treatment for thalassemia is a bone marrow transplantation, but getting a perfect match will be difficult given that Jacob doesn't have any siblings.


18

You suggest that a splenectomy would be the best way forward, but the nurse calls you aside before you can finish your thought. "Doctor, shouldn't we try blood transfusions before putting this child through surgery?"


19

You suggest that both parents should undergo genetic testing, to which they wholeheartedly agree. The reports which arrive a couple of days later show both of them to have beta thalassemia minor.


20

Mrs. Okoye looks deeply disturbed and wants to know what the chances are of her next child having the same condition, as she is currently eight weeks pregnant.


22

You tell the couple that thalassemia is inherited in a recessive manner, but since both parents are affected there is a 25% and 50% chance that their next child will have thalassemia major and minor respectively.


23

You tell the couple that thalassemia is inherited in a dominant manner and there is a 100% chance of their next child being affected. Hearing this, Mrs. Okoye looks confused. "But doctor, I've been reading on the internet and as far as I remember it is a recessive condition."


24

You apologize for your mistake but you can tell the family has lost some of their faith in you. You hope that they won't request for a different doctor, although it would be understandable if they do.


25

You tell the couple that thalassemia is an X-linked recessive condition; the son of a carrier female has 50% chance of being affected while daughters become carriers. There in no father to son transmission. You're halfway through your explanation when you realize this doesn't sound quite right.


26

As you complete your explanation, you notice Mrs. Okoye quickly glance down at her abdomen. You recall that she is currently in the first trimester of her second pregnancy, and immediately realize what her next question is going to be. Just as you expected, Mrs. Okoye wants to know if their next child can be diagnosed prenatally.


28

You explain that a chorionic villus sample and PCR analysis would be the safest at this early stage of pregnancy.


29

You begin explaining your decision to perform an amniocentesis to obtain a DNA sample, but the nurse interrupts you. "Doctor, since she is only eight weeks pregnant, shouldn't we do chorionic villus sampling instead?"


30

Embarrassed by your lapse, you thank the nurse for her timely intervention.


31

The couple thank you for all your help and note down Jacob's next appointment as well as a date for chorionic villus sampling before leaving your office.


32

A young man is waiting in your office as you enter the clinic the following day. You immediately recognize Elijah, now 23 years old.


33

He first came to you at the age of five with a situation not very different from Jacob's.


34

You recall clearly that he was anemic at the time, with target cells and Howell-Jolly bodies on his blood smear, an increased reticulocyte count, and splenomegaly.


35

He was diagnosed with beta thalassemia major and has come in today for his blood transfusion, as he does every two months.


36

You remember that when Elijah was 15 years old you had wanted to rule out a transfusion-related iron overload, as he had been on this therapy for a number of years.


37

You had sent for serum iron, ferritin, and TIBC levels back then. His reports had read as follows: Serum iron: 2000 µg/dL (55-160) Serum ferritin: 380 ng/mL (23-336) TIBC: 200 μg/dL (240-450)


38

What treatment did you prescribe for Elijah at the time?

1. A phlebotomy
2. Penicillamine
3. IV desferrioxamine

39

You decided that a phlebotomy would be the quickest way to get rid of all the excess iron.


40

The nurse had seemed surprised - "Won't this worsen his anemia, doctor?"


41

You had immediately realized this was correct and had changed your line of treatment.


42

You had told Elijah and his family that he would need treatment with penicillamine.


43

On hearing this, the nurse had inquired confusedly - "Doctor, are we suspecting copper, lead or gold toxicity?"


44

Realizing she was right you had hastily apologized for your error.


45

You ordered IV desferrioxamine over a few hours for chelation.


46

Elijah has been on regular transfusions and chelation therapy since then.


47

You snap out of your little reverie as you enter your office and greet Elijah and a young woman whom he introduces as his wife. They tell you that they have been married for six months now and are ready to start a family. The couple would like to know what the chances are of their child having the disease.


48

Elijah's wife has already gotten herself tested; she is not a carrier.


50

You tell the couple that since only one of them is affected there is a 50-50 chance their child will either have the disease or be a carrier.


51

Elijah looks panicked. "Was what I read online incorrect then, that all our children will be carriers?"


52

Embarrassed, you apologize for your error, but they look a little unsettled.


53

You explain that children get two genes responsible for thalassemia from either parent, one from their father and one from their mother; each can be either normal or mutated. However, since it is a recessive condition, a child would need two "bad" genes to produce the disease.Having only one "bad" gene would make them a carrier. Since Elijah has two mutated genes while his wife has none, their kids will have one mutated and one normal gene each.


54

So in summary, all children will be carriers, or have the thalassemia trait, but not thalassemia major.


55

You tell the couple that all their children will, unfortunately, have thalassemia major.


56

Halfway through your statement, it strikes you that thalassemia is autosomal recessive, not dominant. Glad to have caught yourself in time, you rectify your response.


57

You reassure the disheartened couple that thalassemia minor is a mild condition and is commonly asymptomatic.


58

Their faces brighten and they thank you, telling you how much they're looking forward to starting a family. They leave your office looking relieved and content. Well done!