1. Endocrine dysfunction (Hormone imbalances) in Diamond Blackfan Anemia
Dr Amit Lahoti
Dr Phyllis Speiser
Cohen Children’s Medical Center of New York
North Shore LIJ Hospital System

2. Diamond Blackfan Anemia (DBA)
is a rare condition.
Really!!!

3. DBA Beta thalassemia Sickle-cell disease 5-7 per 1,000,000 live births
1 per 500 African-American live births
Sickle-cell disease

4. Role of a registry
For rare conditions, clear guidelines on how to manage the disease or its complications often not available. A registry provides a unique opportunity to do systematic research. Until more research data are available, doctors use best practices learned from other somewhat similar conditions.

5. Treatment course of DBA
BMT recipients
In a cross-sectional analysis of the DBAR at a given timepoint, 40% of patient are receiving transfusions, 40% are on steroids, and 20% have received a BMT or are in remission.
There is a 20% chance of going into remission but not 20% of the patients are in remission at any given time.

6. Pros and cons of DBA treatments
Corticosteroids
Chronic Transfusions
Bone marrow transplant
Pros
No risk of iron overload
First line treatment for severe anemia under 1y
Can lead to resolution of anemia
Can improve quality of life
Cons
Risk of low bone density
Frequent hospital visits for transfusions
Risk of Graft versus Host Disease (GVHD), and infection
Excess weight gain & impaired growth
Endocrine complications of iron overload
Risk of graft rejection
Increased risk of diabetes (at high doses)
Side-effects of immunosuppressive drugs & radiation

7. Where do hormones come from and what do they do?

8. Risk of
Hormone disorders
in patients with DBA:
Is it real?

9. *Unpublished data presented at Pediatric Endocrine society meeting at Washington DC, 2013

10. You or some one sitting next to you may have a similar story….
At 6 months: Diagnosed with DBA
Monthly transfusions started.
Subsequently developed Iron overload
Chelation therapy with Desferal started
At 14.5 years, 7/2004: went to ER for frequent urination, excessive thirst and 15 lb weight loss. Blood glucose markedly elevated. Diagnosed with Diabetes mellitus,
Insulin therapy started
Two months later, 9/2004: Thyroid function tests show Thyroid gland failure.
Thyroid hormone started
Desferal started by nightly subQ pump

11. In the next year…
At 15 years, 12/2004: Teen non-compliant with insulin regimen & diet. Poor blood glucose control, stunted growth, despite normal GH levels. Diagnosed Growth hormone resistance.
Growth hormone therapy started
At years, 10/2005: Delayed puberty with evidence of Pituitary failure.
Testosterone therapy started.
At 16.5 years, 5/2006: Multiple seizures related to low blood glucose despite not being compliant with insulin regime. Diagnosed with Adrenal insufficiency
Hydrocortisone therapy started.

12. And as time went by…
Two months later, 7/2006: Complaints of frequent urination at night. Diagnosed Diabetes insipidus.
DDAVP treatment started.
At 17.5 years, 8/2007: Evidence of Diabetic kidney damage.
Enalapril treatment started.
At 18 years, 2/2008: Growth hormone therapy stopped. Adult height: 5 feet.

13. Hormone problems can start in childhood!
You are never “too young” to be tested.
Early diagnosis can avoid later problems.

14. Questions?
What are these conditions? How common are these? Are you at risk? How can you be tested for these? How are they treated?

15. Hypogonadism
What is it?
Absent or delayed puberty

16. Hypogonadism What is Delayed Puberty?
In girls, no breast development by 13 years, or no periods by 15 years or by 2 years after breast development.
In boys, no testicular enlargement by 14 years

17. Hypogonadism How common? How to diagnose? How to treat?
With iron overload: %
After BMT:
Females- ovarian malfunction in ~100%
Males- testicular dysfunction in 0-40%
How
common?
Blood sampling for pituitary puberty-regulating hormones (LH and FSH) and
sex hormones (Testosterone or Estradiol). Bone age x-ray of hand.
How to
diagnose?
Males: Testosterone injections or skin gel.
Females: Estrogen oral or skin gel.
How to
treat?

18. Insufficient thyroid hormone
Hypothyroidism
Insufficient thyroid hormone
What is it?

19. Hypothyroidism Or, no symptoms at all!!! ( especially in early stages)
Feeling cold
out of ordinary
How you may feel?
Not growing well
Or, no symptoms at all!!! ( especially in early stages)

20. Hypothyroidism How common? How to diagnose? How to treat?
Patients with iron overload: 2-20 %
Patients on steroids and after BMT:
Less common, frequency unknown
How
common?
By measuring blood levels of:
Thyroid stimulating hormone (TSH); and
Total and free Thyroid hormone (T4)
How to
diagnose?
How to
treat?
Once a day thyroid hormone (tablets)

21. Adrenal insufficiency
Not enough adrenal hormones
What is it?
Stress hormone (cortisol)
Salt retaining hormone (Aldosterone)
Male hormones

22. Adrenal insufficiency
Dark color of non-sun- exposed areas
Low BP and dizziness
Extreme tiredness
Nausea, vomiting, abdominal pain, diarrhea, constipation
Muscle weakness
Although the picture I have used is of an old lady, not everybody who develops this is old
Symptoms may be missed or attributed to anemia or missed!

23. Adrenal insufficiency
Patients on steroids: considered to have adrenal insufficiency Patients with iron overload: biochemical adrenal insufficiency (often partial): 18-45%
How
common?
Blood measurements of:
8 AM cortisol level,
Plasma renin activity, aldosterone, Androstenedione and DHEAS levels
How to
diagnose?
Hydrocortisone: to replace stress hormone.
May only be needed during periods of stress.
Fludrocortisone: salt-retaining hormone.
How to
treat?

24. Quiz Time!!!

25. Question #1
Which of the following is NOT a part of the endocrine system?
Thyroid
Pituitary
Appendix
Adrenals

26. Question #2
This gland is sometimes called the master gland, though it is only about the size of a pea
Thyroid
Pituitary
Pineal
Hypothalamus

27. Question #3
Which of the following is the largest endocrine gland in the body:
Thyroid
Parathyroid
Pancreas
Adrenal

28. Diabetes mellitus
What is it?
Not enough insulin hormone

31. Diabetes mellitus Both iron overload and glucocorticoids lead to:
↓in insulin secretion; and
↓ in insulin sensitivity

32. Diabetes mellitus How common? How to diagnose? How to treat?
With Iron overload: 9-14%
On Chronic glucocorticoids: dose dependent. May be reversible.
BMT: depends on pre-transplant factors.
How
common?
Fasting blood glucose
Fructosamine level (HbA1c may not be
reliable if on transfusions)
Oral glucose tolerance test
How to
diagnose?
Diet changes,
Insulin therapy and/or
Oral medications
How to
treat?

33. Growth Problems For patients <18 years age:
How many of you are shown your/ your child’s growth chart during the visit with the pediatrician or hematologist?
How many of you have asked to see your/ your child’s growth chart during these visits?
Growth chart is an important tool to detect poor growth or short stature at an early age!!!

35. Growth problems Short stature Anemia and ?DBA itself
Absent/ Abnormal puberty
Iron overload
Short stature
Hypothyroidism
Low Growth hormone
Glucocorticoids
Multiple causes of poor growth in DBA patients

36. Growth problems How common? How to diagnose? How to treat?
DBA itself: Reported short stature ~30%
Effect on growth due to iron overload or
steroids alone is hard to quantify in
DBA due to this.
BMT: may improve growth.
How
common?
Regular growth monitoring for early
detection
Laboratory testing to rule out specific
endocrine causes.
How to
diagnose?
When to treat?
Specific to the cause.
However, final height may still be low for
mid-parental height.
How to
treat?

37. Bone disorders
How?

38. Bone disorders Weak bones Hypogonadism
Low Vitamin D & parathyroid gland failure
Iron overload
Weak bones
Diabetes mellitus
? Low Growth hormone
Glucocorticoids
Multiple causes of poor bone density in DBA patients

39. Bone disorders How common? How to diagnose? How to treat?
With Iron overload: upto 50%
On Chronic glucocorticoids: Dose and duration dependent.
After Bone marrow transplant: Not known
How
common?
Test for other endocrine problems
Blood levels of Calcium, parathyroid
hormone and vitamin D
Bone mineral density scan
How to
diagnose?
When to treat?
Treat any co-existing hormone problem
Vitamin D supplements: Adequate level?
Other medications: Bisphosphonates
Newer drugs being developed.
How to
treat?

40. Importance of Screening
Vague symptoms may also be seen with anemia itself.
Often no/minimal symptoms in early stages.
14%
impaired glucose tolerance
1.5%
Diabetes mellitus
84.5%: normal
Diabetes screening in non- diabetic otherwise asymptomatic beta thalassemia patients

42. Importance of Chelation
Impaired glucose tolerance (IGT)
Years
12.4%
Normal glucose tolerance
~10 Years
Insulin dependent diabetes mellitus
Intensive chelation in patients with IGT can improve beta-cell function, improve blood glucose values.
Less effective in patients who have developed DM and in improving insulin resistance.

43. Treatable nature of most of these conditions
Treatable nature of most of these conditions!- That’s what I love about endocrinology!!!
Timely diagnosis & treatment can prevent morbidity and possible mortality associated with some endocrine conditions.
Versus possible long-term adverse effects of an untreated endocrine problem.

44. What do we need to do?
The only published reports about hormone problems in DBA patients are in form of case reports or case series with few patients.
Collect more information about endocrine problems in DBA patients like you. Vs

45. About our research study
SPECIFIC AIMS:
To study the effects of iron overload on various endocrine glands in DBA patients receiving transfusions.
To estimate how common are these hormone abnormalities in the DBA population and correlate it with measures of iron overload.
To recommend a possible method to screen the at-risk DBA patients for endocrine dysfunctions at regular intervals.
To compare the presence of endocrine dysfunction in chronic transfusion dependent DBA population with DBA patients not on chronic transfusions and beta thalassemia major patients on chronic blood transfusions.

46. About our research study
Eligibility Criteria:
Inclusion criteria:
Age 1-39 years; and
Diagnosed with DBA and enrolled in DBA Registry (DBAR), or
Diagnosed with beta thalassemia major and followed at NSLIJ pediatric hematology division.
Exclusion criteria:
Pregnant; or
Having received a bone marrow transplant

47. About our research study
Participation involves a standard endocrine evaluation.
This includes blood tests that can be ordered and drawn at
your primary institution. The participation consent asks for
permission for us to receive the endocrine evaluation results.
Our goal is 75 DBA patients and 25 thalassemia patients total for the study. THANK YOU IN ADVANCE FOR YOUR PARTICIPATION!!!

48. Thanks for listening!!!