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DC Management and Treatment
Part 2
Camp SunshineSeptember 16, 2016
Alison A. Bertuch, MD, PhDAssociate Professor
Baylor College of MedicineBone Marrow Failure Program Director
Texas Children’s HospitalEmail: abertuch@txch.org
What needs to be screened?
1. Head, neck and dental
2. Skin
3. Peripheral blood, bone marrow, immune system
4. Eyes
5. Gastrointestinal, liver
6. Bones
7. Lungs (not pulmonary fibrosis)
8. Growth/development
2
3b. Myelodysplastic syndrome (MDS)
3
NORMAL
Normal cell numbers
Normal cell appearance
APLASTIC ANEMIA
Decreased cell numbers
Normal cell appearance
Few cells mature
MYELODYSPLASIA
Cell numbers normal or
abnormal
Abnormal cell appearance
Cells do not mature normally
How is MDS different from aplastic
anemia?
4
MYELODYSPLASIA
Cell numbers normal or abnormal
Cells do not mature normally
Cells entering the
bloodstream have
a shortened
survival
Immature cells
accumulate in the
bone marrow
May progress to
leukemia
Risk of MDS is increased in DC
5Alter et al., Br J Haematol 2010
Observed/expected
cases= 2,663
When and How to Treat MDS in DC
• Dysplasia affecting more than one bone marrow lineage
• Progressive dysplasia
• Increasing blasts
• Associated chromosomal abnormalities
– Loss of chr 5 (5q-) – Deletion or loss of chr 7
– Extra chr (trisomy) 8 – 20q abnormalities
– 11q23 translocation – 3q abnormalities
• Hematopoietic stem cell transplantation
– Need approach tailored to DC Drs. Tolar and Agarwal
6
When and How to Treat MDS in DC
• Dysplasia affecting more than one bone marrow lineage
• Progressive dysplasia
• Increasing blasts
• Associated chromosomal abnormalities– Loss of chr 5 (5q-) – Deletion or loss of chr
7
– Extra chr (trisomy) 8 – 20q abnormalities
– 11q23 translocation – 3q abnormalities
• Role of agents such as azacitidine (Vidaza) and decitabine (Dacogen) has not been determined
7
What can you do?
8
Screening for MDS
• Monitor or be aware of signs and symptoms
– Paleness, fatigue
– Easy bruisability, bleeding, petechiae
– Infections (bacterial, fungal, severe viral)
• Complete blood counts (CBC)
– If normal counts, every 4-6 months; spread out to once a year if
stable in select patients (e.g., mid adulthood onset pulmonary
fibrosis)
– If counts ABnormal, get CBCs more often based on your doctor’s
advice
• Bone marrow exams including aspirate, biopsy,
cytogenetics and MDS FISH studies
– Every year (or sooner if declining counts)
– Flow cytometry for leukemic cells if dysplastic cells are observed
on initial review 9
3c. Immunologic Abnormalities in DC
10
Stems from bone marrow failure and deficiencies
in lymphocyte development
11
Immunologic Abnormalities in DC
• May be prominent in patients, especially with HHS
• Reduction in antibody producing (B) cells most commonly observed
– Decrease in circulating antibodies
– Decreased antibody responses to specific antigens, including vaccines
– Increased risk of sinopulmonary infections
• May also have a reduction T cells, increasing risk to opportunistic infections, e.g.,
– Pneumocystis jirovecii infection (pneumonia)
• If PJP prophylaxis is recommended, do not use trimethoprim/sulfamethoxazole (Bactrim) due to risk of bone marrow suppression
12
Immunologic Abnormalities in DC
• Spectrum of presentations
– Severe combined immunodeficiency (SCID) in infancy
with noninfectious, severe enteropathy with
intractable diarrhea (HHS, some with RTEL1
mutations)
– Common variable immunodeficiency (CVID) in
adolescence
13
What can you do?
14
Immunologic Abnormalities in DC
Testing to evaluate for the immune systems
• Quantitative levels for immunoglobulins
(antibodies) IgG; IgM and IgA
• Lymphocyte T, B, and NK cell subsets
• Lymphocyte proliferative responses to mitogens
and antigens
• Antibody titers to specific antigens (e.g., tetanus,
diphtheria, poliomyelitis and pneumococcal)
• IgM isohemagglutinin titers
15
Treatment of Immunologic Abnormalities
Type is dependent on the specific deficiency
• Low IgG level – routine intravenous or subcutaneous immunoglobulin
• Recurrent infection with specific antibody deficiency – routine intravenous or subcutaneous immunoglobulin
• Poor T (CD4) cell numbers – antibiotic prophylaxis for Pneunocystis jirovecii pneumonia
• Flu vaccine for all
• HCST
16
4. Eye Complications
• Up to 40% of patients with DC
17
Eye Complications
Tsilou et al,
Ophthalmology. 2010
Tear duct present Tear duct absent
18
Obliteration of the lacrimal draining system,
most common problem >
• Constant tearing
• Conjunctivitis
• Inflammation of the eyelids (blepharitis)
• Corneal ulcers
Eye Complications
19
Obliteration of the lacrimal draining system:
treatment >
• Surgical creation of a channel from the
lacrimal sac to the nasal cavity
• Placement of glass implants to allow draining
from corner of the eye into the nose
Eye Complications
20
Eyelashes growing in
and irritating the eye
Misdirected eye lashes (trichiasis) and in turning
(entropion) or out turning (ectropion) of the eyelid or
eye lashes >
• Conjunctivitis, blepharitis
• Corneal inflammation and scarring
• May eventually lead to impairment of vision
Tsilou et al,
Ophthalmology. 2010
Eye Complications
21
Treatments:
• Early recognition is key > be seen by an
ophthalmologist
• Surgical repair of lids; removal of misdirected
eyelashes
Tsilou et al,
Ophthalmology. 2010
Eyelashes growing in
and irritating the eye
Eye Complications
22
Eye Complications
Exudative retinopathy:
Revesz syndrome (TINF2)
Coats’ plus (CTC1/STN1)
23
Eye Complications
24
Other retinal changes:
• Atherosclerosis of the retinal vessels
• Areas lacking blood perfusion
• Areas of abnormal blood vessel growth
• Exudative retinopathy > retinal hemorrhage,
detachment
➢May lead to vision loss and blindness
Early detection is key!
➢Natural history studies needed
5. Gastrointestinal Manifestations
25
• Observed in 15-20% of
children and adults with
telomere disorders
• Cells lining of the gastro-
intestinal tract turnover at
a high rate
Moore, KA and Lemischka, IR. Science 2006
Esophageal Stenosis
26
• Observed in DC, more often males
• May be under-diagnosed
• Symptoms– Difficulty swallowing or feeling that
food is not passing to the stomach
– Unintended weight loss or failure to thrive
– Regurgitation of food or liquids
– Painful swallowing
– Heartburn
• Adaptive behaviors, e.g., prolonged chewing, avoidance of certain goods
http://digestive.niddk.nih.gov/
Esophageal Stenosis
27
• Diagnosis
– Video swallow study
– Upper GI endoscopy
• Treatment
– Dilatation of the esophagus,
possibly multiple times
– Acid blocking medicines http://digestive.niddk.nih.gov/
Enteropathy
28
• Disease of the small intestine
• Nonspecific symptoms that may be chronic and intermittent– Nausea
– Nonlocalizing abdominal pain
– Early satiety (feeling full after a small portion of food)
– Food intolerance or allergies
– Loose stools or diarrhea
– Failure to thrive in infants
– Failure to gain weight or weight loss in older children and adults
Enteropathy
29
• Diagnostic evaluation– Upper GI tract endoscopy and colonoscopy with
biopsies
– Findings may be subtle and nonspecific
– In patients after HCST, may mimic or be due to graft-vs-host disease
• Treatment– Diet adjustment
– Avoidance of gluten, anecdotally helpful
➢Natural history and treatment studies needed!
Enterocolitis
30
• Inflammation of the GI tract
• Mostly seen in infants with HHS
• Symptoms
– Severe abdominal pain
– Bloody diarrhea
– Failure to thrive
• Secondary processes
– Bowel perforation
– Bacterial sepsis
Enterocolitis
31
• Likely due to defects in the lining of the intestine AND immune defects
• Diagnosis – clinical findings
• Colonoscopy may be helpful
Treatment:
• Supportive care
• Bowel rest
• Antibiotic and nutritional support
• May improve following HSCT
Unexplained GI bleeding
• May be mild to severe with significant blood loss
• Patients may experience blood stools and/or blood emesis (vomiting)
• Source of bleeding frequently unclear
• May occur in cases of non-cirrhotic portal hypertension (impaired blood flow through the liver)
• Prevalence in DC population not known
• Empiric treatments utilized
➢Natural history and treatment studies needed!
32
5b. Liver Disease
• May be mild to severe, end-stage disease
• Signs of liver disease
– Increased levels of enzymes released into the blood when the liver is damaged (e.g., ALT/AST)
– Decreased levels of proteins produced by the liver (e.g., albumin, clotting factors)
– Abnormal liver architecture on ultrasound, nodular, heterogeneous appearance
– Portal hypertension
33
Liver Disease Screening
• Annual liver function tests– ALT, AST, GGT, bilirubin
– Prothrombin time (measure of clotting factors)
– Albumin
• Ultrasound of liver and spleen to look for any abnormalities in architecture, tumors, or portal hypertension
• LFTs and ultrasound more frequently if on androgens
• If abnormal, consider liver biopsy
34
Liver Disease Treatment
• No known specific treatments
• ? Liver transplantation if eligible
35
“Prevention” of liver disease
• Minimize or avoid alcohol consumption
• Avoid drugs associated with liver toxicity to the
extent possible
– http://www.hepcnet.net/drugsandliverdamage.html
• Hepatitis A and B immunization
• Weight management to minimize fatty liver
• Assessment and treatment of iron overload in
patients on red cell transfusions
36
7. Pulmonary Arteriovenous
Malformations
• Other names
– Pulmonary arteriovenous fistulae
– Pulmonary arteriovenous aneurysms
– Cavernous angiomas of the lungs
– Pulmonary telangiectasias
• Several case reports and recent case series on
diffuse pulmonary AVM in DC
37
Pulmonary Arteriovenous Malformations
38
Pulmonary Arteriovenous Malformations
Signs and symptoms
– Shortness of breath• Worsens when lying down
• Worsens when upright
– Poor oxygenation
– Unexplained decrease in DLCO
– Clubbing of fingernails• ? Modified in patients with DC and nail dystrophy
Diagnosis
– Bubble study: Transthoracic echocardiogram with intravenous injection of agitated saline bubble contrast
Differential diagnosis– Hepatopulmonary syndrome with or without cirrhosis or
portal hypertension
39
Pulmonary Arteriovenous Malformations
• General treatment
– Endovascular (coiling) interventions for
simple/single AVMs
– Lung transplantation for diffuse disease
40
41
Pulmonary Arteriovenous Malformations
Research Letter
Pulmonary AVM: an uncharacterized phenotype of dyskeratosis congenita. Khincha, P.P., Bertuch, A.A., Agarwal, S., Keel, S., Shimamura, A., Townsley, D.M.,
Young, N.S., Boulad, F., Simoneau, T., Justino, H., Kuo, C., Artandi, S., McCaslin,
C., Cox, D.W., Chaffee, S., Giri, N., Alter, B.P., and Savage, S.A.
Eur Respir J. 2016, Accepted.
13 patients
Median age at of DC/TBD dx - 13 years (range 1-27 years)
Median age of PAVM dx was 15 years (range 3-32 years)
6 patients w/TINF2 mutation
10 s/p HSCT
9 did not have evidence of liver disease at the time of their
PAVM diagnosis
2 were asymptomatic
42
Pulmonary Arteriovenous Malformations
Research Letter
Pulmonary AVM: an uncharacterized phenotype of dyskeratosis congenita. Khincha, P.P., Bertuch, A.A., Agarwal, S., Keel, S., Shimamura, A., Townsley, D.M.,
Young, N.S., Boulad, F., Simoneau, T., Justino, H., Kuo, C., Artandi, S., McCaslin,
C., Cox, D.W., Chaffee, S., Giri, N., Alter, B.P., and Savage, S.A.
Eur Respir J. 2016, Accepted.
No clear effective treatment modality
➢ Natural history and treatment studies needed!
Closing Thoughts
• Not everyone gets all of these complications!
– This advice needs to be tailored to your specific case
• Stringent avoidance of all potentially hepatic,
pulmonary or hematopoietic drugs may delay
treatment or result in suboptimal treatment
– Weigh risks and benefits!
• You may need to educate your doctors
– Share our names as resources
– Refer them to the DCO website, including the guide!
• You know yourself / your child best
– Voice your concerns
– Be your strongest advocate 43
Closing Thoughts
Remember that the treatments of the future may be
different from the treatments of today
44
THANK YOU!!!
Feel free to ask questions!
45
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