Aplastic Anemia and bone marrow failure syndromes

Question 1

What are the physical features seen in Fanconi aplastic anemia?

Answer 1

Thumb abnormalities, short stature, microcephaly, patchy brown pigmentation.

Question 2

What is the underlying abnormality in Fanconi Anemia (what genes are involved)?

Answer 2

Most patients have mutations involving FANCA or FANCC which are involved in DNA repair.

Question 3

What is characteristic about the DNA in Fanconi anemia patients?

Answer 3

Their DNA is hypersensitive to damage induced by DNA crosslinking agents (e.g. DEB and mitomycin C).

Question 4

What is the mode of inheritance for most patients with Fanconi Anemia?

Answer 4

Autosomal recessive

Question 5

How do you diagnose Fanconi Anemia?

Answer 5

By doing chromosome breakage study, the report will tell you the percentage of cells with chromosome aberrations.

Question 6

How do patients with short telomere syndromes present?

Answer 6

Nail dystrophy, skin hyperpigmentation, early graying of hair, and oral leukoplakia.

Question 7

What are the modes of inheritance seen with short telomere syndrome? What is the defect seen here?

Answer 7

Autosomal dominant, autosomal recessive, and X-linked. The teleomerase enzyme is missing to add telomeres.

Question 8

What malignancies are patients with Fanconi Anemia at risk for?

Answer 8

MDS/AML! Also at risk for squamous cell carcinoma of the Head/neck, esophageal, and vulvar/vaginal tumors. Also hepatocellular carcinoma

Question 8

What are some complications seen in short telomere syndrome?

Answer 8

Pulmonary Fibrosis, cirrhosis, vascular complications (AV malformations), hepatopulmonary syndrome.

Question 9

What malignancies are short telomere patients at risk of?

Answer 9

Squamous cell carcinoma of head/neck, anogenital, and GI cancers.

Question 10

What treatment can you offer for short telomere syndrome besides allogeneic transplant?

Answer 10

Androgens-oxymetholone or danazol.

Question 11

What is the defect seen in GATA 2 deficiency?

Answer 11

A GATA 2 mutation causes loss of expression or function of the Zinc finger transcription factor required for hematopoiesis and lymphatic development.

Question 12

What are some clinical features seen in GATA 2 deficiency?

Answer 12

Congenital deafness, lymphedema, autism/ADHD, interstitial lung dx, warts, frequent infections (mycobacteria infections), w/wo cytopenias.

Question 13

What cytogenetic abnormality is commonly seen in GATA 2 def and what does this suggest?

Answer 13

Monosomy 7 and trisomy 8, can suggest development of MDS/AML.

Question 14

What are the clinical features of SMAD 9/9L?

Answer 14

Ataxia, adrenal hypoplasia, ambiguous genitalia

Question 15

How do you make the diagnosis of SMAD 9/9L? What are they at risk for?

Answer 15

They will have monosomy 7 (compensates for mutation) or UPD7q (results in duplication of the wild type 7q arm). MDS/AML

Question 16

What are the clinical features of Shwachman Diamond Syndrome?

Answer 16

BM failure (most often neutropenia), exocrine pancreatic insufficiency (malabsorption)

Question 17

Patients with Shwachman Diamond Syndrome are at high risk of developing what?

Answer 17

MDS/AML

Question 18

What are the clinical features of Diamond Blackfan Anemia? What test can confirm this?

Answer 18

Hypo-proliferative bone marrow with macrocytic anemia, marrow has a high M:E with practically no erythroblasts, thumb anomaly, cleft palate, etc. Fetal Hgb is elevated. RBC ADA levels are high-confirmatory test.

Question 19

What are the treatment options for Diamond Blackfan Anemia?

Answer 19

RBC transfusion support with iron chelation, corticosteroids, and allogeneic HSCT.

Question 20

What patients are eligible for stem cell transplant in aplastic anemia?

Answer 20

Patients less than age 40 who have a HLA matched sibling, if they don’t have one they get treated with IST.

Question 21

What is the hallmark clinical features of PNH? What are the smooth muscle symptoms?

Answer 21

Intravascular hemolysis with DVT/PE (esp in a odd location). Smooth muscle dystonia-esophageal spasm, abd pain, dysphagia, erectile dysfunction.

Question 22

What is the molecular target of Eculizumab and Ravulizumab? This inhibits what part of the complement pathway?

Answer 22

They are C5 inhibitors. The terminal complement pathway (prevents formation of MAC).

Question 23

What are some of the more common side effects of terminal complement inhibitors?

Answer 23

Headache, nasopharyngitis, URI, nausea, pyrexia

Question 24

What is the mechanism of action for Pegcetacoplan? What does this allow to happen?

Answer 24

It block C3! It prevents C3 mediated extravascular hemolysis.

Question 25

What is the vaccination recommendation for those on complement therapy?

Answer 25

You vaccinate against N meningiococcus 2 or more weeks before giving the first dose. You also give antibiotic prophylaxis for the first 2 weeks of therapy.

Question 26

Thymoma, LGL, and CLL can be associated with what?

Answer 26

Pure Red Cell Aplasia