Pediatric-Congenital BM failure disorders Flashcards
1
Q
What is the differential diagnosis for congenital bone marrow failure?
A
- FA (Fanconi Anemia)
- DBA (Diamond-Blackfan Anemia)
- DC (Dyskeratosis Congenita)
- SDS (Shwachman-Diamond Syndrome)
- SCN (Severe Congenital Neutropenia)
- CAMT (Congenital Amegakaryocytic Thrombocytopenia)
- TAR (Thrombocytopenia Absent Radii Syndrome)
2
Q
NWhat is the differential diagnosis for Acquired Neoplastic bone marrow failure?
A
- Hypocellular MDS
- Hairy cell leukemia
- Aleukemic leukemia
- PNH, T-LGL
3
Q
List 5 medication can cause BM failure marrow failure?
A
Drugs:
* Chemicals, ionizing radiation
* Toxins (e.g., benzene, glue vapors, arsenic)
* Anti-seizure agents (carbamazepine, phenytoin)
* Antibiotics (sulfonamides, chloramphenicol)
* NSAIDs (phenylbutazone, indomethacin)
* Anti-thyroid medications (methimazole, propylthiouracil)
* Gold
Miscellaneous:
PNH, thymoma, pregnancy, anorexia nervosa, B12 deficiency
4
Q
List 4 infection can cause BM failure marrow failure?
A
Infection:
Epstein-Barr virus, HIV, other herpes viruses
Seronegative hepatitis
Immune disorders:
Eosinophilic fasciitis, systemic lupus erythematosus, GVHD
5
Q
List 2 immune diseases can cause BM failure marrow failure?
A
- Eosinophilic fasciitis
- systemic lupus erythematosus,
- GVHD
6
Q
Miscellaneous:
A
- PNH
- thymoma
- pregnancy
- anorexia nervosa
- B12 deficiency
7
Q
What are the clinical features of Fanconi anemia?
A
- Bone marrow failure (80% by age 20)
- No physical findings (~20%)
- More likely to be diagnosed in adulthood
- Short stature
- Microcephaly
- Cafe au lait spots (intense patchy brown pigmentation)
- Kidney and thumb malformations
Increased:
MCV, ADA, HbF
Macrocytic anemia
8
Q
What is the pathophysiology of Fanconi anemia?
A
- Hypersensitivity to genetic damage due to mutations affecting the Fanconi anemia core complex (FANC) or other proteins in the DNA repair pathway.
- Progressive DNA damage causing aplastic anemia is uncertain, but it is thought to involve the accumulation of DNA damage in hematopoietic progenitors (HP).
9
Q
What are the genetics of Fanconi anemia?
A
- At least 15 different genes can be affected.
- 8 FA proteins make up the core complex (A, B, C, D, E, F, G, L, and M).
- > 80% of cases involve mutations in FANC-A, C, or G.
- FANCD1 is associated with a severe phenotype.
- The FA pathway coordinates DNA repair in response to genotoxic insults (e.g., detecting interstrand crosslinks).
10
Q
What is the inheritance pattern of Fanconi anemia?
A
- Autosomal recessive (usually)
- or X-linked recessive (FANCB) (rare).
- FANCR is autosomal dominant (AD).
- Homozygosity or double heterozygosity is required to cause disease.
- Very heterogeneous phenotype
11
Q
What is the lab diagnosis for Fanconi anemia?
A
- Chromosome breakage studies on phytohemagglutinin-stimulated peripheral blood lymphocytes, cultured with and without clastogenic agents.
- Report results by comparing chromosomal aberrations to control populations.
12
Q
What are two clastogenic agents used in Fanconi anemia testing?
A
Mitomycin C
Diepoxybutane
13
Q
Compare and contrast Fanconi anemia, Ataxia telangiectasia, and Nijmegen breakage syndrome:
A
14
Q
Name 3 syndromes associated with chromosome fragility.
A
- Fanconi anemia
- Ataxia telangiectasia
- Nijmegen breakage syndrome
15
Q
What is the association between Fanconi anemia and AML?
A
700-fold increased risk of AML.
30% of FA patients have a solid tumor by age 45.
16
Q
Fanconi
What are the main problems with HSCT in Fanconi anemia?
A
Only treatment for BM failure and risk of MDS/AML, but doesn’t address non-hematopoietic malignancies.
Inherent chromosomal fragility limits chemotherapy and radiation options, increasing the risk of other cancers.
Difficult to find related stem cell donors without familial disease.
17
Q
What are the diagnostic criteria for dyskeratosis congenita?
A
1) Two out of four classic features:
* Abnormal reticular skin pigmentation
* Nail dystrophy
* Leukoplakia
* Bone marrow failure (BM failure)
2) Two or more other somatic features associated with DC
18
Q
What is the underlying pathophysiology of dyskeratosis congenita?
A
Telomeropathy
9 genetic abnormalities affecting telomere maintenance have been identified.
Defective telomere maintenance leads to cellular senescence (aging).
19
Q
What is the inheritance pattern of dyskeratosis congenita?
A
- Can be X-linked (DKC1)
- Can be autosomal dominant or autosomal recessive
- Genetic heterogeneity
- Genetic anticipation is prominent (phenotype worsens and appears earlier in second-generation patients)
20
Q
What is the male to female ratio of dyskeratosis congenita?
A
10:1 (more common in males)
21
Q
What are the consequences of telomeropathy in dyskeratosis congenita?
A
- Genomic instability
- Stem cell loss
- Defective cellular repair and regeneration → Leads to liver fibrosis and pulmonary fibrosis.
22
Q
How is dyskeratosis congenita diagnosed?
A
Flow FISH is used to identify telomere shortening in lymphocytes.
Sequencing is done to identify specific mutations.
23
Q
What are the four main genes involved in dyskeratosis congenita and their inheritance patterns?
A
* X-linked gene:
DKC1 (best characterized form of DC)
Autosomal dominant genes:
TERC, TERT, TINF2
TERT and TERC can also be autosomal recessive
24
Q
What is Hoyeraal-Hreidarsson syndrome?
A
A severe X-linked form of dyskeratosis congenita
Associated with cerebellar hypoplasia.
25
What is the most common clinical manifestation of dyskeratosis congenita that is NOT part of the classic triad?
Idiopathic pulmonary fibrosis
Patients can also develop hepatic fibrosis.
## Footnote
TRIAD: oral leukoplakia, nail dystrophy, and reticular hyperpigmentation
26
What is the main cause of mortality in dyskeratosis congenita?
60-70% die of bone marrow failure.
27
What are the two main treatment options for dyskeratosis congenita?
Hematopoietic stem cell transplantation (HSCT)
Oxymetholone (an anabolic steroid that improves hematopoietic function in 2/3 of patients)
28
What is Diamond-Blackfan anemia (DBA)?
A congenital bone marrow failure syndrome that causes red cell aplasia (congenital pure red cell aplasia).
No other cytopenias are present.
The underlying genetics are poorly understood.
29
What are the two treatment options for Diamond-Blackfan anemia?
Low dose steroids
Transfusion support
30
What are the 4 diagnostic criteria for DBA?
Age < 1 year
Macrocytic anemia with no other significant cytopenias
Reticulocytopenia
Normal marrow cellularity with a paucity of erythroid precursors
31
What are the supportive criteria for diagnosing DBA in patients who do not meet the main criteria?
Major criteria:
Presence of a gene mutation associated with DBA
Positive family history
Minor criteria:
Elevated ADA activity
Congenital anomalies associated with DBA
Elevated Hgb F
No evidence of another inherited bone marrow failure syndrome
32
What are the clinical features of Diamond-Blackfan anemia?
Progressive reticulocytopenia, usually macrocytic anemia in infancy or early childhood.
Normal cellularity of the BM with decreased or absent erythroid precursors.
Congenital malformations in 50% of patients (craniofacial, thumb or upper limb abnormalities, cardiac defects, urogenital malformations, cleft palate).
Increased risk of malignancies.
Increased risk of endocrine dysfunction.
33
hat are the bone marrow features of Diamond-Blackfan anemia?
Presents in the first year of life with macrocytic anemia.
Paucity of red cell precursors on bone marrow examination.
Normal cellularity with markedly decreased or absent erythroid precursors.
34
What are the genetics of DBA? Name 5 genes and specify which is most common and which is X-linked.
**AD genes:**
RPS19 (most common, 25%)
RPS7, RPS10, RPS17, RPS24, RPL35A, RPL11, RPS26
**XLR gene:**
GATA1
Mutations in genes encoding ribosomal subunit proteins, leading to increased p53, favoring apoptosis.
35
What is the underlying pathophysiology of Shwachman-Diamond syndrome?
90% of cases have a mutation in the SBDS gene at 7q11.
The SBDS gene plays an important role in the maturation of the 60S ribosomal subunit, making SDS a disorder of ribosome biogenesis.
36
What are the bone marrow features of Shwachman-Diamond syndrome?
Hypocellular bone marrow with granulocytic hypoplasia.
37
What are the clinical features of Shwachman-Diamond syndrome?
Pancytopenia (often), but primarily neutropenia, which may be cyclical.
Pancreatic exocrine insufficiency.
Growth retardation.
Skeletal abnormalities.
38
What is severe congenital neutropenia (SCN)?
A group of disorders that affect granulopoiesis.
* Typically presents in infancy with severe life-threatening bacterial infections.
39
1-How many types of severe congenital neutropenia are there?
2- What is the most common type of severe congenital neutropenia, and what gene is involved?
1-At least 7 genetic lesions have been identified, each causing different clinical phenotypes.
2- SCN1 is the most common form, accounting for 60-80% of cases.
It is an autosomal dominant disorder caused by mutations in the ELANE gene on chromosome 19p13.3, which encodes neutrophil elastase.
40
What is the typical inheritance pattern of severe congenital neutropenia?
It is variable, but the most common type (SCN1) is autosomal dominant.
41
# SCN
What is the treatment for severe congenital neutropenia?
Most cases of SCN respond to treatment with G-CSF (Granulocyte Colony-Stimulating Factor).
42
43
# TAR
What is TAR syndrome?
* Thrombocytopenia Absent Radii syndrome
* Genetic disorder characterized by the absence of the radius bone and thrombocytopenia.
44
What are common physical findings in TAR syndrome?
* Absence of the radius bone
* Thrombocytopenia
* Other findings: anemia, heart problems, renal conditions.
45
What is the platelet volume in TAR syndrome?
Thrombocytopenia with normal platelet volume.
46
What is the mutation in TAR syndrome?
Most cases have a variant and a rare null allele at the RBM8A locus.
47
What is Pearson syndrome?
* A multiorgan mitochondrial DNA disorder associated with marrow failure and pancreas dysfunction.
* Treatment is supportive, and most patients die in infancy.
* Part of mitochondrial DNA deletion syndromes with overlapping phenotypes:
* Kearns-Sayre syndrome (KSS)
* Pearson syndrome
* Progressive external ophthalmoplegia (PEO)
48
Do we differentiate RCMD from RCUD in children?
No, all are categorized as Refractory Cytopenia of Childhood (RCC).
49
What is the most common cytogenetic abnormality in Refractory Cytopenia of Childhood (RCC)?
Monosomy 7
50
What is the unique feature of RCC cellularity compared to adults?
75% of cases are hypocellular (usually 5-10% of normal cellularity).
Easily confused with aplastic anemia (AA).
51
What are **9 disorders that can mimic Refractory Cytopenia** of Childhood (RCC)?
* Aplastic anemia
* PNH
* Congenital bone marrow failure syndromes
* Mitochondrial deletions (Pearson syndrome)
* Autoimmune disease (ALPS, Rheumatic disease)
* Metabolic disorders (Mevalonate kinase deficiency)
* Vitamin deficiencies (B12, Folate, E)
* Infections (CMV, Parvo, Herpes)
52
What is **WHIM syndrome**, and what cytopenia is it associated with?
* Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis.
* Associated with neutropenia, caused by mutations in** CXCR4.**
53
What is myelokathexis?
A congenital disorder causing severe chronic leukopenia and neutropenia.
54
What are the hematologic effects of copper deficiency?
**Common: Anemia and neutropenia.**
*Uncommon:* Thrombocytopenia.
Can show dysplastic changes (ring sideroblasts, vacuolated erythroids and granulocytes), and mimic MDS.
55
What is Acquired Red Cell Aplasia?
* Acquired production defect in red blood cells due to various etiologies.
* Results in near absence of erythroid lineage in bone marrow, with normochromic normocytic anemia and reticulocytopenia.
56
What is the MCV in Acquired Red Cell Aplasia?
Normochromic normocytic anemia with reticulocytopenia.
57
What are the Medications can cause of Acquired Red Cell Aplasia?
* Recombinant EPO for CRD
* Antiepileptic medications
* Azathioprine
* MMF
* Chloramphenicol
* Sulfonamides
* Isoniazid
* Procainamide
58
Name 4 infection causes of Acquired Red Cell Aplasia?
Parvovirus B19, HSV, HIV, Hepatitis
59
Name 2 collagen vascular causes of Acquired Red Cell Aplasia?
SLE, Scleroderma, Dermatomyositis, Polymyositis, Rheumatoid arthritis, Polyarteritis nodosa
60
Name 4 neoplasms causes of Acquired Red Cell Aplasia?
* Thymoma
* T-cell large granular lymphocytic leukemia (esp. in China)
* Chronic lymphocytic leukemia
* MDS (infrequent)
61
Name other causes of Acquired Red Cell Aplasia?other causes
* ABO-incompatible stem cell transplant:
* Major ABO group mismatch of donor
* Pregnancy
* Idiopathic, immune-mediated
62
Is the aplasia caused by viral infections transient or chronic?
* Parvovirus: Transient and self-limited aplastic crisis
* HIV & immunosuppressed: May be more chronic
63
What is the mechanism of PRCA in Thymoma?
** Possible mechanism: Altered function of T lymphocytes.**
* Abnormal thymus unable to suppress autoreactive T-cell clones, leading to suppression of erythropoiesis.
* Thymectomy can lead to systemic autoimmune disorders over time.
64
How does the disease course for pure red cell aplasia differ between adults and children?
In children: Acute, self-limited form is more common.
In adults: Chronic, persistent forms are more common, often secondary to an underlying disease.
65
# ???
The work-up for pure red cell aplasia should always include investigation of?
Various underlying secondary causes.
66
What are the peripheral blood findings in pure red cell aplasia?
Isolated normochromic normocytic anemia
Low reticulocyte count
Unremarkable red cell morphology
67
What are the bone marrow findings in **pure red cell aplasia (PRCA)?**
* Normocellular bone marrow
* Normal numbers of granulocytes and megakaryocytes
* Near absence of erythroid cells (pure red cell aplasia)
* No significant dysplasia in any cell lineage
68
How does parvovirus B19 cause transient arrest in erythropoiesis or PRCA?
## Footnote
Besides erythrocytes, where else is P antigen expressed?
*** Virus selectively enters erythroid progenitors **and is toxic to them.
* **P antigen is the receptor for parvovirus B19.**
* Normal individuals produce antibodies to destroy the virus and resolve infection.
* In patients with hemolytic disorders (e.g., HS, SS), it can cause transient aplastic crisis.
* In immunosuppressed patients who can't produce antibodies, it can cause chronic PRCA.
## Footnote
Platelets, heart, liver, lung, kidney, endothelium, synovium.
69
Why is parvovirus resistant to heat/detergent inactivation?
Lack of envelope.
70
How is parvovirus transmitted?
Respiratory droplets (community-acquired, most common).
Blood products (rare transmission via transfusion).
71
How is parvovirus normally cleared in healthy individuals?
By antibody-mediated rapid clearance
72
What is the issue with parvovirus in immunocompromised individuals?
Unable to produce virus-neutralizing antibodies and clear the virus.
Develops persistent infection and chronic hypoproliferative anemia.
73
What is the incidence of parvovirus?
* Very common in the general population, with seroprevalence increasing with age.
* Up to 80% of adults have been exposed.
74
How quickly do immunocompetent individuals clear a parvovirus infection?
Within 5-10 days.
75
What are the peripheral blood findings in parvovirus-induced red cell aplasia?
Normochromic normocytic anemia
Normal erythrocyte morphology
Markedly reduced reticulocyte count
76
What are the 9 categories of presentation for parvovirus B19?
* Subclinical
* Transient aplastic crisis (immunocompromised)
* Transient red cell aplasia (HbSS patients)
* Sustained pure red cell aplasia (immunocompromised)
* Erythema infectiosum (slapped cheek or fifth disease)
* Hydrops fetalis (congenital red cell aplasia)
* Migratory polyarthropathy (adult women)
* Onset of autoimmune/CVD
* Meningoencephalitis
77
What is erythema infectiosum?
Parvovirus B19 infection (fifth disease), characterized by a "slapped-cheek" rash.
No anemia or other sequelae.
78
What is the classic bone marrow finding in parvovirus-related PRCA?
* Paucity of erythroid precursors (especially late-stage)
* Pronormoblasts with viropathic changes, including large size and nuclear pseudoinclusion (lantern cell)
No significant erythroid maturation
Normal myeloid and megakaryocytic lineages
Markedly increased M/Eratio due to erythroid hypoplasia
79
Who is at risk for sustained red cell aplasia in parvovirus infection?
Immunocompromised patients (hematologic malignancies, HIV/AIDS, SLE, SCID, bone marrow transplant).
80
What are the lab tests for parvovirus B19?
CBC: Normocytic, normochromic anemia, low/absent reticulocytes.
Serology: IgG and IgM.
PCR for parvovirus.
81
What is the treatment for parvovirus-induced red cell aplasia?
No specific medication.
IVIG for immunocompromised/pregnant patients.
Vaccine research is ongoing.
82
What is the prognosis for parvovirus-induced red cell aplasia?
Full recovery in immunocompetent individuals.
Relapse/persistence in immunocompromised individuals.
83
What additional test can be performed on bone marrow to look for parvovirus?
Immunohistochemistry for parvovirus B19:
Positivity in rare remaining erythroid precursors
Very high specificity
Moderate sensitivity (negativity does not exclude parvovirus)
84
What investigations are useful in the work-up for PRCA?
* History of medications and toxins
* Evaluation for infections (e.g., parvovirus PCR, HIV, viral serologies)
* Liver and kidney function tests
* Immunologic evaluation (including autoantibodies)
* Bone marrow examination to confirm red cell aplasia and investigate for leukemia/lymphoma
* Chromosomal analysis for clonal malignancy
* PCR-based T-cell gene rearrangement (for clonality in T-LGL)
* Imaging to rule out thymoma or other solid tumors
85
What are the treatment options for PRCA?
* Corticosteroids
* Cyclophosphamide
* Cyclosporin A
* Antithymocyte globulin
* Rituximab (anti-CD20 monoclonal antibody)
* Alemtuzumab (anti-CD52 monoclonal antibody)
* Intravenous immunoglobulin (IVIG) (treatment of choice for parvovirus B19-related PRCA)
*
* Surgical approaches:
Thymectomy (if thymoma is the cause, but often requires adjuvant immunosuppressive therapy)
86
What are the therapy for refractory cases of PRCA?
* Splenectomy
* Plasmapheresis
* Bone marrow transplant (rarely indicated)
87
Which drug is favored for treating PRCA associated with parvovirus B19 infection?
Intravenous immunoglobulin (IVIG)
88
What is the target of Alemtuzumab?
Anti-CD52 monoclonal antibody
89
What is Transient Erythroblastopenia of Childhood (TEC) and what is the typical age of presentation?
* Erythroblastopenia with anemia.
* Median age of presentation: **18-26 months** (can affect children aged 6 months to 10 years).
* I**diopathic, self-limited red cell aplasia **characterized by:
* **Normocytic/normochromic anemia**
* **Reticulocytopenia**
* Decreased erythroid lineage in the bone marrow
90
What is the clinical course of Transient Erythroblastopenia of Childhood (TEC)?
Most patients recover completely within 1–2 months.
Some cases may last 18-24 months or longer.
91
What is the etiology of Transient Erythroblastopenia of Childhood?
Unknown, but thought to be triggered by viral infection.
Possible immune-related disruption of erythropoiesis.
92
Who gets TEC?
Rare disorder: 4.3 per 100,000 children ≤ 3 years.
Usual age = 1-4 years.
Equal male-to-female ratio.
93
How long does TEC last and does it recur?
TEC is transient, with spontaneous recovery within 1-2 months.
NO recurrence.
94
What is the long-term survival impact of TEC?
None. It is transient and has no effect on survival.
95
What lab tests should be done in a suspected case of TEC?
CBC with reticulocyte count
Blood smear
EPO (increased)
Parvovirus PCR (negative)
96
Is Parvovirus positive or negative in TEC?
Negative
97
What is the treatment for TEC?
None, occasional transfusion may be required.
98
What are the peripheral blood findings in TEC?
Normocytic normochromic anemia
Reticulocytopenia
Minimal anisopoikilocytosis
Platelets and WBCs are morphologically normal
99
What are the bone marrow findings in TEC?
* Markedly reduced erythroid lineage
* Only scattered erythroblasts in marrow
* No parvovirus cytopathologic effects (no lantern cells)
* Hematogones may be abundant
100
What is the differential diagnosis for TEC, and how is it differentiated?
**Parvovirus**
PCR testing
Viral inclusions/cytopathic effect (lantern cells)
**Diamond-Blackfan Anemia**
Genetic testing (RPS19, RPS7, GATA1)
Dysmorphic features, family history
DBA vs. Parvovirus-induced RCA vs. Acquired RCA
101
