Inherited Bone Marrow Failure Syndromes (IBMFS) - for slide share.pptx

All roads lead to stem cell transplantation
Mustafa Selim, MD
Lecturer of Pediatric Hema/Onc, NCI, Cairo University

Objectives
I n h e r i t e d B o n e M a r r o w F a i l u r e S y n d r o m e s ( I B M F S )
Definition - Why, when and what?
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Clinical, laboratory and genomic approach?
Key features of the clinical & lab evaluation?
Malignancy risk, treatment, follow up
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Bone marrow failure
can be
Types
Idiopathic Aplastic Anemia
Acquired
B o n e M a r r o w F a i l u r e ( B M F )
Inherited
Seconday BMF
 Drugs/Chemicals/Toxins
 Viruses (eg., EBV, CMV, HCV, HIV, ...)
 Radiation
 Thymoma
 Autoimmune disorders
 MDS, PNH
Account for 10 - 25% of pediatric AA

Definition
IBMFS are a heterogenous group of diseases with varying clinical presentation
and underlying disease mechanisms all characterized by failure of production in at
least one haematopoietic cell lineage
Resulting from germline mutations that affect key cellular pathways (eg, DNA
repair)
These syndromes have variable prognoses and risk of developing
hematological or solid malignancies.

①
BMF
②
Physical
abnormalities
③
Cancer risk
Timely treatment is essential Suspicion May be the 1st presentation
Regular screening for early detection
Inherited Bone Marrow Failure Syndromes
characterized by

What are the
challenges in
the mangement
of IBMFS?
When we
should suspect
IBMFS?
Why we
should know
IBMFS?
IBMFS

Why we
should know
IBMFS?

Why we should know IBMFS?
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General Pediatrician is the first one to see

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Cancer risk (hematological & solid tumors)

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Require different treatments (RIC if HSCT)

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Need support from different specialties
(Immunodeficiency, pulm, cardiac, renal)

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HSCT is the only currative option

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Genetic diagnosis & family counseling

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Long term surveillance

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HSCT is the only currative option .

When we
should suspect
IBMFS?

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Presence of characteristic
physical anomalies + hematological abnormalities
Children with aplastic anemia or MDS
Cancer in patient at an atypically early age:
• Head/neck/esophogeal cancer <40 years
• Vulvar cancer <30 year
Unexplained macrocytosis +/-
characteristic birth defects
Patients with malignancy who are highly
sensitive to chemotherapy or RTH
Family members with any of the above
When we should suspect IBMFS?

What are the
challenges in the
mangement of
IBMFS?

• Physicians not familure with the different cases scenario
• Late diagnosis in adolescenc or adulthood
• The 1st presentation may be the malignancy
• Overlapping manifestations
• Need special treatment in a specific Pediatric hematology centers
• BMT is the is the only curative treatment.
• Availability of donor
What are the challenges in the mangement of IBMFS?

Definition
BMF is a rare disease, life threatening condition, caused by ineffective/defective
hematopoiesis in BM → Cytopenia / pancytopenia,
→ ± Clonal evolution, and
→ ± Increased risk of hematological malignancies.
It can be inherited or acquired
Blood cell lifespans:
 RBCs: 3 months
 WBCs: 13 - 20 days
 Plat: 7 - 10 days

Aetiology
Reversible causes:
• Viral infections,
• Nutritional deficiencies, and
• Medications - chemicals - toxins
(The BM is the blood factory)
May be exposed to damage or failure
Non-reversible causes:
• Inherited BM Failure Syndromes (FA, DC, DBA, SDS, CAMT, TAR, SCN),
• Malignant diseases, and
• Idiopathic (aplastic anemia - diagnosis of exclusion).

Severity of BMF (cytopenia should be presistent)
Mild Moderate Severe
• ANC < 1500/mm3 <1000/mm3 <500/mm3
• Platelets ≥50000/mm3 <50000/mm3 <30000/mm3
• Hb ≥ 8 g/dl <8 g/dl <8 g/dl

Severity of AA based on modified Camitta criteria *
- Bone marrow biopsy (1 of two BMB criteria)
• Either markedly hypocellular (<25% normal) or
• Moderately hypocellular (25%-50%) but with <30% remaining cells being haematopoietic
- Severe AA (Two of three peripheral blood criteria)
• Platelets <20 × 109/L
• Neutrophils <0.5 × 109/L
• Reticulocytes <60 × 109/L (automated analyser) or <20 × 109/L (manual) (< 1% corrected)
- severe AA
• As for SAA but neutrophils <0.2 × 109/L
- Non-severe AA
• Not fulfilling either SAA or VSAA
* Rovo A, Tichelli A, Dufour C. Diagnosis of acquired aplastic anemia. Bone Marrow Transplant. 2013;48(2):162-167

History Genetic
Clinical Lab
Approach to a patient suspected
to have IBMFS?

Timely identification of patients with non-
reversible BMF
IBMFS
 Benefits:
• It reduces the risks of invasive infections and bleeding
complications and simultaneously
• Allows for risk-adapted organ and cancer monitoring and
family counseling.
• In addition, it results in the prompt initiation of a treatment
regimen.

1. History
A p p r o a c h t o a p a t i e n t s u s p e c t e d t o h a v e I B M F S
• Duration of cytopenias: Lifelong→ mild–moderate cytopenias are suggestive of an IBMF
• Past medical history: IUGR/SBW - failure to thrive - developmental delay/ learning disabilities/ behavioural problems.
• Drugs (AA): Antibiotics, antiepileptics, immunosuppressive therapy, chemotherapy, immunotherapy, herbal medicines
• Infections (AA): Mycobacterial, human papillomavirus.
• Previous diagnosis of autoimmune disease
• Childhood illnesses: failure to thrive, recurrent infections (SDS & DC “underlying immune deficiency”)
• Prior malignancy:
 Cancer in patient at an atypically early age (Head/neck/esophogeal cancer <40 years - Vulvar cancer <30 year)
 Patients with malignancy who are highly sensitive to chemotherapy or RTH
• Family history: Family members with any of the following:
 Consanguinity,
 Unexplained cytopenias or AA,
 Unexplained fetal loss or congenital anomalies
 Haematological or solid malignancy, including age of onset, recurrent infections

2.a Clinical assessment
• Skin and nail changes:
• Café au lait spots or hyperpigmentation (FA)
• Abnormal skin pigmentation (hyper/hypo/lacy), dystrophic
fingernails, oral leucoplakia (classic triad of DC)
• Erythema nodosum (GATA2)
• Warts and molluscum (GATA2)
• Skeletal and limb abnormalities:
• Abnormal thumbs (FA/DBA)
• Absent radii (TARS)
• Abnormal radii and/or humeri (FA, GATA2)
• Osteoporosis and avascular necrosis (DC)
• Short stature (FA, DC, DBA, SDS, SAMD9)
• Lymphoedema (GATA2)
• Dental anomalies: such as dysmorphic teeth, enamel hypoplasia, or oral leukoplakia (DC)
• Facial abnormalities:
• Microcephaly (FA/DC)
• Hypertelorism, Epicanthal folds (DBA)
• Subtle dysmorphia (SDS)
• Ophthalmic:
• Small palpebral fissures, microphthalmia, ptosis,
epicanthal folds (FA)
• Lacrimal drainage abnormalities, retinal changes
including abnormal pigmentation, exudative retinopathy
and neovascularization, cataracts (DC)
• Cardiopulmonary:
• Pulmonary fibrosis (DC)
• Congenital heart defects (FA, DC, DBA, MECOM)
• Pulmonary hypertension

2.b Clinical assessment
• Hepatic:
• Fibrosis and cirrhosis (DC)
• Hepatocellular carcinoma (FA, DC)
• Fat malabsorption such as steatorrhea (SDS) “exocrine pancreatic dysfunction”
• Renal and urinary tract: Cysts - Horse shoe kidney - Other malformations
• Neurological: Cerebellar ataxia (SAMD9L)
• Gonadal dysgenesis
• Hearing loss (many germline)
• Normal physical examination:
• Severe congenital neutropenia
• Congenital amegakaryocytic thrombocytopenia
• Hereditary predisposition to haematological malignancy conditions (with the exception of the syndromic subgroup)

3.a Laboratory
• CBC:
 Cytopenia (single or multilineage)→ often alam the patients to seek the medical advice
 Macrocytosis
 The presence or absence of anemia does not predict a worse outcome
 It can be masked in patients with iron deficiency or thalassemia trait
 Do not ignore these cases, as they may be clinically significant.
 Monocytopenia and lymphopenia (GATA2)
 MDS / AML / malignancy may be the 1st presentation
 First sign is Pancytopenia (FA and DC), Anemia (DBA), Isolated neutropenia (SCN, SDS), Thrombocytopenia (TAR, CAMT)
• Blood film: Dysplasia - Large platelets - Polychromasia
• Reticulocyte count: Diagnostic criteria for AA (< 1% corrected)

3.b Laboratory
• B12 / Folate / Iron studies / Thyroid functions / Liver functions
• Viral serology: Hepatitis B and hepatitis C, HIV, parvovirus, EBV & CMV
• Immunoglobulins: Hypogammaglobulinaemia may be due to GATA2 deficiency
• HbF: ↑↑ in multiple germline conditions including DBA
• BMA (morphology, cellularity, dysplasia, BM flow cytometry), cytogentics (eg, monosomy 7)
• PB flow cytometry: (reduced B, T and NK cells potentially indicative of GATA2 deficiency)

3.c Laboratory (Specific tests according TO suspected disorder)
• Chromosome fragility:
 Can be done on peripheral blood (PB) leucocytes or cultured skin fibroblasts
 Fragile chromosomes upon stress with mitogens (accumulate chromosomal breaks and undergo G2 arrest) indicative of FA
 False positives: following chemotherapy
 False negatives: in PB in setting of somatic mosaicism
• Telomere length:
 < 1st centile—very low telomere lengths are in keeping with telomeropathy (eg, DC)
 1st-10th centile—low telomere length may be normal or may be seen in association with other BMF (eg, DBA)
 Potential transient changes that can occur following chemotherapy
• Red cell Erythrocyte Adenosine Deaminase (eADA): ↑↑ in DBA
• Serum trypsinogen, pancreatic isoamylase, and 72 h faecal fat (eg, SDS)
• Platelet functions tests: Abnormal platelet aggregation to various agonists in the inherited thrombocytopenias with
predisposition to myeloid malignancy
• Imaging/ solid organ assessment:
 Plain X-ray to asses for skeletal dysplasia (FA, SDS, TARS, MECOM)
 Electrocardiogram and echocardiogram
 CT and ultrasound to examine for solid organ abnormalities, malignancy

4. Genetic
• Germline mutation analysis (Next-generation sequencing Sample type for DNA extraction):
 Cultured skin fibroblasts (preferred) √√√
 Peripheral blood and bone marrow
 It is not a germline sample→ as it is the “diseased” compartment
 Both somatic and germline lesions can occur in some genes (eg, RUNX1, DDX41, GATA2, CEBPA)
 False negatives may occur testing blood or BM only due to Somatic reversion (eg,FA genes or SAMD9/SAMDL)
 Hair bulb
 Buccal swab or saliva (beware white blood cell contamination)
• Somatic mutation analysis: Consider in both acquired and germline diseases
• SNP array
• Whole exome sequencing
• TPMT gene testing: Germline TPMT mutations may result in impaired thiopurine metabolism. Consider testing if
BMF has developed following exposure to 6-thioguanine, 6-mercaptopurine or azathioprine

Proper diagnosis shapes treatment
Precise determination of underlying germline
genetic change in IBMFS

1. Screening of potentially affected family members and appropriate surveillance of those genetically but as yet clinically
unaffected.
1. In certain conditions such as GATA2 haploinsufficiency, outcomes are optimized by upfront alloSCT prior to the
development of overt haematological malignancy or severe infections25
2. Avoid stem cell donation from genetically affected but as yet clinically unaffected family member: donor-derived leukaemia,
disease persistence or failed engraftment are possible adverse outcomes26,27
3. Optimize conditioning prior to stem cell transplant (eg, minimize toxicity in a patient with BMF due to FA)28
4. Family planning—a clinical diagnosis of an IBMF, for example DKC, where inheritance may be AD, AR or X linked is insufficient to
counsel regarding the risk of affected future offspring
5. Enable preimplantation genetic diagnosis in setting of clinically significant disease
6. Screening for disease-specific associated phenomena, for example annual ENT surgical review given risk of head and neck
squamous cell cancer in FA
7. Potential for future personalized therapies (currently in research setting only)
Precise determination of underlying germline
genetic change in IBMFS*
* Fox, L.C., Wood, E.M., Ritchie, D.S. and Blombery, P., 2020. Diagnostic evaluation and considerations in hypocellular bone marrow failure—A
focus on genomics. International journal of laboratory hematology, 42, pp.82-89.

History Genetic
Clinical Lab
Approach to a patient suspected
to have IBMFS?
• A newly presenting patient with BMF will frequently present many differential diagnoses.
• A high index of suspicion for rare congenital and acquired causes of BMF is critical when evaluating patients of all ages with
unusual cytopenias.
• A detailed history (including family history) and physical examination are critical.
• Occult presentation of germline disease should always be considered, even in patents of advanced age.
• These guide the subsequent laboratory workup, surveillance schedule for malignancy, and potential therapeutic options.
Home take message

1. They are not rare disease (under-recognized - my present as AA or malignancy)
2. Distinction between the IBMFS and acquired aplastic anemia is critical.
3. 50% of these patients with IBMF$ are diagnosed in adulthood.
4. >25% of pediatric patients who present with AA have inherited aetiology.
5. The most common $→ FA
IBMF$

6. Diagnostic testing is recommended for all siblings of patients with IBMF$.
7. Testing of parents for $ with a dominant pattern of inheritance (eg DBA).
8. Today, the research focus has shifted towards treatment and prevention of
cancer and mitigating the adverse effects of treatment.
9. High risk for cancer during childhood: FA, SDS, SCN
10. Low risk for cancer during childhood: DBA, DC, Thrombocytopenic
syndromes,
IBMF$

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• The IBMFS confer a heightened risk of development of haematological malignancy and were incorporated
in the most recent WHO classification of haematological malignancies, in which a categorization
describing germline predisposition to myeloid malignancy (and in some cases lymphoid) was included for
the first time.*
• This classification incorporates mutations in CEBPA, DDX41, RUNX1, ANKRD26, ETV6 and GATA2, and
recognizes the varying presentations that accompany lesions in specific genes.
 For example, germline CEBPA or DDX41 AML most frequently presents like de novo AML, with no
physical abnormalities or preceding cytopenias.
 Conversely, germline lesions in RUNX1, ANKRD26 and ETV6 are associated with lifelong moderate
thrombocytopenia with many patients having been erroneously diagnosed as having immune
thrombocytopenia.
IBMF$
* Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood.
2016;127(20):2391-2405.

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Subtypes of myeloid neoplasms associated with
germline predisposition *
* Khoury, J.D., Solary, E., Abla, O., Akkari, Y., Alaggio, R., Apperley, J.F., Bejar, R., Berti, E., Busque, L., Chan, J.K. and Chen, W., 2022. The 5th
edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia, 36(7),
pp.1703-1719.

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DC
02
CAMT
06
SDC
04
SCN
05
DBA
03
FA
01
Inherited Bone Marrow Failure Syndromes(IBMFS)

Summary of the etiology of IBMFS
Vissers, L.T., van der Burg, M., Lankester, A.C., Smiers, F.J., Bartels, M. and Mohseny, A.B., 2023. Pediatric Bone Marrow Failure: A Broad
Landscape in Need of Personalized Management. Journal of Clinical Medicine, 12(22), p.7185.

Summary of the etiology of IBMFS
Inderjeet Dokal,Hemanth Tummala,Tom Vulliamy, Inherited bone marrow failure in the pediatric patient, Blood, 2022

DC XLR, AD, AR, de novo
FA AR, XLR, AD
SDS AR
DBA AD, XLR
CAMT AR
SCN AD, AR, XLR
TAR AR
SUM UP
Mode of inheritance Affected pathway
Main Hematological
Manifestation Treatment
DNA repair defect
Defects in ribosome
biogenesis
Ineffective
megakaryopoiesis
mRNA processing
Pancytopenia
Pancytopenia
Neutropenia
Anemia
Neutropenia
Thrombocytopenia
Androgen/HSCT
Pancreatic enzyme
replacement, G-CSF/ HSCT
HSCT
G-CSF/ HSCT
Watch & wait
Inherited Bone Marrow Failure Syndromes (IBMFS)
Impaired telomere
maintenance
Defects in ribosome
biogenesis and maturation
Neutrophil maturation
defect
Thrombocytopenia
Androgen/HSCT
Steroid/HSCT

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Fanconi anemia (FA)
Discovered 1927
Main Hematological Manifestation: pancytopenia (Thrombocytopenia usually precedes
neutropenia and anemia)
Onset of hematological $: mostly in childhood (a peak→ 10 years)
Clinical features (present in 60-75%): Thumb defects, Short stature, Microphthalmia,
Microcephaly, Skin hyperpigmentation, Genitourinary malformations.
Oncology: AA, MDS, AML, H&N SCC, brain, and vulvar SCC
Gold standard diagnostic tool: Chromosomal breakage test
− Accumulate chromosomal breaks and undergo G2 arrest
Treatment:
− Supportive care (irradiated blood products),
− Androgen therapy (68% response)***
− HSCT (RIR) is the only curative treatment (↑ risk of cancer)
− Gene therapy trials ongoing
− Long term follow up
• Incidence: 1–5 cases / 1 million (most common, M:F→ 1.2:1)
• Mode of inheritance: AR, XLR, AD
• Affected pathway: DNA repair defect (22 genes)
 FANCA (64%)→ late onset of BM
 FANCC (12%), and FANCG (8%)→ have severe course
 FANC B/D1 ~ BRCA 2; very early onset MDS/AML
 FANC D1, N – Wilm’s Tumor, medulloblastoma
• Cancer risk: the highest risk for developing cancer,
 Cumulative risk of 15–20% at the age of 40 years.*
 Cumulative risk of 40% at theage of 50 years.*
 An overall risk of any cancer of 20- to 50-fold. **
01
* Alter, B.P.; Giri, N.; Savage, S.A.; Peters, J.A.; Loud, J.T.; Leathwood, L.; Carr, A.G.; Greene, M.H.; Rosenberg, P.S. Malignancies and survival patterns in the National Cancer
Institute inherited bone marrow failure syndromes cohort study. Br. J. Haematol. 2010, 150, 179–188.
** Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in the National Cancer Institute Inherited Bone Marrow Failure Syndrome Cohort After 15 Years of Follow-up. Washington,
DC: American Society of Hematology; 2016
*** Paustian, L.; Chao, M.M.; Hanenberg, H.; Schindler, D.; Neitzel, H.; Kratz, C.P.; Ebell, W. Androgen therapy in Fanconi anemia: A retrospective analysis of 30 years in Germany.
Pediatr. Hematol. Oncol. 2016, 33, 5–12.
Low birth
weight
Disease progress through stages:
- 1st stage (infancy & early childhood): congenital anomalies
- 2nd stage (first decade): thrombocytopenia, macrocytosis before BM
- 3rd stage (adolescence & adulthood): ↑ RISK OF MDS/AML, H&N SCC, brain, and vulvar SCC
- Throughout life: genetic reversion or or clonal evolution

Q1: Why is diagnosis of FA delayed until adulthood?
- Perhaps related to late complications from FA,
- It is the presence of somatic hematopoietic mosaicism, by which a stem cell may have undergone
a molecular partially or fully gene correction, and thus the offspring cells populating the blood and
marrow may have a selective advantage over uncorrected FA cells (somatic reversion).*
Q2: What are indications for HSCT in FA?**
- Severe cytopenia,
- Progression into MDS, or
- Poor cytogenic abnormalities (e.g., monosomy 7, gain of chromosome 3q, complex anomalies or RUNX1 abnormalities)
Fanconia Anemia
* Alter, B.P., 2017. Inherited bone marrow failure syndromes: considerations pre-and posttransplant. Hematology 2014, the American Society of Hematology Education Program Book, 2017(1), pp.88-95.
* * Dufour, C.; Pierri, F. Modern management of Fanconi anemia. Hematol. Am. Soc. Hematol. Educ. Program. 2022, 2022, 649–657.
* * Dufour, C. How I manage patients with Fanconi anaemia. Br. J. Haematol. 2017, 178, 32–47.

Q3: Is HSCT currative for patients with FA?
- The bone marrow of FA is cured by HSCT, but the non-hematopoietic organs remain at the same or
even increased risk of FA complications.*
Q4: Is androgen therapy should be offered for all patients with FA?
- Pre-HSCT androgen administration is associated with higher GVHD rates and decreased OS.**
- In addition, high rates of hepatic adenomas are observed in patients treated with androgens.***
- Thus, androgens should only be used for patients with severe symptoms that are not eligible for HSCT.
Fanconia Anemia
* Alter, B.P., 2017. Inherited bone marrow failure syndromes: considerations pre-and posttransplant. Hematology 2014, the American Society of Hematology Education Program Book, 2017(1), pp.88-95.
* * Ebens, C.L.; DeFor, T.E.; Tryon, R.; Wagner, J.E.; MacMillan, M.L. Comparable Outcomes after HLA-Matched Sibling and Alternative Donor Hematopoietic Cell Transplantation for Children with Fanconi Anemia and Severe Aplastic Anemia. Biol. Blood Marrow Transpl. 2018, 24, 765–771.
*** Paustian, L.; Chao, M.M.; Hanenberg, H.; Schindler, D.; Neitzel, H.; Kratz, C.P.; Ebell, W. Androgen therapy in Fanconi anemia: A retrospective analysis of 30 years in Germany. Pediatr. Hematol. Oncol. 2016, 33, 5–12

- Diagnosis is challenging, start with suspicion
 MDS or AML in young patient
 Suggestive physical features
 Positive family history
 Spontaneous chromatid breaks
 Unbalanced 1q, 3q, or 7q translocations on BM karyotype
 Excessive toxicity of usual chemotherapy
- Investigations:
 Non-hematopoietic cells (skin fibroblasts) is very helpful
 Avoid blood samples especially after chemotherapy or buccal swabs (highly contaminated)
 BMA: ↑↑ blast count is the most reliable morphologic evidence of MDS in FA
(dyserythropoiesis or Hypocellularity are not reliable)
Fanconia Anemia
Q5: How we can diagnose FA in patient with MDS or AML?

• Around 35% of BM from FA patients harbor cytogenetic abnormalities
• Some clones may be transient & some persist for years without adverse clinical consequences
• 75% of these are unbalanced gains or losses in 1q+, 3q+, 7/7q-, and 11q
• Patients with clonal cytogenetic abnormalities are at >10- fold higher risk for developing
MDS/AML (35% vs. 3%)
Fanconia Anemia
Q6: What is the significance of presence of cytogentics abnormalaties in
patient with FA?

Fanconia Anemia
Q7: What is the frequency of abnormalities in patients with FA?*
Q8: What are thee bone deformities in patients with FA?
• Primarily radial deformities
- Partial or total absence of pre-axial border
- Bilateral in 50% of cases
- Ulna thickened, bowed toward absent radius
• Hypoplastic thumb – subgroup of radial deficiency
• Scapula, thenar eminence often reduced in size
- Skeletal 71% - Skin pigmentation 64%
- Short stature 63% - Eyes (microophthalmia) 38 %
- Male genital (hypogenitalia, undescended testes, hypospadias) 20%
- Mental retardation 16%, GIT 14%, cardiac anomalies 13%,
- No abnormalaties 30%
* Zhu, X., 2015. Current insights into the diagnosis and treatment of inherited bone marrow failure syndromes in China. Stem Cell Investigation, 2.

63
02
Dyskeratosis Congenita (DC)
Discovered 1910
• Incidence: (2nd most common) (M:F→ 4:1)
• Mode of inheritance: XLR, AD, AR, de novo
• Affected pathway: impaired telomere maintenance (18 genes)
 (DKC1, TERC, TERT, TINF2, NHP2, NOP10, WRAP53, CTC1, and RTEL1)
 Affected genes found in 80% of patients who meet clinical criteria
 20% have a clinical phenotype with unknown genotype
• Cancer risk: ↑↑↑ overall risk of cancer.
 Aplastic anemia: up to 50% in 2nd to 3rd decade
 Solid organ cancers and leukemia in 3rd to 4th decades
• Main Hematological Manifestation: pancytopenia (occars in 90%)
• Onset of mucocutenous $: mostly < 10 years
• The median age of diagnosis→ 14-15 years
• Clinical features:* triad of (dystrophic nails, lacey skin pigmentation, oral
leukoplakia), early graying of hair or hair loss, pulmonary fibrosis
• Oncology: AA, MDS, AML, tongue SCC, brain, and anorectal
• Gold standard diagnostic tool: flow-FISH to detect short telomere
• Short telomere (below the 1st percentile found in normal)**
• A shortened length of telomere correlates with the severity of cytopenia but the
correlation with BM aplasia remains unclear.***
• Treatment:
− Supportive care, androgen therapy (response rate 50-70%)
− HSCT (RIR) is the only curative treatment (↑ VOD)
− Gene therapy trials ongoing
* The absence of this feature does not eliminate DC from the list of differential diagnoses in young individuals.
** Other non-DC IBMF syndromes such as DBA, SDS, and FA also show short telomerase. However, the non-DC patients show telomere length clusters in the
low normal range.
*** Alter BP, Giri N, Savage SA, Rosenberg PS. Telomere length in inherited bone marrow failure syndromes. Haematologica 2015; 100:49–54
Low
birth
weight
Short stature, developmental delay,
blepharitis, peridontal disease, eosophageal
and ureatheral stenosis
Functions of Telomere: protein:DNA complexes at end of chromosome:
• Prevent premature shortening (aging)
• Prevent end-to-end fusions, translocations, breaks

Q1: What is Hoyeraal-Hreidarsson syndrome?*
- It is a severe form of DC, affecting multisystem organs. It is characterized by:
• Microcephaly, cerebellar hypoplasia,
• Intrauterine growth retardation,
• Severe aplastic anemia, and immunodeficiency.
Q2: What is Reversz syndrome?**
- It is another severe form, causes bilateral exudative retinopathy in addition to features of classic
DC.
Dyskeratosis Congenita
* Dokal I. Dyskeratosis congenita. Hematology Am Soc Hematol Educ Program. 2011; 2011:480-6.
* * Revesz T, Fletcher S, al-Gazali LI, DeBuse P. Bilateral retinopathy, aplastic anaemia, and central nervous system abnormalities: a new syndrome? J Med Genet. 1992; 29:673-5.

Q3: Mechanisms of action Androgens therapy
D: Androgens may stabilize red cell membrane, preventing
hemolysis and erythrocyte clearance.
A: Androgens bind steroid receptors, inducing a higher expression of
telomerase, which leads to stabilization of chromosomes and
restoration of hematopoiesis.
B: Androgens synergize with erythropoietin enhancing
downstream signaling and boosting erythropoiesis.
C: Androgens may act on phagocytes of innate immunity, decreasing
platelet clearance.
Bosi, A., Barcellini, W., Passamonti, F. and Fattizzo, B., 2023. Androgen use in bone marrow failures and myeloid neoplasms: Mechanisms of action and a
systematic review of clinical data. Blood Reviews, p.101132.

Q4: Why the clinical diagnosis of DC is challenging?
- It is due to:
• Phenotypic heterogeneity
• Different modes of inheritance (XLR, AD, AR, de novo)
• Variable age of onset (BMF develops in the 2nd or 3rd decade of life but it can occur at birth
or as late as the 7th decade of life)
Q5: What is the new name for DC?
- The term DC is now used interchangeably with telomere biology disorders and short telomere
syndromes.

Q6: What is the frequency of abnormalities in patients with DC?*
- Mucocutaneous traid (skin pigmentation 89%, nail dystrophy 88%, leukoplakia 78%)
- Bone marrow failure 88.8%
- Epiphora 30%
- Learning difficulties/ mental retardation 25.5%
- Pulmonary disease 20%
- Short stature 19.5%
- Dental caries/loss 17%
- esophageal stricture 17%
* Zhu, X., 2015. Current insights into the diagnosis and treatment of inherited bone marrow failure syndromes in China. Stem Cell Investigation, 2.

69
03
Diamond Blackfan Anemia
(DBA) Discovered 1936
• Incidence: most common type of IBMFS in 1st year of life (M:F→ 1.1:1)
• Mode of inheritance: AD, XLR
• Affected pathway: Defects in ribosome biogenesis (26 genes)
 Most commonly in the RPS19 gene (25% of all cases)
• Cancer risk: ↑↑ 5 fold overall risk of cancer.
• But it seems depend on the underlying mutation
• RPS26 mutations been associated with MDS or cancer thus far.*
• The main challenges: diagnosis difficulty and the side effects of TTT.
• Main Hematological Manifestation: anemia (macrocytic anemia + reticulocytopenia)
• Onset of hematological $: mostly in utero, at birth, or within the 1st year.
• The median age of diagnosis→ 3 months
• Clinical features: 50% of patients have physiacal abnormalaties including skeletal
abnormalities (triphalangeal thumb, short stature), craniofacial and cardiac defects.
• Oncology: MDS, AML, osteosarcoma, colorectal cancer
• Gold standard diagnostic tool: (↑↑eADA, ↑↑ HBF)
• Erythrocyte adenosine deaminase (eADA) is ↑↑ in 85% of DBA patients
• Treatment: age based
− < 1 year: chronic RBC transfusions
− >1 year: Corticosteroids therapy (80% initially respond→ responses
can decline over time)
− Iron chelation is often needed
− HSCT is the only curative treatment (for transfusion dependent patients)
− Long term Follow up
• was seen in few patients (an adequate HB level
without the need of treatment lasting for at least 6 months)**
* Lipton, J.M.; Molmenti, C.L.S.; Desai, P.; Lipton, A.; Ellis, S.R.; Vlachos, A. Early Onset Colorectal Cancer: An Emerging Cancer Risk in Patients with Diamond
Blackfan Anemia. Genes 2021, 13, 56.
** Lee, H.; Lyssikatos, C.; Atsidaftos, E.; Muir, E.; Gazda, H.; Beggs, A.H.; Lipton, J.M.; Vlachos, A. Remission in Patients with Diamond Blackfan Anemia (DBA)
Appears to Be Unrestricted by Phenotype or Genotype. Blood 2008, 112, 3092.
Low birth
weight
Blue sclera (50%)

Q1: What is the DD for DBA?
- It is TEC (acquired):
• Spontaneous cessation of erythropoiesis in an otherwise healthy child (after infection with parv
virus B19)
- May also involve neutrophils and platelets
- Temporal reticulocytopenia m
- Marked reticulocytosis with high MCV (during recovery phase)
• Typically self limited (spontanous recovery is a rule)
• Serial blood counts, increase in reticulocytes as first sign of marrow recovery
• Transfusion if necessary for Hgb<5 with reticulocytopenia
• Follow to resolution
Diamond Blackfan Anemia (DBA)

72
Shwachman–Diamond Syndrome
(SDS) Discovered 1964
• Incidence: (M:F→ 1.5:1)
• Mode of inheritance: AR
• Affected pathway: Defects in ribosome biogenesis and maturation (4 genes)
 SBDS gene mutation was found in 90% of all cases
 Ribosome biogenesis and Mitotic spindle stabilization
• Cancer risk: ↑ overall risk of cancer.
• Only of SDS patients develops severe cytopenia or malignancies.
• Preemptive transplantation is not recommended*
• The diagnosis: depend on traid of Neutropenia, skletal dysplasia, and
Pancreatic insufficiency with malabsorption (often manifest as diarrhea)
• Main Hematological Manifestation: neutropenia (mild to moderate)
• Onset of hematological $: mostly in the infancy (4-6 months)
• The median age of diagnosis→ 1 year
• Clinical features: exocrine pancreatic insufficiency, skletal dysplasia (bell shaped
chest), short stature, neutropenia.
• Oncology: AA, MDS, AML, - ( )
• Gold standard diagnostic tool: Trypsinogen, isoamylase, 72 h faecal fat
• Treatment:
− Supportive care (G-CSF): recurrent infections and/or severe neutropenia
− HSCT is indicated in:
• Patients with severe neutropenia are unresponsive to G-CSF or
• If progression to MDS or AML occurs.
− HSCT should be done before its progressing into MDS/AML.**
– OS of HSCT for BMF is around 70%
– OS of HSCT for secondary MDS or AML15-30%
− Pancreatic enzyme replacement
− Long term Follow up (3-year OS of 62% vs 28% for those without FU)***
* Donadieu, J.; Fenneteau, O.; Beaupain, B.; Beaufils, S.; Bellanger, F.; Mahlaoui, N.; Lambilliotte, A.; Aladjidi, N.; Bertrand, Y.; Mialou, V.; et al. Classification of and risk
factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome. Haematologica 2012, 97, 1312–1319. [
** Vissers, L.T., van der Burg, M., Lankester, A.C., Smiers, F.J., Bartels, M. and Mohseny, A.B., 2023. Pediatric Bone Marrow Failure: A Broad Landscape in Need of
Personalized Management. Journal of Clinical Medicine, 12(22), p.7185.
*** Myers, K.C.; Furutani, E.; Weller, E.; Siegele, B.; Galvin, A.; Arsenault, V.; Alter, B.P.; Boulad, F.; Bueso-Ramos, C.; Burroughs, L.; et al. Clinical features and
outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: A multicentre, retrospective, cohort study.
Lancet Haematol. 2020, 7, e238–e246.
04
Low birth
weight
• Genetic testing can confirm diagosis, but a negative
test does not exclude the diagnosis.
• DD of SDS:
 Cycstic fibrosis (the most common cause of exocrine
pancreatic insufficiency in children)
 Congenital neutropenia
 Pearson syndrome

• Refractory sideroblastic anemia by 6 months of age
• Exocrine pancreatic dysfunction (fat malabsorption)
• Associated usually mild neutropenia, thrombocytopenia
• Marrow: vacuolated precursors/ringed sideroblasts
• Death usually as a consequence of acidosis, sepsis, liver or renal failure related to tubular dysfunction
• Median survival is age 3 years
• Genetics: Mitochondrial DNA deletion (maternal inheritance)
Pearson Syndrome

75
05
Inherited Bone Marrow Failure Syndromes(IBMFS) • Incidence: (M:F→ 1.2:1)
• Mode of inheritance: AD & AR, XLR
• Affected pathway: neutrophil maturation defect
 Heterozygous ELANE mutation (AD or AR) in 50% of patients
 CSF3R mutation (AR), which are associated with:*
 An absent, low, or decreasing response to GCSF
 A higher risk of progression to secondary myeloid malignancy
 HAX1 mutation (AR): associated with developmental delay (Kostman $)
 WAS mutation (XLR)
• Definition: chronic neutropenia (<500/uL) lasting for ≥ 3 months.
• Main Hematological Manifestation: neutropenia
• Onset of hematological $: often within the firts few months of life
• The median age of diagnosis→ 3 months
• Clinical features: no or limited extra-hematological features.
• Oncology: MDS, AML, - ( )
• Gold standard diagnostic tool:
• Bone marrow aspirate (neutrophil maturation arrest)
• Treatment:
− G-CSF (90% of cases will show response)
− A wait and see approach for patients who showed response to G-CSF
− HSCT is indicated in patinets who have a low or absent response or
require high doses of G-CSF
• Long term follow up
Severe Congenital Neutropenia
(SCN)
* Rosenberg, P.S.; Zeidler, C.; Bolyard, A.A.; Alter, B.P.; Bonilla, M.A.; Boxer, L.A.; Dror, Y.; Kinsey, S.; Link, D.C.; Newburger, P.E.; et al. Stable long-term risk of
leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy. Br. J. Haematol. 2010, 150, 196–199.
60% of
European/Middle Eastern patients with ELANE mutations

Q1: What are congenital neutropenia?
- It is include:
• Severe Congenital Neutropenia (Kostmann’s syndrome)
• Cyclic Neutropenia
• Myelokathexis/WHIM syndrome.
Q2: What is cyclic neutropenia?
- It is another form of neutropenia, cycles of 21+7 days with ANC< 200/uL for 3-5 days
- Caused by heterozygous mutations in GF11 gene (AD vs sporadic)
- Symptoms often improve with age
Q3: What is Myelokathexis/WHIM Syndrome?
• - It is Noncyclic neutropenia with myeloid hyperplasia of marrow (AD mutations in CXCR4)
- Kathexis/retention of myeloid cells in marrow
- Retained cells with condensed nuclei connected by stringy filaments and vacuolated cytoplasm
- Severe neutropenia with Warts, Hypogammaglobulinemia, Infections, and Myelokatheis
Congenital Neutropenia

78
06
Congenital Amegakaryocytic Thrombocytopenia
(CAMT)
• Incidence: (M:F→ 0.8:1)
• Affected pathway: ineffective megakaryopoiesis
 c-MPL mutation in the majority of patients [encoding for the
thrombopoietin (THPO) receptor]
 THPO mutation
 MECOM and rarely in HOXA11 mutations: associated with
radio-ulnar synostosis (RUSAT)
• Main Hematological Manifestation: thrombocytopenia→ progress to
pancytopenia during 1st year of life
• Onset of hematological $: since birth
• Clinical features: no or limited extra-hematological features
 Non syndromatic thrombocytopenia
• Oncology: AA, MDS, AML, - ( )
• Bone marrow aspirate (decreased megakaryocytes)
• Treatment:
− HSCT is the only curative treatment
− THPO receptor agonist
MECOM-associated syndromes: Radioulnar
synostosis, clinodactyly, hearing loss, cardiac/renal
malformation

80
Thrombocytopenia Absent Radii
(TAR) • Incidence: (M:F→ 0.7:1)
• Affected pathway: mRNA processing
• Abnormal transcription of RBM8A gene results in bilateral
absent radii and thrombocytopenia
• Main Hematological Manifestation: thrombocytopenia
(thrombocytopenia usually stabilizes after two years)*
• Onset of hematological $: 0 - 6 months
• Clinical features: bilateral absent radii - but thumbs present (to
distinguish from FA)
• BMA (decreased and/or abnormal megakaryocytes)
• Treatment:
− Watch and wait approach
− Supportive care: platelet transfusions +/- platelet-stimulating
agents such as romiplostim.*
− HSCT it is not recommended ( was seen)
* Cowan, J.; Parikh, T.; Waghela, R.; Mora, R. Thrombocytopenia with Absent Radii (TAR) Syndrome Without Significant Thrombocytopenia. Cureus 2020, 12,
e10557.
07

DC
FA AR, XLR, AD
SDS AR
DBA AD, XLR
CAMT AR
SCN AD, AR, XLR
TAR AR
SUM UP
Mode of inheritance Affected pathway
Main Hematological
Manifestation Treatment
mRNA processing
Pancytopenia
Pancytopenia
Neutropenia
Anemia
Thrombocytopenia
Neutropenia
Thrombocytopenia
Androgen/HSCT
Steroid/HSCT
HSCT
G-CSF/ HSCT
Watch & wait
XLR, AD, AR, de novo
Impaired telomere
maintenance
Defects in ribosome
biogenesis
Defects in ribosome
biogenesis and maturation
Neutrophil maturation
defect
DNA repair defect
Ineffective
megakaryopoiesis
Androgen/HSCT
Pancreatic enzyme
replacement, G-CSF/ HSCT

Mutant genes in the IBMFS
SUM UP

Management of hematologic complications in the IBMFS
SUM UP

SUM UP
Schratz, K.E., 2023. Clonal evolution in inherited marrow failure syndromes predicts disease progression. Hematology, 2023(1), pp.125-134.

85
08
Aplastic Anemia (AA)
Idiopathic vs secondary • Incidence: (M:F→ 0.7:1)
• Mode of inheritance: acquired
• Affected pathway: immunologic etiology (immune dysregulation)
• Definition: patients with peripheral cytopenia and hypoplastic bone
marrow with an unidentified (genetic) cause (idiopathic) despite
extensive diagnostics.
• Main Hematological Manifestation: often present with thrombocytopenia→
pancytopenia
• Onset of hematological $: often insidious with at least 6 to 8 weeks previously
• Clinical features:
• Gold standard diagnostic tool: Bone marrow aspirate (pancytopenia)
• Treatment:
− Supportive care: PRBCS/platelet transfusions, antibiotic and antifungal prophylaxis.
− HSCT it is the standard of care for upfront treament
− IST is indicated for those cases where HSCT is not feasible
• ATG (40 mg/kg/day x 4 days)
• Cyclosporine (6-12 months, counts stable x3months)
• Androgen (response rate 30-50%)
• High-dose cyclophosphamide (Salvage therapy for response failure in 3-6
months)
• MCV is increased with a normal RDW
• Fetal hemoglobin and “i” antigen increased

①
GATA2
deficiency
②
SAMD9/9L
disorders
③
RUNX1
NEW
Myeloid malignancy predisposition Syndromes
are
4. ERCC6L2 syndrome: a genetic predisposition syndrome assochiated
with a high risk of developing that can cause
treatment

87
01
GATA2 DEFICIENCY
• Incidence: diagnosis needs a high index of suspicion
• Mode of inheritance: AD, sporadic cases
• Affected pathway: Haematopoietic stem and endothelial cell development
• Definition: GATA2 deficiency is a germline immunodeficiency syndrome
with a high lifetime risk for MDS and AML.
• Cancer risk: ↑↑ overall risk of cancer.
• Approximately 72% of adolescents with MDS and monosomy 7 have
GATA2 deficiency, thus making it one of the most common causes of
MDS in children.*
• Main Hematological Manifestation: monocytopenia / NK cell/B cell deficiency
• Onset of hematological $: Many remains asymptomatic into adulthood.
• Clinical features: recurrent severe infections (non-tuberculous
mycobacteria, viral; EBV and papilloma, fungal), warts, Pulmonary alveolar
proteinosis, Lymphedema, hearing loss.
• Oncology: MDS, AML (occur in 75% of patients), - ( )
• Detect germline pathogenic variants in GATA2
• Treatment:
* Wlodarski MW, Hirabayashi S, Pastor V, et al. Prevalence, clinical character_x0002_istics, and prognosis of GATA2-related myelodysplastic syndromes in
chil_x0002_dren and adolescents. Blood 2016; 127:1387–1397; quiz 1518.
New, Discovered 2011
Presentation vary widely among affected members even
within the same family

88
02
SAMD9/SAMD9L SYNDROMES
• Incidence: diagnosis needs a high index of suspicion
• Mode of inheritance: AR (2 gene)
• Affected pathway: Cell proliferation and endosome fusion
• Definition: it is a germline pathogenic gain of function variants in the SAMD9
and SAMD9L genes association with several clinical disorders, including
myelodysplasia, infections, restriction of growth, adrenal hypoplasia, genital
phenotypes and enteropathy (MIRAGE) syndrome, MDS and ataxia pancytopenia
syndrome (ATXPC).
• Approximately 50% of pediatric MDS patients have SAMD9 & SAMD9L
syndromes and GATA2 deficiency.*
• Main Hematological Manifestation:
• Onset of hematological $: Affected individuals display a highly variable clinical
course that ranges from mild and transient dyspoietic changes in the BM to a rapid
progression of MDS or AML with monosomy 7.
• Clinical features: MIRAGE syndrome & Ataxia-pancytopenia syndrome
• Detect germline gain of function pathogenic variants in SAMD9/SAMD9L
• Genetic testing with non-blood material is recommended for all patients
with paediatric MDS and monosomy 7 (as both SAMD9 and SAMD9L lie on
chromosome 7).**
• Treatment:
− Watch and wait approach: some patients can undergo spontaneous
hematopoietic remission.***
New
* Chin X, Sreedharan AV, Tan EC, et al. MIRAGE syndrome caused by a De Novo c.3406G>C (p. Glu1136Gln) mutation in the SAMD9 gene presenting with
neonatal adrenal insufficiency and recurrent intussusception: a case report. Front Endocrinol (Lausanne) 2021; 12:742495.
** University of Chicago Hematopoietic Malignancies Cancer Risk Team. How I diagnose and manage individuals at risk for inherited myeloid malignancies. Blood
2016; 128:1800–1813.
*** Sahoo SS, Kozyra EJ, Wlodarski MW. Germline predisposition in myeloid neoplasms: unique genetic and clinical features of GATA2 deficiency and
SAMD9/SAMD9L syndromes. Best Pract Res Clin Haematol 2020; 33:101197
Affected individuals display a highly variable clinical
course that ranges from mild and transient dyspoietic changes in
the BM to a rapid progression of MDS or AML with monosomy 7

89
03
RUNX1
• Incidence: one of the most frequently mutated gene in the hematological
malignancies. It is a member of the core binding factor family of
transcription factors (hematopoiesis).
• Mode of inheritance: A
• Affected pathway: Haematopoietic stem and endothelial cell development
• Definition: germline RUNX1 mutation is assochiated with familial platlet
disorders and malignancies.
• Approximately 72% of a
• Main Hematological Manifestation: thrombocytopenia before progression
to pancytopenia
• Onset of hematological $:
• Clinical features:
• Oncology: MDS, AML (may occur in early age), - ( )
• Detect germline mutation in RUNX1
• Treatment:
New

The immune status in pediatric patients with IBMFS?*
* Giri N, Alter BP, Penrose K, et al. Immune status of patients with inherited bone marrow failure syndromes. Am J Hematol 2015;90:702-8
B cell NK cell Immunoglobulin Total lymphocytes CD4 T cells
FA ↓ ↓ normal normal normal
DC ↓ ↓ normal ↓
DBA normal normal

• Gene therapy for IBMFSs is still in its infancy.*
• For FA and DC, a clinical trials are now ongoing.
• Gene therapy is based on two different strategies.**
1. Viruses can be exploited to incorporate genes into the DNA.**
 Most commonly and safely, lenti viruses are used to integrate genes in both dividing and nondividing cells.***
 Although excellent safety, the risk of cancer remains due to insertional oncogenesis.****
2. Gene editing techniques are able to modify genes.
 Most commonly, the clustered regularly interspaced short palindromic repeat and CRISPR-associated protein 9
 (CRISPR/Cas9), induce a site-specific double-strand break (DSB).
 DSB can be repaired with non-homologous end joining (NHEJ) or homology-directed repair (HDR).
 NHEJ is error-prone, resulting in insertions or deletions around the break.
 HDR uses homologous repair. HDR can be used to replace a sequence or to insert a novel gene segment.**
 CRISPR/Cas9 is not entirely safe yet, as it can cause off-target effects and DNA rearrangements.****, *****
Gene Therapy
as a Novel Treatment Strategy
* Vissers, L.T., van der Burg, M., Lankester, A.C., Smiers, F.J., Bartels, M. and Mohseny, A.B., 2023. Pediatric Bone Marrow Failure: A Broad Landscape in Need of Personalized Management. Journal of Clinical Medicine, 12(22), p.7185.
** Kohn, D.B. Gene therapy for blood diseases. Curr. Opin. Biotechnol. 2019, 60, 39–45. [CrossRef]
*** Dufait, I.; Liechtenstein, T.; Lanna, A.; Bricogne, C.; Laranga, R.; Padella, A.; Breckpot, K.; Escors, D. Retroviral and lentiviralvectors for the induction of immunological tolerance. Scientifica 2012, 2012, 694137.
**** Ferrari, G.; Thrasher, A.J.; Aiuti, A. Gene therapy using haematopoietic stem and progenitor cells. Nat. Rev. Genet. 2021, 22, 216–234.
***** Uddin, F.; Rudin, C.M.; Sen, T. CRISPR Gene Therapy: Applications, Limitations, and Implications for the Future. Front. Oncol. 2020, 10, 1387.

Home take message
SCN CAMT TAR AA
FA DC DBA SDS
CATEGORY: High risk Spontaneous remission Low risk
Pancytopenia
AR, XLR, AD
Deficient DNA repair
Pancytopenia
XLR, AD, AR
Telomere biology
Neutropenia
AD & AR, XLR
Neutrophil
maturation defect
Thrombocytopenia
AR
Ineffective
megakaryopoiesis
Anemia
AD, XLR
Ribosome biogenesis
Neutropenia
AR
Ribosome biogenesis aand
maturation
Thrombocytopenia
AR
mRNA processing
Pancytopenia
Acquired

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