Fanconi anemia differential diagnosis: Difference between revisions

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{{Fanconi anemia}}
{{Fanconi anemia}}


{{CMG}}; {{AE}}  
{{CMG}}; {{AE}} {{shyam}}


==Overview==
==Overview==
Fanconi anemia must be differentiated from [[aplastic anemia]], [[paroxysmal nocturnal hemoglobinuria]], chromosomal breakage syndromes, and hereditary bone marrow failure syndromes ([[dyskeratosis congenita]] and other short telomere syndromes). Each disease has a different pathophysiology, exam findings, and histopathology.


Fanconi Anemia must be differentiated from Aplastic Anemia, Paraoxysomal Nocturnal Hemoglobinuria, and Chromosomal breakage syndrome and Hereditary Bone marrow failure syndrome (Dyskeratosis congenita and other short telomere syndromes).
==Differentiating Fanconi anemia from other diseases==
*Fanconi anemia must be differentiated from other diseases (as noted below).<ref name="pmid24237973">{{cite journal| author=Hartung HD, Olson TS, Bessler M| title=Acquired aplastic anemia in children. | journal=Pediatr Clin North Am | year= 2013 | volume= 60 | issue= 6 | pages= 1311-36 | pmid=24237973 | doi=10.1016/j.pcl.2013.08.011 | pmc=3894991 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24237973  }}</ref><ref name="pmid27069254">{{cite journal| author=Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM et al.| title=The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. | journal=Blood | year= 2016 | volume= 127 | issue= 20 | pages= 2391-405 | pmid=27069254 | doi=10.1182/blood-2016-03-643544 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27069254  }}</ref>


==Differentiating X from other Diseases==
===Differential Diagnosis===
*Fanconi Anemia must be differentiated from other diseases that cause Pancytopenia, Congenital anomalies, and associated with malignancy such as Aplastic Anemia, Rare chromosomal breakage syndrome and inherited bone marrow failure.
 
*As Fanconi Anemia resembles with variety of other diseases that causes pancytopenia.
*Must be differentiated on basis on congenital anomalies and chromosomal breakage test.
 
===Preferred Table===
{| class="wikitable sortable mw-collapsible"
{| class="wikitable sortable mw-collapsible"
|+
|+
Line 41: Line 37:


Eyes- Microphthalmia, ptosis, epicanthal folds, strabismus
Eyes- Microphthalmia, ptosis, epicanthal folds, strabismus
|Inherited defect in DNA Repair causes loss of HSC that leads  
|Inherited defect in DNA Repair causes loss of HSC that leads to bone marrow failure.
 
|Anemia: normocellular or hypercellular bone marrow
to bone marrow failure.
|Gastrointestinal  Atresias, imperforate anus, TE fistula, malrotation,
|Anemia
normocellular or hypercellular bone marrow
|Gastrointestinal  Atresias, imperforate
anus, TE fistula, malrotation,


Kidney – Abnormal, ectopic, horseshoe, hypoplastic, or absent kidney; hydronephrosis
Kidney – Abnormal, ectopic, horseshoe, hypoplastic, or absent kidney; hydronephrosis
|
|
|FA gene  
|FA gene sequencing   
sequencing   
|Increased chromosomal breakage in response to mitomycin C or diepoxybutane (quite sensitive but not entirely specific)
|Incrreased chromosomal breakage in response to mitomycin C or diepoxybutane (quite sensitive but not entirely specific)
|-
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |Acquired Aplastic Anemia
| style="background: #DCDCDC; padding: 5px; text-align: center;" |Acquired Aplastic Anemia
| style="background: #F5F5F5; padding: 5px;" |infections  mucosal hemorrhage menorrhagia  
| style="background: #F5F5F5; padding: 5px;" |Infections, mucosal hemorrhage, menorrhagia  
| style="background: #F5F5F5; padding: 5px;" |especially pallor and petechiae.
| style="background: #F5F5F5; padding: 5px;" |Pallor and petechiae
The liver, spleen, and lymph nodes are typically enlarged in AA, if its enlarged it may suggest alternative diagnosis
The liver, spleen, and lymph nodes are typically enlarged in AA, if its enlarged it may suggest alternative diagnosis
|cause remains
|No known causes 70% cases, known cases are caused by drugs, virus, radiation
obscure in most cases.
 
Immune system abnormalitis and genetic predisposition
 
may play role
| style="background: #F5F5F5; padding: 5px;" |Anemia
| style="background: #F5F5F5; padding: 5px;" |Anemia
normocellular or hypercellular bone marrow
normocellular or hypercellular bone marrow
| style="background: #F5F5F5; padding: 5px;" |Gastrointestinal  Atresias, imperforate
| style="background: #F5F5F5; padding: 5px;" |Gastrointestinal  Atresias, imperforate anus, TE fistula, malrotation,
 
anus, TE fistula, malrotation,


Kidney – Abnormal, ectopic, horseshoe, hypoplastic, or absent kidney; hydronephrosis
Kidney – Abnormal, ectopic, horseshoe, hypoplastic, or absent kidney; hydronephrosis
| style="background: #F5F5F5; padding: 5px;" |
| style="background: #F5F5F5; padding: 5px;" |
| style="background: #F5F5F5; padding: 5px;" |hypocellular bone
| style="background: #F5F5F5; padding: 5px;" |Hypocellular bone marrow  
marrow  
| style="background: #F5F5F5; padding: 5px;" |Rapid onset
| style="background: #F5F5F5; padding: 5px;" |rapid onset
|-
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |Paroxysmal nocturnal hemoglobinuria (PNH)
| style="background: #DCDCDC; padding: 5px; text-align: center;" |Paroxysmal nocturnal hemoglobinuria (PNH)
Line 90: Line 73:
●Erectile dysfunction  
●Erectile dysfunction  


Chest pain  
●Chest pain  


●Thrombosis  
●Thrombosis  
Line 96: Line 79:
●Renal insufficiency  
●Renal insufficiency  
| style="background: #F5F5F5; padding: 5px;" |
| style="background: #F5F5F5; padding: 5px;" |
|
|Acquired mutation in PIGA gene --> problem in synthesis of
 
DGI ---> complement mediated Intravascular hemolysis
| style="background: #F5F5F5; padding: 5px;" |Anemia
| style="background: #F5F5F5; padding: 5px;" |Anemia
normocellular or hypercellular bone marrow  
normocellular or hypercellular bone marrow  
Line 123: Line 108:
•Hyperhidrosis – 15 percent
•Hyperhidrosis – 15 percent


Ophthalmologic/Epiphora
●Ophthalmologic/Epiphora
 
 (excessive tearing/lacrimal 


duct stenosis)  
 (excessive tearing/lacrimal duct stenosis)  


●Neurologic/Cognitive
●Neurologic/Cognitive
Line 137: Line 120:
•Microcephaly  
•Microcephaly  


Pulmonary disease (pulmonary fibrosis)  
●Pulmonary disease (pulmonary fibrosis)  


●Endocrine/Growth/Urologic 
●Endocrine/Growth/Urologic 
Line 167: Line 150:


●Cancer  
●Cancer  
|
|(DC) and  telomere related disorders, mutations in genes that maintain telomere length in rapidly dividing cells that lead to premature cell death, senescence, or genomic instability, which in turn results
 
in impaired function and cellular homeostasis in many organs and tissues.
| style="background: #F5F5F5; padding: 5px;" |Reticular dysgenesis
| style="background: #F5F5F5; padding: 5px;" |Reticular dysgenesis
| style="background: #F5F5F5; padding: 5px;" |
| style="background: #F5F5F5; padding: 5px;" |
Line 212: Line 197:


breakage syndrome (''DDX11'').
breakage syndrome (''DDX11'').
| style="background: #F5F5F5; padding: 5px;" |microcephaly, short stature increased
| style="background: #F5F5F5; padding: 5px;" |Microcephaly, short stature increased
malignancy
malignancy
| style="background: #F5F5F5; padding: 5px;" |
| style="background: #F5F5F5; padding: 5px;" |
|
|NBS: chromosomal instability disorder  caused by mutations in the nibrin ''(NBN)'' gene
| style="background: #F5F5F5; padding: 5px;" |no specific findings
 
| style="background: #F5F5F5; padding: 5px;" |Gastrointestinal  Atresias, imperforate
DNA breaks are not efficiently repaired in the absence of fibrin.


anus, TE fistula, malrotation,
oxidative/alkylating stress damages the cells
| style="background: #F5F5F5; padding: 5px;" |No specific findings
| style="background: #F5F5F5; padding: 5px;" |Gastrointestinal  Atresias, imperforate anus, TE fistula, malrotation,


Kidney – Abnormal, ectopic, horseshoe, hypoplastic, or absent kidney; hydronephrosis
Kidney – Abnormal, ectopic, horseshoe, hypoplastic, or absent kidney; hydronephrosis
| style="background: #F5F5F5; padding: 5px;" |
| style="background: #F5F5F5; padding: 5px;" |
| style="background: #F5F5F5; padding: 5px;" |abnormal chromosomal breakage test
| style="background: #F5F5F5; padding: 5px;" |Abnormal chromosomal breakage test
| style="background: #F5F5F5; padding: 5px;" |No bone  
| style="background: #F5F5F5; padding: 5px;" |No bone marrow
marrow


failure  
failure  
|-
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |De novo myelodysplastic syndrome (MDS)
| style="background: #DCDCDC; padding: 5px; text-align: center;" |De novo myelodysplastic syndrome (MDS)
| style="background: #F5F5F5; padding: 5px;" |MDS can arise de novo or secondary to another bone marrow disorder;
| style="background: #F5F5F5; padding: 5px;" |MDS can arise de novo or secondary to another bone marrow disorder  
| style="background: #F5F5F5; padding: 5px;" |
| style="background: #F5F5F5; padding: 5px;" |
|
|
| style="background: #F5F5F5; padding: 5px;" |bone marrow failure
| style="background: #F5F5F5; padding: 5px;" |Bone marrow failure
| style="background: #F5F5F5; padding: 5px;" |
| style="background: #F5F5F5; padding: 5px;" |
| style="background: #F5F5F5; padding: 5px;" |Positive
| style="background: #F5F5F5; padding: 5px;" |Positive
chromosomal breakage tests
chromosomal breakage tests
| style="background: #F5F5F5; padding: 5px;" |
| style="background: #F5F5F5; padding: 5px;" |
| style="background: #F5F5F5; padding: 5px;" |Negitive
| style="background: #F5F5F5; padding: 5px;" |Negative chromosomal breakage tests
chromosomal breakage tests
|}
|}



Latest revision as of 16:49, 4 May 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]

Overview

Fanconi anemia must be differentiated from aplastic anemia, paroxysmal nocturnal hemoglobinuria, chromosomal breakage syndromes, and hereditary bone marrow failure syndromes (dyskeratosis congenita and other short telomere syndromes). Each disease has a different pathophysiology, exam findings, and histopathology.

Differentiating Fanconi anemia from other diseases

  • Fanconi anemia must be differentiated from other diseases (as noted below).[1][2]

Differential Diagnosis

Clinical manifestations Pathophysiology Para-clinical findings Gold standard Additional findings
Lab Findings Imaging Histopathology
Disease Symptom Physical exam Blood profile Anamalies
Fanconi Anemia Short stature, delicate features, upper limbs absent or hypoplastic thumbs, supernumerary, bifid clinodactyly

infection, petechia, pallor

Skin – Generalized hyperpigmentation; hypopigmented areas; large freckles, café-au-lait spots

Head – Microcephaly or hydrocephaly; birdlike face, mid-face hypoplasia, Sprengel's deformity of neck,

Eyes- Microphthalmia, ptosis, epicanthal folds, strabismus

Inherited defect in DNA Repair causes loss of HSC that leads to bone marrow failure. Anemia: normocellular or hypercellular bone marrow Gastrointestinal  Atresias, imperforate anus, TE fistula, malrotation,

Kidney – Abnormal, ectopic, horseshoe, hypoplastic, or absent kidney; hydronephrosis

FA gene sequencing Increased chromosomal breakage in response to mitomycin C or diepoxybutane (quite sensitive but not entirely specific)
Acquired Aplastic Anemia Infections, mucosal hemorrhage, menorrhagia Pallor and petechiae

The liver, spleen, and lymph nodes are typically enlarged in AA, if its enlarged it may suggest alternative diagnosis

No known causes 70% cases, known cases are caused by drugs, virus, radiation Anemia

normocellular or hypercellular bone marrow

Gastrointestinal  Atresias, imperforate anus, TE fistula, malrotation,

Kidney – Abnormal, ectopic, horseshoe, hypoplastic, or absent kidney; hydronephrosis

Hypocellular bone marrow Rapid onset
Paroxysmal nocturnal hemoglobinuria (PNH) Fatigue

●Dyspnea

●Hemoglobinuria

Abdominal pain

●Bone marrow suppression

●Erectile dysfunction

●Chest pain

●Thrombosis

●Renal insufficiency

Acquired mutation in PIGA gene --> problem in synthesis of

DGI ---> complement mediated Intravascular hemolysis

Anemia

normocellular or hypercellular bone marrow

●Hypo/Hyper

/Normo

cellular,

Flow cytometry
Other inherited bone marrow failure syndromes

(Dyskeratosis congenita and other short telomere syndromes)

Bone marrow failure

Classic mucocutaneous and additional dermatologic findings

•Skin dyspigmentation

•Nail irregularities

•Leukoplakia

•Premature graying/hair loss

•Hyperhidrosis – 15 percent

●Ophthalmologic/Epiphora

 (excessive tearing/lacrimal duct stenosis)

●Neurologic/Cognitive

•Developmental delay

•Ataxia/cerebellar hypoplasia – approximately

•Microcephaly

●Pulmonary disease (pulmonary fibrosis)

●Endocrine/Growth/Urologic 

features

•Short stature

•Intrauterine growth retardation

•Hypogonadism/Undescended

 testes

•Urethral stricture/phimosis 

•Osteoporosis and related complications

Unlike Fanconi anemia, individuals with DC do not appear to have impaired fertility

●Dental manifestations (caries)

●Gastroenterologic/Hepatologic 

manifestations

•Esophageal strictures

•Liver disease (cirrhosis, fibrosis) or gastroenteropathy

●Cancer

(DC) and telomere related disorders, mutations in genes that maintain telomere length in rapidly dividing cells that lead to premature cell death, senescence, or genomic instability, which in turn results

in impaired function and cellular homeostasis in many organs and tissues.

Reticular dysgenesis Flow cytometry - chromosomal breakage test.
Drug-induced or infection-associated pancytopenia
Rare syndromes,

Nijmegen breakage

syndrome (NBS),

Bloom syndrome

(BLM), ataxia

telangiectasia

(ATM), LIG4

syndrome (LIG4),

NHEJ1 deficiency

(NHEJ1), Seckel syndrome (ATR),

 cohesinopathies

Roberts

syndrome (ESCO2)

Warsaw

breakage syndrome (DDX11).

Microcephaly, short stature increased

malignancy

NBS: chromosomal instability disorder caused by mutations in the nibrin (NBN) gene

DNA breaks are not efficiently repaired in the absence of fibrin.

oxidative/alkylating stress damages the cells

No specific findings Gastrointestinal  Atresias, imperforate anus, TE fistula, malrotation,

Kidney – Abnormal, ectopic, horseshoe, hypoplastic, or absent kidney; hydronephrosis

Abnormal chromosomal breakage test No bone marrow

failure

De novo myelodysplastic syndrome (MDS) MDS can arise de novo or secondary to another bone marrow disorder Bone marrow failure Positive

chromosomal breakage tests

Negative chromosomal breakage tests

References

  1. Hartung HD, Olson TS, Bessler M (2013). "Acquired aplastic anemia in children". Pediatr Clin North Am. 60 (6): 1311–36. doi:10.1016/j.pcl.2013.08.011. PMC 3894991. PMID 24237973.
  2. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM; et al. (2016). "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia". Blood. 127 (20): 2391–405. doi:10.1182/blood-2016-03-643544. PMID 27069254.

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