Fanconi anemia differential diagnosis

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

Overview

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 X from other Diseases

  • 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

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

Incrreased chromosomal breakage in response to mitomycin C or diepoxybutane (quite sensitive but not entirely specific)
Acquired Aplastic Anemia infections mucosal hemorrhage menorrhagia especially 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 nibrin,

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

Negitive

chromosomal breakage tests

References

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