Fanconi anemia differential diagnosis

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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).

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