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 mechanism in 70% cases, major reason is exposure of drugs, radiation, infection.	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			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		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			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