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

[Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3].

OR

[Disease name] must be differentiated from [[differential dx1], [differential dx2], and [differential dx3].

Differentiating X from other Diseases

• Fanconi Anemia must be differentiated from other diseases that cause Pancytopenia, [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3].
• [Disease name] must be differentiated from [differential dx1], [differential dx2], and [differential dx3].

• As [disease name] manifests in a variety of clinical forms, differentiation must be established in accordance with the particular subtype. [Subtype name 1] must be differentiated from other diseases that cause [clinical feature 1], such as [differential dx1] and [differential dx2]. In contrast, [subtype name 2] must be differentiated from other diseases that cause [clinical feature 2], such as [differential dx3] and [differential dx4].

Preferred Table

Clinical manifestations							Para-clinical findings							Gold standard	Additional findings
Symptoms				Physical examination
							Lab Findings			Imaging			Histopathology
Symptom 1		Symptom 2	Symptom 3	Physical exam 1	Physical exam 2	Physical exam 3	Lab 1	Lab 2	Lab 3	Imaging 1	Imaging 2	Imaging 3
Short stature, delicate features, upper limbs absent or hypoplastic thumbs, supernumerary, bifid clinodactyly	Fanconi Anemia	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	Complete blood count Peripheral blood smear   Reticulocyte count Complete metabolic panel Prothrombin time/partial  thromboplastin time (PT/PTT) Blood type and screen	Cytopenia, Bone marrow failure			Gastrointestinal anomalies – Atresias, imperforate anus, tracheoesophageal fistula, malrotation, Kidney – Abnormal, ectopic, horseshoe, hypoplastic, or absent kidney; hydronephrosis	Cardiopulmonary anomalies – Congenital heart disease (patent ductus arteriosus, atrial or ventricular septal defects, coarctation, situs inversus)		FA gene sequencing	Incrreased chromosomal breakage in response to mitomycin C or diepoxybutane (quite sensitive but not entirely specific)
recurrent infections due to neutropenia, mucosal hemorrhage or menorrhagia due to thrombocytopenia, or fatigue and cardiopulmonary findings associated with progressive anemia.	Acquired Aplastic Anemia	infections including bacterial and fungal in cases of severe neutropenia		especially pallor and petechiae.	The liver, spleen, and lymph nodes are typically enlarged in AA, if its enlarged it may suggest alternative diagnosis.		Complete blood count Peripheral blood smear   Reticulocyte count Complete metabolic panel Prothrombin time/partial  thromboplastin time (PT/PTT) Blood type and screen	Serum chemistries, including electrolytes, liver function tests (including lactate dehydrogenase [LDH]), and renal function tests should be performed, Also serum B12 and Folate should be performed to exclude						Bone marrow aspiration and Biopsy= hypocellular bone marrow in the absence of an abnormal infiltrate or marrow fibrosis.	typically a more rapid onset and progression of cytopenias; and a response to immunosuppressive therapy
Fatigue ●Dyspnea ●Hemoglobinuria	Paroxysmal nocturnal hemoglobinuria (PNH)	Abdominal pain ●Bone marrow suppression ●Erectile dysfunction	Chest pain ●Thrombosis ●Renal insufficiency				Anemia ●Increased reticulocyte count ●Increased lactate dehydrogenase (LDH) and bilirubin ●Decreased haptoglobin ●Free serum hemoglobin with pink/red serum Bone Marrow: PNH usually have a normocellular or hypercellular bone marrow with erythroid hyperplasia. Stainable iron is often absent	hemolytic anemia (indirect hyperbiliribinemia)  Intravascular hemolysis in PNH can lead to ARF and CRD.		●Hemoglobinuria with pink/red urine, positive dipstick for heme, and negative sediment for red blood cells ●Negative direct antiglobulin (Coombs) test (DAT) ●Hypocellular, normocellular or hypercellular bone marrow, often with erythroid hyperplasia; erythroid dysplasia is not uncommon ●Findings of iron deficiency may be seen in some patients due to excessive iron loss from hemoglobinuria and hemosiderinuria (eg, low iron, low ferritin, increased transferrin, absent bone marrow iron				FLAER: Flow cytometry detect (GPI) anchored proteins, which are reduced or absent on blood cells in PNH. Acquired mutations in the PIGA gene result in the dominance of a hematopoietic progenitor cell clone lacking glycosylphosphatidylinositol (GPI) anchors
Transient pancytopenia and bone marrow hypoplasia may be caused by a number of exposures including medications, chemicals, certain viral infections, and sepsis or other severe bacterial infections.	Other inherited bone marrow failure syndromes														negative chromosomal breakage test.
Symptom 1	Diseases	Symptom 2	Symptom 3	Physical exam 1	Physical exam 2	Physical exam 3	Lab 1	Lab 2	Lab 3	Imaging 1	Imaging 2	Imaging 3	Histopathology	Gold standard	Additional findings
	Drug-induced or infection-associated pancytopenia
Like FA, these rare chromosomal instability syndromes are associated with multiple congenital anomalies, often including microcephaly, short stature, and increased risk of malignancy. Also like FA, t.	Rare chromosomal breakage syndromes, Nijmegen breakage syndrome (NBS), Bloom syndrome (BLM), ataxia telangiectasia (ATM), LIG4 syndrome (LIG4), NHEJ1 deficiency (NHEJ1), Seckel syndrome (ATR), and the cohesinopathies Roberts syndrome (ESCO2) and Warsaw breakage syndrome (DDX11).						compared to FA, these conditions show subtle differences in the associated congenital anomalies, the spectrum of associated malignancies, and the specific abnormalities seen within chromosomal breakage testing (eg, increased chromosome 7 and 14 abnormalities in NBS, railroading figures in cohesinopathies).							these syndromes will often cause an abnormal chromosomal breakage tes	patients with NBS do not typically exhibit bone marrow failure except in the setting of evolving malignancy.
MDS can arise de novo or secondary to another bone marrow disorder;	De novo myelodysplastic syndrome (MDS)	many patients with FA develop secondary MDS in child/young adults.					de novo MDS can cause bone marrow failure	variable cytopenias, multilineage dysplasia, cytogenetic abnormalities, and increased blasts					, individuals with MDS in whom FA is being considered should have chromosomal breakage tests performed on skin fibroblasts rather than hematopoietic cells, because bone marrow cytogenetic abnormalities associated with MDS clones may skew chromosomal breakage results performed on lymphocyte		Unlike FA or FA with secondary MDS, de novo MDS is not associated with congenital anomalies, an abnormal chromosome breakage test, or FA mutations