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 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 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. 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.

●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 ●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 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

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 (RD) is a type of severe combined immunodeficiency caused by mutations in the AK2 gene that may also be associated with bone marrow aplasia,

unlike FA, patients with RD develop bone marrow aplasia in infancy associated with sensorineural hearing loss and severe adaptive immune dysfunction

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

References

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