Genetics · MU Sofia

18. Hypoplastic anemias: Fanconi anemia, Blackfan-Diamond anemia.

Covers the two main inherited hypoplastic anaemias, Fanconi anaemia as a DNA repair disorder with pancytopenia and Diamond-Blackfan anaemia as a ribosome biogenesis disorder with pure red cell aplasia. For each it sets out the genetic basis, pathogenesis, clinical features, diagnosis and management. It closes with a side-by-side comparison table of defect, inheritance, age of onset, marrow findings, anomalies, cancer risk and treatment.

Inside: 5 sections · 2 labelled pictures · 1 table · 14 flashcards · 3 min

Topic 18 of 65 in the MU Sofia syllabus for Genetics (Medicine, Year 3). The free AceMed note covers it in 5 sections, about 400 words (3 min of reading), with 14 flashcards.

In this note

  1. Hypoplastic anemias: Fanconi anemia, Blackfan-Diamond anemia.
  2. I. Introduction
  3. II. Fanconi Anemia (FA)
  4. III. Diamond-Blackfan Anemia (DBA)
  5. IV. Comparison: FA vs DBA

I. Introduction

Hypoplastic anemias are genetic disorders where the bone marrow fails to produce sufficient blood cells. They differ from hemolytic anemias (where RBCs are destroyed) because here the problem lies in impaired production. The two major inherited forms are:

  • Fanconi anemia (FA) – a disorder of DNA repair with pancytopenia.
  • Diamond-Blackfan anemia (DBA) – a disorder of ribosome biogenesis with pure red cell aplasia.

II. Fanconi Anemia (FA)

Molecular Basis

  • Autosomal recessive (rarely X-linked).
  • Caused by mutations in Fanconi anemia (FANC) genes (FANCA, FANCC, FANCG, etc.) involved in DNA interstrand crosslink repair.
  • Defective DNA repair → chromosomal breakage and apoptosis of bone marrow stem cells.

Pathogenesis

  1. 1. Stem cell failure in bone marrow → progressive pancytopenia.
  2. 2. Chromosomal instability → predisposition to cancers, especially acute myeloid leukemia (AML) and squamous cell carcinomas.
  3. 3. Developmental anomalies due to impaired cell proliferation during embryogenesis.

Clinical Features

  • Onset: childhood (5–10 years).
  • Bone marrow failure: aplastic anemia with anemia, leukopenia, thrombocytopenia.
  • Physical anomalies (present in ~75%):
  • Short stature, microcephaly.
  • Abnormal thumbs (hypoplastic, bifid).
  • Café-au-lait spots, skin pigmentation abnormalities.
  • Renal malformations, hypogonadism.
  • Cancer predisposition: ↑ risk of AML, myelodysplastic syndrome (MDS), head & neck cancers, gynecologic cancers.

Diagnosis

  • CBC: pancytopenia.
  • Bone marrow: hypocellular (fatty replacement).
  • Chromosomal breakage test (exposure to DNA crosslinking agents like diepoxybutane or mitomycin C → ↑ breaks).
  • Genetic testing for FANC mutations.

Management

  • Supportive: transfusions, infection prophylaxis.
  • Androgen therapy: can stimulate hematopoiesis temporarily.
  • Hematopoietic stem cell transplantation (HSCT): only curative therapy.
  • Regular cancer surveillance essential due to high malignancy risk.

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