It is group of disorders characterized by

• Anemia which is noted in infancy or childhood (Macrocytic normochromic)
• Presence of multinuclear erythroid precursors in bone marrow
• Ineffective erythropoiesis due to intramedullary cell death
• Normal myelopoiesis and megakaryopoiesis
• Iron overload with raised ferritin
• Splenomegaly is often present
• Unconjugatedhyperbilirubinemia

CDA-I

• Autosomal recessive inheritance
• Mutation of CDAN1 gene located on 15q13 leading to decreased codanin which is cell cycle regulatory protein
• Defect in nucleoprotein/ nuclear membrane.
• Associated dysmorphic features are
  • Syndactyly
  • Hypoplasia of phalanges
  • Supplementary metatarsal
  • Club foot
  • Small stature
  • Almond shaped blue eyes
  • Hypertelorism
  • Micrognathism
  • Patches of brown skin pigmentation
  • Pigeon chest deformity
  • Varus deformity of hips
  • Flattened vertebral bodies
  • Congenital ptosis
  • Madelung deformity of wrist
  • Deafness
• Peripheral smear: Marked poikilocytosis and Cabbot's rings
• Hemoglobin level- 6-11 gm/dL
• Bone marrow shows megaloblasts and binucleated erythroblasts (incomplete division of nuclear segments) with internuclear chromatin bridges.
• Electron microscopy shows “Swiss cheese” nuclear abnormality.  (Widened nuclear pores with spongy appearance of heterochromatin, invasion by cytoplasm containing various organelle)
• Decreased RBC membrane protein 4.1R
• Prognosis: Severe forms present with hydropsfetalis

CAD-II (HEMPAS = Hereditary erythroblasticMultinuclearity with positive acidified serum test)

• Autosomal recessive inheritance.
• Most common form of CDA.
• Etiopathogenesis

Mutation of SEC23B gene on chromosome 20p11

↓

Deficiency of α-mannosidase II N-acetyl glucosaminyltransferase II

↓

Defect in glycosylation pathway

↓

Abnormalities in glycoprotein bands 3 and 5.5 and Glycophorin A

↓

Defective vesicle trafficking between endoplasmic reticulum and golgi apparatus

• Transfusion dependence is uncommon
• Peripheral smear: Anisocytosis, anisochromia, spherocytes
• Bone marrow
  • Erythroblasts show multinuclearity (up to7)- Seen in 10-30% of erythroblasts
  • Pleuripolar mitosis and karyorrhexis are seen
  • Pseudogoucher cells are seen
• Ham’s (Acidified serum) test- Positive.(Unlike in PNH, hemolysis is seen with acidified normal serum but not by patient’s own serum)
• Sucrose hemolysis test – Negative.
• Electron microscopy - peripheral arrangement of endoplasmic reticulum giving appearance of double membrane.
• Clinical features  
  • Anemia at birth
  • Variable degree of jaundice.
  • Hepatomegaly, splenomegaly
  • Cirrhosis.
  • Diabetes.

CDA-III

• Autosomal dominant inheritance.
• Giant erythroblasts measuring up to 50microns are seen which contain up to 16 nuclei. They contain coarse basophilic granules.
• Clinically mild form
• They have tendency to develop retinal angioid streaks and myeloma
• Electron microscopy- Clefts and blebs in nuclear area, Some iron filled mitochondria, autophagic vacuoles and myeline figures in cytoplasm

Treatment of CDA

• Blood transfusion (As minimum as possible) with chelation therapy once ferritin crosses 1000.
• If anemia is moderate and well compensated, periodic phlebotomy may be used to decrease the iron load
• Folic acid supplementation 
• Splenectomy for transfusion depended cases  (useful in CAD II)
• INF-α (useful in CAD-I)
• Bone marrow transplantation