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380 Part IV Disorders of Hematopoietic Cell Development

Future Directions was identified in highly inbred Israeli Bedouins. The gene product,
codanin-1, may be involved in nuclear envelope integrity, but this is
Registries and DBA patient databases will continue to broaden our uncertain, and little is known about pathogenesis. The functions of
understanding of the genetic origins and epidemiology of DBA. C15ORF41 are unknown.
Specimen collection and distribution to qualified research laboratories The onset of anemia, jaundice, and other symptoms may be noted
globally will identify the remaining DBA genes. Genetically based at any age, especially in neonates. Eighty percent of infants in a recent
DBA diagnosis and pedigree analysis will underscore the broad large series required blood transfusions during the first month of life.
dimensions of the DBA phenotype, from clinically silent to life- Case with anemia in utero requiring intrauterine exchange transfu-
threatening severe. Genotype–phenotype correlations will facilitate sions at the third trimester have been reported. Affected patients often
HSCT donor selection, allow counseling for reproductive options, have some degree of icterus and splenomegaly.
and be predictive of cancer risk. Deciphering the pathogenesis of BM CDA I can be associated with a variety of congenital anomalies.
failure and other disease manifestations using animal models and The following have been catalogued: patches of brown skin pigmen-
iPSCs may allow the development of effective erythropoietic stimula- tation, syndactyly in the feet, absence of phalanges and nails in the
tors for use in this disease. fingers and toes, an additional phalanx, duplication or hypoplasia of
metatarsals, short stature, pigeon chest deformity, varus deformity of
Congenital Dyserythropoietic Anemias hips, flattened vertebral bodies, a hypoplastic rib, congenital ptosis,
Madelung deformity of the wrist, and deafness. The pigmentation,
syndactyly and absence of phalanges and nails are not common in
Background CDA I patients but appear to be quite specific for this subtype.
Dysmorphic features are seen in up to 65% of patients. Three siblings
The designation congenital dyserythropoietic anemia (CDA) refers to from a Bedouin family presented with neonatal pulmonary hyperten-
a family of inherited refractory anemias characterized by BM ery- sion. In a French family, three siblings had sensorineural deafness and
throid multinuclearity, ineffective erythropoiesis, and secondary a lack of motile sperm cells.
hemosiderosis. The ineffective erythropoiesis is reflected by BM
erythroid hyperplasia, inappropriately low reticulocyte counts for the Laboratory Abnormalities. The degree of anemia is usually mild to
degree of anemia, and intramedullary RBC destruction. Splenomegaly moderate (hemoglobin in the range of 6.6–11.6 g/dL), and RBCs
and chronic or intermittent jaundice are additional features. Granu- appear macrocytic. Peripheral blood RBC morphology is character-
lopoiesis and thrombopoiesis are normal. These disorders are geneti- ized by anisocytosis and poikilocytosis, and occasionally Cabot rings
cally transmitted and result in anemia with a blunted erythropoietic are seen. Cabot rings appear to be unique to CDA I and are not seen
response. Some patients, especially with CDA type I, have congenital in types II and III. White blood cells and platelets are normal.
anomalies. Examination of the BM reveals erythroid hyperplasia with some
Three classic forms of CDA have been described as well as a megaloblastic erythropoiesis and a small number of erythroblasts with
number of variants. An arbitrary classification used in practice for dyserythropoietic features. The unique morphologic abnormality
these three is based on the inheritance pattern, the peripheral blood seen in CDA I is the presence of chromatin bridges between nuclei
and BM morphology, and the serologic findings in each case. The of two separate erythroblasts, a reflection of impaired cellular division
distinguishing features of the three types of CDA are as follows: (Fig. 29.11). This internuclear bridging of erythroblasts seen with
light microscopy is also a common feature in MDS. Electron
• Type I: Autosomal recessive; macrocytosis; megaloblastic erythroid microscopy reveals additional abnormalities that include widening of
precursor cells; 2% to 5% binucleated erythroid precursor cells; the nuclear membrane pore space with cytoplasmic invagination into
internuclear chromatin bridges involving polychromatic erythro- the nucleus, separation of nuclear chromatin, and chromatin conden-
blasts; negative acidified serum lysis test (Ham test) results. sation, all of which give the general appearance of a spongy nucleus
• Type II: Autosomal recessive; normocytic RBCs; normoblastic (Fig. 29.12). Dyserythropoiesis seems limited mostly to more mature
erythroid precursor cells; 10% to 40% binucleated late normo- RBC precursors. In contrast to CDA II, there are no unique serologic
blasts; positive acidified serum lysis test (Ham test) results. features.
• Type III: Autosomal dominant (or sporadic); macrocytosis; mega- The defect in CDA I is at the stem cell level. The numbers of
loblastic erythroid maturation; giant multinucleated erythroid CFU-E and BFU-E colonies are normal but contain a mixture of
precursors with up to 12 nuclei per cell; negative acidified serum normal and abnormal cells when examined by electron microscopy.
lysis test (Ham test) results. This suggests that the abnormality is expressed variably in the mature
progeny of each stem cell. Erythroid precursors also demonstrate S
The designation “type IV” is defunct but was briefly used to classify phase arrest and morphologic features of apoptosis. In some CDA I
cases of morphologic CDA type II with a negative Ham acidified patients, hemoglobin A 2 levels are increased. Also, some cases show
serum test result. Because some of these were reclassified as CDA type unbalanced globin chain synthesis. Patients do not have thalassemia,
II after retesting using a large panel of heterologous sera, “type IV” and the cause of these findings is not known.
is no longer used as a category. There are also several other forms of
CDA that are distinct from CDA types I, II, and III. Some of these CDA Type II (HEMPAS)
variants have been identified in three or more families and have been CDA II is commonly known as HEMPAS, an acronym for hereditary
tentatively classified phenotypically into CDA groups (not types) IV, erythroblastic multinuclearity with a positive acidified serum test. It
V, VI, and VII (see later section, Other CDAs). Additional CDAs are is inherited in an autosomal recessive manner. The disorder is caused
associated with specific gene mutations other than those seen in CDA by biallelic mutant SEC23B.The wild-type gene encodes the SEC23B
I and II. The growing number of variants underscores the complex component of the coat protein (COP) II complex. COP II vesicles
nature of CDA and the current direction to reclassify these disorders transport secretory proteins from the endoplasmic reticulum to the
accurately by genotype rather than by morphology. Golgi complex. Mutations result in misglycosylation and an impaired
clearance of endoplasmic reticulum cisternae past a given point
Etiology, Genetics, Pathophysiology, during erythroid differentiation. The mutations in SEC23B are local-
ized along the entire coding sequence of the gene, in splicing sites
and Clinical Features and in regulatory regions, no case with biallelic mutations has been
described, suggesting an essential role of the gene.
CDA Type I A significant body of knowledge has been accumulated about
CDA I is inherited in an autosomal recessive manner. The disorder the pathogenesis of CDA II. At the stem cell level, in vitro culture
is caused by biallelic mutations in CDAN1 or in C15ORF41. CDAN1 of CDA II erythroid progenitors produces CFU-E and BFU-E