Anemia, Congenital Dyserythropoietic, Type Ib

A number sign (#) is used with this entry because congenital dyserythropoietic anemia type Ib (CDAN1B) is caused by homozygous mutation in the C15ORF41 gene (615626) on chromosome 15q14.

Description

Congenital dyserythropoietic anemia type I is an autosomal recessive hematologic disorder characterized by congenital macrocytic anemia secondary to ineffective erythropoiesis. The bone marrow shows erythroid hyperplasia, with nuclear abnormalities in most erythroblasts. Up to 3% of erythroblasts have interchromatin bridges, and erythroblast nuclei are abnormally electron dense with spongy ('Swiss cheese-like') heterochromatin on electron microscopy. Some reported patients have distal digital abnormalities (summary by Ahmed et al., 2006).

For a general phenotypic description and a discussion of genetic heterogeneity of CDA, see CDAN1A (224120).

Clinical Features

Sabry et al. (1997) reported 3 sibs, born of related Kuwaiti parents, with congenital dyserythropoietic anemia apparent from early childhood. All had a history of jaundice, skin pallor, hepatosplenomegaly, and blood transfusion. Laboratory studies showed increased bilirubin and reticulocytes. Bone marrow biopsies showed erythroid hyperplasia, internuclear chromatin bridges, and multinuclear erythrocyte precursors. The findings were consistent with type I congenital dyserythropoietic anemia. The patients also had skeletal anomalies that varied in severity, including short stature, hypoplastic nails, phalangeal hypoplasia of both the hands and feet, deformed or duplicated metatarsals, and cutaneous syndactyly of the toes. One patient had ptosis and reduced bone age.

Ahmed et al. (2006) reported 2 Pakistani sisters, born of consanguineous parents (family C), with clinical and hematologic findings of type I congenital dyserythropoietic anemia. A substantial proportion of erythroblasts showed 'Swiss-cheese' appearance of heterochromatin on electron microscopy. Linkage and sequence analysis excluded mutations in the CDAN1 gene (607465).

Babbs et al. (2013) restudied the 3 sibs reported by Sabry et al. (1997). Hematologic features included megaloblastic erythropoiesis with severe dyserythropoietic changes, bi- and multinuclear erythroblasts, and internuclear chromatin bridges. All patients were severely affected, requiring transfusion support during childhood.

Inheritance

The transmission pattern of CDAN1B in the families reported by Babbs et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of 3 unrelated consanguineous families with congenital dyserythropoietic anemia type Ib, Babbs et al. (2013) identified 2 different homozygous missense mutations in the C15ORF41 gene (L178Q, 615626.0001 and Y94C, 615626.0002). The mutation in the first family was found by whole-genome sequencing, whereas the mutation in the other 2 families was found by direct sequencing of the C15ORF41 gene in 9 probands with the disorder. Functional studies of the mutations were not performed. Two of the families had previously been reported by Sabry et al. (1997) and Ahmed et al. (2006), respectively.

Exclusion Studies

By linkage analysis and direct sequencing, Ahmed et al. (2006) excluded mutations in the CDAN1 gene (607465) in the Kuwaiti sibs with CDA type I reported by Sabry et al. (1997). By the same methods, Ahmed et al. (2006) excluded the CDAN1 gene in 2 Pakistani sisters with CDA type I.