Somatic Mosaicism and Variable Expressivity in Diamond Blackfan Anemia (DBA): A Large Deletion Involving the 19q13 Locus in a Patient with Transient Anemia.

DBA (MIM 205900) is a rare, pure red blood cell aplasia of childhood due to an intrinsic defect in erythropoietic progenitors, accompanied by somatic malformations in about 40% of cases. Anemia is corrected by steroid treatment in half of patients; non-responders need chronic transfusions or stem cell transplantation. Heterozygous mutations in the RPS19 gene, mapping in the chromosomal region 19q13.2 and encoding for a ribosomal protein of the small subunit, are found in 25% of patients. Deletions spanning the 19q13 locus and involving RPS19 gene have yet been reported in literature; these patients showed more severe manifestations of the disease with skeletal malformations, profound anemia unresponsive to steroids needing regular red blood transfusions and mental retardation.

We report the first case of DBA due to mosaicism for a deletion on chromosome 19q13 involving RPS19 gene. The large deletion involving the maternal allele, spanning an interval restricted by loci D19S220 and D19S178, was identified by segregation analysis of 19q polymorphic markers. To assess the degree of mosaicism semiquantitative SNapShot analysis was performed with detection of one RPS19 copy in 60% of peripheral blood mononuclear cells. Mosaicism was also found in oral and urinary epithelium cells. Our patient had been affected since infancy by hyporegenerative anemia, that had spontaneously remitted at the age of ten; he showed neither malformations nor overt mental retardation. His parents and a brother are healthy and do not carry the deletion.

The involvement of tissues of different embryologic origin suggests that the deletion has appeared in an early stage of embryological development. Our findings explain the milder than expected phenotype and suggest that somatic mutations that lead to tissue mosaicism might contribute to variable expressivity of DBA. The presence of blood cells without deletion might also justify the observed hematologic remission. Mosaicism must be taken into account for genetic counselling in this patient.