A De Novo Frameshift Mutation in RPL5 with Classical Phenotype Abnormalities and Worsening Anemia Diagnosed in a Young Adult-A Case Report and Review of the Literature

Abstract

Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome associated with malformations. DBA is related to defective ribosome biogenesis, which impairs erythropoiesis, causing hyporegenerative macrocytic anemia. The disease has an autosomal dominant inheritance and is commonly diagnosed in the first year of life, requiring continuous treatment. We present the case of a young woman who, at the age of 21, developed severe symptomatic anemia. Although, due to malformations, a congenital syndrome had been suspected since birth, a confirmation diagnosis was not made until the patient was referred to our center for an evaluation of her anemia. In her neonatal medical history, she presented with anemia that required red blood cell transfusions, but afterwards remained with a stable, mild, asymptomatic anemia throughout her childhood and adolescence. Her family history was otherwise unremarkable. To explain the symptomatic anemia, vitamin deficiencies, autoimmune diseases, bleeding causes, and myeloid and lymphoid neoplasms were investigated and ruled out. A molecular investigation showed the RPL5 gene variant c.392dup, p.(Asn131Lysfs*6), confirming the diagnosis of DBA. All family members have normal blood values and none harbored the mutation. Here, we will discuss the unusual evolution of this case and revisit the literature.

Keywords: Diamond–Blackfan anemia; RPL5; bone marrow failure; eltrombopag; erythroaplasia; pure red cell aplasia; ribosomopathy.

Figure 1

Pathophysiology of RPL and RPS mutations. RPL and RPS mutations can affect erythropoiesis in various ways that are emphasized in hematopoietic tissues. They lead to higher levels of p53, which, in its role as a tumor suppressor, leads to cell cycle arrest, thus impeding erythropoiesis. Reduced levels of heat shock protein 70 (HSP70) affect erythropoiesis through its interactions with the erythroid transcription factor GATA1 and p53. Additionally, the impaired balance in the heme/globin ratio leads to a detrimental increase in radical oxygen species.

Figure 2

Congenital anomalies. (A) Lateral cleft lip after surgical correction. (B) Polysyndactylie (“double thumb”), 2 pictures: childhood/adulthood. (C) Growth curve of the patient. As she was not treated with steroids in infancy, the accentuated growth retardation was partially corrected with the administration of somatotropin between the ages of 6 and 10 years’ treatment [15].

Figure 2

Congenital anomalies. (A) Lateral cleft lip after surgical correction. (B) Polysyndactylie (“double thumb”), 2 pictures: childhood/adulthood. (C) Growth curve of the patient. As she was not treated with steroids in infancy, the accentuated growth retardation was partially corrected with the administration of somatotropin between the ages of 6 and 10 years’ treatment [15].

Figure 3

Pedigree of the family. Proband is indicated by arrow. Symbols: □ = male, ○ = female; • = heterozygous mutation in the RPL5 gene, variant c.392dup, p.(Asn131Lysfs*6).