Hereditary spherocytic pyropoikilocytosis: Expanding the clinical and genetic spectrum of red blood cell membrane disorders Free

Red blood cell (RBC) membrane disorders are a phenotypically and genetically heterogeneous group, leading to hemolytic anemia of variable severity and caused by defects in several genes coding for proteins of the RBC membrane skeleton. Pathogenic variants of the SPTA1 gene may alter the quantity or quality of α-spectrin. Decreased quantity of this structural protein leads to the phenotype of hereditary spherocytosis (HS), disrupting the vertical association of the membrane skeleton with the lipid bilayer. Qualitative defects of the same protein disrupt the horizontal assembly of the membrane skeleton, causing hereditary elliptocytosis (HE) or hereditary pyropoikilocytosis (HPP). A mixed phenotype between HS and HE has also been described, named hereditary spherocytic elliptocytosis (HSE), characterized by the presence of sphero-ovalocytes and spherocytes and caused by truncated α- or β-spectrin chains (Jarolim et al, Br J Haematol. 1995, Fournier et al, Blood 1997).

Next Generation Sequencing (NGS) has afforded over the last 15 years a widespread genetic evaluation of patients with hereditary hemolytic anemias (HHA), revealing novel SPTA1 pathogenic variants which lead to shortened transcripts or may affect the assembly at the junctional complex, likely causing co-occurrent quantitative and qualitative α-spectrin abnormalities. Patients with these variants present with a hybrid phenotype between HS and HPP, therefore, termed hereditary spherocytic pyropoikilocytosis (HSPP). We present here clinical, morphological, and genetic characteristics of this underrecognized RBC membrane disorder.

Patients with HSPP have hemolytic anemia of variable severity and may require frequent or chronic transfusions. In severe cases, splenectomy improves anemia, providing transfusion independence. However, unlike HS, hemolysis continues intravascularly post-splenectomy with increased frequency of fragmented cells seen on peripheral blood smear. In contrast to HPP, increased osmotic fragility is noted, indicating decreased surface-to-volume ratio, spherocytes are present on the blood smear in addition to elliptocytes and fragmented poikilocytes, and ektacytometry provides a curve more indicative of HS rather than HE/HPP. Persistent intravascular hemolysis post-splenectomy is likely to indicate increased risks for post-splenectomy vascular complications.

We report ten patients from three unrelated families presenting with the phenotype of HSPP, as demonstrated by ektacytometry and blood smear review. NGS panel for HHA or whole exome sequencing identified the causative SPTA1 variants. In one family, who reportedly was diagnosed in the past with HE, the mother and two children were compound heterozygous for SPTA1 c.7091T>C p.(Leu2364Pro) in trans to SPTA1 α-LELY c.5572C>G;6531–12C>T p.[(Leu1858Val;?)]. The mother had splenectomy in young adulthood due to anemia and splenomegaly during her pregnancy and was later diagnosed with a transient ischemic attack and a subclavian artery thrombosis at the age of 41 with no other cause of thrombophilia identified. In a related branch of the same extended family, the father and two children had the same compound heterozygosity for SPTA1 c.7091T>C p.(Leu2364Pro) in trans to α-LELY (the mother was homozygous for α-LELY), with the same laboratory findings of HSPP. In a second family, the child had hemolytic anemia requiring frequent transfusions since infancy; genetic evaluation with family studies revealed that she was compound heterozygous for a maternally inherited SPTA1 p.(Lys1449Asn) variant on the α-LEPRA (c.4339-99C>T) background, and a paternally inherited p.(Arg1281Cys) variant on the α-LELY background. In the third family, two siblings with transfusion-dependent hemolytic anemia until splenectomy soon after the age of 5 were found to have a novel homozygous intronic variant in SPTA1 c.5834-18A>G, predicted to affect splicing. These siblings as well as the mother in the first family continue to have significant chronic reticulocytosis after splenectomy.

In conclusion, we define HSPP as a distinct clinical entity resulting from co-occurrent quantitative and qualitative defects in α- and β-spectrin. Accurate diagnosis is essential to guide management, avoid inappropriate treatment, and prevent complications. Total splenectomy should likely be avoided if not necessary, while if it is needed due to transfusion dependency, post-splenectomy thromboprophylaxis and monitoring may be advisable.