Case of Twins with Rare Stem Cell Disorder Wins Best Overall Abstract at Congress on MPNs

The Best Overall Abstract Award at the 14th International Congress on Myeloproliferative Neoplasms was presented to Brynn Parsegov, MPAS, PA-C, concerning her and her fellow investigators’ research at the Huntsman Cancer Institute on a unique case of 2 patients with a rare stem cell disorder.¹

Parsegov discussed a pair of fraternal, or dizygotic, female twins diagnosed with essential thrombocythemia (ET). One twin, labeled Twin A in the study, was diagnosed at the age of 16 and the other, labeled Twin B, at the age of 17. Parsegov’s research led to the conclusion that the mutation leading to the disease developed in 1 twin and was transferred to the other via stem cells passing through the placenta.

“The occurrence of ET at such a young age in these twins, with sequential appearance of the ET phenotype in Twin B 15 months later, lets us hypothesize that the initial JAK2 mutation occurred in utero in Twin A, and was followed by subsequent transfer of 1 or a small number of JAK2-mutated stem cells to Twin B via placental anastomoses,” Parsegov explained in her presentation.

Myeloproliferative neoplasms (MPNs) arise from somatic mutations that may be acquired in childhood or as early as 33 weeks’ gestation in utero, affecting the stem cells in the bone marrow. These mutations may be more likely based on the function and self-renewal of stem cells.

Twin A presented in 2017 at the age of 16 with frequent migraines and easy bruising and bleeding and was found to have a platelet count of 1500 x 109/L, characteristic of ET. Moreover, she was found to have a JAK2 V617F mutation with variant allele frequency (VAF) of 40%, and a bone marrow biopsy then confirmed MPN with mild reticulin fibrosis. At this time, Twin B was found to be asymptomatic and negative for a JAK2 mutation, but 15 months later she presented with a platelet count of 700 x 109/L and showed a JAK2 mutation with a 4.8% VAF.

Now, at the age of 21, Twin A’s disease has transformed to myelofibrosis now managed with fedratinib (Inrebic). Twin B suffered a superior sagittal sinus thrombosis and was then started on hydroxurea (Hydrea) and apixaban (Eliquis). They were both assessed for clonal hematopoiesis with an X-chromosome transcription-based array, and Twin A’s granulocytes and platelets were found to be clonal from a single X chromosome going back to 2017. However, Twin B’s hematopoietic cells were polyclonal from both maternal and paternal X chromosomes.

The investigators concluded that the disease in both twins originated from a somatic mutation in Twin A. While dizygotic twins have 2 different placentas, they may fuse and create an anastomosis, which is a connection that stem cells could have passed between. This would lead to a case of chimerism, in which an organism contains cells with multiple sets of DNA. Parsegov said that chimerism may occur in 8% of dizygotic twins.

“Further supporting our conclusions that the initial somatic mutation occurred in Twin A was that she presented first, 15 months before her sister, had a higher VAF at diagnosis, is clonal, and clinically has more advanced disease,” Parsegov said.

However, the investigators’ work is ongoing, and they continue to research this case to rule out the event of a separate somatic mutation in Twin B, though it would be unlikely according to them. They are also working to confirm their conclusion by determining an identical extended JAK2 haplotype in the twins’ parents and their healthy sibling.

^Reference

^{Parsegov B, Song J, Kim SJ, Prchal JF, Prchal JT. Dizygotic twins with JAK2V617F mutation positive myeloproliferative neoplasms arising from a potential chimerism occurring through placental anastomoses. Presented at: 14th International Congress on Myeloproliferative Neoplasms; October 27-28, 2022; New York, NY.}