Evolution of Graves’ Disease during Immune Reconstitution following Nonmyeloablative Haploidentical Peripheral Blood Stem Cell Transplantation in a Boy Carrying Germline SAMD9L and FLT3 Variants

Abstract

Graves’ disease, characterized by hyperthyroidism resulting from loss of immune tolerance to thyroid autoantigens, may be attributable to both genetic and environmental factors. Allogeneic hematopoietic stem cell transplantation (HSCT) represents a means to induce immunotolerance via an artificial immune environment. We present a male patient with severe aplastic anemia arising from a germline SAMD9L missense mutation who successfully underwent HSCT from his HLA-haploidentical SAMD9L non-mutated father together with nonmyeloablative conditioning and post-transplant cyclophosphamide at 8 years of age. He did not suffer graft-versus-host disease, but Graves’ disease evolved 10 months post-transplant when cyclosporine was discontinued for one month. Reconstitution of peripheral lymphocyte subsets was found to be transiently downregulated shortly after Graves’ disease onset but recovered upon antithyroid treatment. Our investigation revealed the presence of genetic factors associated with Graves’ disease, including HLA-B*46:01 and HLA-DRB1*09:01 haplotypes carried by the asymptomatic donor and germline FLT3 c.2500C>T mutation carried by both the patient and the donor. Given his current euthyroid state with normal hematopoiesis, the patient has returned to normal school life. This rare event of Graves’ disease in a young boy arising from special HSCT circumstances indicates that both the genetic background and the HSCT environment can prompt the evolution of Graves’ disease.

Anti-Thymocyte Globulin (ATG)-Free Nonmyeloablative Haploidentical PBSCT Plus Post-Transplantation Cyclophosphamide Is a Safe and Efficient Treatment Approach for Pediatric Acquired Aplastic Anemia

“…We also observed both SAMD9L mutation-associated AA patients (Cases 2 and 9) not only showed evidence of immune-mediated pathophysiology resulting in AA but also presented with significantly shorter telomeres upon presenting with cytopenia. As demonstrated for Case 9 [ 18 ], telomere length deficiency could be corrected upon successful haploidentical PBSCT.…”

“…Six patients (Cases 1, 2, 4, 8, 9, 12) were subjected to whole-exome sequencing. Two patients (Cases 2 and 9) were identified as carrying missense SAMD9L variants among a panel of genes associated with inherited bone marrow failure at an allelic balance consistent with a germline origin and with a variant allele frequency (VAF) of 53.19% (SAMD9L p.W1435R) and 54.04% (SAMD9L p.C1267F), respectively, and confirmed by Sanger’s sequencing (Case 2: Figure 1 c, Case9: [ 18 ]). No other significant germline variants related to inherited bone marrow failure syndromes or telomeric disorders were identified.…”

“…Cases 1, 2, 3, 6, 9, 11 were found in association with other immune disorders, including preceding inflammatory bowel disease (IBD), preceding hemophagocytic lymphohistiocytosis (HLH), post-immunosuppressive treatment alopecia areata, post-transplantation Evans syndrome, post-transplantation Graves’ disease, and preceding idiopathic hepatitis, respectively. Cases 2 and 9 were also identified as carrying a germline SAMD9L mutation [[ 18 ] and see Figure 1 ]. Detailed descriptions of the patients having other immune disorders are as follows.…”

“…Leukocyte telomere lengths of seven of the AA patients, as well as the mothers of Case 2 and Case 9, respectively (both carriers of germline SAMD9L mutations), and age-matched controls were determined ( Figure 2 a). The two SAMD9L -mutation-associated AA patients, i.e., Case 2 ( Figure 2 b) and Case 9 [ 18 ], displayed shorter telomere lengths compared to age-matched controls.…”

“…None of the patients developed Epstein-Barr virus-associated post-transplantation lymphoproliferative disorders. One notable complication was occurrence of Graves’ disease in Case 9, which has been reported separately [ 18 ]. All six patients reached sustained complete response between days +17 and +158: Cases 7, 9, and 11 reached complete response within a month; the delayed complete response of Cases 8, 10, and 12 could be attributable to ABO/Rh incompatibility, severe infections, and menorrhea rebound after estrogen withdrawal, respectively.…”