Challenges during diagnosis and curative hematopoietic stem cell transplantation for a

teenager with combined LRBA/XIAP deficiency

Background

We describe the challenges during hematopoietic stem cell transplantation (HSCT) in a

teenager with XIAP/LRBA deficiency.

Patients and methods

Master N is a 14 years old boy, first born to parents of non-consanguineous marriage. He was

well until one year of age when he started developing recurrent episodes of febrile illnesses

requiring admissions and intravenous antibiotics. In March 2020, he developed a perianal

abscess for which he received intravenous antibiotics. In April 2020, he was diagnosed with

DCT-negative autoimmune hemolytic anemia for which he received steroids for a period of 4

months, which were gradually tapered and stopped.

He presented to us with the above history in December 2020, when he required admission in

the pediatric intensive care unit for 48 hours for septic shock and perianal abscess. Whole

exome sequencing revealed a hemizygous missense variation in exon 2 of the XIAP gene

(p.Cys227Tyr; ENST00000371199.7), and a heterozygous missense variation in exon 12 of

the LRBA gene (p.Gly524Ser; ENST00000357115.9). He underwent TCR alpha/beta

depleted haploidentical HSCT from his father with peripheral blood stem cells and a CD34

dose of 10x10*6/kilogram recipient body weight.

Results

He achieved neutrophil and platelet engraftment by D+12 and D+30 respectively. Complete

donor chimerism was documented on several occasions. Post-HSCT course was complicated

by grade 3 gut graft versus host disease (GVHD), responsive to steroids and ruxolitinib. He
had documented cytomegalovirus reactivation for which he was started on ganciclovir and

cidofovir for persistent copies. He is now 6 months post HSCT, with complete chimerism,

and no active infections. His GVHD has settled and he remains on calcineurin inhibitors and

low dose tapering prednisolone.

Discussion

Hematopoietic stem cell transplantation (HSCT) can be challenging in inborn errors of

immunity, particularly in those with underlying immune dysregulation such as XIAP

deficiency and LRBA deficiency. XIAP deficiency is complicated by features of

hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD) which

can result in significant co-morbidities peri-transplant. Outcomes have been reported to be

superior if the HLH is in remission and immune dysregulation has been controlled. In our

patient, with heterozygous mutation for XIAP/LRBA deficiency, his presentation included

perianal abscess, septic shock and hemolytic anemia. IBD associated with XIAP deficiency

has been found to persist despite a successful HSCT and needs to be monitored closely.

Conclusion

HSCT with myeloablative conditioning is feasible and curative for XIAP/LRBA deficiency.

Close follow up for IBD and other features of autoimmunity is essential.