Fludarabine-based Reduced Intensity Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in a Pediatric Patient With Bone Marrow Failure Syndrome Type 3

Abstract

Bone marrow failure syndrome (BMFS) type 3 is a rare genetic heterogeneous disorder, considered to be one of Inherited BMFSs related to ribosomopathies. It caused by a novel Homozygous variant in DNAJC21 gene, which affects cytoplasmic maturation of 60S ribosomal, leading to increase cell death, and inhibits cellular proliferation causing shwachman-diamond Syndrome-like syndrome. Only 15 cases of BMFS type 3 have been published in the literature. Therefore, the full phenotypic spectrum and the experience of hematopoietic stem cell transplantation (HSCT) are limited. Herein, we report an uncomplicated HSCT from human leukocyte antigenidentical sibling for a BMFS-3 patient at 22 months of age, who suffered from chronic diarrhea, severe failure to thrive and cytopenia required transfusions. We used a reduced intensity conditioning regimen including fludarabine, low-dose cyclophosphamide, and antithymocyte globulin with cyclosporine for prevent graft versus host disease. This regimen was safe and sufficient to achieve rapid engraftment without significant toxicity. Although, Mixed chimerism between 80% and 90% was observed since day +30, she gained 2 kg during 12 months post-transplant and no need for transfusions has been reported any more. Thus, we recommend HSCT with fludarabinebased reduced intensity conditioning regimen in this syndrome as progressive cytopenia occurs and an human leukocyte antigenmatched family donor is available.

Case Report: Novel Biallelic Variants in DNAJC21 Causing an Inherited Bone Marrow Failure Spectrum Phenotype: An Odyssey to Diagnosis

“…Recognizing the inherited nature of bone marrow failure is crucial to prevent inappropriate treatment with immunosuppressant agents and to offer hematopoietic stem cell transplant with an adapted regimen, when needed. Importantly, identifying the genetic cause will help select the healthy donor and provide genetic counseling to the family (Barhoom et al, 2021). Even more, understanding the genetic cause may improve the management of several associated syndromic features.…”

“…The indication and optimal planning for bone marrow transplant remain to be established. An attenuated induction regimen was suggested, considering the probable high sensitivity to chemotherapeutic agents (D'Amours et al, 2018;Barhoom et al, 2021).…”

“…Failure to thrive was observed in the first 3 months of life. In infancy and childhood, he had Tummala et al, 2016;Dhanraj et al, 2017;Bluteau et al, 2018;D'Amours et al, 2018;Ji et al, 2019;Barhoom et al, He also had low weight for height with a body mass index (BMI) that ranged from −3.5 SD to −1.5 SD. Growth charts are presented in the supplementary file.…”

“…At the time of writing this report, 17 people with biallelic DNAJC21 pathogenic variants were reported. D'Amours et al reported 15 patients in 2018, while afterward, two more people were reported (Ji et al, 2019;Barhoom et al, 2021). Cardinal features involve multiple organs and systems as follows: bone marrow failure, growth retardation, failure to thrive, developmental delay, recurrent infections, and skeletal, skin, dental, and hair anomalies.…”

DNAJC21‐related thrombocytopenia in a young adult female

“…Bone marrow failure type 3 (BMFS3) (MIM:617052) is a subtype of inherited bone marrow failure syndromes (IBMFS) caused by homozygous pathogenic variants in DNAJC21 (Tummala et al, 2016). It was first defined in 2016, and to date, 19 patients have been reported from different ethnic groups (Barhoom et al, 2021; Chirita‐Emandi et al, 2022; D'Amours et al, 2018; Ji et al, 2019; Tummala et al, 2016). Besides the bone marrow failure findings, patients also present with variable extra hematopoietic features that overlap with Fanconi anemia (FA), Shwachman‐Diamond syndrome (SDS), dyskeratosis congenita (DC), and Diamond‐Blackfan anemia (DBA) (D'Amours et al, 2018).…”