DNAJC21 – Bone Marrow Failure Syndrome Type 3

Autosomal recessive bone marrow failure syndrome type 3 is a rare ribosomopathy caused by biallelic loss-of-function variants in DNAJC21, characterized by cytopenias, growth failure, gastrointestinal disturbances, and multisystem involvement. Only 15 cases have been reported to date (PMID:34935734).

Genetically, two unrelated probands have been described: one presenting with a novel homozygous DNAJC21 variant treated by HSCT (PMID:34935734), and an 8-year-old boy harboring compound heterozygous variants c.148C>T (p.Gln50Ter) and c.643_644delinsTTT (p.Lys215PhefsTer71) identified by genome sequencing (PMID:35464845). These biallelic predicted loss-of-function alleles segregate with disease in both families under an autosomal recessive model.

Clinically, affected individuals exhibit pancytopenia, severe failure to thrive, chronic diarrhea, recurrent infections, ectodermal abnormalities (skin, hair, teeth), skeletal dysplasia, joint hypermobility, ptosis, high myopia, and failure to thrive (PMID:34935734; PMID:35464845). Telomere shortening and multisystem overlap with Fanconi anemia, Shwachman-Diamond syndrome, and dyskeratosis congenita highlight diagnostic complexity.

Functional studies in a zebrafish dnajc21 knockout model recapitulate key patient phenotypes including cytopenia, impaired hematopoietic differentiation, reduced growth, and defective ribosomal maturation. Combined tp53 mutation accelerates myelodysplastic changes, and nucleoside supplementation rescues neutrophil counts, underscoring a loss-of-function mechanism (PMID:39138265).

Therapeutically, fludarabine-based reduced-intensity conditioning HSCT from an HLA-matched sibling achieved stable engraftment, weight gain, and transfusion independence without significant toxicity in a 22-month-old patient, supporting early transplant consideration in progressive cytopenia (PMID:34935734).

In summary, biallelic DNAJC21 loss-of-function variants cause autosomal recessive bone marrow failure syndrome type 3, with robust genetic and experimental evidence. Early molecular diagnosis enables tailored management including HSCT and metabolic support, improving clinical outcomes.

References

• Journal of Pediatric Hematology/Oncology • 2022 • Fludarabine-based Reduced Intensity Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in a Pediatric Patient With Bone Marrow Failure Syndrome Type 3. PMID:34935734
• Frontiers in Genetics • 2022 • Novel Biallelic Variants in DNAJC21 Causing an Inherited Bone Marrow Failure Spectrum Phenotype: An Odyssey to Diagnosis. PMID:35464845
• Leukemia • 2024 • Loss of Dnajc21 leads to cytopenia and altered nucleotide metabolism in zebrafish. PMID:39138265

Evidence Based Scoring (AI generated)