TOP2B – B-cell immunodeficiency, distal limb anomalies, and urogenital malformations

The association between TOP2B deficiency and B-cell immunodeficiency with distal limb and urogenital malformations is supported by multiple unrelated cases and functional studies. To date, 14 patients from seven families have been reported with germline pathogenic variants in TOP2B under an autosomal recessive model, displaying consistent phenotypes including immunodeficiency, facial dysmorphism, limb anomalies, and urogenital defects ([PMID:40656194]). A newly described infant with de novo infantile epileptic spasms syndrome expands the phenotype and reinforces this gene–disease relationship.

Genetic evidence includes autosomal recessive inheritance, segregation in seven families, and 14 probands with loss-of-function and missense variants. The novel de novo variant c.1901A>G (p.Tyr634Cys) was identified in a child presenting with infantile spasms, hypsarrhythmia, developmental arrest, B-cell immunodeficiency, and dysmorphic facial features, further enriching the mutational spectrum ([PMID:40656194]). All reported variants impair TOP2B enzymatic function, and recurrence in multiple pedigrees supports pathogenicity.

Functional studies demonstrate that TOP2B haploinsufficiency disrupts neural development and transcriptional regulation. Knockout mouse models exhibit defects in postmitotic neuronal differentiation and survival, including retinal degeneration and reduced neuronal populations ([PMID:24463367]). Promoter analyses revealed critical NF-Y and Sp1 binding sites necessary for TOP2B transcriptional activity, suggesting dosage sensitivity ([PMID:12197834]). Concordant findings in neural differentiation assays and animal models underpin a loss-of-function mechanism.

No conflicting evidence has been reported for the association with B-cell immunodeficiency and urogenital anomalies. Rather, the phenotype continues to broaden, now encompassing infantile epileptic spasms as an inaugural presentation of TOP2B deficiency.

Key take-home: TOP2B should be included in genetic testing panels for autosomal recessive immunodeficiency syndromes with limb and urogenital anomalies, as identification of pathogenic variants enables early diagnosis, management of infections with immunoglobulin replacement, and anticipatory care for neurological complications.

References

• Frontiers in pediatrics • 2025 • Infantile epileptic spasms syndrome as a new phenotype in TOP2B deficiency caused by a de novo variant: a case report and literature review. PMID:40656194
• Molecular genetics & genomic medicine • 2020 • A de novo TOP2B variant associated with global developmental delay and autism spectrum disorder. PMID:31953910
• The Biochemical journal • 2002 • Characterization of the human topoisomerase IIbeta (TOP2B) promoter activity: essential roles of the nuclear factor-Y (NF-Y)- and specificity protein-1 (Sp1)-binding sites. PMID:12197834
• Biology open • 2014 • Topoisomerase IIbeta is required for proper retinal development and survival of postmitotic cells. PMID:24463367

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