Precursor B‐cell acute lymphoblastic leukemia in a pediatric patient with Bainbridge–Ropers syndrome

Abstract

The additional sex combs like (ASXL) gene family, comprised of the ASXL1, ASXL2, and ASXL3 genes, encodes proteins involved in epigenetic regulation, embryogenesis, and carcinogenesis. [1][2][3] Despite the implication of somatic ASXL mutations in a variety of malignancies, germline ASXL mutations do not appear to have an association with increased malignancy risk. Bainbridge-Ropers syndrome (BRPS) is a rare autosomal dominant genetic disorder with an estimated 89 known cases 4 that results from de novo ASXL3 gene mutations, 5 characterized by poor growth, hypotonia, intellectual disability, language delay, and dysmorphic facial features. 6 Many affected patients have autism disorder, and approximately one-third of patients have epilepsy. 7,8 The few published reports of cancer in patients with germline ASXL mutations are limited to patients with ASXL1 mutations, implicated in Bohring-Opitz syndrome (BOS), a phenotypically similar neurodevelopmental syndrome to BRPS. These include two patients with bilateral Wilms tumor, 9 and a father and son with identical germline ASXL1 mutations with acute myeloid leukemia. 10 Unlike BOS, there are no reported cases of malignancy in patients with BRPS. Here, we report the clinical course of a 3-year-old male with BRPS found to have precursor B-cell acute lymphoblastic leukemia (ALL).At age 10 months, the patient underwent neurologic evaluation due to developmental delay, feeding difficulties, and growth failure. He was hypotonic and had subtle dysmorphic features, including arched eyebrows and anteverted nares. A trio-based Autism/ID Xpanded Panel (GeneDx, LLC 2019) sent with samples from biological parents demonstrated a de novo pathogenic variant (c.4678C>T; p.R2560X) in the ASXL3 gene (RefSeq transcript NM_030632.1, human genome build GRCH37/UCSC hg19), consistent with BRPS.At age 3 years, he presented with feeding intolerance, fatigue, and abdominal pain. Laboratory analysis showed white blood cells (WBCs) 12.7/mm 3 with 27% peripheral blasts, hemoglobin 8.3 g/dl, and platelet count 69,000/mm 3 . Peripheral flow cytometry identified an immature lymphoid population, consistent with precursor B-cell ALL (Table 1).Bone marrow analysis revealed no detectable clonal abnormalities on standard cytogenetics, and fluorescence in situ hybridization (FISH)

ASXL3‐related disorder: Molecular phenotyping and comprehensive review providing insights into disease mechanism

“…This is not relevant to ASXL3‐related disorder, which describes germline ASXL3 variants. There has been one report of cancer (precursor B‐cell acute lymphoblastic leukaemia) in a child with ASXL3‐related disorder 65 . Individuals with ASXL3‐related disorder are not thought to be at any increased risk of cancers.…”

PAX5 fusion genes in acute lymphoblastic leukemia: A literature review

“…Moreover, several inherited disorders have been linked to ALL, including Down syndrome, [ 7 ] Swyer syndrome, [ 8 ] and Bainbridge-Ropers syndrome. [ 9 ] It has been indicated earlier that there is a correlation between numerous germline alleles, variants passed down from parent to child, and somatic mutations in children with ALL. [ 10 , 11 ] Several alleles have been linked to ALL, including IKZF1, [ 12 ] PAX5, [ 13 ] and ETV6 [ 14 ] in the germline, and KRAS, NRAS, PTPN11, JAK2, and FLT3 [ 15 , 16 ] in the somatic mutations.…”

“…[ 29 ] A study uncovered adult B-ALL’s genetic and molecular architecture, revealing 2 distinct variants that aid in diagnosing patients with Swyer syndrome [ 8 ] and Bainbridge. [ 9 ] For this review, we will focus specifically on the role of PAX5 mutations in the development of ALL.…”