Unique Familial MLL(KMT2A)-Rearranged Precursor B-Cell Infant Acute Lymphoblastic Leukemia in Non-twin Siblings

Area of Science:

• Pediatric Oncology
• Hematology
• Genetics

Background:

• Infant acute lymphoblastic leukemia (ALL) is typically confined to monozygous twins due to twin-to-twin metastases.
• Familial occurrence of infant ALL in non-twin siblings is exceptionally rare.

Observation:

• A family presented with two non-twin siblings diagnosed with mixed-lineage leukemia-rearranged (MLL-R) ALL, 26 months apart.
• One affected sibling had a dichorionic monozygous co-twin who was unaffected.
• Both affected siblings experienced fatal outcomes.

Findings:

• Genetic analyses revealed distinct MLL-rearranged ALL subtypes in the siblings, with no evidence of vertical transmission or related translocations.
• The complex karyotype in one sibling suggested a potential genotoxic insult, though no specific exposure was identified.
• The probability of such an occurrence by chance alone is extremely low (1 in 1.198 × 10^9 families).

Implications:

• MLL-R infant ALL can occur in non-twin siblings through mechanisms other than chance, possibly involving transplacental exposure or an unknown predisposition.
• The discordance in monozygous twins suggests dichorionic placentation may play a role in differential susceptibility.
• This case underscores the need for further investigation into rare familial patterns of infant leukemia.