Background Recently a novel syndromic form of overgrowth with intellectual disability and distinct facial features was identified caused by constitutional mutations in the epigenetic regulator DNA-methyltransferase 3A (DNMT3A), referred to as Tatton-Brown-Rahman syndrome (TBRS). Somatically acquired mutations in DNMT3A occur in haematological malignancies and are frequently present in acute myeloid leukaemia (AML) affecting in more than 50% the arginine residue at position 882 (R882). To date, additional cases with TBRS have been published but so far none of the reported cases with TBRS developed AML.

Methods and results Here we present the first case of TBRS who developed AML at the age of 15 years. Whole-exome sequencing identified a constitutional heterozygous DNMT3A R882C mutation. Our case exhibits macrocephaly, intellectual disability, distinct facial dysmorphism and other recurrent features fitting with the TBRS phenotype. The AML of the myelomonocytic subtype harboured only few additional somatically acquired mutations, that is, an aberrant karyotype and a recurrent PTPN11 mutation.

Discussion The peculiarity of the specific R882 mutation in contrast to other DNMT3A mutations is discussed, including the hypothesis of the more aggressive nature of this variant.

Our case represents the first evidence of the possible increased risk of the development of haematological malignancies in particular AML in cases with TBRS.