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Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar DNMT3A R882 mutation
  1. Iris H I M Hollink1,
  2. Ans M W van den Ouweland1,
  3. H Berna Beverloo1,
  4. Susan T C J M Arentsen-Peters2,3,
  5. C Michel Zwaan2,3,
  6. Anja Wagner1
  1. 1 Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
  2. 2 Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Sophia Children’s Hospital, Rotterdam, The Netherlands
  3. 3 Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
  1. Correspondence to Iris H I M Hollink, Department of Clinical Genetics, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; i.hollink{at}


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.

  • DNMT3A
  • acute myeloidleukaemiaAML
  • overgrowth
  • Tatton-Brown-Rahman syndromeTBRS

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  • Contributors IH, AW and CZ clinically characterised the subject and collected the samples. AO, HB and TA-P performed the genetic studies and/or data analysis and interpretation. IH and AW designed the study and wrote the manuscript. All authors critically revised and approved the manuscript.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.