ESPE Abstracts (2016) 86 P-P1-815

6-Year-Old Girl with Mutation in DNMT3A - A New Overgrowth Syndrome

Ann-Margrethe Rønholta, Martin Boxila, Uffe Jensenb & Birgitte Hertza

aPaediatric Department Regional Hospital, Viborg, Denmark; bClinical Genetic Department Aarhus University Hospital, Aarhus, Denmark

Background: Overgrowth disorders are a heterogeneous group of conditions characterized by increased growth and other clinical features. Overgrowth may be apparent at birth and can be static or progressive. Some syndromes are associated with increased tumor risk.

Objective and hypotheses: A 6-year-old girl with accelerated growth rate was referred. She was born at term and was 55 cm long at birth (+2.4 SD). At 6 years, she was 134.4 cm tall (+3.7 SD) with a high growth rate at 8.9 cm/year. The weight was 30.2 kg (+2.3 SD). Her growth was above the range for her family. There were no signs of precocious puberty except an advanced bone age of more than 3 years. She had cognitive impairment and slightly retarded motor development. The only dysmorphic sign was heavy horizontal eyebrows. Because of the phenotype a mutation in the DNM3TA was considered.

Method: Standard DNA sequencing of all coding exons and flanking UTR regions of DNMT3A was performed.

Results: A de novo mutation (DNMT3A c.1232dup) was detected. In 2014, Katrina Tatton-Brown et al described a study where they found 13 different DNMT3A mutations in 152 individuals with overgrowth phenotype. A consistent phenotype was evident amongst the 13 individuals with DNMT3A mutations: distinctive facial appearance, tall stature and intellectual disability. DNMT3A is a frequently mutated gene in acute myeloid leukemia and have also been reported in other hematological malignancies.

Conclusion: When assessing a child with tall stature and intellectual disability mutations in DNMT3A is important to have in mind. In general, follow-up of children with overgrowth syndrome should be conducted due to the potential increased tumor risk. However, the DNMT3A related tumor risk may be linked to a different mechanism and may not be present in patients with truncating mutations.

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