ESPE Abstracts

Background: Advances in genetic analysis techniques has greatly contributed to recent discovery of causative genes associated with overgrowth with intellectual disability (OGID). Tatton-Brown-Rahman syndrome (TBRS) (OMIM #615879) was one of them, characterized by tall stature, a distinctive facial appearance, and intellectual disability. This syndrome was first reported in 2014. Thus, long-term clinical courses are unknown. We present our Japanese case with OGID who was diagnosed TBRS by Whole Exome Sequencing supported by the IRUD (Initiative on Rare and Undiagnosed Diseases).

Case report: A 9-year-old Japanese girl first visited our outpatient clinic, complaining of tall stature and developmental delay. She was born from healthy nonconsanguineous parents (father 179 cm, mother 168 cm). She was born at 40 weeks’ gestation with a birth height of 51 cm, and body weight of 3604 g. She had no history of prenatal abnormalities. At six years developmental delay was pointed out. She had a distinctive face (round face, heavy horizontal eyebrows, and narrow palpebral fissures) and intellectual disability (IQ 68). Physical findings at age 10 were the following; height 166.4 cm (+3.9 S.D.), body weight 44.1 kg (+1.25 S.D.), arm span172 cm, breast development Tanner 3-4, no menarche, arachnodactyly, Marfanoid habitus. No abnormalities were found in endoclinological, cardiac and ophthalmological analysis. Laboratory findings are listed below; IGF-1 325 ng/mL, LH 5.4 mIU/mL, FSH 8.2 mIU/mL, estradiol 63 pg/mL, G-banding 46, XX. Urinary homocysteine was not detected. Cranial MRI showed no abnormalities. Bone age was 11.1 years. She received estrogen therapy from 10.8 to 13.6 years old (175 cm) to accelerate epiphyseal closures. At 26 years old her height was176 cm and body weight was 63kg. We performed a whole exome analysis for her excessive growth. It revealed de novo heterozygous mutation in the DNMT3A (DNA cytosine 5 methyltransferase 3A) gene (exon15, c.1761_1762del: p.G587fs. hetero), which was confirmed by Sanger Sequencing. No hematologic malignancy has been developed so far. She has spent her daily life without any special support and worked in disability employment.

Conclusion: TBRS resulted from constitutional mutations in the epigenetic regulation gene DNMT3A. Somatically acquired mutations in DNMT3A occur in hematological malignancies, but the association between OGID and malignancies has been veiled. Other epigenetic regulation genes such as NSD1, EZH2 and HIST1H1E cause OGID. Features specific to mutations of each gene should be elucidated. Case reports of OGID may help to make differential diagnosis and reveal risk of malignancies in OGID.