The genetic cause of Tatton-Brown-Rahman syndrome (TBRS) was first reported in 2014 and is characterized by intellectual disability and tall stature. Other common phenotypes include macrocephaly, autistic spectrum disorder, and distinct facial features (including low-set, heavy, horizontal eyebrows) (1–3). It is caused by pathogenic variants in the DNMT3A (DNA methyltransferase 3 alpha) gene, which is a DNA methyltransferase that adds de novo methyl groups to cytosine moieties and thus involved in epigenetic regulation of gene expression during development (1). Somatic mutations in DNMT3A are also commonly identified in acute myeloid leukemia (4–6). Most of the genetic variants causing TBRS are de novo, heterozygous DNMT3A missense variants, but microdeletions at 2p23.3 including DNMT3A have also been reported (1, 2).

The options available to prevent extreme tall stature in children are limited and includes estrogen (girls) or testosterone (boys) treatment, to advance skeletal maturation and therefore growth cessation, or surgical treatment to physically destroy selected growth plates and thereby limit growth. During percutaneous epiphysiodesis surgery the most accessible growth plates of the legs, ie. growth plates of distal femur, proximal tibia, and proximal fibula, are drilled and curetted to induce bone bridge formation in all quadrants of the growth plates (7) and thereby prevent most of the remaining leg growth. Previous studies have shown that epiphysiodesis surgery performed at the right time have the potential to significantly decrease the remaining growth of the legs and thereby reduce adult height in both males and females (7–9).

We report on the clinical outcome and genetic background of tall stature management with bilateral epiphysiodesis surgery in a girl with TBRS.

The subject of this case report participated in a study cohort for the evaluation of efficacy and safety of percutaneous epiphysiodesis surgery to prevent extreme tall stature (7), and a study of genetic causes for short and tall stature that was approved by the Swedish Ethical Review Authority, Sweden, (reference no. 2015/1787-31; 2018/581-32; 2021-01694) and written informed consent was obtained from the subject and her parents. Height, weight, head circumference were plotted on the Swedish growth charts, and z-scores were calculated using the Swedish growth reference data (10). For sitting height and sitting height index, the reference of Fredriks AM et al., was used (11). The evaluation of puberty was assessed according to the methods described by Tanner (12), while bone age was assessed by two independent readers according to the Greulich and Pyle method (13).

The patient underwent percutaneous epiphysiodesis due to a concern of extreme tall stature. Predicted final height based on bone age exam resulted in a final height of 187.1 cm (+ 3.4 SDS) whilst her actual adult height was similar at 187.4 cm. Similarities between her predicted final height and her adult height despite epiphysiodesis surgery could potentially be due to the lack of effect of the surgery. However, this is unlikely as the growth plates are identified and the position of the instruments are continuously monitored using an X-ray image intensifier (C-arm) and the surgery was performed by an experienced surgeon. A more likely explanation is that the height prediction underestimated the amount of remaining growth. Height predictions are based on normal populations with very few numbers and thus weak statistical power at the extremes and are not validated for individuals with specific growth syndromes. This interpretation is supported by the finding that the legs only grew less than 2 cm after the surgery whereas sitting height increased by more than 10 cm and arm span increased by more than 20 cm. In other words, if her legs would have grown as much as her arms, ie. 10 cm each, after the surgery, she would have reached an adult height of 195 cm or more.

The c.958 C > T nonsense variant in DNMT3A found in the proband has previously been reported in association with TBRS in the ClinVar database and also been reported in the Catalogue of somatic Mutations in Cancer (COSMIC) database (3). It introduces a premature stop codon, i.e., a nonsense variant, and is predicted to result in a truncated protein and is pathogenic according to FATHMM prediction. This variant likely results in a non-functional protein product, likely rendering the patient functionally haploinsufficient for DNMT3A. DNMT3A is a methyltransferase responsible for de novo methylation of cytosines in CpG dinucleotides, which is an epigenetic mark associated with repression of gene expression (17). Therefore, it may be speculated that the mechanism of overgrowth in TBRS involves derepression and thus increased expression of growth-promoting genes in growth plate chondrocytes. This would be a mechanism similar to the one we previously proposed for overgrowth in Weaver syndrome (18).

In summary, we report a young female with a rare, de novo variant in DNMT3A and TBRS who underwent percutaneous epiphysiodesis surgery that successfully limited the remaining growth of her legs. These findings support the pathogenicity of the c.958C>T (p.Arg320*) variant in TBRS, suggest that adult height predictions may underestimate the remaining growth in individuals with TBRS, and that percutaneous epiphysiodesis surgery may be considered in individuals with TBRS and other overgrowth syndromes in order to mitigate extreme tall stature.

All data included in this study are available from the corresponding author upon request.

The studies involving human participants were reviewed and approved by Etikprövningsmyndigheten, Uppsala, Sweden. The patients/participants provided their written informed consent to participate in this study.

OL retrieved data from the medical records, generated the table, and wrote the first draft of the manuscript. ON was responsible for the study design and the interpretation of the findings, generated the figures, retrieved data from the medical records and edited all versions of the manuscript. ML, E-LS, HW, and LS contributed expertise in diagnosis and management of tall stature syndromes and read and edited the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by grants from the Swedish Research Council (project K2015–54X-22 736–01–4 & 2015-02227), the Stockholm County Council, Novo Nordisk Foundation, Erik och Edith Fernström Foundation for Medical Research, HKH Kronprinsessan Lovisas förening för barnasjukvård, Sällskapet Barnavård, Stiftelsen Frimurare Barnhuset i Stockholm, Promobilia, Sällsynta Fonden, Nyckelfonden, and Karolinska Institutet, Stockholm, Sweden, and Örebro University, Örebro, Sweden.

ON has received consulting fees from Kyowa Kirin and Biomarin and speakers’ honoraria from Merck, Pfizer, Kyowa Kirin, Biomarin and research funds to the department of ON from Kyowa Kirin and Novo Nordisk Foundation.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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