Tatton-Brown-Rahman Syndrome (DNMT3A)

An overgrowth–intellectual disability syndrome caused by germline loss of function of DNMT3A, with a DNA hypomethylation signature, predisposition to haematological neoplasms, and aortic disease; it includes Heyn-Sproul-Jackson syndrome, the reciprocal allelic gain-of-function disorder.

Literature and regulatory information updated: 18 October 2026.

0. Reference Summary Table

1. Introduction

1.1. Discovery and founding paper

Tatton-Brown-Rahman syndrome (TBRS) was described in 2014 by the Childhood Overgrowth Study group at the Institute of Cancer Research in London, led by Katrina Tatton-Brown and Nazneen Rahman, whose surnames gave rise to the eponym [27]. Exome sequencing of 10 proband–parent trios with overgrowth identified two de novo variants in DNMT3A; targeted sequencing of the gene in another 142 individuals with overgrowth found 11 additional de novo variants, for a total of 13 in 152 cases, versus none in 1000 UK controls (p < 0.0001) [27]. The 13 patients had tall stature (mean +3.0 SD), increased HC (mean +2.5 SD), a round face, heavy horizontal eyebrows, and narrow palpebral fissures; ID was moderate in 11 and mild in 2, and none had a haematological neoplasm [15]. The variants affected the functional domains of the protein, and structural modelling suggested interference with interdomain interactions and histone binding, without in vitro functional studies [15]. The authors proposed the name DNMT3A overgrowth syndrome, which the Washington University (St. Louis) group retains under the acronym DOS [3, 12, 15].

1.2. Clinical delineation and phenotypic expansion

In 2017, analysis of 710 individuals with overgrowth (height and/or HC ≥ +2 SD) and ID identified the cause in one of 14 genes in 50% (353/710); six epigenetic regulator genes (NSD1, EZH2, DNMT3A, CHD8, HIST1H1E, and EED) accounted for 44% (311/710), placing DNMT3A among the main causes in this group [28]. In 2018, the same group published a clinical series of 55 individuals with de novo constitutional variants, including the original 13, which defined ID and overgrowth as major associations (≥80%) and an evolving facial gestalt, joint hypermobility, obesity, hypotonia, behavioural and psychiatric problems, kyphoscoliosis, and afebrile seizures as frequent associations (20–80%) [18]. The 2022 GeneReviews chapter compiled more than 90 published cases [1]; in 2024, the French national series counted 100 individuals with de novo variants described in the literature [29]. From 2017 onward, reports accumulated of acute myeloid leukaemia (AML) in germline carriers of Arg882 variants [30–32], and in 2022 the series by Ferris and colleagues, built with the patient organisation, proposed classifying TBRS as a haematological cancer predisposition syndrome [3]. Between 2023 and 2026, aortic disease with dissection [19, 33], cardiomyopathy [34], multiple endocrine neoplasia [35], melanoma [36], familial spontaneous pneumothorax [37], and non-malignant haematopoietic and immune abnormalities [38, 39] were added to the phenotype.

1.3. Heyn-Sproul-Jackson syndrome

In 2019, Heyn, Sproul, Jackson, and colleagues in Edinburgh described three unrelated patients with microcephalic dwarfism and de novo missense variants in the PWWP domain of DNMT3A, with hypermethylation of genomic regions regulated by the Polycomb complex; the eponym combines the surnames of the lead authors [10, 14]. OMIM describes HESJAS (OMIM 618724) as the reciprocal phenotype of TBRS, with microcephaly and short stature instead of macrocephaly and tall stature [4]. In 2023 a fourth patient, with craniosynostosis, was published [14], and ClinGen curation classified the gene–disease relationship as limited [16].

1.4. Nomenclature and definition of the entities

TBRS (OMIM 615879; ORPHA:404443) is defined by a heterozygous pathogenic or likely pathogenic germline loss-of-function variant in DNMT3A in an individual with a compatible phenotype, i.e., overgrowth and ID of variable severity; there are no consensus clinical criteria [1, 2]. HESJAS (OMIM 618724; ORPHA:658595) is defined by a germline gain-of-function variant in the PWWP domain together with microcephalic dwarfism and global developmental delay [4, 5]. The 1.5-Mb contiguous deletion at 2p23.3 that includes DNMT3A produces a predominantly TBRS phenotype and is treated as part of the spectrum [1, 40]. Somatic DNMT3A variants in clonal haematopoiesis and adult haematological neoplasms do not constitute TBRS and do not imply hereditary predisposition [1]. Germline gain-of-function variants in patients with paragangliomas [41, 42] and the congenital myopathy with rhabdomyolysis described in one patient [43] are isolated reports without their own OMIM phenotype entry, discussed as allelic phenotypes in section 2.

2. Molecular Genetics and Pathophysiology

2.1. The DNMT3A gene and protein

DNMT3A maps to 2p23.3 (NC_000002.12; chr2:25,227,874–25,342,590 on GRCh38) and encodes one of the de novo DNA methyltransferases, which catalyse the conversion of cytosine to 5-methylcytosine at CpG dinucleotides [6, 7, 16]. Maintenance of methylation after replication is the role of DNMT1; DNMT3A establishes methylation patterns during development and is required for parent-of-origin methylation of most imprinted loci in germ cells and for the re-establishment of methylation during embryogenesis [1, 6, 44, 45]. According to the original description, the gene has 26 exons, with alternative noncoding first exons, and gives rise to two main protein isoforms: the long isoform DNMT3A1, with an N-terminal domain, the PWWP (proline-tryptophan-tryptophan-proline) domain, the ADD (ATRX-DNMT3-DNMT3L–type zinc finger) domain, and the C-terminal catalytic methyltransferase (MTase) domain; and the short isoform DNMT3A2, transcribed from within intron 6 and lacking the 223 N-terminal residues [11]. The PWWP domain recognises dimethylated and trimethylated lysine 36 of histone H3 (H3K36me2/3) and directs DNMT3A to gene bodies and intergenic regions, keeping it away from CpG islands [10, 11]. This reading of the H3K36me mark links DNMT3A to the histone methyltransferases NSD1 and SETD2, which deposit it; NSD1 haploinsufficiency causes Sotos syndrome, which explains the phenotypic convergence between the two syndromes [10, 46].

2.2. Mechanism of TBRS: loss of function and hypomethylation

Truncating variants, splice variants, and whole-gene deletions cause haploinsufficiency; missense variants cluster in the PWWP, ADD, and MTase domains and produce a hypomethylation pattern similar to that of loss-of-function variants [1, 12]. In mouse models and in patients, TBRS variants are associated with a characteristic hypomethylation signature with broad effects on gene expression [1]. Overgrowth-associated PWWP variants, such as p.(Trp297del) and p.(Ile310Asn), reduce protein levels through instability, unlike HESJAS variants [10]. Whole-genome bisulfite sequencing (WGBS) of peripheral blood from 11 patients (3 with an Arg882 variant and 8 with other variants, including one gene deletion) showed canonical focal hypomethylation in all, more severe with Arg882 variants [12]. In a lymphoblastoid cell line from a patient with deletion of residue 297, global methylation was 60.34% versus 66.77% in the control sibling, with preferential hypomethylation at enhancers and 1068 differentially methylated regions (DMRs), including the HOXA cluster [38].

Arg882 variants (p.Arg882His, p.Arg882Cys, and others) account for more than half of somatic DNMT3A variants in AML and encode a dominant-negative protein: the mutant protein does not form active homodimers (activity reduced by about 80%) and sequesters the wild-type protein into inactive heterodimers, blocking the formation of active tetramers [12, 47]. This dominant-negative effect explains the more pronounced hypomethylation in germline carriers of Arg882 variants and may explain their higher frequency among patients with neoplasms [1, 12]. Single-cell RNA sequencing in a patient with p.(Arg882His) at age 14 years, compared with his sibling, showed fewer naïve CD4+ T cells (13.94% vs 4.77%) and more natural killer (NK) cells (3.09% vs 15.88%) and NKT cells (T cells with NK markers), with 242 differentially expressed genes, of which only 38 lay within 10 kb of a DMR [12]. The germline Dnmt3a R878H/+ mouse (murine numbering, homologue of human p.(Arg882His)) recapitulates the phenotype: weight divergence after 100 days (37.73 g vs 31.2 g at 380 days), increased fat mass without increased lean mass and without hyperphagia, a longer femur, and altered exploratory behaviour, learning, and anxiety [12].

2.3. Mechanism of HESJAS: gain of function and hypermethylation of Polycomb regions

In HESJAS variants, tryptophan 330 and aspartate 333 form part of the "aromatic cage" of the PWWP domain that surrounds methylated lysine 36; structural modelling predicted that p.(Trp330Arg) destabilises the interaction, and binding assays confirmed that the mutant PWWP binds neither H3K36me2 nor H3K36me3 [10]. Unlike overgrowth-associated PWWP variants, the orthologous murine W326R protein (murine numbering, homologue of human p.(Trp330Arg)) is stable [10]. Fibroblasts from patients with p.(Trp330Arg) had 1878 shared DMRs, mostly hypermethylated (1140), with the same signature in peripheral blood leucocytes and in the patient with p.(Asp333Asn); these DMRs were absent in patients with TBRS [10]. The hypermethylation extended over tens of kilobases across "DNA methylation valleys" (DMVs), normally hypomethylated Polycomb-marked (H3K27me3) regions containing developmental genes such as HOX, SOX1, and FOXA1, with a secondary reduction of H3K27me3 and H3K4me3 in these regions and normal total levels of EZH2 and H3K27me3 [10]. Loss of H3K36me2/3 reading relocates the mutant protein to CpG islands enriched in H2AK119ub ubiquitination, deposited by the PRC1 complex, which explains the hypermethylation of CpG islands [11]. In W326R murine stem cells, hypermethylation emerged with differentiation, with a transcriptional shift towards neurogenic genes; W326R/+ mice were viable and proportionately small, with reduced body and brain weight [10]. The authors proposed that the gain of function prematurely depletes progenitors and reduces the final cell number, the opposite of the TBRS mechanism [10].

2.4. Variant spectrum and nomenclature

In the series of 55 individuals, the spectrum comprised missense variants in 36 (30 distinct variants), stop gain in 6, frameshift in 6, whole-gene deletions in 4 (including identical twins), in-frame deletions in 2, and one splice-site variant [18]. In the patient organisation database analysed by Tovy and colleagues, the variants of 48 individuals were distributed across the PWWP, ADD, and MTase domains, with about 30 novel variants and 2 whole-gene deletions [38]. Sequencing detects more than 90% of pathogenic variants, and targeted deletion/duplication analysis less than 10% [1]. The germline spectrum of TBRS overlaps with that of sporadic haematological neoplasms [32]. The table lists recurrent or illustrative variants, normalised to the MANE Select transcript NM_022552.5 by conversion through the genomic coordinate in VariantValidator or via the ClinVar record; c. and p. numbering is identical on NM_175629.2, the transcript used in GeneReviews and most articles [8, 9].

The conflicting classifications of p.(Tyr735Ser), p.(Arg736Cys), and p.(Arg635Gln) partly reflect the nature of DNMT3A as a clonal haematopoiesis gene: somatic alleles acquired with age appear in blood-derived population databases, which limits the use of gnomAD frequency as a criterion against pathogenicity [1, 18, 34]. The historical designation R882H/R882C corresponds, without conversion, to p.(Arg882His)/p.(Arg882Cys) on the MANE transcript; the splice variant c.1012_1014+3del was validated in VariantValidator as NM_022552.5:c.1012_1014+3del, with protein effect p.? [8]. Some variants in other reports were published by the authors on NM_022552.5, such as c.1585G>A p.(Asp529Asn) in the ADD domain, c.1443C>A p.(Tyr481Ter), c.1627G>C p.(Gly543Arg), and c.2635A>G p.(Asn879Asp), and are reproduced as published [37, 49–51].

2.5. Genotype–phenotype correlations, penetrance, and expressivity

Of the 8 patients with a haematological neoplasm in the Ferris series, 5 had missense variants at Arg882, as in sporadic neoplasms, suggesting that germline variants at this residue confer a higher risk [1, 3]. Of the 5 patients with psychotic symptoms described at that time, 4 had missense variants clustered in the MTase domain [1, 18, 48]. In the peer review of the 2018 series, W. Shen noted that all individuals without overgrowth had missense variants and that all carriers of truncating variants or deletions had overgrowth; two carriers of Arg882 variants did not have overgrowth (height −0.2 SD and HC −0.8 SD in one of them), an observation that did not derive from formal analysis [18]. Families with vertical transmission show variable expressivity: in the Belgian family, the carrier father had no ID but had autistic traits, polyarthrosis, and late-onset lymphocytosis, whereas his son had ID, epilepsy, and psychiatric problems [34]; in the Brazilian family, the father and half-brother had a mild phenotype [13]. Adults diagnosed late because of aortic disease, cardiomyopathy, endocrine neoplasia, or pneumothorax show that a mild phenotype can go undiagnosed into adulthood [33–35, 37].

2.6. Allelic disorders and related entities

Besides HESJAS, germline gain-of-function DNMT3A variants have been described in patients with paragangliomas: de novo p.(Lys299Ile) in a 22-year-old woman with laryngeal, carotid, and jugulotympanic paragangliomas, and p.(Arg318Trp) in a 54-year-old woman with two head and neck paragangliomas, both with a hypermethylated tumour profile [11, 41]. The p.(Gly332Arg) variant, located between the HESJAS residues, was found in a patient with bilateral carotid paragangliomas, papillary thyroid carcinoma, and ID, with hypermethylation in saliva [42]. These variants lose H3K36me reading and relocate the protein to CpG islands, like those of HESJAS [11]. A patient with congenital myopathy, episodes of rhabdomyolysis, severe myalgia, and features of TBRS had a de novo missense variant with a methylation profile identical to that of haploinsufficient cases [43]. The 1.5-Mb deletion at 2p23.3 that includes DNMT3A and adjacent genes produces a predominantly TBRS phenotype [1, 40].

Somatic DNMT3A variants are established drivers of clonal haematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS) and are included in the myeloid and lymphoid panels recommended for haematological neoplasms [52, 53]. In sporadic AML, Ley and colleagues found somatic DNMT3A variants in 62 of 281 patients (22.1%), 37 of them at residue Arg882, and none in the 79 patients with a favourable-risk cytogenetic profile [11, 54]. DNMT3A variants are an independent predictor of poor prognosis in AML and an early event in clonal haematopoiesis, predisposing to but insufficient for transformation [54, 55]. In nodal follicular helper T-cell lymphoma, coexisting somatic TET2, DNMT3A, and IDH2 variants are associated with an adverse prognosis [52]. DNMT3A CHIP is associated with adverse outcomes in the general population [53]. A DNMT3A variant found in a blood sample therefore cannot be presumed to be germline (section 5.5) [6].

2.7. Dosage sensitivity and gene–disease validity

ClinGen assigns DNMT3A a haploinsufficiency score of 3 (sufficient evidence) and a triplosensitivity score of 0 (no evidence) [16]. The ID and autism curation group classified the relationship with TBRS as definitive (2023-06-08) and the relationship with HESJAS as limited (2023-06-07) [16]. The loss-of-function constraint score (pLI) of DNMT3A in gnomAD v4.1.0 is 0, with a missense Z score of 2.78; Braz and colleagues showed high constraint at codon 635 of the MTase domain, where 16 of the 20 possible substitutions are predicted to be pathogenic [13]. Haploinsufficiency rests on whole-gene deletions and truncating variants in patients with the full phenotype [1, 16].

3. Clinical Spectrum and Manifestations by System

3.1. Reference cohorts

The natural history of TBRS is known mainly from case series ascertained through genetics services, predominantly children and patients with ID, which limits frequency estimates in adulthood and in mild phenotypes [1, 18]. There are no prospective population-based cohorts; the available data describe untreated disease in the sense of no targeted therapy, and treated complications (leukaemia, aortic surgery, epilepsy) are reported case by case.

3.2. Frequency of manifestations

Orphanet frequencies, based on the HPO system, diverge from those of GeneReviews: macrocephaly is listed as very frequent (80–99%) and joint hypermobility as occasional (5–29%), whereas clinical series give about 50% and about 75%, respectively [1, 2]. Frequencies from series with an explicit denominator are preferable.

3.3. Growth

Overgrowth is present from early childhood. At birth, in the subset with data, mean weight was +1.3 SD (−1.1 to +4.0), mean HC +2.3 SD (+0.6 to +6.5), and mean length +1.6 SD (0.0 to +4.4) [1, 18]. In childhood and adulthood, height ranges from −0.3 to +6 SD, HC from −1.2 to +8.0 SD, and weight from −1.1 to +4.5 SD; absence of overgrowth, seen in fewer than 20% of patients, does not exclude the diagnosis [1]. TBRS is more strongly associated with increased weight than the other overgrowth–ID syndromes, often with rapid weight gain in late childhood [18, 57]. In the R878H/+ mouse model, increased fat mass arose without hyperphagia and with normal leptin, triglycerides, cholesterol, glucose, and free fatty acids [12].

3.4. Facial gestalt and dysmorphic features

The facial gestalt is less recognisable than in Sotos syndrome and becomes more characteristic in early adolescence, being less specific in early childhood and in adulthood [1, 18]. It includes a round face with coarse features (loss of definition of the nose, lips, mouth, and chin), heavy, horizontal, low-set eyebrows close to the orbit, vertically narrow palpebral fissures, and large, prominent upper central incisors [1, 18]. Short, widely spaced toes are frequent, without a quantified prevalence [1, 18]. The French series added hypertrichosis [29]. Automated facial analysis tools (Face2Gene) suggested TBRS in isolated reports, sometimes ranking it second after Sotos syndrome [34, 49].

3.5. Neurodevelopment, cognition, and behaviour

All published individuals have some degree of developmental delay or ID [1]. Of the 83 described in detail in GeneReviews, ID was mild in 23 (28%), moderate in 48 (58%), and severe in 12 (14%); with mild ID, mainstream schooling with support and independent adult living are expected; with moderate ID, language development and supported or sheltered adult living; and with severe ID, special education and considerable support in adulthood [1]. In the series of 55, the distribution was 18%, 65%, and 16% [18]. In the study by Lane and colleagues (n=18, 7–33 years), mean general conceptual ability was 53 (39–76), with nonverbal and spatial reasoning more affected than verbal reasoning; 8 of 18 (44%) met autism criteria on the ADOS-2 (Autism Diagnostic Observation Schedule, 2nd edition), and autistic traits were less prevalent in older individuals, in a cross-sectional design that does not allow conclusions about improvement with age [1, 56].

In the series of 55, behavioural or psychiatric problems (28/55) included ASD in 20, anxiety in 3, neurodevelopmental regression in 4 (2 in adolescence), psychosis or schizophrenia in 3, aggressive outbursts in 2, and bipolar disorder in 2 [18]. The Spanish series of 7 patients described neuropsychiatric disease in 4, including schizophrenia and psychotic behaviour [48]. A young Saudi adult with ASD and attention-deficit/hyperactivity disorder (ADHD), treated with methylphenidate in childhood, had regression in early adulthood, with loss of speech and self-care, incontinence, and psychotic symptoms, associated with gastrointestinal disease [58]. The hypothesis that catalytic dysfunction of the MTase domain affects brain metabolic pathways lacks longitudinal confirmation [1]. In the R878H/+ mouse, reduced exploratory behaviour, deficits in voluntary movement, and altered learning, memory, and anxiety were observed [12].

3.6. Nervous system: epilepsy and neuroimaging

Seizures occur in about 20% (afebrile seizures in 12/55), both febrile and afebrile, with little information on seizure types, age at onset, or comparative efficacy of antiseizure medications [1, 18]. In the patient organisation registry, more than half of participants had had at least one seizure (unpublished data) [17]. Datta described a girl with focal seizures at age 2.5 years and developmental and epileptic encephalopathy with spike-wave activation in sleep (DEE-SWAS) at 3.5 years, with spike-wave discharges occupying more than 80% of NREM sleep and regression of sphincter control, gait, and language; magnetic resonance imaging (MRI) showed incomplete right hippocampal inversion [21]. MRI shows no specific abnormalities; ventriculomegaly and Chiari malformation occur in fewer than 10% [1]. In a Spanish study of 4 patients with structural MRI and tractography, all had corpus callosum abnormalities, a small posterior fossa, a deep left Sylvian fissure, asymmetry of the uncinate and arcuate fasciculi, and increased cortical thickness, findings the authors consider underappreciated [59]. The French series described neurological and electroencephalographic (EEG) findings in detail [29]. Cerebral atrophy has been described in adults [34, 48].

3.7. Musculoskeletal system

Generalised joint hypermobility is frequent and may be associated with musculoskeletal pain and joint instability; dislocations are rare [1]. Kyphoscoliosis occurs in about 30% and hypotonia in most patients, sometimes requiring physiotherapy [1, 18]. Adults may have polyarthrosis [34]. Severe pectus excavatum prompted the evaluation that detected aortic root dilatation in a 10-year-old patient [17].

3.8. Cardiovascular system

Cardiovascular disease was initially estimated at about 10%, mainly congenital heart disease (atrial septal defect, ventricular septal defect, patent ductus arteriosus) and aortic root dilatation [1]. In the series of 55, 9 patients had cardiac anomalies: atrial septal defect, mitral or tricuspid regurgitation, patent ductus arteriosus (in identical twins with a deletion of more than 40 genes), aortic root dilatation, and atrioventricular reentrant tachycardia [18]. Single cases of mitral valve prolapse, dilated cardiomyopathy, and arrhythmia have been described [1, 60]. In 2022, GeneReviews recorded no aortic dissection or sudden death, and it was unknown whether the dilatation was static or progressive [1].

Subsequent data changed this picture. Totten and colleagues described 8 new patients with arterial dilatation and/or dissection, mainly thoracic aortic aneurysm, and reviewed 7 published cases (15 in total); 3 of the 8 had dissection requiring emergency surgery, and the authors concluded that arterial disease is a potentially lethal, age-dependent manifestation, with a prevalence far higher than in the general population and possible involvement of other arteries [19]. In a Lithuanian family with p.(Ser775Tyr), diagnosed in adulthood, the 34-year-old proband had progressive aortic dilatation, mitral regurgitation, left ventricular dilatation, and ventricular arrhythmias, and his mother and brother had mitral regurgitation, left ventricular dilatation, and arrhythmias [33]. In the Belgian family, father and son had cardiomyopathy, aortic root dilatation, mitral valve prolapse, and arrhythmia [34]. A 13-year-old child with c.2408+1G>A (NM_175629.2) had a large pericardial effusion, left ventricular dilatation, mitral annular disjunction, and mitral valve prolapse with moderate regurgitation [61]. The patient organisation registry reports heart disease or a structural anomaly in about 54% of participants (unpublished data, with possible participation bias) [17]. The patient organisation's compilation lists 15 cases of aortic dilatation or dissection:

Source: TBRS Community, Appendix 1, compiled from Totten 2024, Zebrauskiene 2024, Kumps 2023, and others, without case-by-case attribution [17].

3.9. Respiratory system and sleep

Central sleep apnoea has been described in several patients [1, 62]. British identical twins with mild ID, identified through the 100,000 Genomes Project, had spontaneous pneumothorax at age 24 years (right-sided, with apical bullae, treated by video-assisted thoracoscopic surgery after failed chest drainage) and at 27 years (bilateral, with pleurectomy), with arm span exceeding height (2.04 m vs 1.85 m) and Beighton scores of 6/9 and 5/9; the familial pneumothorax panel was negative, and the de novo variant c.1585G>A p.(Asp529Asn) was reclassified from VUS to likely pathogenic after parental testing and methylation profiling [37]. An earlier report of a father and son with p.(Arg736Cys) included pneumothorax in the son [37].

3.10. Non-malignant haematopoiesis and immunity

In the Baylor cohort, total leucocytes, haemoglobin, and erythrocytes did not differ from controls, but there was an increased percentage of neutrophils, reduced monocytes and lymphocytes, and increased mean corpuscular volume (MCV) and mean corpuscular haemoglobin without a change in concentration: 10 of 14 patients had an MCV ≥90th percentile and 8 of 14 above the 97th percentile for age and sex at least once [38]. Flow cytometry (15 patients, 10 controls) showed neutrophil expansion, a relative reduction in CD19+, CD20+, and CD22+ B cells, and an increased CD4/CD8 ratio [38]. One of the 18 patients had hypogammaglobulinaemia requiring intravenous immunoglobulin; the authors suggest measuring immunoglobulins, especially in the presence of recurrent infections, and consider isolated macrocytosis a probably benign variant that warrants only observation [38]. The scoping review of chromatinopathies identified one published case of chronic lymphoproliferative disorder of NK cells and suggests that immune dysregulation may be underestimated [39]. A girl with p.(Gly543Arg) had immune thrombocytopenic purpura at 5 months, without a demonstrated association [50].

3.11. Haematological neoplasms

The series by Ferris and colleagues gathered 8 patients with a haematopoietic neoplasm and 1 with chronic multilineage cytopenias, recruited with the patient organisation in the USA, UK, Netherlands, and Norway; median age at diagnosis was 9.6 years according to the authors, with equal numbers of males and females and variants scattered throughout the gene, Arg882 being the most frequent site [3]. The table reproduces Table 1 of the article, supplemented by the supplementary material; AML subtypes follow the French-American-British (FAB) classification:

Source: Ferris 2022, Table 1 and Supplementary Appendix [3]. The DNMT3A variants refer to NM_022552.5; Ferris gives only the historical protein designation (Y528X, I310F, Y735C), and the c. notation for I310F and Y735C is that of the Braz 2026 review, confirmed in VariantValidator; the nucleotide change for Y528X was not published (c.1584C>A and c.1584C>G both produce p.(Tyr528*)) [3, 8, 13]. Ages at diagnosis range from 1.6 to 34 years, and the AML cases occurred at 12, 12, 15, and 20 years. The 2.5- to 12-year range given in GeneReviews does not match the original table, because 2.5 is the follow-up time of case 5 [1, 3]. OMIM assigns the R882C variant to the patient with the CLTC variant (Ferris case 3; Balci patient 5), but the Ferris supplement and the Balci abstract give p.(Arg882His), which is adopted here [3, 15, 62].

With 202 cases known to the patient organisation in October 2021 (maximum age 39 years, mean 14), the authors estimated a prevalence of haematopoietic neoplasia of about 4% (8/202) and, by comparison with the incidence of leukaemia and lymphoma from 0 to 39 years (about 150 per million), an increase that could exceed 250-fold [3]. This estimate is subject to ascertainment bias and uses a patient-community denominator; it is neither a cumulative incidence nor a cohort relative risk, and the lifetime risk remains unknown because most patients are young [1, 3]. In the 2018 series, AML occurred in 1 of 55 and, including the cases published at the time, in 2 of 77 individuals with constitutional variants, numbers the authors considered insufficient to quantify the risk [18]. In the TARGET paediatric AML database, Ferris identified two patients with germline variants (p.(Arg882His) with IDH2 R172K, and p.(Asn501Ser) with trisomy 10), without enough documented phenotype to classify them as TBRS; both died [3].

In the Swedish national prospective study of 181 children with acute leukaemia, with a 189-gene germline panel by genome sequencing, trio genome sequencing in 11 high-suspicion families identified de novo c.2635A>G p.(Asn879Asp) in a child with T-ALL and undiagnosed TBRS (hydrocephalus, Chiari 1, hydrocele, developmental delay, hypotonia, nystagmus, recurrent infections); DNMT3A was not on the 2020 panel, and the diagnosis was made possible only by trio genome sequencing [51]. The leukaemia had somatic focal loss of 9p (PAX5, CDKN2A/B), loss of IKZF1, and partial deletion of ETV6, and was treated on the ALLTogether intermediate-high risk protocol without modifications [51]. A case of Hodgkin lymphoma in a child with p.(Arg882Cys) was published in 2026 [13, 63].

Mouse models support the predisposition. The germline R878H/+ mouse developed fatal spontaneous haematopoietic neoplasms in 6 of 80 animals after 1 year, versus 0 of 65 wild-type animals (2 myelodysplastic syndromes, 2 B-cell neoplasms with plasma cells, 1 AML, and 1 chronic myelomonocytic leukaemia–like neoplasm) [12]. Mice with deletion of residue 293 (equivalent to human 297) had neoplasms by 15 months in 8 of 36 versus 1 of 35 wild-type animals, 7 of them haematological, and the authors concluded that the relative risk is high but with low penetrance and long latency, so that most patients will not develop blood cancer [38].

3.12. Solid and endocrine tumours

The solid tumours described are isolated cases without a demonstrated association: medulloblastoma with p.(Gln842Arg) [64], neuroblastoma and benign glioma [1, 48], growth hormone–secreting pituitary macroadenoma with acromegaly in a patient with an additional germline variant in AIP [13, 65], ganglioneuroblastoma (Ferris case 3) [3], a presumed pineal gland tumour without histological confirmation in an R882C carrier [66], and low-grade fibromyxoid sarcoma in the Brazilian family (section 10) [13]. An adult with a germline loss-of-function variant (F414fs according to the patient organisation) had dermatofibrosarcoma protuberans and early-onset melanoma with nodal metastases; the tumour had a second, acquired missense DNMT3A variant (p.(Arg749Cys)) in the dominant clone; according to the patient organisation, the dermatofibrosarcoma occurred at age 20 years, the melanoma (stage IIIA) at 34, and the patient died at 39 of metastatic melanoma [17, 36]. The patient organisation reports 2 more unpublished melanomas and premalignant lesions in the community, even in childhood [17]. A woman with a genomic diagnosis at age 35 years (c.2172C>A p.(Tyr724Ter) according to Braz) had primary hyperparathyroidism at 13 years, a pituitary cyst at 14, an adrenal tumour at 21, and metastatic insulinoma at 34, with multiple lipomas and hemihypertrophy, after the classic multiple endocrine neoplasia syndromes had been excluded [13, 35]. In the review by Braz and colleagues, there was no consistent evidence of loss of heterozygosity at the DNMT3A locus in the tumours [13]. The Braz table lists the Kosaki 2017 case among the AML cases, but the description of this patient at age 6 years and the Ferris series record no leukaemia; the article title refers to p.(Arg882His) as an AML-associated variant [3, 15, 31].

3.13. Other systems

Cryptorchidism occurs in about 20% of boys; vesicoureteral reflux and hypospadias have been described in a few patients [1]. Dental anomalies include malocclusion, caries, double teeth, agenesis of upper incisors, ectopic eruption, and abnormal roots [1, 67, 68]. Congenital diaphragmatic hernia has been described in one patient and autonomic dysfunction (postural orthostatic hypotension, episodic vasomotor instability of the extremities) in 4 [1, 62]. Central hypothyroidism has been described in one case [3]. Eczema with elevated IgE has been described in one adult [58].

3.14. Heyn-Sproul-Jackson syndrome

Heyn's three patients had intrauterine growth restriction and severe postnatal growth failure, with proportionate short stature (−3.2 to −5.4 SD), low weight (−2.6 to −5.2 SD), and microcephaly (−4.1 to −6.6 SD), normal growth hormone and IGF-1 levels, and normal brain MRI in the two who were evaluated [4, 10]. Patient 1, born at 38 weeks weighing 1.9 kg (−2.8 SD), had no language at 13 years, had 11 pairs of ribs and mild leucopenia in childhood (2.4–2.8 × 10⁹/L), with a poor response to some vaccines and no clinical immunodeficiency [69]. Patient 2, evaluated at 19 months, had recurrent bronchiolitis, mildly delayed bone age, and short, broad metacarpals and phalanges [69]. Patient 3, of Spanish ancestry, had strabismus, epicanthal folds, a broad forehead, sparse hair, macroorchidism (5 mL bilaterally at 4.5 years), recurrent bronchitis and otitis, and a normal growth hormone response to stimulation [11, 69]. The Korean patient of Kim and colleagues, with c.1012_1014+3del, at 5 years 7 months weighed 17 kg (−1.3 SD) and had an HC of 48 cm (−2.3 SD), severe delay (independent walking at 36 months; developmental equivalents of 17–34 months on the Bayley-III), normal MRI, and sagittal and bilateral lambdoid craniosynostosis on three-dimensional computed tomography, not operated on [14].

Sources: Kim 2023, Table 1, and the supplementary clinical note of Heyn 2019 [14, 69].

4. Clinical Recognition and Red Flags

4.1. When to suspect

GeneReviews proposes considering TBRS in the presence of generalised overgrowth (height or length and/or HC ≥2 SD) with developmental delay or mild to severe ID and any of the following findings in childhood or adolescence: facial dysmorphism, joint hypermobility, hypotonia, kyphoscoliosis, seizures (including afebrile seizures of variable types), cryptorchidism, behavioural problems (especially ASD), or AML and possibly other haematological neoplasms [1]. Because overgrowth is absent in fewer than 20% of patients and the facial gestalt is subtle before adolescence, suspicion rests more on the combination of ID, overweight, and hypermobility than on any single feature [1, 18]. In the general approach to overgrowth, overgrowth is defined as a value above 2 SD (about the 98th percentile), and a syndrome is suspected when global overgrowth coexists with ID and/or a congenital anomaly [57].

For HESJAS, suspicion arises in the presence of proportionate microcephalic dwarfism with intrauterine growth restriction, global developmental delay, and normal growth hormone levels, once chromosomal causes and chromosome instability syndromes have been excluded [4, 69].

4.2. Red flags and emergency signs

4.3. Newborn screening

There is no newborn screening for TBRS or HESJAS; the diagnosis is clinical and molecular [1].

5. Diagnosis: Criteria, Testing, and Algorithms

5.1. Criteria

No consensus clinical diagnostic criteria have been published [1]. The diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic or likely pathogenic DNMT3A variant classified according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) standards; a VUS neither establishes nor excludes the diagnosis [1, 70]. HESJAS requires a variant with a gain-of-function effect in the PWWP domain and the reciprocal phenotype; with four published patients, the relationship has limited validity [10, 14, 16].

5.2. Initial clinical evaluation of overgrowth

Evaluation of a patient with overgrowth includes a three-generation pedigree with parental birth weights and heights and any cases of ID in the family; pregnancy history (gestational diabetes, assisted reproduction, fetal growth, polyhydramnios); neonatal data (weight, HC, length, and gestational age, abdominal wall defect, hypoglycaemia); the postnatal growth curve, development, and skeletal, cardiac, renal, and neurological history [57]. The examination records height, weight, and HC in SD, facial dysmorphism, ears (creases and pits in Beckwith-Wiedemann syndrome), tongue (macroglossia; midline groove in Simpson-Golabi-Behmel syndrome), supernumerary nipples, hands (polydactyly, brachydactyly, syndactyly), hemihypertrophy, skin (penile freckling, lipomas, and haemangiomas in the PTEN spectrum; connective tissue naevi in Proteus syndrome), spine, cardiac auscultation, and abdomen [57].

5.3. Testing algorithm

Fragile X testing (FMR1) is indicated if there is developmental delay and the diagnosis has not been established, and DNA from an alternative tissue (skin) when mosaicism is suspected [57]. In the series of 710 patients with overgrowth and ID, the 14 genes studied accounted for 50% of cases [28].

5.4. Proportion of variants detected by method

These values indicate the proportion of variants found by each method among patients with a molecular diagnosis; they are not the clinical sensitivity of the test in a patient with suspected TBRS [1].

5.5. DNA methylation episignature

The TBRS episignature has been among those included in the EpiSign platforms since the version that mapped 42 syndromes with 34 robust signatures, and version 2, with 57 episignatures for 65 syndromes, included 27 TBRS samples in the classifier [73, 74]. In the independent French validation of 10 published episignatures (101 carriers of pathogenic or likely pathogenic variants, 57 VUS carriers, and 25 controls; k-nearest-neighbour classifier with leave-one-out validation), specificity was 100% (95% CI 86–100%) in all configurations, and the 139-probe TBRS signature had 100% sensitivity, in the robust group with ATRX, NSD1, and KMT2D [20]. TBRS and Sotos syndrome both cause marked hypomethylation with extensive probe overlap, with a slight risk of misclassification between the two; even in the robust groups, some VUS remained unclassified, and the authors recommend that episignatures not be used as automatic binary tools [20]. One TBRS sample with c.2525A>G p.(Gln842Arg) scored high for Rubinstein-Taybi syndrome type 2 because of overlapping nonspecific hypomethylation and required hierarchical clustering for correct interpretation [74]. In the EpiSign clinical network (2399 cases), the yield was 18.7% for full screening and 32.4% for targeted analysis (assessment of sequence or copy-number VUS, or a clinical diagnosis without molecular confirmation), overall figures not specific to TBRS [71].

The episignature supported the pathogenicity of specific variants: p.(Arg736Cys) in the Belgian family, with conflicting classifications in ClinVar [34]; p.(Asp529Asn) in the twins with pneumothorax, by methylation sequencing of more than 2 million CpGs [37]; and the variant of the patient with congenital myopathy [43]. HESJAS has a hypermethylation profile that is reproducible between fibroblasts and leucocytes and distinct from the hypomethylation of TBRS, but no clinically validated episignature exists for this entity in the sources consulted [10].

5.6. Test limitations and interpretation

The main interpretive pitfall is clonal haematopoiesis. The germline spectrum of TBRS overlaps with that of sporadic haematological neoplasms, and a DNMT3A variant detected in blood may be somatic, especially in adults or in patients with a haematological neoplasm [6, 32]. Germline status is confirmed in non-haematopoietic tissue (cultured fibroblasts, buccal mucosa) or by the combination of a variant allele fraction consistent with heterozygosity and a constitutional phenotype [6]. Hollink confirmed his patient's variant in blood in remission and in fibroblasts [18, 30]; in Ferris case 3, the variant appeared on a ganglioneuroblastoma tumour panel with a variant allele fraction of 0.45 and was confirmed by blood exome sequencing; in case 4 it was confirmed in buccal mucosa; in the TARGET cases, the variant allele fraction was 0.52 and 0.31 in marrow-derived fibroblasts [3]. In Ferris case 1, the AML had, in addition to the germline p.(Arg882Cys) variant, a second somatic p.(Arg882His) variant in a subclone, showing that an AML panel can simultaneously detect germline and somatic alleles of the same gene [3].

Somatic clonal haematopoiesis variants are enriched in population databases derived from peripheral blood, so the presence of a variant in gnomAD is not, by itself, evidence against pathogenicity [1, 18, 34]. Parental mosaicism may be missed in leucocyte DNA, and germline-only mosaicism is undetectable [1]; in the Belgian family, the father had the variant in 40% of reads in blood, buccal mucosa, and hair bulbs [34]. Exome sequencing may miss small intragenic deletions and duplications, deep intronic variants, and low-level mosaicism, and a negative result does not exclude the diagnosis in the presence of a typical phenotype; in that scenario, the episignature, microarray, and genome are the next steps [1, 20]. Childhood leukaemia predisposition panels may not include DNMT3A, as in the Swedish study, in which the diagnosis was made only by trio genome sequencing [51]. Familial pneumothorax and aortic disease panels that lack DNMT3A also miss this diagnosis [34, 37].

5.7. Report content

The report should state the gene, the versioned transcript (NM_022552.5, MANE Select), the variant in Human Genome Variation Society (HGVS) c. and p. nomenclature, the genomic coordinate with the genome build, zygosity, variant allele fraction, the tissue analysed, the ACMG/AMP class with the criteria applied, and, when applicable, a recommendation for parental testing and confirmation in non-haematopoietic tissue [6, 8, 70]. For Arg882 variants, it is advisable to note the known dominant-negative effect and the association with AML; for PWWP domain variants, the possibility of a gain-of-function effect and a reciprocal phenotype if the clinical picture is one of microcephaly and short stature [10, 12]. Recording the criteria used (e.g., PS2, PM1, PM2, PM5, PP4, and episignature) allows the classification to be reassessed as new data emerge [13, 14].

5.8. Prenatal and preimplantation diagnosis

Once the variant has been identified in an affected family member, prenatal diagnosis and preimplantation genetic testing are possible [1]. The sources consulted describe no specific fetal ultrasound findings; fetal macrosomia was reported in the father and son of the Belgian family [34].

6. Differential Diagnosis

6.1. Comparison table

6.2. Sotos syndrome

Sotos syndrome is the main differential because of clinical and episignature overlap. The Sotos facial gestalt is most recognisable in early childhood, whereas that of TBRS becomes defined in early adolescence; in adults, childhood photographs help distinguish the two [1, 57]. Overweight is more frequent in TBRS than in the other overgrowth–ID syndromes [18]. Bone age is advanced in most patients with Sotos syndrome (normal in about 15%), and in Sotos syndrome carpal ossification lags behind phalangeal and metacarpal ossification, the reverse of Weaver syndrome [57, 77]. Facial dysmorphism is very characteristic in patients with an NSD1 variant and less so in carriers of SETD2 or DNMT3A variants [46]. Both episignatures are robust but share extensive hypomethylation, with a slight risk of misclassification; the distinction requires a multiclass classifier and confirmation by sequence [20, 73]. Tatton-Brown-Rahman syndrome is one of the entities in which patients with a clinical diagnosis of Sotos syndrome were reclassified after genetic testing [78]. Sotos syndrome is part of the differential diagnosis.

6.3. Weaver syndrome

Weaver syndrome, caused by EZH2 variants (7q36.1, not 7q35 as stated in the Oxford Desk Reference), shares tall stature, macrocephaly, and variable ID, from mild to severe, with some patients of normal intellect [7, 57, 75]. It is distinguished by dysmorphism that is most recognisable between 1 and 3 years (round face, frontal bossing, hypertelorism, "stuck-on" chin with a horizontal crease), camptodactyly of the fingers and/or toes, soft doughy skin, a hoarse low-pitched cry in infancy (46%), umbilical hernia, and accelerated skeletal maturation, with carpal centres more advanced than phalangeal ones [75–77]. Reported final height is 194.2 cm in males and 176.3 cm in females (above +3.5 SD) [76]. The Weaver GeneReviews chapter records neuroblastoma in 5–7% and tumours in 7 of 70 individuals, with no demonstrated increase in haematological neoplasms [75]; the 2024 American Association for Cancer Research (AACR) update estimates the neuroblastoma risk at about 9% (5/56 in the largest review) and considers neuroblastoma screening justified, without Wilms tumour or hepatoblastoma surveillance [79, 80]. TBRS appears in the differential of the Weaver GeneReviews chapter as tall stature with variable ID and ASD [75]. The EZH2, EED, and SUZ12 genes encode components of Polycomb repressive complex 2 (PRC2), and Cohen-Gibson (EED) and SUZ12-related syndromes have a Weaver-like phenotype [76]. ClinGen classifies the EZH2–Weaver relationship as definitive [16]. Weaver syndrome is part of the differential diagnosis.

6.4. Other differentials

Malan syndrome overlaps with Sotos syndrome and is distinguished by the frequency of ophthalmological anomalies and normalisation of growth in adolescence [1]. CHD8-related overgrowth is associated with ASD and macrocephaly, with a distinctive facial gestalt [1]. In the PTEN spectrum, macrocephaly is disproportionate to stature and there are characteristic skin lesions [57]. In adults with tall stature, hypermobility, aortic dilatation, and pneumothorax, Marfan syndrome is the main differential; the presence of ID, even mild, and the absence of an FBN1 variant point towards DNMT3A, and the authors of the family reports recommend including the gene in familial thoracic aneurysm panels with cardiomyopathy and considering TBRS in the presence of tall stature, pneumothorax, and ID [34, 37]. Bostanova and colleagues included Sotos, Weaver, and Cowden syndromes in the differential of a 10-year-old boy with mild TBRS and a nonsense variant [49]. In children with leukaemia and ID, germline predisposition syndromes to myeloid and lymphoid neoplasms are part of the differential diagnosis.

6.5. Differential diagnosis of HESJAS

HESJAS belongs to the differential of microcephalic primordial dwarfism. Heyn and colleagues compared the patients' fibroblasts with PCNT-null fibroblasts, used as a control for microcephalic dwarfism of another cause, and did not find the hypermethylated DMRs in them, showing that the methylation profile is not a nonspecific effect of growth restriction [10]. In the published patients, karyotype, diepoxybutane chromosome breakage testing, microarray, metabolic studies, growth hormone, and IGF-1 were normal, as was Angelman syndrome testing in the Korean patient [14, 69]. The distinction rests on the germline variant in the PWWP domain; in the adult with paragangliomas and ID, gain-of-function variants in the same domain constitute a distinct allelic phenotype [41, 42].

7. Treatment and Risk Management Strategies

7.1. General principles

There is no therapy targeting the cause of TBRS or HESJAS, nor are there clinical practice guidelines from professional societies [1, 78]. Because most patients are in good general health, GeneReviews and the London group recommend a pragmatic approach: baseline evaluations at diagnosis, education of the patient and family about possible complications, and regular review of symptoms with a low threshold for investigation and treatment as needed [1, 18]. In October 2025, the patient organisation TBRS Community published management and surveillance recommendations based on GeneReviews, the 2024–2025 literature, and the patient registry, which add aortic, endocrine, and skin surveillance; the document itself states that it does not constitute prescriptive medical guidance [17, 22].

7.2. Evaluation after diagnosis

7.3. Treatment of manifestations

7.4. Neurodevelopment, motor function, and behaviour

GeneReviews recommendations for developmental delay follow the US model: early intervention from 0 to 3 years (occupational therapy, physiotherapy, speech and feeding therapy, infant mental health services, special educators), a developmental preschool programme from 3 to 5 years with an individualised education plan reviewed annually, a transition plan in adolescence, and follow-up by a developmental paediatrician [1]. Physiotherapy aims to maximise mobility and reduce late orthopaedic complications such as contractures, scoliosis, and hip dislocation, with appropriate equipment and positioning; occupational therapy addresses fine motor skills (feeding, grooming, dressing, writing) [1]. Augmentative and alternative communication should be assessed by a speech and language therapist and does not hinder speech development [1]. For hypertonia or dystonia, GeneReviews mentions in general terms baclofen, tizanidine, botulinum toxin (Botox®), antiparkinsonian drugs, or orthopaedic surgery, without specific evidence in TBRS and without syndrome-specific dosing [1]. In ASD, interventions include applied behaviour analysis, and ADHD medication is prescribed by a developmental paediatrician or child psychiatrist; methylphenidate was used in one patient with ASD and ADHD [1, 58]. The review by Atterton and colleagues also mentions sensory processing abnormalities and sleep disturbances in overgrowth–ID syndromes, to be addressed in the individual therapeutic plan [78].

7.5. Epilepsy and cannabidiol

Epilepsy is treated with standard antiseizure medications, chosen according to seizure type and electroclinical syndrome; no drug has been studied specifically in TBRS [1]. The only targeted therapeutic report is that of Datta: in the girl with DEE-SWAS, clobazam (1 mg/kg), sulthiame (20 mg/kg), and ethosuximide were ineffective or poorly tolerated; the combination of valproate semisodium and lamotrigine (valproic acid 25 mg/kg and lamotrigine 3 mg/kg in the EEG records) suppressed clinical seizures at age 6 years, but DEE-SWAS persisted [21]. These doses fall within the ranges of the Portuguese SmPCs: clobazam (Castilium®) as add-on therapy in epilepsy above 6 years of age, with a usual starting dose of 5 mg/day and maintenance of 0.3–1.0 mg/kg/day, with no paediatric maximum dose defined in the SmPC (maximum of 60 mg/day in adults and adolescents over 15 years) [81]; valproic acid (Depakine®) with a usual paediatric dose of about 30 mg/kg/day, with no maximum dose defined in the SmPC, which requires close monitoring above 50 mg/kg/day [82]; lamotrigine (Lamictal®) in combination with valproate from 2 to 12 years, with maintenance of 1–5 mg/kg/day and a maximum of 200 mg/day [83]. Sulthiame is not authorised by the FDA or the EMA and is not listed in Infomed, so the 20 mg/kg dose in the report has no reference label in these jurisdictions. At 9.5 years she started highly purified cannabidiol (Epidiolex®) at 10 mg/kg/day (label maximum of 20 mg/kg/day in Lennox-Gastaut and Dravet syndromes) [84], continuing valproate and lamotrigine; within 5 months the parents reported cognitive and language improvement, and ambulatory EEG showed resolution of DEE-SWAS at 5 and 17 months; subsequent neuropsychological assessment showed moderate ID [21]. The author attributes the effect to reduced hyperexcitability (GPR55 inhibition, TRPV1 desensitisation, blockade of adenosine reuptake) and to anti-inflammatory effects, and hypothesises that cannabidiol partially counteracts the methylation dysregulation, without demonstration [21]. This is a single case of off-label use, with no evidence of efficacy generalisable to TBRS, and the report does not describe hepatic monitoring.

The dosing of cannabidiol (INFARMED nonproprietary name; Epidyolex® in the European Union, Epidiolex® in the USA), a 100 mg/mL oral solution containing 79 mg/mL ethanol and refined sesame oil, is that of the approved indications, from 1 year of age in the USA and from 2 years in the EU [84, 85]:

Sources: Epidyolex® summary of product characteristics (SmPC), sections 4.2–4.4; FDA label for Epidiolex®, section 2 [84, 85].

Hepatic monitoring stems from the risk of dose-related hepatocellular injury: before starting, the transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and total bilirubin are measured; the European SmPC provides for repeat testing at 1, 3, and 6 months and periodically thereafter, and an intensified schedule at 2 weeks and at 1, 2, 3, and 6 months in patients with elevated baseline transaminases or taking valproate, like Datta's patient [84, 85]. The schedule restarts with each dose increase above 10 mg/kg/day or each change in drugs with hepatic effects [84]. Cannabidiol is contraindicated with transaminases above 3 times the upper limit of normal (ULN) and bilirubin above 2 times the ULN, and should be discontinued with that combination or with transaminases persistently above 5 times the ULN [84]. The other adverse effects to monitor are somnolence and sedation (more frequent with clobazam), increased seizure frequency, suicidal ideation and behaviour, and weight loss, with a possible slight reduction in height gain [84].

7.6. Regulatory status of cannabidiol

Access to Epidyolex® in Portugal (INFARMED) and Brazil (ANVISA) was not verified in the sources consulted.

7.7. Clinical trials and therapeutic research

There are no therapeutic trials, positive or negative, registered for TBRS or HESJAS; the European clinical trials register was not searched, and a negative search does not prove absence [87]. The therapeutic proposals are preclinical hypotheses: antisense oligonucleotides to increase expression of the wild-type DNMT3A allele (acting on untranslated regions, secondary structures, or microRNAs) or to modulate shared pathways such as the H3K36 pathway, and viral gene therapy or CRISPR editing, limited by the dosage sensitivity of the gene [78]. In R882H clonal haematopoiesis, metformin reduced the competitive advantage of mutant haematopoietic stem cells in mouse models and in edited human cells, and UK Biobank participants taking it had a lower prevalence of R882 clonal haematopoiesis; these data concern somatic clonal haematopoiesis and have not been studied in TBRS [11].

7.8. Developments in the past 12 months (October 2025 to October 2026)

There were no regulatory actions or clinical trials of drugs targeting TBRS during this period [87].

7.9. Management of haematological neoplasms

Neoplasms in patients with TBRS have been treated with standard protocols, with no modifications described on account of the germline variant [1, 3, 51]. In Ferris case 1, FAB M4 AML was treated with cytarabine, daunorubicin, and etoposide for induction and three further cycles with mitoxantrone, cytarabine, etoposide, and L-asparaginase, with remission and clearance of the leukaemic clones 4.4 years later, followed by chronic immune thrombocytopenia without bleeding [3]. The high-risk hyperdiploid B-ALL in case 2 responded to four-drug induction and augmented Berlin-Frankfurt-Münster (BFM) consolidation, with no relapse at 6 years [3]. The T-cell lymphoblastic lymphoma/leukaemia in case 3 was refractory to multiple lines, including nelarabine, and the patient died less than 2 years after diagnosis [3]. The patient with AML at age 20 years (case 5) underwent allogeneic haematopoietic stem cell transplantation from a matched unrelated donor, and the patient with refractory Hodgkin lymphoma (case 6) autologous transplantation; the essential thrombocythaemia in case 7 was controlled with hydroxycarbamide and aspirin [3]. In the R878H/+ mouse, count recovery after doxorubicin and cytarabine was similar to that of wild-type animals, which does not suggest increased haematological toxicity from chemotherapy, in a preclinical finding [12].

The sources consulted do not describe related-donor selection or specific treatment adjustments for germline carriers of DNMT3A variants [3, 51]. In germline predisposition to myeloid neoplasms, allogeneic transplantation uses a donor without the familial variant; its application to TBRS has not been studied, and because most variants are de novo, the issue arises mainly in families with vertical transmission or parental mosaicism [1, 34]. In a child or young adult with AML or ALL and ID or overgrowth, germline testing should include DNMT3A and be performed on non-haematopoietic tissue [3, 6, 51].

7.10. Special populations

The sources consulted do not describe pregnancies in women with TBRS or obstetric management; the Weaver syndrome GeneReviews chapter advises planning delivery in view of the possibility of a large baby, a recommendation that the sources have not carried over to TBRS [1, 75]. Published anaesthetic experience is limited to an 11-year-old child with ASD and an atrial septal defect who underwent full dental rehabilitation under general anaesthesia after multidisciplinary preoperative assessment, without complications [68]. In anaesthetic preparation, the problems described in the syndrome that warrant prior assessment are structural heart disease and aortic dilatation, sleep apnoea (including central apnoea), hypotonia, and autonomic dysfunction [1, 19, 62]. In the transition to adult care, late diagnoses at ages 27, 34, and 35 years and in the twins at 24 and 27 years were prompted by aortic disease, cardiomyopathy, multiple endocrine neoplasia, or pneumothorax, which justifies continuing cardiology follow-up with echocardiography, endocrinology, and surveillance for haematological and skin signs in adulthood [33–35, 37]. Le Collen and colleagues suggest endocrinological follow-up for adults [35].

7.11. Guideline recommendations and divergences

The central divergence concerns periodic complete blood counts. The Washington University group proposes an annual complete blood count, with the stated aim of learning the natural history and in a research setting [3]; GeneReviews, the London group, and the Atterton review favour clinical surveillance of symptoms [1, 18, 78]; the patient organisation recommends a baseline complete blood count and notes that some experts suggest an annual count, without consensus [17]. The AACR guidelines rely on a 1% risk threshold in North America, versus the 5% usually applied in Europe, for recommending screening, and the 2024 update on predisposition to haematopoietic neoplasms does not address TBRS [79, 89]. With an estimated prevalence of haematological neoplasms of about 4% in a patient-community denominator, TBRS falls between the two thresholds, with no cumulative incidence estimate that would allow either to be applied rigorously [3, 79]. In Ferris case 4, the treating team opted for complete blood counts every 6 months and annual bone marrow biopsy from diagnosis, detected megakaryocytic and erythroid dysplasia without an identified clone, and evaluated the patient for allogeneic transplantation; this is an individual team decision, not a recommendation [3].

7.12. Heyn-Sproul-Jackson syndrome

There is no specific treatment for HESJAS. The published patients had normal growth hormone and IGF-1, so hormone deficiency does not explain the short stature; the sources consulted do not describe growth hormone treatment [4, 69]. The sagittal and bilateral lambdoid craniosynostosis of the Korean patient was not operated on, given her age of 5 years and severe delay [14]. The recurrent respiratory infections and mild leucopenia described in two patients warrant clinical attention, without demonstrated immunodeficiency [69]. Management of developmental delay follows the general principles of intellectual disability management.

8. Reproductive Options and Family Counselling

8.1. Inheritance and origin of variants

TBRS is autosomal dominant, and in probands whose parents have been tested, the variant is almost always de novo [1]. Familial transmission has been described from unaffected or mildly affected mosaic parents [1, 62, 90] and from affected parents [1, 91]. The review by Braz and colleagues compiled the published families with transmission:

Source: Braz 2026, Table 3 [13]. In the Belgian family, the father had the variant in about 40% of reads in blood, buccal mucosa, and hair bulbs, consistent with somatic mosaicism not excluded in the central nervous system, and the siblings and paternal relatives did not carry the variant [34]. In the Brazilian family, the variant was found in the father (192 cm) and in the proband's sister, and the paternal half-brother with tall stature, congenital heart disease, and behavioural problems was not tested [13]. Variable expressivity within families, with parents without ID, shows that a carrier parent may have gone undiagnosed [13, 34].

8.2. Recurrence risks by scenario

Leucocyte DNA may not detect all somatic mosaicism and does not detect germline-only mosaicism; a parent with somatic and germline mosaicism may be mildly or minimally affected [1]. When testing the parents of a DNMT3A carrier, a variant detected in blood at a low variant allele fraction may reflect constitutional mosaicism or acquired clonal haematopoiesis, especially in older parents; analysis of other tissues, such as buccal mucosa and hair bulbs, distinguishes the two situations [6, 34].

8.3. Cascade testing and at-risk relatives

Molecular testing of the proband's parents is recommended [1]. The risk to other relatives depends on the parents' status; GeneReviews refers the evaluation of at-risk relatives to genetic counselling, without a specific surveillance recommendation [1]. In families with vertical transmission, identifying carriers with a mild phenotype has its own consequences, because adult carriers may have aortic disease, cardiomyopathy, or neoplasms, as occurred in the Belgian and Lithuanian families [33, 34]. The sources consulted do not specifically address testing of minors; in families with transmission, diagnosing a sibling with compatible signs allows the cardiovascular and haematological surveillance described in section 11 to be started.

8.4. Family planning and prenatal and preimplantation diagnosis

The optimal time to determine genetic risk and discuss prenatal diagnosis and preimplantation genetic testing is before pregnancy, and genetic counselling should be offered to parents of affected children [1]. Once the variant has been identified in an affected family member, both procedures are possible; perspectives on their use differ among professionals and families, and the decision is a personal one [1].

8.5. Content of counselling

Counselling should cover the nature of the disorder and the variability of ID; the risk of haematological neoplasia of about 4% among known cases, with the caveat that this is not a lifetime incidence; the warning signs of leukaemia; the possibility of age-related aortic disease; the absence of targeted therapy; and support resources [1, 3, 17, 19]. In cases detected in an oncological setting (e.g., by a tumour or AML panel), counselling should explain the difference between the constitutional germline variant and the somatic variants of the tumour [3, 51].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The prevalence of TBRS is unknown, and none of the published estimates derives from a population study [1].

HESJAS has an Orphanet prevalence class of <1/1,000,000, based on Heyn's 3 patients [5]. Probable underdiagnosis in regions with little access to genomic testing and among adults with ID who have never had genetic testing limits all counts [1, 3]. For comparison, Sotos syndrome and Beckwith-Wiedemann syndrome have a prevalence of about 1/14,000 [57], and Malan syndrome an estimated incidence of 2.6/100,000 live births [78].

9.2. Geographic distribution and ancestry

Of the 202 cases known to the patient organisation in 2021, 92 (45%) lived in North America and 89 (44%) in Europe; 112 of 199 (56%) were male, with a mean age of 14 years and a maximum of 39 [3]. Published series and cases come mainly from the UK [18, 27, 56], the USA [12, 32, 38, 60, 62], Canada [90, 91], France [29, 64, 92], Spain [19, 48, 59], the Netherlands [30], Belgium [34], Lithuania [33], Japan [31, 40, 93], South Korea [14], Saudi Arabia [58, 68], Colombia [67], Sweden [51], and Brazil [13]. HESJAS has been described in patients from the USA, New Zealand, Spain, and South Korea [14, 69]. No founder effect has been described: the variants are almost all de novo and scattered throughout the gene, with mutational recurrence at Arg882, Arg749, Arg736, and Pro904 [1, 18].

According to the authors, the first published Brazilian cases are those of the Rio de Janeiro family with p.(Arg635Gln) [13]. The sources consulted include no data from Portugal. In Europe, the French national cohort of the AnDDI-Rares network (24 patients) is the only published national series [29].

9.3. Special populations

Adults with TBRS are probably under-recognised, because the association was described in 2014 and many adults with ID have not had genomic testing [1]. In adults, with complications described between ages 24 and 49 years, the diagnosis often arose from aortic, cardiac, endocrine, oncological, or respiratory disease [17, 33–35, 37]. Children with acute leukaemia and ID or overgrowth are a population in which the diagnosis may be made in the oncological setting [3, 51].

9.4. Reference networks and patient organisations

The relevant European network is ERN ITHACA (European Reference Network on Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders) [23]; the authors of the Spanish vascular series were affiliated with ERN ITHACA and with VASCERN, the network for multisystemic vascular diseases [19]. TBRS Community (https://tbrsyndrome.org) maintains, with NORD (IAMRARE), the TBRS and DNMT3A registry, open to patients and researchers, and a biorepository with samples and induced pluripotent stem cell lines [24, 25, 87]. In 2023, TBRS Community and the Malan Syndrome Foundation founded the Overgrowth Syndromes Alliance, which covers 13 overgrowth–ID syndromes and a network of more than 120 professionals [78]. The Child Growth Foundation (UK) supports families and has funded research by the London group [1, 26]. The sources consulted identified no specific organisations in Portugal or Brazil.

10. Illustrative Clinical Case

Braz and colleagues, from the Instituto Nacional de Câncer (Rio de Janeiro), described in 2026 a Brazilian family with TBRS and paternal transmission of the variant [13]. The proband, a 20-year-old man, was born to nonconsanguineous parents after an uneventful pregnancy; in the neonatal period he had feeding difficulties and jaundice treated with phototherapy. Global developmental delay, ASD, and epilepsy were diagnosed in early childhood, and ADHD and mild to moderate ID later. He had a height of 210 cm (above the 95th percentile), macrocephaly, a long face, heavy eyebrows, narrow palpebral fissures, prominent incisors, and scoliosis [13].

At 17 years he developed a low-grade fibromyxoid sarcoma in the left lumbar region, with the histological diagnosis supported by diffuse MUC4 expression on immunohistochemistry. Treatment consisted of neoadjuvant radiotherapy and chemotherapy (3 cycles of ifosfamide with doxorubicin followed by 3 cycles of ifosfamide alone), followed by wide surgical resection with mesh reconstruction [13]. The nCounter fusion panel (172 probes) detected no fusions but contained no probes for FUS-CREB3L2 or FUS-CREB3L1, so the diagnosis lacked molecular confirmation [13].

Exome sequencing of saliva DNA (mean coverage 180×, 98.2% of target bases at ≥20×) identified a single relevant variant, NM_022552.5(DNMT3A):c.1904G>A p.(Arg635Gln), in exon 16, MTase domain, heterozygous in blood and tumour, without loss of heterozygosity on comparison of Sanger chromatograms, a method of low sensitivity for this purpose [13]. The variant was found in the father (192 cm) and the sister (143 cm at 7 years, above the 95th percentile, with macrocephaly, dysmorphic features, and a neurodevelopmental disorder); a paternal half-brother measuring 190 cm, with congenital heart disease, dysmorphic features, and behavioural problems could not be tested, and several paternal relatives had overgrowth and behavioural problems [13]. The gnomAD v4.1.0 frequency was 0.002191%, there were 5 ClinVar submissions (at least one de novo, from Yokoi 2020), and the predictors were discordant (REVEL 0.828; AlphaMissense 0.415), so the authors did not apply the PP3 criterion and classified the variant as pathogenic with criteria PS4, PM1, PM5, PP1, PP2, and PP4; in ClinVar, the variant has conflicting classifications [9, 13, 93].

Figure 1 of the article, consulted, shows the facial gestalt of the proband and his sister (long face, heavy eyebrows, narrow palpebral fissures), the 210-cm proband taller than the doorway, the electropherograms with the variant, the pedigree, and a protein diagram with the position of p.Arg635Gln in the MTase domain: https://pmc.ncbi.nlm.nih.gov/articles/PMC13617805/figure/Fig1/ [13]. Figure 2 shows the tumour histology on haematoxylin-eosin staining and cytoplasmic MUC4 expression: https://pmc.ncbi.nlm.nih.gov/articles/PMC13617805/figure/Fig2/ [13].

The case illustrates vertical transmission with variable expressivity, since the carrier father went undiagnosed until his son was tested; the diagnosis of TBRS in a young adult followed in oncology; and the interpretation of a missense variant with conflicting classifications through family segregation [13]. The authors do not demonstrate a causal relationship between TBRS and the sarcoma and acknowledge that it may be coincidental; low-grade fibromyxoid sarcoma is not among the neoplasms associated with TBRS, and the oncological management described is that of the tumour, not a recommendation for the syndrome [13]. The article does not describe the course after surgery.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Data on life expectancy in TBRS are limited, because the association was described in 2014, most known patients are young (mean age 14 years and maximum 39 in the 2021 denominator), and adults are probably under-recognised [1, 3]. Most patients are in good general health [1, 18]. Functional prognosis depends mainly on the degree of ID: with mild ID (about 18–28%), independent adult living with support is expected; with moderate ID (58–65%), supported or sheltered living; and with severe ID (14–16%), considerable support [1, 18]. Autistic traits were less prevalent in older individuals in a cross-sectional study of 18 patients, without longitudinal demonstration [1, 56]. Neurodevelopmental regression, including in adolescence or early adulthood, and psychosis affect the course in a minority [18, 58].

The causes of severe morbidity and death described are neoplasms and arterial disease. In the Ferris series, the patient with refractory T-ALL (less than 2 years after diagnosis) and the patient with essential thrombocythaemia (COVID-19 complications) died, and the others were alive 2.5 to 12 years after diagnosis [3]. One patient died at age 39 years of metastatic melanoma, according to the patient organisation [17]. Arterial disease is age-dependent and potentially lethal, with dissections that required emergency surgery and a ruptured iliac aneurysm at 49 years [17, 19]. The risk of haematological neoplasia estimated at about 4% (8/202) is a prevalence among known cases and not a lifetime risk; in mouse models, penetrance is low and latency long [3, 12, 38]. In HESJAS, the oldest published patient was 13 years old and nonverbal, and there are no adult data in the sources consulted [4, 69].

11.2. Surveillance

The TBRS Community recommendations come from a patient organisation, built on GeneReviews and the literature, and not from a professional society [22]. GeneReviews sets no interval for the complete blood count or the echocardiogram [1]. Isolated macrocytosis found on a surveillance complete blood count is probably a benign variant of the syndrome and warrants only observation [38]. The experience of Ferris case 4 (complete blood counts every 6 months and annual bone marrow biopsy) is an individual team decision and is not part of the recommendations [3].

11.3. Adult follow-up and transition

The transition to adult care should maintain cardiovascular surveillance with echocardiography, attention to haematological and skin signs, and endocrinological follow-up, because the aortic complications, cardiomyopathy, endocrine neoplasms, melanoma, and pneumothorax described arose mainly in adulthood [33–37].

12. Summary and Concluding Remarks

Tatton-Brown-Rahman syndrome results from heterozygous germline loss of function of DNMT3A, the de novo DNA methyltransferase that reads the H3K36me2/3 mark through its PWWP domain, and is defined by the combination of ID in all patients, overgrowth in more than 80%, overweight, joint hypermobility, hypotonia, ASD, and a facial gestalt that becomes characteristic in early adolescence. Most variants are de novo, but transmission from parents with a mild or mosaic phenotype makes it necessary to test the parents in tissues other than blood. The DNA hypomethylation signature is robust and useful for reclassifying VUS, with the limitation of its overlap with Sotos syndrome, the main differential; Weaver syndrome is distinguished by camptodactyly, a hoarse cry, accelerated carpal maturation, and neuroblastoma risk.

Two areas have changed follow-up since the 2022 GeneReviews chapter. The first is the predisposition to haematological neoplasms, with 8 cases among 202 known patients (about 4%), AML between ages 12 and 20 years, and a predominance of Arg882 variants, which have a dominant-negative effect; this figure is not a lifetime incidence, and surveillance proposals diverge between an annual complete blood count in a research setting and clinical surveillance of symptoms with a baseline complete blood count. The second is age-dependent arterial disease, with aneurysms and dissections that required emergency surgery, which justifies a baseline echocardiogram with serial studies according to aortic root size and cardiology follow-up for all patients. The overlap between the germline spectrum and that of clonal haematopoiesis makes confirmation in non-haematopoietic tissue mandatory when the variant is found in the blood of a patient with a neoplasm or at a low variant allele fraction.

There is no targeted therapy, no registered clinical trial, and no professional society guideline; management is symptomatic and multidisciplinary, and cannabidiol has been used off-label in a single case of epileptic encephalopathy, with dosing and hepatic monitoring following the SmPC and the FDA label. Heyn-Sproul-Jackson syndrome, caused by gain of function in the PWWP domain, is the mirror image of TBRS, with microcephalic dwarfism and hypermethylation of Polycomb-regulated regions, and has at least four published patients. The main gaps are the lack of prospective cohorts, of data on pregnancy and related-donor transplantation, and of data from Portugal; according to the authors, the Rio de Janeiro family is the first Brazilian report.

13. References

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