P326: Cardiovascular features in adult individuals affected with Tatton-Brown-Rahman syndrome
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Bibliographic record
Abstract
Tatton-Brown-Rahman syndrome (TBR) is a rare genetic disorder caused by pathogenic variants in the DNMT3A gene. Close to 100 patients have been reported in the literature (mainly children), but the natural history of the disease has not been completely elucidated, particularly in adulthood. The cardiovascular anomalies that have been described in this syndrome include: atrial septal defects, patent ductus arteriosus, patent foramen ovale, mitral and tricuspid valve incompetence, atrio-ventricular re-entry tachycardia, aortic root enlargement and cardiomyopathy. We report on two patients with cardiovascular manifestations, adding new findings to the TBR syndrome features in adulthood. The first patient was a 41-year-old male known for “Sotos syndrome” and moderate intellectual disability, referred for the study of a cardiomyopathy of undetermined origin. He was born with overgrowth after an uneventful pregnancy and showed global developmental delay and high stature early in childhood as well as learning difficulties. He was also known for myopia, sleep apnea, absences, headaches, hypotension and venous insufficiency. On physical exam, he had high stature (202 cm), obesity (146 Kg), macrocephaly (60 cm), dysmorphic signs (long oval face, sparse hair in frontotemporal area, heavy horizontal eyebrows, narrow palpebral fissures, malar flush, overcrowding teeth, high arched palate), umbilical hernia, scoliosis, acnes, large hands and feet, pes planus, varicose veins in lower limbs and hypotonia. At the age of 38 years, he had a paroxysmal atrial fibrillation. Three years later, he presented with atrial fibrillation and heart failure, this time the echocardiogram showed a biventricular cardiomyopathy (severe left and right ventricular dilatation) with severe bi-atrial dilatation as well as mild aortic dilatation. At the age of 46 years, he had a right common iliac aneurysm needing an aortobiiliac bypass. At the age of 48 years, his echocardiogram showed moderate dilatation of the aortic root (4.9 cm) and the ascending aorta (4.2 cm). The TBR syndrome diagnosis was established through the identification of the pathogenic variant c.2296_2297delAA (p.Lys766Glufs*15) in the DNMT3A gene. The second patient was a 38-year-old male referred due to an abdominal aorta aneurysm with dissection and joints hypermobility. He was born through cesarian section after an uneventful pregnancy, and he had high stature and global developmental delay from early childhood. He was diagnosed with attention deficit hyperactivity disorder and mild intellectual deficiency. He was also known for myopia, sleep apnea, psoriasis, hypertension and a thymic epidermoid carcinoma. On physical exam, he had high stature (188.5 cm), obesity (129 Kg), macrocephaly (59.8 cm), dysmorphic signs (dolichocephaly, round face, frontal baldness, heavy horizontal eyebrows, downslanting palpebral fissures, enophthalmos, malar hypoplasia, thin upper lip), pes planus, hindfoot deformity, sandal gap and generalized joints hypermobility. At the age of 38 years he was diagnosed with a dissection of an abdominal aortic aneurysm (7.5 cm), and the echocardiogram showed severe left ventricular dilatation, mild right ventricular dilation, and severe bi-atrial dilatation, with an ejection fraction of 20%. He also presented atrial fibrillation. He went into surgery for correction of the aneurysm, which was extending into the iliac arteries; a high tissue fragility was observed, and he succumbed to electromechanical dissociation. He carried the likely pathogenic variant c.1975dup (p.Arg659Profs*9) in the DNMT3A gene. The atrial fibrillation and the bilateral ventricular and atrial dilatation represent new cardiac features in adults affected with TBR syndrome, therefore this diagnosis should be considered in adult individuals presenting with these manifestations and a high stature intellectual disability syndrome. At the same time, we recommend that children diagnosed with this condition have a regular cardiovascular follow up extending into adulthood.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it