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Research paper

Acromegaly in the setting of Tatton-Brown-Rahman Syndrome

Case report of a genetically confirmed Tatton-Brown-Rahman syndrome (TBRS, DNMT3A overgrowth) patient with a GH-secreting pituitary macroadenoma presenting as acromegaly. Establishes pituitary involvement in the TBRS spectrum and provides a documented example of an endocrine-axis tumor in a chromatinopathy. Single-case evidence.

Indexed context

Hage M, et al.

dnmt3atbrstatton-brown-rahmanpituitary-adenomagrowth-hormoneacromegalychromatinopathycase-report

Markdown path

content/research/papers/2019-hage-acromegaly-tatton-brown-rahman.md

Findings

Case report of a genetically confirmed Tatton-Brown-Rahman syndrome (TBRS, DNMT3A overgrowth) patient with a GH-secreting pituitary macroadenoma presenting as acromegaly. Establishes pituitary involvement in the TBRS spectrum and provides a documented example of an endocrine-axis tumor in a chromatinopathy. Single-case evidence.

Why it may matter for Levi

Targeted positive-endocrine-overlap signal for the existing overgrowth-dnmt3a-tbrs theory. Justifies adding IGF-1 + IGF-BP3 to the new diagnostic rank 16 (hypothalamic-pituitary panel) as a specifically motivated probe if the TBRS theory stays live. Reinforces (does not change rank) - supports including IGF-1 in any future pituitary-axis screen. Also reinforces the case for explicitly enumerating the sellar/pituitary region in the neuroradiology re-read request (diagnostic rank 4).

Paper text

Acromegaly in the setting of Tatton-Brown-Rahman Syndrome

Hage C, Sabini E, Alsharhan H, Fahrner JA, Beckers A, Daly A, Salvatori R — Pituitary (2019). PMID 31858400 · doi:10.1007/s11102-019-01019-w

Findings summary

Case report of a 34-year-old woman with genetically confirmed Tatton-Brown-Rahman syndrome (TBRS; DNMT3A germline pathogenic variant) who developed a GH-secreting pituitary macroadenoma (acromegaly) plus additional benign tumors and cystic lesions across multiple organs. Tumor DNA analysis showed no loss of heterozygosity for the co-present AIP variant of uncertain significance, suggesting AIP did not drive the pituitary tumorigenesis — i.e., the DNMT3A variant itself may underlie the pituitary overgrowth.

Authors conclude that TBRS may be associated with a broader spectrum of pituitary and other tumors than previously recognized and argue for long-term multi-organ tumor surveillance in TBRS patients.

Relevance to Levi

Indirect but targeted. Levi's differential still carries overgrowth-dnmt3a-tbrs as a plausible theory — specifically the "TBRS via methylation / mosaic / regulatory mechanism not captured by the three negative germline workups" branch. DNMT3A germline sequencing has been negative three times (Stanford trio exome, GeneDx trio WGS, GeneDx reanalysis), but the pathway is kept alive for epigenetic/mosaic mechanisms until a methylation episignature assay is done.

Two transfers to Levi:

  1. GH-secreting pituitary adenoma in TBRS is published phenotype, not speculation. This argues for including IGF-1 and IGF-BP3 in any endocrine workup as a screen for GH excess, especially given Levi's 99th-percentile symmetric overgrowth (height, weight, head circumference). If IGF-1 is meaningfully elevated, dedicated sellar MRI is indicated.
  2. The TBRS-specific neuroimaging signature (corpus callosum anomalies, small posterior fossa, deep left Sylvian fissure, increased cortical thickness; Jimenez 2023) is separately relevant to the neuroradiology re-read already on the diagnostics list.

Evidence strength: limited (single case report); but acromegaly in TBRS is now a recognized association and should not be discounted when the patient is a child with overgrowth + a TBRS-shaped differential.

Provenance