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Management of Pediatric Gigantism Caused by the TADopathy, X-Linked Acrogigantism

ABSTRACT: X-linked acrogigantism (X-LAG) is a rare form of pituitary gigantism that is associated with growth hormone (GH) and prolactin-secreting pituitary adenomas/pituitary neuroendocrine tumors (PitNETs) that develop in infancy. It is caused by a duplication on chromosome Xq26.3 that leads to misexpression of the gene GPR101, a constitutively-active stimulator of pituitary GH and prolactin secretion. GPR101 normally exists within its own topologically associating domain (TAD) and is insulated from surrounding regulatory elements. X-LAG is a TADopathy in which the duplication disrupts a conserved TAD border, leading to a neoTAD in which ectopic enhancers drive GPR101 over-expression causing gigantism. Here we trace the full diagnostic and therapeutic pathway of a female patient with X-LAG from 4C-seq studies demonstrating the neoTAD through to medical and surgical interventions and detailed tumor histopathology. The complex nature of treating young children with X-LAG is illustrated, including the achievement of hormonal control using a combination of neurosurgery and adult doses of first-generation somatostatin analogs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE249129 | GEO | 2024/01/23

REPOSITORIES: GEO

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Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism [RNA-Seq]

Project description:X-linked acrogigantism (X-LAG) is the most severe form of pituitary gigantism and is characterized by aggressive growth hormone (GH)-secreting pituitary tumors that occur in early childhood. X-LAG is associated with chromosome Xq26.3 duplications (the X-LAG locus typically includes the VGLL1, CD40LG, ARGHEF6, RBMX, and GPR101 genes) that lead to massive pituitary tumoral expression of GPR101, a novel regulator of GH secretion. In this work, we aimed to unravel the mechanism by which the duplications lead to marked pituitary misexpression of GPR101 alone. Using 4C-seq, we characterized the normal chromatin structure at the X-LAG locus. Using GPR101, RBMX, and VGLL1 viewpoints, we showed that GPR101 is located within a topologically associating domain (TAD) delineated by a tissue-invariant border that separates it from centromeric genes and regulatory sequences. Then, we showed that the duplications in multiple patients led to ectopic interactions that crossed the invariant TAD border, indicating the existence of a similar and consistent mechanism of neo-TAD formation in X-LAG. Rewiring GPR101-enhancer interaction within the new regulatory unit is likely to cause the high levels of aberrant expression of GPR101 in X-LAG pituitary.

2022-02-23 | GSE193113 | GEO

Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism [4C]

2022-02-23 | GSE193112 | GEO

Integrating methylome and transcriptome signatures expands the molecular classification of the pituitary tumors [RNA-seq]

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2023-01-26 | GSE209903 | GEO

Transcriptomic effects of medical treatment on gene expression of growth hormone secreting pituitary neruoendocrine tumour biology

Project description:Pituitary neuroendocrine tumours (PitNET) are rare neoplasms of the pituitary gland that can overproduce pituitary hormones or cause headaches and visual impairment due to mass effect. Growth hormone overproducing somatotroph PitNETs cause acromegaly leading to wide range of connective tissue, metabolic and oncologic disorders. The medical treamment of acromegaly is somatostin analogues (SSA) in specific cases combined with dopamine agnoists (DA), but almost half of patients excert SSA resistence and potential causes of this is unknown. The aim of this study was to characterize transcriptomic patterns of somatotroph PitNETs specifically assessing impact of SSA treatment effects. We investigated gene expession on several levels and functional models of GH PitNETs - tumour tissue of patients with and without SSA preoperative treamtment, tumour derived pituisphere model and classically used GH3 cell line treated with SSA.

2022-04-08 | GSE200175 | GEO

Integrating methylome and transcriptome signatures expands the molecular classification of the pituitary tumors

Project description:Abnormal DNA methylation contributes to tumor progression and is emerging as a prognostic marker in several types of cancers. Pituitary tumors (PitNETs) tumorigenesis is still not completely understood. Few studies have integrated exome, methylome, and transcriptome analyses. Taking advantage of a comprehensive phenotypic characterized Brazilian cohort, which has heterogeneous ethnic origin, we combined methylome and transcriptome analysis of the three major subtypes of surgically resectable PitNETs (n = 77): GH-secreting (acromegaly, n = 18), ACTH-secreting (Cushing disease, n = 13), and non-functioning (n = 46) PitNETs. Here, we included methylome and basal patient / tumor data.

2023-01-26 | GSE207937 | GEO

Genome wide analysis of circulating miRNAs in growth hormone secreting pituitary neuroendocrine tumor patients' plasma

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2022-02-16 | GSE196647 | GEO

Transcriptome analysis reveals key genes and pathways that the ligand AA-14 acts on pituitary

Project description:Our research is helpful to understand the physiological and pathological level changes caused by the ligand AA-14 acting on the receptor GPR101 on pituitary, to find the mechanism of the signaling pathway downstream of GPR101 under the action of the ligand, and to determine which signaling pathway is mediated by GPR101

2023-08-30 | GSE241719 | GEO

Transcriptomic Profiling of Lactotroph Pituitary Neuroendocrine Tumors via RNA Sequencing and Ingenuity Pathway Analysis

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