| Topic | Specific data point | Value(s) with units or percentages | Source (first author year, journal) | PMID if known | URL | Evidence type |
|---|---|---|---|---|---|---|
| Genetics/Epidemiology | Proportion of pituitary gigantism cohort with GPR101 duplication/X-LAG | 12/153 patients = 7.8%; females 10/58 = 17.2% of female gigantism cases | Iacovazzo 2016, *Acta Neuropathologica Communications* (pqac-00000005, pqac-00000017) |  | https://doi.org/10.1186/s40478-016-0328-1 | Human cohort |
| Epidemiology | Share of pituitary gigantism attributable to X-LAG | ~10% of pituitary gigantism cases | Daly 2024, *Endocrine Reviews* (pqac-00000018, pqac-00000021) |  | https://doi.org/10.1210/endrev/bnae014 | Review of human cohorts |
| Epidemiology | Total reported X-LAG cases in review cohort | 39 reported patients; ~40 cases over first 10 years since discovery | Daly 2024, *Endocrine Reviews* (pqac-00000018, pqac-00000020) |  | https://doi.org/10.1210/endrev/bnae014 | Review of human cohorts |
| Epidemiology | Sex distribution | Female 30/39 (76.9%); male 9/39 (23.1%) | Daly 2024, *Endocrine Reviews* (pqac-00000020, pqac-00000022, pqac-00000047) |  | https://doi.org/10.1210/endrev/bnae014 | Review of human cohorts |
| Genetics | Germline vs mosaic pattern | Females: germline duplications; sporadic males: often somatic mosaic duplications; familial maternal transmission reported | Iacovazzo 2016, *Acta Neuropathologica Communications*; Daly 2016, *Endocrine-Related Cancer*; Daly 2024, *Endocrine Reviews* (pqac-00000005, pqac-00000021) |  | https://doi.org/10.1186/s40478-016-0328-1 | Human cohort |
| Genetics | Inheritance/penetrance summary | X-linked dominant; familial cases reported; full penetrance reported in familial X-LAG | Daly 2024, *Endocrine Reviews*; Nadhamuni 2020, *Endocrine Reviews* (pqac-00000004, pqac-00000019) |  | https://doi.org/10.1210/endrev/bnae014 | Review of human cohorts |
| Phenotype | Median age at onset | 18 months in review cohort; 1.9 years in 2016 cohort | Daly 2024, *Endocrine Reviews*; Iacovazzo 2016, *Acta Neuropathologica Communications* (pqac-00000020, pqac-00000005) |  | https://doi.org/10.1210/endrev/bnae014 | Human cohort/review |
| Phenotype | Median age at diagnosis | ~4 years in review cohort; 4.4 years in 2016 cohort | Daly 2024, *Endocrine Reviews*; Iacovazzo 2016, *Acta Neuropathologica Communications* (pqac-00000022, pqac-00000005) |  | https://doi.org/10.1210/endrev/bnae014 | Human cohort/review |
| Phenotype | Height excess at presentation | Median height SDS +5.4 in XLAG cohort | Iacovazzo 2016, *Acta Neuropathologica Communications* (pqac-00000005) |  | https://doi.org/10.1186/s40478-016-0328-1 | Human cohort |
| Phenotype | GH/IGF-1 excess | Basal GH elevated in all patients; median IGF-1 ~2.9× upper limit of normal | Iacovazzo 2016, *Acta Neuropathologica Communications* (pqac-00000005) |  | https://doi.org/10.1186/s40478-016-0328-1 | Human cohort |
| Tumor pathology | Macroadenoma frequency | 9/12 = 75% macroadenomas in 2016 cohort; 82.1% macroadenomas in 2024 review cohort | Iacovazzo 2016, *Acta Neuropathologica Communications*; Daly 2024, *Endocrine Reviews* (pqac-00000005, pqac-00000016) |  | https://doi.org/10.1186/s40478-016-0328-1 | Human cohort/review |
| Tumor pathology | Hyperplasia frequency | 3/12 = 25% diffuse pituitary hyperplasia in 2016 cohort; 10.3% hyperplasia and 7.7% adenoma + hyperplasia in 2024 review table | Iacovazzo 2016, *Acta Neuropathologica Communications*; Daly 2024, *Endocrine Reviews* (pqac-00000005, pqac-00000004, pqac-00000047) |  | https://doi.org/10.1186/s40478-016-0328-1 | Human cohort/review |
| Tumor pathology | Typical tumor lineage | Mixed GH–prolactin adenoma common; mixed GH/PRL lesions 72% in review table | Daly 2024, *Endocrine Reviews* (pqac-00000004, pqac-00000047) |  | https://doi.org/10.1210/endrev/bnae014 | Review of human cohorts |
| Tumor pathology | Prolactin co-secretion / hyperprolactinemia | PRL elevated in 10/12 patients (83.3%) in 2016 cohort; prolactin co-secretion 77% in 2024 review | Iacovazzo 2016, *Acta Neuropathologica Communications*; Daly 2024, *Endocrine Reviews* (pqac-00000005, pqac-00000004, pqac-00000011) |  | https://doi.org/10.1186/s40478-016-0328-1 | Human cohort/review |
| Tumor pathology | Histologic architecture | Sinusoidal/lobular architecture; mixed densely granulated somatotrophs and lactotrophs; Ki-67 usually <3% in cohort cases | Iacovazzo 2016, *Acta Neuropathologica Communications* (pqac-00000009, pqac-00000011) |  | https://doi.org/10.1186/s40478-016-0328-1 | Human pathology cohort |
| Treatment outcomes | Any pituitary axis hypopituitarism after treatment | 26/39 = 66.7% had hypopituitarism affecting any axis | Daly 2024, *Endocrine Reviews* (pqac-00000004, pqac-00000047) |  | https://doi.org/10.1210/endrev/bnae014 | Review of human cohorts |
| Treatment outcomes | Radiotherapy use | 15/39 = 38.5% received radiotherapy | Daly 2024, *Endocrine Reviews* (pqac-00000004, pqac-00000047) |  | https://doi.org/10.1210/endrev/bnae014 | Review of human cohorts |
| Treatment outcomes | Control without hypopituitarism | 8/39 = 20.5% achieved control without hypopituitarism | Daly 2024, *Endocrine Reviews* (pqac-00000004, pqac-00000047) |  | https://doi.org/10.1210/endrev/bnae014 | Review of human cohorts |
| Treatment outcomes | General medical therapy response | First-generation SSA resistance common; pegvisomant often effective for IGF-1 control | Daly 2024, *Endocrine Reviews* (pqac-00000004, pqac-00000008) |  | https://doi.org/10.1210/endrev/bnae014 | Review/expert analysis |
| Treatment outcomes | Example of real-world pediatric case | Octreotide/lanreotide and cabergoline did not normalize GH/IGF-1; pegvisomant lowered IGF-1 but control remained inconsistent and lipohypertrophy occurred | Caruso 2024, *Frontiers in Endocrinology* (pqac-00000001) |  | https://doi.org/10.3389/fendo.2024.1345363 | Human case report |
| Diagnostics | Example baseline pediatric biochemical values | Random GH 62 ng/mL; IGF-1 752.1 ng/mL; prolactin 2,656 mIU/L; pituitary mass 17 × 12 mm | Caruso 2024, *Frontiers in Endocrinology* (pqac-00000001) |  | https://doi.org/10.3389/fendo.2024.1345363 | Human case report |
| Diagnostics | Pathogenic structural criterion at GPR101 locus | Pathogenic duplications disrupt the invariant centromeric TAD boundary and create a neo-TAD enabling ectopic enhancer adoption; duplications preserving the boundary are neutral/non-pathogenic | Daly 2024, *Genome Medicine* (pqac-00000031, pqac-00000032, pqac-00000033, pqac-00000035) |  | https://doi.org/10.1186/s13073-024-01378-5 | Human genomic mechanism/clinical translational study |
| Diagnostics | Clinical utility of 4C-seq/Hi-C | 4C-seq/Hi-C used to reclassify suspected X-LAG CNVs and discontinue unnecessary endocrine surveillance in neutral cases | Daly 2024, *Genome Medicine* (pqac-00000031, pqac-00000036) |  | https://doi.org/10.1186/s13073-024-01378-5 | Human translational diagnostics study |
| Mechanism | Primary molecular lesion | Xq26.3 tandem duplication involving GPR101 with topological domain disruption and pituitary GPR101 misexpression (>1000-fold overexpression reported) | Daly 2024, *Endocrine Reviews*; Daly 2024, *Genome Medicine* (pqac-00000007, pqac-00000032) |  | https://doi.org/10.1210/endrev/bnae014 | Human molecular/review |
| Mechanism | Receptor signaling partners | Constitutive coupling to Gs, Gq/11, and G12/13; increases cAMP, IP1/IP3, and Rho signaling | Abboud 2020, *Nature Communications*; Daly 2024, *Endocrine Reviews* (pqac-00000023, pqac-00000024, pqac-00000028) |  | https://doi.org/10.1038/s41467-020-18500-x | Animal model/in vitro |
| Mechanism | Downstream pathways | PKA and PKC activation drive GH secretion; phospho-PKC increased in mouse pituitary and human tumors with high GPR101 expression | Abboud 2020, *Nature Communications* (pqac-00000023, pqac-00000025, pqac-00000026, pqac-00000027) |  | https://doi.org/10.1038/s41467-020-18500-x | Animal model/in vitro/human tumor validation |
| Mechanism | Secretory vs proliferative effect in model | Ghrhr-Gpr101 transgenic mice developed elevated GH, IGF-1, PRL and gigantism but no pituitary adenoma or hyperplasia | Abboud 2020, *Nature Communications* (pqac-00000023, pqac-00000024, pqac-00000027) |  | https://doi.org/10.1038/s41467-020-18500-x | Animal model |
| Clinical trial | Pediatric pegvisomant trial design | NCT03882034; Phase 3; open-label single-group; n=12; ages 2 to <18 years; 10 mg SC daily with dose adjustment | ClinicalTrials.gov/NICHD 2019 (pqac-00000039, pqac-00000043) |  | https://clinicaltrials.gov/study/NCT03882034 | Clinical trial |
| Clinical trial | Pediatric pegvisomant primary endpoints | Percent change in IGF-1 z-score from baseline to 12 months; efficacy target: >50% decrease in IGF-1 z-score; safety/tolerability co-primary | ClinicalTrials.gov/NICHD 2019 (pqac-00000039, pqac-00000043) |  | https://clinicaltrials.gov/study/NCT03882034 | Clinical trial |
| Clinical trial | Pediatric pegvisomant secondary endpoints | Normalization of age/sex-adjusted IGF-1, change in growth velocity, symptom/QoL measures, cardiac structure/function, PK studies | ClinicalTrials.gov/NICHD 2019 (pqac-00000039, pqac-00000043) |  | https://clinicaltrials.gov/study/NCT03882034 | Clinical trial |


*Table: This table summarizes key quantitative and mechanistic findings for GPR101/X-linked acrogigantism, used here as the closest evidence base for GPR101-related pituitary adenoma 2. It consolidates cohort statistics, pathology, mechanism, diagnostic interpretation, and relevant pediatric trial endpoints into a structured format for downstream knowledge-base use.*