| Section | Disease / Study | Year | Design / Source | n | Identifier / USP8 prevalence | Key findings | URL / DOI | Citation |
|---|---|---:|---|---:|---|---|---|---|
| Nomenclature / identifiers | Pituitary adenoma 4 | 2025 | GeneReviews table of genetic syndromes associated with pituitary tumors | NR | **OMIM 219090** | Listed as **“Pituitary adenoma 4 (OMIM 219090)”**; described as “most often due to somatic pathogenic variants; one germline de novo pathogenic variant reported”; phenotype noted as “small corticotropinoma with high ACTH secretion, USP8 predominantly occurring in young females.” | https://www.ncbi.nlm.nih.gov/books/ | (pqac-00000036) |
| Nomenclature / identifiers | Pituitary-dependent Cushing’s disease | 2025 | Open Targets disease-target association | NR | **EFO_1001110** | Open Targets identifies USP8 association with **“pituitary-dependent Cushing’s disease”** under EFO_1001110. | https://platform.opentargets.org/ | (pqac-00000000) |
| Nomenclature / identifiers | ACTH-independent Cushing syndrome | 2025 | Open Targets disease listing | NR | **MONDO_0020529** | Seen in Open Targets results as a separate MONDO entity; included here because it was one of the only explicit MONDO IDs present in the retrieved evidence, but it is **not** the target disease equivalent of pituitary-dependent Cushing’s disease. | https://platform.opentargets.org/ | (pqac-00000000) |
| Nomenclature / identifiers | Cushing syndrome due to macronodular adrenal hyperplasia | 2025 | Open Targets disease listing | NR | **EFO_0009041** | Additional controlled-vocabulary disease ID present in the retrieved evidence; distinct from USP8-related pituitary disease. | https://platform.opentargets.org/ | (pqac-00000000) |
| Nomenclature / identifiers | Pituitary adenoma / corticotroph adenoma causing Cushing’s disease | 2015 | Multicenter genetic study | 145 | USP8-mutated corticotroph adenomas described as adenomas “causing Cushing’s disease” | Provides disease framing and phenotype spectrum (central obesity, moon face, buffalo hump, muscle weakness, easy bruising, depression, reproductive disorders) for ACTH-secreting pituitary adenomas harboring USP8 variants. | https://doi.org/10.1210/jc.2015-1453 | (pqac-00000014) |
| Cohort statistics | Perez-Rivas et al., JCEM | 2015 | Multicenter retrospective genetic analysis of functioning and silent corticotroph adenomas | 145 (134 functioning, 11 silent) | **36%** overall (48/145); **41%** adults vs **17%** pediatric; **43%** females vs **17%** males | All mutations affected **Ser718 or Pro720**; mutations absent in 11 silent corticotropinomas; adults with mutated tumors were younger at diagnosis (**36 vs 44 years**); inversely associated with postoperative adrenal insufficiency. | https://doi.org/10.1210/jc.2015-1453 | (pqac-00000005, pqac-00000014) |
| Cohort statistics | Ma et al., Cell Research | 2015 | Discovery whole-exome + targeted sequencing cohort | 108 ACTH-secreting PAs (plus 150 non-ACTH PAs screened) | **62.04%** (67/108) | **17 distinct USP8 variants**; all in **exon 14 / 14-3-3 binding motif**; none in **150 non-ACTH PAs**; mutated tumors were **smaller** and had **higher ACTH production**, **higher EGFR expression**, and **higher POMC mRNA**; EGFR blockade reduced ACTH secretion in primary USP8-mutant cells. | https://doi.org/10.1038/cr.2015.20 | (pqac-00000008, pqac-00000032) |
| Cohort statistics | Pękul et al., Frontiers in Endocrinology | 2024 | Retrospective cohort of corticotroph PitNETs | 147 (100 CD, 47 silent) | **41%** in Cushing’s disease; **8.5%** in silent tumors | USP8 mutations were more prevalent in women and associated with **higher biochemical remission**, **non-invasive growth**, **smaller size**, and **densely granulated histology**; multivariable survival analyses did **not** confirm independent prognostic value. | https://doi.org/10.3389/fendo.2024.1302667 | (pqac-00000016) |
| Cohort statistics | Nerubenko et al., IJMS | 2024 | Single-cohort sequencing + transcriptomic/clinical correlation study | 35 | **51%** (18/35) | USP8 variants more common in women (**94% vs 76%**, p=0.001); **microadenomas 44% vs 29%** (mutant vs WT, p=0.04); all tumors **≥20 mm were WT**; **recurrence 44% vs 22%**; **remission 55% vs 60%**; all USP8-mutant tumors were **SST5-positive**, and **73%** were **SST5+/SST2+**; 50% of WT tumors were double-negative. | https://doi.org/10.3390/ijms252312886 | (pqac-00000004, pqac-00000007, pqac-00000011) |
| Cohort statistics | Hashemi-Madani et al., BMC Endocrine Disorders | 2024 | Iranian case series + systematic review | 20 samples from 19 patients; systematic review size NR in excerpt | **35%** pooled prevalence in systematic review; reported literature range **11–62%** | Most frequent hotspot at **codon 720 / p.Pro720Arg (~25%)**; authors identified two somatic exon-14 variants including **p.Pro720Arg** and **p.Ser718GlnfsTer3**; EGFR overexpression/signaling positively associated with ACTH/cortisol levels and recurrence; genotype-phenotype correlations remain inconsistent. | https://doi.org/10.1186/s12902-024-01619-z | (pqac-00000006, pqac-00000012, pqac-00000013) |
| Cohort statistics | Torres-Morán et al., Cancers | 2023 | Review of hotspot somatic variants in PitNETs | NR | **21–62%** across corticotropinomas | Summarizes USP8 as the **most common genetic cause** of Cushing disease; hotspot at **codons 718–720** in **exon 14**; reports mixed clinical associations across studies, including female predominance, smaller tumors and higher remission in some cohorts, but larger size or earlier recurrence in others; increased **SST5** and **MGMT** immunoreactivity noted in mutant tumors. | https://doi.org/10.3390/cancers15235685 | (pqac-00000001, pqac-00000023) |


*Table: This table consolidates the disease naming/identifier evidence retrieved for USP8-related pituitary adenoma 4 and pituitary-dependent Cushing’s disease, then summarizes the main cohort-level statistics on USP8 mutation prevalence and genotype-phenotype correlations. It is useful for mapping the disease concept and for comparing how different cohorts report sex bias, tumor size, recurrence/remission, and receptor-expression patterns.*