Alternative titles; symbols
SNOMEDCT: 190502001; ICD10CM: E24.0; ORPHA: 96253; DO: 7004;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q21.2 | Pituitary adenoma 4, ACTH-secreting, somatic | 219090 | 3 | USP8 | 603158 |
A number sign (#) is used with this entry because of evidence that pituitary adenoma-4 (PITA4) is caused by somatic mutation in the USP8 gene (603158) on chromosome 15q21.
Adrenocorticotropic hormone (ACTH) hypersecretion by corticotroph adenomas of the pituitary result in excess cortisol secretion, or Cushing disease. The clinical features of Cushing disease include central obesity, moon facies, 'buffalo hump,' diabetes, hypertension, fatigue, easy bruising, depression, and reproductive disorders. Cushing disease is associated with increased morbidity and mortality, mainly due to cardiovascular or cerebrovascular disease and infections (summary by Perez-Rivas et al., 2015).
Mutations in the USP8 gene, leading to an upregulated epidermal growth factor receptor (EGFR; 131550) pathway, have been identified in about 36 to 62% of corticotroph adenomas (summary by Mete and Lopes, 2017).
Salti and Mufarrij (1981) described Cushing disease in a 28-year-old woman and her niece, aged 25 years. The parents of the niece were first cousins; thus, the aunt and the niece were related to each other also as first cousins once removed. Endocrine studies established pituitary ACTH excess. The sella was normal-sized in the aunt and enlarged in the niece; both received external pituitary irradiation which in the aunt had produced clinical and hormonal remission for 9 years.
Swinburn and Holdaway (1988) described 2 teenaged sisters with pituitary-based Cushing syndrome. In 1 patient, the disorder was cured by pituitary radiation; in the other, biopsy showed pituitary adenoma. Swinburn and Holdaway (1988) granted that 'despite the negative family history, these patients could still represent the first generation of a MEN I family.'
Gardner et al. (1989) reported the cases of black sisters, aged 38 and 40 years, with Cushing disease due to ACTH-immunostaining pituitary adenoma demonstrated at transsphenoidal pituitary surgery. Gardner et al. (1989) considered it unlikely that these sisters had MEN I, because usually hyperparathyroidism is present at the time of diagnosis of MEN I. Serum calcium levels were normal on repeated occasions in these patients. Furthermore, there was no clinical evidence of pancreatic islet cell tumor in either patient.
The clinical features of 79 Cushing syndrome patients with somatic mutations in the USP8 gene reported by Ma et al. (2015) included weight gain, moon facies, 'buffalo hump,' striae, peripheral edema, amenorrhea or menstrual abnormalities, thinning of hair or alopecia, acne, fatigue or weakness, emotional lability or depression, and easy bruising. A few patients had thin skin, recurrent or difficult to treat infections, and pigmentation. About half of the patients also had diabetes mellitus, hypertension, osteoporosis or osteopenia, or hypokalemia. Ma et al. (2015) identified USP8 mutations in significantly more females (67.7%) than males (38.1%). USP8-mutated tumors were small and diffusely distributed within the sella, whereas wildtype USP8 tumors were large and extended into the parasellar space. Recurrence rate and average recurrence period were unrelated to USP8 mutational status.
Cushing disease is a condition associated with increased blood cortisol resulting from ACTH-producing pituitary tumors that are resistant to glucocorticoid negative feedback. Bilodeau et al. (2006) found that 17 (47%) of 36 human corticotroph adenomas had altered expression and/or subcellular localization of either BRG1 (603254) or HDAC2 (605164) compared to adjacent normal pituitary tissue. The findings indicated that these proteins were essential for glucocorticoid-induced transrepression of the POMC gene (176830) via the glucocorticoid receptor (GCCR; 138040) in the negative feedback regulation mechanism.
By exome sequencing of tumor/germline DNA sample pairs from 10 patients with Cushing disease, Reincke et al. (2015) identified heterozygous somatic missense mutations in the USP8 gene in 4 tumors. They then sequenced the entire coding sequence of USP8 in 43 additional adenomas, including 7 corticotroph adenomas, 2 Nelson tumors, 14 somatotroph adenomas, 10 prolactinomas, and 10 nonfunctional adenomas, and identified mutations in 6 of the pituitary adenomas but in none of the other tumors. All of the patients with USP8 mutations were female and appeared to have small tumors. A mutational hotspot was located between residues 713 and 720, within or adjacent to the 14-3-3 (see YWHAE, 605066) binding motif and close to the protein's catalytic domain.
By whole-exome sequencing of 12 ACTH-secreting pituitary adenomas and matched blood samples, Ma et al. (2015) identified 3 recurrent heterozygous somatic mutations in the USP8 gene (603158.0002-603158.0004), all in exon 14, in 8 of the tumors. By screening an additional 258 pituitary adenomas, including 108 ACTH-secreting, 50 GH-secreting, 50 PRL-secreting, and 50 nonfunctional, they identified somatic USP8 mutations in 67 of the 108 ACTH-secreting tumors and in none of the other tumor types. The 3 recurrent mutations accounted for over 77% of the USP8 mutations. No germline USB8 mutations were identified. None of the 17 USP8 mutations identified were present in the dbSNP (build 138) or 1000 Genomes Project database.
By Sanger sequencing in 134 functioning and 11 silent corticotroph adenomas from patients with Cushing disease, Perez-Rivas et al. (2015) identified heterozygous USP8 mutations in 48 functioning tumors (36%) but in none of the silent tumors. All of the mutations affected residues ser718 or pro720. Mutations reduced the interaction between USP and 14-3-3 and enhanced USP activity. USP8 mutants diminished EGFR ubiquitination and included POMC promoter activity in corticotropin cells.
Bilodeau, S., Vallette-Kasic, S., Gauthier, Y., Figarella-Branger, D., Brue, T., Berthelet, F., Lacroix, A., Batista, D., Stratakis, C., Hanson, J., Meij, B., Drouin, J. Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease. Genes Dev. 20: 2871-2886, 2006. [PubMed: 17043312] [Full Text: https://doi.org/10.1101/gad.1444606]
Gardner, D. F., Barlascini, C. O., Jr., Downs, R. W., Jr., Sahni, K. S. Case report: Cushing's disease in two sisters. Am. J. Med. Sci. 297: 387-389, 1989. [PubMed: 2544092] [Full Text: https://doi.org/10.1097/00000441-198906000-00012]
Ma, Z.-Y., Song, Z.-J., Chen, J.-H., Wang, Y.-F., Li, S.-Q., Zhou, L.-F., Mao, Y., Li, Y.-M., Hu, R.-G., Zhang, Z.-Y., Ye, H.-Y., Shen, M., and 34 others. Recurrent gain-of function USP8 mutations in Cushing's disease. Cell Res. 25: 306-317, 2015. [PubMed: 25675982] [Full Text: https://doi.org/10.1038/cr.2015.20]
Mete, O., Lopes, M. B. Overview of the 2017 WHO classification of pituitary tumors. Endocr. Path. 28: 228-243, 2017. [PubMed: 28766057] [Full Text: https://doi.org/10.1007/s12022-017-9498-z]
Perez-Rivas, L. G., Theodoropoulou, M., Ferrau, F., Nusser, C., Kawaguchi, K., Stratakis, C. A., Faucz, F. R., Wildemberg, L. E., Assie, G., Beschorner, R., Dimopoulou, C., Buchfelder, M., and 12 others. The gene of the ubiquitin-specific protease 8 is frequently mutated in adenomas causing Cushing's disease. J. Clin. Endocr. Metab. 100: E997-E1004, 2015. Note: Electronic Article. [PubMed: 25942478] [Full Text: https://doi.org/10.1210/jc.2015-1453]
Reincke, M., Sbiera, S., Hayakawa, A., Theodoropoulou, M., Osswald, A., Beuschlein, F., Meitinger, T., Mizuno-Yamasaki, E., Kawaguchi, K., Saeki, Y., Tanaka, K., Wieland, T., Graf, E., Saeger, W., Ronchi, C. L., Allolio, B., Buchfelder, M., Strom, T. M., Fassnacht, M., Komada, M. Mutations in the deubiquitinase gene USP8 cause Cushing's disease. Nature Genet. 47: 31-38, 2015. [PubMed: 25485838] [Full Text: https://doi.org/10.1038/ng.3166]
Salti, I. S., Mufarrij, I. S. Familial Cushing disease. Am. J. Med. Genet. 8: 91-94, 1981. [PubMed: 7246609] [Full Text: https://doi.org/10.1002/ajmg.1320080111]
Swinburn, B. A., Holdaway, I. M. Familial Cushing's disease. Aust. New Zeal. J. Med. 18: 169-171, 1988.