Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Aug 14;28(5):92.
doi: 10.1007/s11102-025-01557-6.

Genetic evaluation of pediatric pituitary adenomas and USP8-related genotype-phenotype correlations in Cushing's disease

Rida Zainab  1 , Sukhvir Kaur  1 , Justin Lack  2 , Morgan Similuk  3 , Mayank Tandon  2 , Rajarshi Ghosh  3 , Bryce A Seifert  3 , Mari Tokita  3 , Chelsi Flippo  4 , Jia Yan  3 , Magdalena Walkiewicz  3 , Prashant Chittiboina  5 , Christina Tatsi  6
Affiliations

Genetic evaluation of pediatric pituitary adenomas and USP8-related genotype-phenotype correlations in Cushing's disease

Rida Zainab et al. Pituitary. .

Abstract

Purpose: Pituitary adenomas (PAs) constitute a rare pediatric diagnosis and their pathogenetic mechanisms are not clearly understood. The aim of this study was to evaluate the prevalence of genetic defects in pediatric PAs through germline and tumor testing, and to describe genotype-phenotype correlations.

Methods: Fifty-four pediatric patients with PAs and available germline and/or tumor samples were studied. Germline and/or tumor sequencing were reviewed for variants in genes previously associated with pituitary tumorigenesis.

Results: Germline genetic testing revealed a pathogenic variant in AIP gene in 2 patients with growth hormone excess (GHE) and a likely pathogenic variant in CDKN2A in a patient with Cushing's disease (CD). Somatic gene sequencing identified pathogenic variants in GNAS in 4/7 patients (57.1%) with GHE. 6/38 patients (15.8%) with CD had pathogenic variants in USP8 gene, and in one tumor pathogenic variants in PRKAR1A, TP53 and MEN1 genes were identified. Overall, pathogenic/likely pathogenic germline or somatic variants were identified in 14/54 patients (25.9%). When evaluating the genotype-phenotype correlations in patients with CD, patients with somatic USP8 pathogenic variants had larger tumors (median size: 9.5 mm [6.5, 13.3] vs. 6 mm [4.0, 7.0], p = 0.048), trend towards higher incidence of cavernous sinus invasion (50% vs. 12.5%, p = 0.06), and higher risk of non-remission after surgery (33.3% vs. 0%, p = 0.021) compared to patients without USP8 variants.

Conclusions: Somatic USP8 pathogenic variants correlate with worse tumor behavior and patient outcomes in pediatric-onset CD. Unlike GH-secreting PAs, the genetic basis of the majority of pediatric corticotroph PAs remains unclear. Further studies are needed to explore the genetic drivers of pediatric CD.

Gov id: NCT00001595, NCT03206099.

Keywords: Corticotroph tumor; Cushing; Gigantism; Pediatric pituitary adenomas; Somatotroph tumor.

PubMed Disclaimer

Conflict of interest statement

Declarations. Competing interests: The authors declare no competing interests. Disclosure Statement: CT received research funding for studies on treatment of abnormal growth hormone secretion by Pfizer, Inc, and for studies on treatment of Cushing’s disease by Recordati.

Figures

Fig. 1
Fig. 1
Yield of pathogenic/likely pathogenic germline and somatic variants in pediatric patients with Cushing’s disease (A) and growth hormone excess (B). *Some patients did not have both germline and tumor analysis available
Fig. 2
Fig. 2
(A-C) Representative post-contrast magnetic resonance imaging (MRI) studies of pituitary corticotropinomas in three patients with Cushing’s disease and USP8 pathogenic variants showing larger tumors with signs of cavernous sinus invasion (asterisk). (D) Representative post-contrast MRI study of a patient with Cushing’s disease without USP8 pathogenic variant showing a typical microadenoma (arrow)
Fig. 3
Fig. 3
(A) Tumor size in patients with Cushing’s disease with or without USP8 pathogenic variants (line shows median and whiskers 10-90th percentile). (B) Remission after surgery in patients with Cushing’s disease with or without USP8 mutation. (C) Time-to-event plot of probability of recurrence based on USP8 status
See this image and copyright information in PMC

References

    1. Agustsson TT, Baldvinsdottir T, Jonasson JG, Olafsdottir E, Steinthorsdottir V, Sigurdsson G et al (2015) The epidemiology of pituitary adenomas in iceland, 1955–2012: a nationwide population-based study. Eur J Endocrinol 173:655–664. 10.1530/EJE-15-0189 - PubMed
    1. Broder MS, Neary MP, Chang E, Cherepanov D, Ludlam WH (2015) Incidence of Cushing’s syndrome and Cushing’s disease in commercially-insured patients < 65 years old in the United States. Pituitary 18, 283–289. 10.1007/s11102-014-0569-6 - PubMed
    1. Souteiro P, Maia R, Santos-Silva R, Figueiredo R, Costa C, Belo S et al (2019) Pituitary incidentalomas in paediatric age are different from those described in adulthood. Pituitary 22:124–128. 10.1007/s11102-019-00940-4 - PubMed
    1. Tatsi C, Stratakis CA (2019) The genetics of pituitary adenomas. J Clin Med 9. 10.3390/jcm9010030 - PMC - PubMed
    1. Martinez de LaPiscina I, Hernandez-Ramirez LC, Portillo N, Gomez-Gila AL, Urrutia I, Martinez-Salazar R et al (2020) Rare germline DICER1 variants in pediatric patients with cushing’s disease: what is their role?? Front Endocrinol (Lausanne) 11:433. 10.3389/fendo.2020.00433 - PMC - PubMed

Publication types

Substances

Associated data