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Evaluation of Hypothalamic and Pituitary Disorders

  • Christina Tatsi, MD, MHSc, PhD, Head, Unit on Hypothalamic and Pituitary Disorders
  • Sukhvir Kaur, MSc, PhD, Lab Technician
  • Rida Zainab, BS, Postbaccalaureate Fellow
  • Samah Agabein, MBBS, CCRC, Research Coordinator
Christina Tatsi

The goal of our research is to phenotype patients with rare hypothalamic and pituitary disorders and to identify biomarkers for disease diagnosis and of presentation and progression. We are also continuing to investigate the genetic mechanisms underlying pituitary tumorigenesis, which, along with novel biomarkers, will ultimately provide new therapeutic targets.

Defining the trajectory of manifestations of pediatric exposure to hormone excess

Our team has one of the largest national cohorts of patients with pPitNETs (pediatric pituitary neuroendocrine tumors). In our published work over the last years, we studied various aspects of clinical, biochemical, and imaging presentation of these patients that offer guidance for clinical practice [Piña et al. J Endoc Soc 2024;8:bvae064; Nguyen et al. Horm Metab Res 2024;56:604]. We described the baseline characteristics of the largest cohort (more than 350 patients) of pediatric-onset Cushing’s syndrome (CS) and confirmed that patients with pediatric-onset Cushing’s disease (CD) have significantly elevated CRFs (cardiovascular risk factors), including weight gain/obesity (present in 75% of patients), cardiovascular complications/hypertension (50% of patients), hyperglycemia/insulin resistance (30% of patients), hyperlipidemia (50% of patients), and hepatic steatosis (60% of patients) (Figure 1) [Reference 4]. This observational study set the stage for identifying areas of interest for future focused studies. In a follow-up study, we showed that obesity constitutes a contributing factor for CRFs, and patients with CS and obesity had a significantly higher risk of hypertension, insulin resistance, and hepatic steatosis than CS patients without obesity [Reference 1].

In the protocol of long-term follow-up of pediatric survivors of CD, we have now evaluated approximately 35 patients with the goal of defining the long-term outcomes in survivors of pediatric CD.

As part of defining the trajectory of pPitNETs, our team is also investigating medical therapies, none of which are currently FDA–approved for children and adolescents. We have two clinical trials for the management of patients with pediatric CD and growth hormone excess (GHE), which are unique trials throughout the country and serve the mission of NICHD to study rare pediatric disorders.

Molecular genetics of pituitary disorders

Known genetic factors do not explain most pPitNETs, but genotype-phenotype correlations are present.

In collaboration with the Centralized Sequencing Project at NIAID, we perform germline whole-genome sequencing (WGS) for all patients with pPitNETs. In our data from patients genotyped between 2021–2023 (38 patients with pPitNETs), we noted that known germline genetic defects explain fewer than 8% of patients with CD, while known somatic gene defects are found in 20% of patients. In cases of unknown germline or somatic cause, we are investigating novel pathogenic variants in genes not previously directly associated with pPitNETs.

Although most of the genetic causes of pPitNETs are still unknown, there are apparent genotype-phenotype correlations that predict disease presentation and prognosis.

Spatial transcriptomics (ST) in pPitNETs reveal pathways of interest.

Aside from DNA genotyping in pPitNETs, we explored other methods that can highlight pathways and genes of interest. Given the small size of these tumors, we performed a novel approach for transcriptomic analysis of pPitNETs, the first ST analysis in CD retrieved from a single slide [Piña et al. J Endoc Soc 2024;8:bvae064]. We demonstrated concordance of histologic annotation by an expert pathologist with the transcriptional annotation based on gene expression profiles, and we described for the first time the intra-tumor heterogeneity in a spatial approach. ST analysis also revealed concordance with proliferation markers, such as the Ki-67 index, suggesting that it is a reliable alternative for this and other prognostic biomarkers. Lastly, ST revealed gene pathways of interest; for example, p53 and MAPK pathways were annotated across multiple tumors, suggesting a common pathogenesis and possible therapeutic targets for these tumors.

Immunologic effects of hypercortisolemia

Glucocorticoids have many effects on the immune system, which makes them one of the most commonly prescribed medications. Patients with ACTH–secreting pituitary adenomas present with endogenous hypercortisolemia and are a model for the evaluation of the immune effects of glucocorticoids, especially in the pediatric population, where other confounding co-existing morbidities are rare. We started our investigation on the immune effects of hypercortisolemia by looking at the complete blood count (CBC) of these patients, and we reported that simple inflammatory biomarkers can be used for the diagnosis of these patients. We further collaborated with Sergio Rosenzweig's group to describe specific cytokine patterns that may be involved in the pathophysiology of glucocorticoid-related immunosuppression. Luis Franco’s group is currently conducting a study to further characterize the immune phenotype of our patients.

Novel approaches and markers of disease diagnosis and prognosis

Novel approaches of liquid biopsy in patients with pPitNETs

We are applying novel techniques to investigate minimally invasive markers of disease diagnosis and prognosis (studies in progress).

Additional Funding

  • Recordati Pharma

Publications

  1. Padilla C, Stratakis CA, Tatsi C. The phenotype of the pediatric patient with Cushing syndrome but without obesity. Eur J Endocrinol 2024 191:399–406
  2. Xekouki P, Konstantinidou A, Tatsi C, Sertedaki A, Settas N, Loutradis D, Chrousos GP, Kanaka-Gantenbein C, Dacou-Voutetakis C, Voutetakis A. HNF1A gene mutations and premature ovarian failure (POF): evidence from a clinical paradigm combining MODY 3 and POF. Hormones 2024 23:345–350
  3. Tatsi C, Pitsava G, Faucz FR, Keil M, Stratakis CA. The spectrum of growth hormone excess in Carney complex and genotype-phenotype correlations. J Clin Endocrinol Metab 2025 110(3)e694–e702
  4. Tatsi C, Kamilaris C, Keil M, Saidkhodjaeva L, Faucz FR, Chittiboina P, Stratakis CA. Paediatric Cushing syndrome: a prospective, multisite, observational cohort study. Lancet Child Adolesc Health 2024 8:51–62
  5. Maschio C, Weinberg J, Keil M, Saidkhodjaeva L, Chittiboina P, Chang R, Stratakis CA, Tatsi C. False negative inferior petrosal sinus sampling in young-onset Cushing disease: what happens n ext. Horm Res Paediatr 2023 10:1159
  6. Weinberg JR, Voudouri M, Keil M, Stratakis CA, Tatsi C. The utility of IGF1 in the evaluation of pediatric patients with endogenous hypercortisolemia. Pediatr Res 2024 95:758–761

Collaborators

  • Prashant Chittiboina, MD, Neurosurgery Unit for Pituitary and Inheritable Diseases, NINDS, Bethesda, MD
  • Ryan Dale, PhD, Bioinformatics and Scientific Programming Core, NICHD, Bethesda, MD
  • Luis M. Franco, MD, Functional Immunogenomics Section, NIAMS, Bethesda, MD
  • Sergio Rosenzweig, MD, PhD, Department of Laboratory Medicine, NIH Clinical Center, Bethesda, MD
  • Morgan Simulak, ScM, Centralized Sequencing Program, NIAID, Bethesda, MD