The new joint call by Fondazione Telethon and Fondazione Cariplo, dedicated to studying the less explored areas of the human genome, funded 26 projects across Italy in 2025 for a total of 3.6 million euros. Among them is the project led by Giampaolo Trivellin, Assistant Professor at Humanitas University, selected to investigate the genetic mechanisms underlying rare pituitary diseases. The initiative, carried out in collaboration with the group of Gianluca Occhi, Professor of Applied and Cellular Biology at the Department of Biology of University of Padua, received funding of 250,000 euros over a two-year period.

The project aims at addressing one of the most complex and still poorly understood topics in endocrinology: how specific genetic alterations can lead to excessive hormone production from early childhood or promote the development of pituitary tumors. The support received offers an opportunity to explore still largely uncharted aspects of pituitary biology, with potential future benefits for patients affected by rare diseases lacking specific therapies.

Investigating X-LAG, PitNETs, and the emerging role of OTOS

The pituitary gland regulates the production of key hormones, including growth hormone (GH) and prolactin (PRL), which are essential for growth, metabolism, and numerous vital functions of the body. This balance, however, can be disrupted by pituitary neuroendocrine tumors (PitNETs), which cause excessive hormone secretion with significant clinical consequences. Among the rarest and most severe conditions is X-linked acrogigantism (X-LAG), an extremely rare genetic disease caused by a duplication in the GPR101 gene, which leads to abnormally high GH and PRL levels from childhood and excessively rapid growth.

In recent years, attention has also turned to the OTOS gene, which may play a key role in both X-LAG and more common forms of PitNETs. OTOS encodes the protein otospiralin, which is particularly abundant in the pituitary gland, and even more so in tumors that simultaneously produce GH and PRL. In patients with X-LAG, the OTOS and GPR101 genes are active in the same tumor areas, suggesting a possible functional link between the two. However, the precise function of OTOS in the pituitary gland and its contribution to hormonal alterations remain largely unclear.

“Understanding how OTOS acts in pituitary cells could allow us to uncover disease mechanisms that have so far remained invisible, especially in tumors that produce GH and PRL,” explains Trivellin. “It’s a missing piece that could rewrite what we know about the origin of these rare and complex conditions.”

The project therefore aims to define the function of OTOS in both healthy and tumoral pituitary tissue. The team will study the behavior of the otospiralin protein, its cellular localization, and its interactions with other molecules, also assessing how changes in otospiralin levels influence the characteristics of tumor cells obtained from patients. A particularly innovative aspect is the use of pituitary organoids – small three-dimensional structures derived from stem cells, including those from X-LAG patients – which make it possible to reproduce the functioning of the gland and its genetic alterations in the laboratory.

The ultimate goal is to determine whether OTOS contributes to excessive GH and PRL production and to the growth of PitNETs. If this hypothesis is confirmed, OTOS could represent a new diagnostic biomarker and a potential therapeutic target for patients affected by both X-LAG and secreting PitNETs.

Towards new diagnoses and targeted therapies

The knowledge generated by the project could have a significant impact both on the study of pituitary tumors and on understanding the genetic mechanisms underlying X-LAG. Clarifying the role of OTOS could lead to the identification of new biomarkers useful for early diagnosis and for more selective treatments. The use of pituitary organoids will also offer new opportunities for personalised approaches based on patients’ specific genetic characteristics.

“Our goal is to turn these discoveries into real tools for clinicians and concrete benefits for patients,” concludes Trivellin. “For those living with such rare conditions, even a small scientific advance can make an enormous difference.”