ENOrphanet Journal of Rare Diseases | Novel Germline CDH23 Variant Linked to Ultra-Giant Prolactinoma
Date: February 01, 2026
Classification: Frontiers
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This study reports a case of an ultra-giant prolactinoma in a patient with a de novo CDH23 gene variant. The tumor was massive and extensively invaded skull base structures, yet showed a remarkable response to low-dose cabergoline, providing new evidence for the genetic mechanisms underlying rare pituitary tumors.
Literature Overview
The article titled 'A novel germline CDH23 variant as a likely cause of an ultra-giant prolactinoma,' published in the Orphanet Journal of Rare Diseases, reviews and summarizes an incidentally discovered invasive ultra-giant prolactinoma in a 53-year-old female. The tumor measured up to 8 cm in diameter, extensively involving the sellar region, middle cranial fossa, and nasopharyngeal structures. Initially misdiagnosed as nasopharyngeal carcinoma, it was confirmed as a prolactinoma via biopsy, with serum prolactin levels reaching as high as 277,500 ng/ml. Whole-exome sequencing revealed a novel germline CDH23 variant (c.2621C > A, p.Ala874Asp), suggesting a potential role of this gene in pituitary tumorigenesis. Following treatment with low-dose cabergoline, the tumor significantly regressed and symptoms markedly improved. The study details the clinical features, pathological findings, molecular genetic discoveries, and treatment response, expanding our understanding of the genetic basis of giant prolactinomas.Background Knowledge
Prolactinoma is the most common functional pituitary adenoma, mostly presenting as microadenomas or macroadenomas. 'Giant prolactinomas' are defined as tumors with a diameter ≥4 cm and serum prolactin >1,000 ng/ml, accounting for 1–5% of all prolactinomas. These tumors are often invasive, extending into the cavernous sinus, skull base, or even the posterior cranial fossa, leading to visual impairment, cranial nerve palsies, and endocrine dysfunction. Although dopamine agonists (e.g., cabergoline) are typically first-line therapy, treatment is sometimes delayed due to tumor size or misdiagnosis. In recent years, increasing attention has been paid to the role of genetic factors in pituitary adenoma pathogenesis. Beyond well-known genes such as MEN1 and AIP, CDH23 (encoding cadherin-related 23) has been associated with both familial and sporadic pituitary adenomas. Variants in CDH23 may impair cell adhesion and promote tumor development. However, its role in giant prolactinomas remains unclear. Additionally, biallelic CDH23 mutations cause autosomal recessive deafness or Usher syndrome, necessitating differentiation of hearing loss etiologies. This study identifies a novel heterozygous CDH23 variant in a sporadic giant prolactinoma via whole-exome sequencing, offering new insights into the gene’s pathogenic mechanisms in pituitary tumors and suggesting genetic evaluation for patients with refractory or giant pituitary adenomas.
Methods and Experiments
The research team conducted a clinical evaluation of a 53-year-old woman who was incidentally found to have a large sellar mass during brain CT/MRI for head trauma. Tumor tissue was obtained via transnasal biopsy for histopathological and immunohistochemical analysis to confirm diagnosis. Serum prolactin levels were measured, and pituitary function was assessed, including TSH, FT4, ACTH, cortisol, IGF-1, and sex hormones. The patient was treated with low-dose cabergoline (0.25–0.5 mg per dose, 2–3 times weekly), with regular monitoring of prolactin levels, symptom changes, and imaging responses. Whole-exome sequencing (WES) was performed to screen for potential pathogenic germline variants, focusing on genes known to be associated with pituitary adenomas (e.g., AIP, MEN1, CDH23), and candidate variants were validated by Sanger sequencing. Bioinformatics tools (e.g., PolyPhen2, SIFT) were used to predict variant pathogenicity, and public databases (gnomAD, ClinVar, HGMD) were consulted to assess variant rarity.Key Conclusions and Insights
Research Significance and Outlook
This study is the first to report a de novo germline CDH23 variant potentially associated with an ultra-giant prolactinoma, expanding the genetic landscape of pituitary adenomas. Although CDH23 has previously been implicated in familial pituitary adenomas, this case is sporadic and features a tumor significantly larger than previously reported, suggesting that this variant may drive more aggressive tumor growth in certain contexts. This finding supports genetic testing in patients with giant or invasive pituitary adenomas to identify potentially heritable variants, aiding family screening and personalized treatment planning.
Moreover, this case demonstrates that dopamine agonists can remain effective as first-line therapy even in cases of extreme tumor burden, avoiding the risks of initial surgical intervention. A low-dose titration strategy successfully induced tumor regression without pituitary apoplexy or cerebrospinal fluid leak, providing a safe therapeutic paradigm for similar cases. Future studies should validate the frequency and functional impact of CDH23 variants in larger cohorts and conduct in vitro or animal model experiments to elucidate their precise pathogenic mechanisms, paving the way for targeted therapies.
Conclusion
This study reports an ultra-giant prolactinoma case associated with a novel germline CDH23 variant. The patient presented with a massive tumor extensively invading the skull base, yet retained relatively preserved pituitary function and showed a significant and sustained response to low-dose cabergoline. Whole-exome sequencing revealed a previously unreported heterozygous CDH23 variant (c.2621C > A, p.Ala874Asp). Combined with bioinformatic predictions and clinical phenotype, this suggests a potentially important role of CDH23 in pituitary tumorigenesis. Despite the lack of familial co-segregation or functional validation, this finding provides new clues into the genetic mechanisms of pituitary tumors. Compared to previous CDH23-related pituitary adenomas, this tumor was larger but exhibited a low proliferation index and slow growth, suggesting the variant may influence tumor initiation rather than malignant progression. The study underscores the importance of genetic evaluation in patients with giant or invasive pituitary adenomas to identify potentially heritable cases. Additionally, it highlights the therapeutic potential of dopamine agonists in extreme scenarios, supporting their use as first-line treatment. Future research should explore the pathogenicity of CDH23 variants and their role in pituitary tumorigenesis in larger cohorts to inform precision medicine. In summary, this study enriches the clinical and genetic spectrum of prolactinomas and offers new perspectives for personalized diagnosis and management of rare pituitary tumors.
