Germline AIP variants in sporadic young acromegaly and pituitary gigantism: clinical and genetic insights from a Han Chinese cohort.

PURPOSE: Variants in the Aryl hydrocarbon receptor-interacting protein (AIP) gene have been identified in sporadic acromegaly and pituitary gigantism, especially in young patients, with a predisposition to aggressive clinical phenotype and poor treatment efficacy. The clinical characteristics of patients with sporadic acromegaly and pituitary gigantism as well as AIP variants in Han Chinese have been rarely reported. We aimed to identify AIP gene variants and analyze the clinical characteristics of patients with sporadic acromegaly and pituitary gigantism in Han Chinese. METHODS: The study included 181 sporadic acromegaly (N = 163) and pituitary gigantism (N = 18) patients with an onset age of no more than 45 years old, who were diagnosed, treated, and followed up in Huashan Hospital. All 6 exons and their flanking regions of the AIP gene were analyzed with Sanger sequencing or NGS. The clinical characteristics were compared between groups with and without AIP variants. RESULTS: Germline AIP variants were found in 15/181 (8.29%) cases. In patients with an onset age ≤30 years old, AIP variants were identified in 12/133 (9.02%). Overall, 13 variants were detected. The pathogenic (P) variants p.R304X and p.R81X were identified in four cases, with two instances of each variant. Six exon variants (p.C254R, p.K103fs, p.Q228fs, p.Y38X, p.Q213*, and p.1115 fs) have not been reported before, which were likely pathogenic (LP). Patients with P/LP variants had younger onset ages, a higher prevalence of pituitary gigantism, larger tumor volumes, and a higher percentage of Ki-67-positive cells in tumors. In addition, the group with P/LP variants showed a less significant reduction of GH levels in an acute octreotide suppression test (OST) [17.7% (0, 65.0%) vs. 80.5% (63.9%, 90.2%), P = 0.001], and a trend of less GH decrease after the 3-month treatment with long-acting somatostatin analogs (SSAs). CONCLUSION: Germline AIP variants existed in sporadic Chinese Han acromegaly and pituitary gigantism patients and were more likely to be detected in young patients. AIP variants were associated with more aggressive tumor phenotypes and less response to SSA treatment.

Growth hormone receptor antagonist pegvisomant and its role in the medical therapy of growth hormone excess.

Pegvisomant is a growth-hormone (GH) receptor antagonist that prevents the formation of the active heterotrimer of the dimerised GH receptor and the GH molecule necessary for downstream signal transduction. Over the past 20 years, it has become a key therapeutic option for physicians treating syndromes of GH/IGF-1 excess. Sufficient longitudinal follow-up data suggest that it can be deemed both safe and effective. It is the drug with the greatest potential for achieving an amelioration of the biochemical effects of GH excess with a corresponding normalisation of IGF-1 levels; however, insufficient dose titration has lessened real-world therapeutic outcomes. Theoretical concerns about stimulating tumour growth have been resolved as this has not been observed, while derangement of liver enzymes and local skin-related adverse reactions may occur in a minority of the patients. It may be a particularly impactful medication for the treatment of children, young people, and those with inherited disorders of GH excess, where other treatment modalities often fail. Combination therapy of pegvisomant with first- and second-generation somatostatin receptor ligands or with dopamine agonists remains an ongoing area of interest and research. High cost remains a barrier to the use of pegvisomant in many settings.