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Background: Our objective was to describe the clinical course and treatment challenges in a very young patient with a pituitary adenoma due to a novel aryl hydrocarbon receptor–interacting protein (AIP) gene mutation, highlighting the limitations of somatostatin receptor immunohistochemistry to predict clinical responses to somatostatin analogs in acromegaly. Case Report: We report the case of a 7-year-old boy presenting with headache, visual field defects, and accelerated growth following failure to thrive. The laboratory results showed high insulin-like growth factor I (IGF-I) (standardised deviation scores ( +3.49) and prolactin levels (0.5 nmol/L), and magnetic resonance imaging identified a pituitary macroadenoma. Tumoral/hormonal control could not be achieved despite 3 neurosurgical procedures, each time with apparent total resection or with lanreotide or pasireotide. IGF-I levels decreased with the GH receptor antagonist pegvisomant. The loss of somatostatin receptor 5 was observed between the second and third tumor resection. In vitro, no effect on tumoral GH release by pasireotide (with/without cabergoline) was observed. Genetic analysis revealed a novel germline AIP mutation: p.Tyr202∗ (pathogenic; class 4). Discussion: In vitro response of tumor tissue to somatostatin may better predict tumoral in vivo responses of somatostatin analogs than somatostatin receptor immunohistochemistry. Conclusion: We identified a novel pathologic AIP mutation that was associated with incipient acrogigantism in an extremely young patient who had a complicated course of disease. Growth acceleration can be masked due to failure to thrive. Tumoral growth hormone release in vivo may be predicted with in vitro exposure to somatostatin receptor analogs, as it cannot be assumed that all AIP-mutated somatotropinomas respond well to pasireotide.

Both unacylated ghrelin (UAG) and acylated ghrelin (AG) exert metabolic effects. To investigate the interactions between AG and UAG on ghrelin receptors we evaluated the effects of AG and UAG on INS-1E rat insulinoma cells, using insulin secretion after 30min static incubation as a read-out. A possible involvement of the growth hormone secretagogue receptor type 1a (GHS-R1a) or the corticotropin-releasing factor 2 (CRF2) receptor (CRF2R), as a putative receptor for UAG, was also studied determining their mRNA expression and the functional effects of receptor antagonists on insulin release. Both UAG and AG stimulated insulin release dose-dependently in the nanomolar range. The AG-induced insulin output was antagonized by two GHS-R1a antagonists ([d-Lys(3)]GHRP-6 and BIM28163), which did not block UAG actions. These effects occurred in the presence of low levels of GHS-R1a mRNA. Neither CRF2R expression nor effects of the CRF2R antagonist (astressin(2)B) on insulin output were observed. In conclusion, we provide a sensitive and reproducible assay for specific effects of UAG, which in this study is responsible for insulin release by INS-1E cells. Our data support the existence of a specific receptor for UAG, other than the CRF2R and GHS-R1a. The stimulatory effect on insulin secretion by AG in this cell line is mediated by the GHS-R1a.

Pegvisomant is the only available member of a new class of drugs: the growth hormone receptor antagonists. It has a proven efficacy in antagonising the effects of growth hormone in acromegalic patients that is better than any of the currently available treatment modalities. Its safety profile looks encouraging, although more long-term safety data are needed. Potential indications for pegvisomant in diabetology and oncology again looks very promising, but the optimism is almost entirely built upon favourable data from pre-clinical studies, whereas data from human studies are not yet available.

A great number of gut endocrine tumours show high expression of receptors for neuropeptides, such as SRIF and VIP. The expression of ssts is essential for the control of hormonal hypersecretion and tumour growth by octapeptide somatostatin analogues. Five different sst subtypes, named sst1-5, have been cloned and characterized. The therapeutic efficacy of the octapeptide analogues is determined by the expression of sst2 (sst3) and sst5 on the tumour. In general, there is a predominant expression of sst1 and sst2 mRNA in gut endocrine tumours. In vivo sst scintigraphy, after injection of [111In]pentetreotide, provides a useful tool for the diagnostic work-up of patients with these tumours. This technique can be used for the localization of the primary tumour(s), for the determination of the extent of metastatic spread and for the selection of potential candidates for therapy with (radiolabelled) octapeptide analogues. Differentiated gut endocrine tumours also show a high expression of VIP-Rs. However, undifferentiated tumours show VIP-R expression to a smaller degree. In vivo scintigraphy with 123I-labelled VIP is a sensitive technique for the in vivo identification of gut endocrine tumours and their metastases. The functional role of the tumoral VIP-Rs is still unclear and at present there are no known therapeutic applications for VIP-R agonists or antagonists in humans.