Resistant Paediatric Somatotropinomas due to <b><i>AIP</i></b> Mutations: Role of Pegvisomant

Abstract

Background: Somatotropinomas are rare in childhood and frequently associated with genetic mutations. AIP mutations are found in 20–25% cases and cause aggressive somatotropinomas, often resistant to somatostatin analogues. Aims: To assess responses to multimodal therapy including pegvisomant in 2 children with sporadic somatotropinomas due to AIP mutations. Case Description: We report 2 children, a boy aged 13 and a girl aged 10, with rapid growth, visual impairment, and growth hormone hypersecretion. Magnetic resonance imaging confirmed a pituitary macroadenoma with parasellar extension in both. Despite multiple surgical attempts to debulk tumour mass, residual tumour persisted. Genetic analysis showed two different AIP mutations (patient 1: c.562delC [p.Arg188Glyfs*8]; patient 2: c.140_ 163del24 [p.Gly47_Arg54del8]). They were initially treated with a long-acting somatostatin analogue (octreotide LAR 30 mg/month) and cabergoline as a dopamine agonist, with the later addition of pegvisomant titrated up to 20 mg/day and with radiotherapy for long-term control. Somatostatin analogue was ceased due to patient intolerance and lack of control. Patient 1 had normalization of insulin-like growth factor-1 (IGF-1) after 5 months of combined therapy with pegvisomant and cabergoline. For patient 2, normalization of IGF-1 was achieved after 2 months of cabergoline and pegvisomant. Conclusion: AIP-associated tumours can be resistant to management with somatostatin analogues. Pegvisomant can safely be used, to normalize IGF-1 levels and help control disease.

Somatic and germline mutations in the pathogenesis of pituitary adenomas

“…Unlike first-generation SSA, similar SSTR5 expression and similar responsiveness to pasireotide irrespective of the AIP expression levels was observed in patients with sporadic acromegaly (107). Given the well-documented hormonal and tumoral resistance of AIP-mutated somatotropinomas to firstgeneration SSAs, treatment with a growth hormone receptor antagonist is an alternative option (115). Such adenomas may also be good candidates for pasireotide treatment.…”

AIP-mutated acromegaly resistant to first-generation somatostatin analogs: long-term control with pasireotide LAR in two patients

“…The molecular mechanism for this relative somatostatin analog resistance may occur via Gai proteins or ZAC1, which are themselves important mediators of SST2 actions (11, 12, 13). Given the relatively poor results achieved with first-generation somatostatin analogs in patients with AIP mutations, the role of other agents such as the GH receptor antagonist pegvisomant has been described in those with AIP mutations (14). Pasireotide is a newer somatostatin analog that is approved for use in patients that are resistant to first-generation agents (15).…”

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

“…Interestingly, the inclusion of aggressive or therapy resistant pituitary disease did not increase the frequency of AIP mutations in a recent study (28). Moreover, in our cohort, the rate of active disease at last follow-up was 10% lower in the AIPmut PitNETs group, suggesting that AIPmut PitNETs can be satisfactorily controlled despite requiring more complex and multimodal therapeutic schemes (12,29,30,33,34). Although these data may seem paradoxical (more aggressive disease at presentation in the AIPmut patients, but better controlled disease at last follow-up), they could be explained by a more aggressive treatment approach in AIPmut cases, especially the use of radiotherapy.…”