Introduction: Non-syndromic pituitary gigantism can result from AIP mutations and the recently identified Xq26.3 microduplications causing X-LAG.
Patients and methods: DNA samples and clinical data were collected from 151 patients with pituitary gigantism. All samples were tested for AIP mutations; AIP mutation negative cases (AIPneg) were screened for Xq26.3 microduplications.
Results: Xq26.3 microduplications were found in ten female simplex patients (6.6%). Two X-LAG cases we previously clinically described (Igreja Hum. Mut. 2010) were included in Trivellin NEJM 2014 and Daly ERC 2015. Median age at onset (1.6 years (0.92.6)) and diagnosis (3.8 years (2.46)) was earlier compared to AIPpos (onset: 15 years (12.515); diagnosis: 16 years (1320)) and AIPneg cases (onset: 15 years (11.216); diagnosis: 18 years (1423)), P<0.0001. Mean IGF-1 was 3×ULN±1.17, not different from AIPpos (2.2±1.33) and AIPneg cases (2.6±1.37). 90% of patients had hyperprolactinaemia, as opposed to 23% of AIPpos and 31% of AIPneg cases (P<0.005). Eight patients had macroadenomas, two had pituitary hyperplasia. Five patients were first managed with medical treatment (SSAs and/or dopamine agonists) with poor results. Seven macroadenoma patients had surgery, resulting in remission in three, the other four also received radiotherapy. Among these, remission was achieved in one; two patients are controlled on SSAs, and one on pegvisomant. One patient was treated with intrasellar Yttrium implants and is now controlled with SSAs. One hyperplasia case was treated with total hypophysectomy; the other did not respond to SSAs and her disease is now controlled on pegvisomant. No other tumours or manifestations other than gigantism were found, including the two oldest patients (now aged 29 and 50 years).
Conclusions: The clinical picture in X-LAG is distinct, being characterised by a very young age at onset, high prevalence of affected females and associated hyperprolactinaemia. Treatment of these patients is challenging, although multi-modal treatment can eventually lead to the successful control of GH excess.