as in small cell lung cancer [Maddison et al., 2010], squamous head and neck carcinomas [Freier et al., 2010], meningiomas [Comtesse et al., 2005], glioblastomas [Schmitz et al., 2007], pancreatic [Sanada et al., 2006], hepatocellular and bladder carcinomas, prostate cancer, and in seminomas [Schoenhals et al., 2009]. These ﬁndings are in contrast to our report whereby SOX2 haploinsufﬁciency, rather than its upregulation, resulted in the development of a pituitary mass, which would suggest that SOX2 can also act as a tumor suppressor. Indeed, the oncogenic/tumor suppressor potential of SOX2 seems to be cell-type dependent. SOX2 expression is downregulated in gastric carcinomas [Li et al., 2004; Otsubo et al., 2008] and in regions of intestinal metaplasia in patients with Barrett’s esophagus. In addi- tion, the esophagus of hypomorphic mutant mice (Sox2EGFP/COND), expressing only 17% of wild-type SOX2 levels, has an appearance resembling mucus metaplasia [Que et al., 2007]. In these cell types, as in the developing pituitary, SOX2 may play a role in the control of the cell cycle through its interaction with the canonical Wnt signal- ing pathway. Wnt signaling plays an essential role during pituitary development in the control of proliferation of Rathke’s pouch pre- cursors and in the differentiation of the Pouf1-lineage (also known as Pit1) [Olson et al., 2006]. Overactivation of the Wnt pathway in the mouse leads to hyperplasia of the embryonic pituitary due to a signiﬁcant increase in proliferation [Gaston-Massuet et al., 2008]. Moreover, overactivating mutations in β-catenin have been detected in up to 90% of adamantinomatous craniopharyngiomas (ACP) in humans [Buslei et al., 2005; Kato et al., 2004], a benign and slow- dividing rare hypothalamo-pituitary tumor, while Wnt inhibitors are downregulated in other pituitary tumors [Elston et al., 2008]. We have recently shown that mice expressing a degradation-resistant mutant β-catenin in Rathke’s pouch develop pituitary tumors that closely resemble human ACP [Gaston-Massuet et al., 2011]. Our luciferase data clearly show that the p.F48X mutant protein can- not repress β-catenin-mediated transcriptional activation, which is compatible with a model whereby the two identiﬁed patients may have developed a pituitary mass during development due to in- creased proliferation. The nonprogressive nature of these otherwise impressive pituitary lesions supports the suggestion that they have an embryological origin. It could be postulated that in these cases failure of SOX2 to repress β-catenin activity may not be sufﬁcient to sustain the growth of the pituitary mass and other factors (includ- ing other members of the SOX family) may be compensating for the impaired SOX2 function. It is intriguing that only the two patients described in this study, out of many known patients with SOX2 haploinsufﬁciency, devel- oped pituitary tumors. Suprasellar lesions have so far been reported in six patients with SOX2 mutations, including three cases of hy- pothalamic hamartomas [Kelberman et al., 2006; Scheider et al., 2009] and three cases of suprasellar arachnoid cysts [Kelberman et al., 2008; Scheider et al., 2009; Wang et al., 2008]. SOX2 mu- tations are associated with considerable variability in phenotypes and apart from the severe ocular defects, patients rarely exhibit the full spectrum of clinical manifestations. The sensitivity of different tissues to altered dosage of SOX2 may in part explain this observation. As illustrated in the two cases reported here, it is possible that for some congenital pituitary tumors careful follow-up, rather than surgical excision, may be the treatment of choice. Acknowledgments We thank Owen Clark for imaging assistance. 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