This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Tajima, T. Articles by Fujieda, K. Search for Related Content PubMed PubMed Citation Articles by Tajima, T. Articles by Fujieda, K. Related Collections Neuroendocrinology and Pituitary Pediatric Endocrinology

OTX2 Loss of Function Mutation Causes Anophthalmia and Combined Pituitary Hormone Deficiency with a Small Anterior and Ectopic Posterior Pituitary

Department of Pediatrics (T.T., K.I.), Hokkaido University School of Medicine, Sapporo, Japan 060-0835; Department of Pediatrics (A.O., M.H., S.A., N.S.), School of Medicine, Saitama Medical University, Saitama, Japan 350-0495; Department of Pediatrics (K.F.), Asahikawa Medical College School of Medicine, Asahikawa, Japan 078-8510

Address all correspondence and requests for reprints to: Toshihiro Tajima, M.D., Ph.D., Department of Pediatrics, Hokkaido University School of Medicine, N15, W7, Sapporo, Japan 060-0835. E-mail: tajeari{at}hokudai.med.ac.jp.

Context: Orthodenticle homeobox 2 (OTX2) is a transcription factor necessary for ocular and forebrain development. In humans, heterozygous mutations of OTX2 cause severe ocular malformations. However, whether mutations of OTX2 cause pituitary structural abnormalities or combined pituitary hormone deficiency (CPHD) has not been clarified.

Objectives: We surveyed the functional consequences of a novel OTX2 mutation that was detected in a patient with anophthalmia and CPHD.

Patient: We examined a Japanese patient with growth disturbance, anophthalamia, and severe developmental delay. He showed deficiencies in GH, TSH, LH, FSH, and ACTH. Brain magnetic resonance imaging revealed a small anterior pituitary gland, invisible stalk, ectopic posterior lobe, and Chiari malformation.

Results: Sequence analysis of OTX2 demonstrated a heterozygous two bases insertion [S136fsX178 (c.576-577insCT)] in exon 3. The mutant Otx2 protein localized to the nucleus, but did not activate the promoter of the HESX1 and POU1F1 gene, indicating a loss of function mutation. No dominant negative effect in the presence of wild-type Otx2 was observed.

Conclusion: This case indicates that the OTX2 mutation is a cause of CPHD. Further study of more patients with OTX2 defects is necessary to clarify the clinical phenotypes and endocrine defects caused by OTX2 mutations.