ESPE Abstracts (2014) 82 P-D-1-3-193

A Novel Mutation of OTX2 Associated with Neonatally Diagnosed Combined Pituitary Hormone Deficiency and Bilateral Microphthalmia

Aya Shimada, Masaki Takagi & Yukihiro Hasegawa

Department of Endocrinology and Metabolism, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan

Background: Orthodenticlehomeobox 2 (OTX2) is a transcription factor implicated in pituitary, ocular, and craniofacial development. To date, more than 30 mutations in OTX2 have been described in congenital hypopituitarism (CH) with or without ocular malformation. The pituitary phenotype varied from isolated GH deficiency (IGHD) to Combined Pituitary Hormone Deficiency (CPHD). However, CPHD including ACTH deficiency from neonatal period was rare among the previous reports. Here, we report a baby with GH, ACTH, TSH, LH, FSH deficiency, and bilateral microphthalmia, carrying a novel missense mutation in OTX2 (R89P). We showed that R89P–OTX2 had markedly decreased transcription activities.

Case: The patient was born at 40 weeks of gestation to the non consanguineous Japanese parents with a healthy brother. He had congenital cardiac malformations, bilateral microphtahlmia, and micropenis. At the age of 5 days, he was diagnosed as having CPHD on the basis of multiple low anterior pituitary hormones.

Methods: We sequenced all coding exons and flanking introns of OTX2. As a functional analysis, we performed western blotting, nuclear localization analysis, DNA binding analysis, and transactivation analysis. Transcriptional activity of the mutation was evaluated by using HESX1, POU1F1, and GnRH as promoters.

Results: We identified a novel heterozygous mutation (c.266G>C, p.R89P) in the patient and in his healthy father. There were no differences in nuclear localization analysis between WT and R89P. In western blot analysis, WT and R89P proteins were detected at expected size in almost same concentrations. DNA binding capacity was lost only in R89P protein. Transactivational studies showed loss of transactivation activity of R89P to all the promoters. A dominant negative effect was observed only in analysis with POU1F1 promoter.

Conclusions: We showed a case with severe ACTH deficiency from neonatal period, carrying a novel mutation in OTX2. OTX2 mutation carriers exhibit wide phenotypic variability and can present as clinically normal, even though they have a nonfunctional mutation.

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