Novel OTX2 loss of function variant associated with congenital hypopituitarism without eye abnormalities

Mariana Griffero; Anna Flavia Figueredo Benedetti; Marcela Pérez; Luciani Carvalho; Alexander Jorge; Ana Claudia Latronico; Berenice Mendonca; Ivo Arnhold; Verónica Mericq

doi:10.1515/jpem-2021-0719

Article

Novel OTX2 loss of function variant associated with congenital hypopituitarism without eye abnormalities

Mariana Griffero , Anna Flavia Figueredo Benedetti , Marcela Pérez , Luciani Carvalho , Alexander Jorge , Ana Claudia Latronico , Berenice Mendonca , Ivo Arnhold and Verónica Mericq

Published/Copyright: March 24, 2022

Published by

Become an author with De Gruyter Brill

Submit Manuscript Author Information Explore this Subject

From the journal Journal of Pediatric Endocrinology and Metabolism Volume 35 Issue 6

Abstract

Objectives

The normal development of the pituitary gland requires multiple induction signals and transcription factors encoded by more than 30 genes, including OTX2. OTX2 mutations have been described with eye abnormalities and variable congenital hypopituitarism, but rarely with hypopituitarism without ocular manifestations.

Case presentation

We report a girl with hypopituitarism associated with pituitary hypoplasia and pituitary stalk atrophy, without ocular manifestations. NGS revealed a novel heterozygous mutation in OTX2 c.426dupC:p.(Ser143Leufs*2).

Conclusions

Mutations in the transcription factor OTX2 have been associated with ocular, craniofacial, and pituitary development anomalies. Here we describe a novel mutation in OTX2 associated with hypopituitarism without an ocular phenotype.

Keywords: eye; hypopituitarism; OTX2

Corresponding author: Verónica Mericq, MD, Institute of Maternal and Child Research (IDIMI), Faculty of Medicine, University of Chile, P.O. Box 226–3, Santiago, Chile, Phone: +56 2 4248280, Fax: +56 2 4247240, E-mail: vmericq@med.uchile.cl

Funding source: FAPESP http://dx.doi.org/10.13039/501100001807

Award Identifier / Grant number: 2014/50137-5

Award Identifier / Grant number: 2015/26563-7

Award Identifier / Grant number: 2013/02162-8

Award Identifier / Grant number: 2013/03236-5

Research funding: This research was funded by FAPESP grant number 2013/02162-8 to BBM, 2013/03236-5 to AALJ, 2015/26563-7 to LRC, 2014/50137-5 to Mendonca BB.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
Informed consent: A written informed consent was obtained from the parents for publication of the case.
Ethical approval: Not applicable.

References

1. Bosch, L, Katugampola, H, Dattani, M. Congenital hypopituitarism during the neonatal period: epidemiology, pathogenesis, therapeutic options, and outcome. Front Pediatr 2021;8:600962. https://doi.org/10.3389/fped.2020.600962.Search in Google Scholar PubMed PubMed Central

2. Fang, Q, George, A, Brinkmeier, M, Mortensen, A, Gergics, P, Cheung, L, et al.. Genetics of combined pituitary hormone deficiency: roadmap into the genome era. Endocr Rev 2016;37:636–5. https://doi.org/10.1210/er.2016-1101.Search in Google Scholar PubMed PubMed Central

3. Carvalho, LR, Woods, KS, Mendonca, BB, Marcal, N, Zamparini, AL, Stifani, S, et al.. A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction. J Clin Invest 2003;112:1192–4. https://doi.org/10.1172/jci18589.Search in Google Scholar PubMed PubMed Central

4. Gregory, L, Gergics, P, Nakaguma, M, Bando, H, Patti, G, Mc Cabe, M, et al.. The phenotypic spectrum associated with OTX2 mutations in humans. Eur J Endocrinol 2021;185:121–35. https://doi.org/10.1530/eje-20-1453.Search in Google Scholar PubMed PubMed Central

5. Tajima, T, Ohtake, A, Hoshino, M, Amemiya, S, Sasaki, N, Ishizu, K, et al.. OTX2 Loss of function mutation causes anophthalmia and combined pituitary hormone deficiency with a small anterior and ectopic posterior pituitary. J Clin Endocrinol Metab 2009;94:314–9. https://doi.org/10.1210/jc.2008-1219.Search in Google Scholar PubMed

6. Beby, F, Lamonerie, T. The homeobox gene Otx2 in development and disease. Exp Eye Res 2013;11:9–6. https://doi.org/10.1016/j.exer.2013.03.007.Search in Google Scholar PubMed

7. Ragge, N, Brown, A, Poloschek, C, Lorenz, B, Henderson, R, Clarke, M, et al.. Heterozygous mutations of OTX2 cause severe ocular malformations. Am J Hum Genet 2005;76:1008–2. https://doi.org/10.1086/430721.Search in Google Scholar PubMed PubMed Central

8. Matsumoto, R, Suga, H, Aoi, T, Bando, H, Fukuoka, H, Iguchi, G, et al.. Congenital pituitary hypoplasia model demonstrates hypothalamic OTX2 regulation of pituitary progenitor cells. J Clin Invest 2020;130:641–54. https://doi.org/10.1172/JCI127378.Search in Google Scholar PubMed PubMed Central

9. Diaczok, D, Romero, C, Zunich, J, Marshall, I, Radovick, S. A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency. J Clin Endocrinol Metab 2008;93:4351–59. https://doi.org/10.1210/jc.2008-1189.Search in Google Scholar PubMed PubMed Central

10. Coutinho, E, Brandao, CM, Lemos, C. Combined pituitary hormone deficiency caused by a synonymous HESX1 gene mutation. J Clin Endocrinol Metab 2019;104:2851–4. https://doi.org/10.1210/jc.2019-00081.Search in Google Scholar PubMed

Received: 2021-12-02

Accepted: 2022-02-18

Published Online: 2022-03-24

Published in Print: 2022-06-27

You are currently not able to access this content.

Articles in the same Issue

https://doi.org/10.1515/jpem-2021-0719

Keywords for this article

eye; hypopituitarism; OTX2