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Pituitary Transcription Factor Mutations Leading to Hypopituitarism

  • Peter GergicsEmail author
Chapter
Part of the Experientia Supplementum book series (EXS, volume 111)

Abstract

Congenital pituitary hormone deficiency is a disabling condition. It is part of a spectrum of disorders including craniofacial midline developmental defects ranging from holoprosencephaly through septo-optic dysplasia to combined and isolated pituitary hormone deficiency. The first genes discovered in the human disease were based on mouse models of dwarfism due to mutations in transcription factor genes. High-throughput DNA sequencing technologies enabled clinicians and researchers to find novel genetic causes of hypopituitarism for the more than three quarters of patients without a known genetic diagnosis to date. Transcription factor (TF) genes are at the forefront of the functional analysis of novel variants of unknown significance due to the relative ease in in vitro testing in a research lab. Genetic testing in hypopituitarism is of high importance to the individual and their family to predict phenotype composition, disease progression and to avoid life-threatening complications such as secondary adrenal insufficiency.

This chapter aims to highlight our current understanding about (1) the contribution of TF genes to pituitary development (2) the diversity of inheritance and phenotype features in combined and select isolated pituitary hormone deficiency and (3) provide an initial assessment on how to approach variants of unknown significance in human hypopituitarism. Our better understanding on how transcription factor gene variants lead to hypopituitarism is a meaningful step to plan advanced therapies to specific genetic changes in the future.

Keywords

Pituitary hormone deficiency Transcription factor Inheritance Genetic testing Variants of unknown significance 

List of Abbreviations

ACTH

Adrenocorticotropic hormone

AL

Anterior lobe of pituitary

Bmp

Bone morphogenetic protein

CGA

Choriogonadotropin alpha subunit

CNS

Central nervous system

CPHD

Combined pituitary hormone deficiency

Fgf

Fibroblast growth factor

FSH

Follicle-stimulating hormone

GH

Growth hormone

GHD

Growth hormone deficiency

GR

Glucocorticoid receptor

HH

Hypogonadotropic hypogonadism

IAD

Isolated ACTH deficiency

IGHD

Isolated growth hormone deficiency

IL

Intermediate lobe of pituitary

LH

Luteinizing hormone

MSH-α

Melanocyte-stimulating hormone, alpha

ONH

Optic nerve hypoplasia

PC(SK)

Proprotein convertase (subtilisin/kexin)

PL

Posterior lobe of pituitary

POMC

Pro-opiomelanocortin

PRL

Prolactin

RAR

Retinoic acid receptor

Shh

Sonic hedgehog

TF

Transcription factor

TR

Thyroid hormone receptor

TSH

Thyroid-stimulating hormone

VUS

Variants of unknown significance

WES

Whole exome sequencing

Wnt

Wingless-type MMTV integration site family/beta-catenin

Notes

Acknowledgments

This work was supported by the grant entitled “Cell specific expression in the pituitary gland” awarded to Sally A Camper (PI) by the National Institutes of Health (R01 HD034283) with Peter Gergics as co-investigator on this grant. The author apologizes to other colleagues whose work was not cited due to space limitations. The author would like to thank Sally A. Camper for her careful review and feedback on the manuscript, to the members of her lab collecting information on specific genes/variants, and to his family for their continued support toward his research productivity.

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Human Genetics, University of MichiganAnn ArborUSA

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