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.
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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
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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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Gergics, P. (2019). Pituitary Transcription Factor Mutations Leading to Hypopituitarism. In: Igaz, P., Patócs, A. (eds) Genetics of Endocrine Diseases and Syndromes. Experientia Supplementum, vol 111. Springer, Cham. https://doi.org/10.1007/978-3-030-25905-1_13
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