Congenital Hypopituitarism: Various Genes, Various Phenotypes

Abstract

The ontogenesis and development of the pituitary gland is a highly complex process that depends on a cascade of transcription factors and signaling molecules. Spontaneous mutations and transgenic murine models have demonstrated a role for many of these factors, including HESX1, PROP1, PIT1, LHX3, LHX4, SOX2, SOX3, OTX2, PAX6, FGFR1, SHH, GLI2, and FGF8 in the etiology of congenital hypopituitarism. Genetic mutations in any of these factors can lead to congenital hypopituitarism, which is characterized by the deficiency in one or more pituitary hormones. The phenotype can be highly variable, consisting of isolated hypopituitarism or more complex disorders. The same phenotype can be attributed to different gene mutations; while a given gene mutation can induce different phenotypes. This review highlights the genetic variations that lead to congenital hypopituitarism and their associated defects. The overall incidence of mutations in known transcription factors in patients with hypopituitarism is low; therefore many gene mutations or even gene- epigenetic interactions have to be unraveled in the future to explain the vast majority of still unclear cases of congenital hypopituitarism.

The Spectrum of PAX6 Mutations and Genotype-Phenotype Correlations in the Eye

“…Other ocular phenotypes include microphthalmia, optic nerve anomalies, or anterior segment dysgenesis [15]. Systemic features can include neurodevelopmental abnormalities, like autism and attention deficit hyperactivity (ADHD) disorders, language impairment [16][17][18], and in some cases the absence or malformations of the pineal and pituitary gland [19][20][21][22]. Defects in PAX6 have also been associated with obesity and diabetes mellitus due to its role in pancreas development [23,24].…”

Long Term Follow-Up of One of The First Patients to Receive Human Growth Hormone Therapy

“…TSH and ACTH are often normal in early life, but deficiencies often evolve with increasing age (13). Mutations in genes responsible for other transcription factors in the differentiation of anterior pituitary cells have also been associated with deficiencies of multiple pituitary hormones and include LHX3, LHX4, HESX1, OTX2, TBX19, SOX2, SOX3, and GL12 (16).…”

Management of hypopituitarism: a perspective from the Brazilian Society of Endocrinology and Metabolism

“…Hypopituitarism may be secondary to genetic defects, congenital abnormalities, or acquired lesions, such as tumors, vascular abnormalities, trauma, or inflammatory, infiltrative, and infectious diseases. In the pediatric population, the most frequent causes of hypopituitarism are genetic or congenital disorders affecting the hypothalamic-pituitary region, usually associated with mutations or low expression of transcription factors responsible for pituitary development, alteration in hypothalamic hormone receptors, structural defects, or mutations in pituitary hormones or their subunits (11). On the other hand, acquired causes are more prevalent in adulthood.…”

“…The symptoms usually develop insidiously in adults, begin up to several years before diagnosis, and are generally nonspecific, including weakness, tiredness, lethargy, increased sensitivity to cold, discomfort, appetite loss, and weight loss or gain. Most patients with hypopituitarism have multiple pituitary hormone deficiencies, and it is challenging to assign specific signs and symptoms to a single hormone deficiency (1,11,29,30). Hypopituitarism has a variable dynamic throughout its development and follow-up, characterized by a complete or sequential loss of pituitary function, which is usually permanent, although transient deficiencies with recovery years after the initial event may occur (1,14,17,30).…”