Hypothalamic and pituitary development: novel insights into the aetiology

Abstract

The anterior pituitary gland is a central regulator of growth, reproduction and homeostasis, and is the end-product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors leading to the development of this complex organ secreting six hormones from five different cell types. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of combined pituitary hormone deficiency (CPHD). These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2 and SOX3. The expression pattern of these transcription factors dictates the phenotype that results when the gene encoding the relevant transcription factor is mutated. The highly variable phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia and holoprosencephaly. Since mutations in any one transcription factor are uncommon, and since the overall incidence of mutations in known transcription factors is low in patients with CPHD, it is clear that many genes remain to be identified, and the characterization of these will further elucidate the pathogenesis of these complex conditions and also shed light on normal pituitary development.European Journal of Endocrinology 157 S3-S14

A novel HESX1 splice mutation causes isolated GH deficiency by interfering with mRNA processing

“…Suspecting GHD, a GH secretion test was performed in this boy revealing GHD (ITT: peak 4.7 ng/ml; clonidine stimulation: peak 0.6 ng/ml). The rest of the endocrinology was normal (TSH 3 mU/ml; free tri-iodothyronine 3.6 pg/ml and fT 4 15.7 pg/ml). The peaks of TSH and PRL in response to TRH were normal.…”

“…Genes that are expressed early in pituitary embryogenesis are implicated in organ commitment but are also involved in the repression and activation of downstream target genes that have specific roles in directing the cells toward a particular fate. Over the last decade, naturally occurring mutations in these developmental genes, such as HESX1, PROP1, POU1F1, LHX3, LHX4, SOX2, and SOX3 have led to significant insights into pituitary disorders in humans and, the homologous genes, in mouse (3), ranging in severity from central nervous system (CNS) anomalies with no pituitary function to milder forms in which one or more of the pituitary hormones are absent, namely isolated GH deficiency (IGHD) and combined pituitary hormone deficiency (CPHD) (4).…”

Posterior pituitary (PP) evaluation in patients with anterior pituitary defect associated with ectopic PP and septo-optic dysplasia

“…The clinical and biochemical diagnosis of hypopituitarism was followed by a detailed MRI study of the HP and brain structures. The diagnosis of SOD was made by means of three criteria: the presence of optic nerve hypoplasia (ONH), of midline neuroradiological abnormalities (such as agenesis of the corpus callosum and/or absence of the septum pellucidum), and of pituitary hypoplasia with pituitary hormone deficiency (21,(25)(26)(27). Owing to recurrent episodes of hyponatremia and seizures, treatment with desmopressin acetate (desamino-D-arginine-8-vasopressin (DDAVP)) was discontinued during the follow-up period (from 6 months to 3 years before the study) in six patients with SOD previously diagnosed with CDI; in these patients the diagnosis of CDI was made based on a random plasma osmolality (Posm) above 295 mosm/kg and a low urine osmolality during childhood in other hospitals.…”

Inbreeding and Genetic Disorder

“…He was short, weak and quite lean and thin. Mutations in PROP1 are associated with progressive endocrine deficiencies highly variable in both, intensity and in the first clinic sign manifestation (Kelberman & Dattani, 2007;Reynaud et al, 2005). Charles II showed clinical characteristics of hypothyroidism such as muscular weakness, hypotonia, delayed onset of speech and abulic behaviour, and the lack of GH could account for his short stature.…”