Hypogonadotropic Hypogonadism Associated With Other Pituitary Hormone Deficiencies Prop1 Gene Mutations

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Combined pituitary hormone deficiency has been associated with rare abnormalities in gene-encoding transcription factors that are necessary for pituitary development (109). Prop-1 is required for the activation of genes involved in ventral differentiation and proliferation of the four ventral cell types (somatotropes, lac-totropes, thyrotropes, and gonadotropes) (110). Mutations in the gene Prop-1 (Prophet of Pit-1) are the most common cause of both familial and sporadic congenital combined pituitary hormone deficiency. Several different mutations in the Prop-1 gene have been identified and are inherited recessively. The hormonal phenotype includes deficiencies of growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH). Some subjects with Prop-1 mutations also present with LH and FSH deficiencies. However, there is variability in the clinical and hormonal expression of the cases reported thus far. Most affected patients fail to enter puberty and show consistently low LH and FSH responses to GnRH stimulation (111). However, there is a report of two sibships with a homozygous mutation in PROP-1 (Arg120Cys), in which there was spontaneous initiation of puberty followed by pubertal arrest (112). This finding suggests that Prop-1 is not needed for gonadotroph determination but may have a role in gonadotroph differentiation.

HESX1 Gene Mutation

In contrast to the Prop-1 gene, HESX-1 gene is a transcriptional repressor and plays a broader role in the development of multiple placodally derived anterior structures (110). A mutation in the homeobox gene HESX-1 was identified in one family of affected individuals presenting with septo-optic dysplasia, a disorder characterized by panhypopituitarism, optic nerve atrophy, and other midline CNS abnormalities, such as agenesis of the corpus callosum (113). Two siblings were homozygous for an Arg53Cys missense mutation in the HESX-1 homeodomain, with a loss of ability to bind target DNA. During early mouse development, the mouse homolog of HESX- 1, Hesxl, is expressed in prospective forebrain tissue but is later restricted to Rathke's pouch, which becomes the anterior pituitary gland. Mice lacking Hesxl exhibit variable anterior CNS defects and pituitary dysplasia. These data suggest an important role for Hesxl/HESX-1 in forebrain, midline, and pituitary development in mouse and human.

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