Genetic forms of hypopituitarism and their manifestation in the neonatal period

Abstract

The anterior pituitary gland is a central regulator of growth, reproduction and homeostasis. The development of the pituitary gland depends on the sequential temporal and spatial expression of transcription factors and signalling molecules. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of congenital hypopituitarism. These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, PITX1, PITX2, OTX2, SOX2 and SOX3. Mutations in any of the genes involved in pituitary development may result in congenital hypopituitarism, which manifests as the deficiency in one or more pituitary hormones. The phenotype can be highly variable and may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia (SOD) and holoprosencephaly. Neonates with congenital hypopituitarism may present with non-specific symptoms, with or without associated developmental defects such as ocular, midline and genital abnormalities. Alternatively, they may be initially asymptomatic but at risk of developing pituitary hormone deficiencies over time. The overall incidence of mutations in known transcription factors in patients with hypopituitarism is low, indicating that many genes remain to be identified. Their characterization will further elucidate the pathogenesis of this complex condition and will shed light on normal pituitary development.