The molecular basis of congenital hypopituitarism and related disorders

Abstract

Context: Congenital hypopituitarism (CH) is characterized by the presence of deficiencies inone or more of the 6 anterior pituitary (AP) hormones secreted from the 5 different specializedcell types of the AP. During human embryogenesis, hypothalamo-pituitary (HP) development iscontrolled by a complex spatiooral genetic cascade of transcription factors and signalingmolecules within the hypothalamus and Rathke's pouch, the primordium of the AP.Evidence Acquisition: This mini-review discusses the genes and pathways involved in HPdevelopment and how mutations of these give rise to CH. This may present in the neonatalperiod or later on in childhood and may be associated with craniofacial midline structuralabnormalities such as cleft lip/palate, visual impairment due to eye abnormalities such asoptic nerve hypoplasia (ONH) and microphthalmia or anophthalmia, or midline forebrainneuroradiological defects including agenesis of the septum pellucidum or corpus callosum orthe more severe holoprosencephaly.Evidence Synthesis: Mutations give rise to an array of highly variable disorders rangingin severity. There are many known causative genes in HP developmental pathways that areroutinely screened in CH patients; however, over the last 5 years this list has rapidly increaseddue to the identification of variants in new genes and pathways of interest by next-generationsequencing.Conclusion: The majority of patients with these disorders do not have an identified molecularbasis, often making management challenging. This mini-review aims to guide clinicians inmaking a genetic diagnosis based on patient phenotype, which in turn may impact on clinicalmanagement.