Congenital hypopituitarism can be associated with abnormalities in the development of the anterior craniofacial midline, forebrain, and eye. This clinical picture and the growing knowledge of the genetic cascade of signalling molecules and transcription factors involved in hypothalamic- pituitary embryogenesis has led to the discovery of many genetic defects in early developmental genes. As a consequence, overlap with other conditions such as isolated hypogonadotropic hypogonadism and holoprosencephaly is seen in many patients. A well- established clinical syndrome is the pituitary stalk interruption syndrome (PSIS) characterized by con genital hypopituitarism, absent or thin stalk, anterior pituitary hypoplasia, and ectopic posterior pituitary. After a period of extensive study of individual developmental genes, the advent of large parallel sequencing methods like whole- exome sequencing (WES) has led to the discovery of novel genetic factors involved in hypopituitarism and its associated phenotypes. There is an ever- increasing list of candidate genes that is updated on a monthly basis. Here we describe in more detail three genes classically associated with hypopituitarism with defects in early developmental factors. Other genes are cited in Table 1 and Fang et al..
Table1. Imprinting disorders and methylation disturbances in short children born SGA
GLI2
The GLI family zinc finger 2 is a mediator of Sonic hedgehog (Shh) signalling and plays a role during embryogenesis. Mutations in GLI2 were at first associated with holoprosencephaly but the range of possible phenotypes has expanded and includes IGHD or CPHD with or without diabetes insipidus. Other complex phenotypes are developmental delay, seizures, polydactyly, midline craniofacial malformations, and cryptorchidism. On MRI there is a small anterior pituitary with a non- visualized or ectopic posterior pituitary. The mode of inheritance is autosomal dominant with incomplete penetrance. The variants classified as pathogenic are: complete gene deletions; nonsense or frameshift mutations that result in protein truncation; mutations in the universal splicing sites; and mutations within the zinc finger region.
HESX1
HESX homeobox 1 encodes a transcriptional repressor in the developing forebrain and pituitary gland. Homozygous mutations (missense, frameshift, splice donor site) in HESX1 result in CPHD usually with associated phenotypes: SOD, forebrain midline malformations (absent septum pellucidum and agenesis of the corpus callosum), and ophthalmic abnormalities. Heterozygous mutations have incomplete penetrance and lead to a less severe phenotype with IGHD or CPHD and various degrees of SOD. The hypothalamic- pituitary region shows hypoplasia or aplasia of the anterior pituitary with normal, non- visualized or ectopic posterior pituitary.
OTX2
Orthodenticle homeobox 2 encodes a transcription factor that plays a role in brain, craniofacial, and sensory organ development. Heterozygous mutations in OTX2 were initially associated with anophthalmia or microphthalmia, later it was observed that some patients had IGHD or CPHD. On neuroimaging the anterior pituitary can be normal or hypoplastic and the posterior pituitary can be normal or ectopic. Additionally, there are reports of absent or severely hypoplastic infundibulum.
