MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

Abstract

Over the last 5 years, new actors involved in the pathogenesis of combined pituitary hormone deficiency in humans have been reported: they included a member of the immunoglobulin superfamily glycoprotein and ciliary G protein-coupled receptors, as well as new transcription factors and signalling molecules. New modes of inheritance for alterations of genes encoding transcription factors have also been described. Finally, actors known to be involved in a very specific phenotype (hypogonadotroph hypogonadism for instance) have been identified in a wider range of phenotypes. These data thus suggest that new mechanisms could explain the low rate of aetiological identification in this heterogeneous group of diseases. Taking into account the fact that several reviews have been published in recent years on classical aetiologies of CPHD such as mutations of POU1F1 or PROP1, we focused the present overview on the data published in the last 5 years, to provide the reader with an updated review on this rapidly evolving field of knowledge.

DIAGNOSIS OF ENDOCRINE DISEASE: Pituitary stalk interruption syndrome: etiology and clinical manifestations

“…There have recently been great improvements in genetic knowledge concerning CPHD (9). Mutations have been found in early development genes (10,11) involved in pathways critical for hypothalamic-pituitary development such as Wnt, Notch and Sonic Hedgehog (SHH) signaling pathways. After candidate gene approach, whole-exome sequencing made it possible to identify new genetic disorders implicated in PSIS (12,13,14,15,16).…”

“…CHD7, chromodomain helicase DNA-binding protein 7, interacts with SOX2. Heterozygous loss-of-function gene mutation leading to CHARGE syndrome (coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness) have been published, associated with PSIS (11).…”

Hypopituitarism in Patients with Blepharophimosis and <b><i>FOXL2</i></b> Mutations

“…It is therefore possible that our patients' pituitary deficiency was caused by one or several of these genes not included in our panel of 20 genes or by other currently unknown genes. Indeed, molecular causes are only identified in 84-90% of cases [3,4], highlighting the role of other factors in this pathology (genes with suspected but so far unproven involvement, unknown genes, and compounding effects of multiple genes). Future investigations will include whole exome sequencing, which has contributed to the discovery of several new genes associated with hypopituitarism in the past few years [4].…”

“…182230) [5], OTX2 (Axenfeld-Rieger syndrome: ectopic iris, polycoria, and sometimes glaucoma) [6], SOX2 (anophthalmia or severe microphthalmia) [7], PROKR2 (septo-optic dysplasia) [8], FGFR1 (septo-optic dysplasia) [9], and ARNT2 (blindness and neurological and renal diseases) [10] are now known to be implicated in hypopituitarism with eye anomalies. However, a molecular cause is only found in a minority of cases of congenital hypopituitarism, with previous studies identifying proportions of about 10% in Western Europe [3] and 30% in Eastern Europe [11]. This suggests that other factors involved in hypothalamopituitary development remain to be discovered.…”

“…Our knowledge of the molecular causes of congenital hypopituitarism has improved in recent years [3,4]. Studies of patients with associated extrapituitary malformations, notably of the eyes, can point toward new candidate genes.…”