STUDY OF THE MOLECULAR ETIOLOGY OF THE ECTOPIC NEUROHYPOPHYSIS WITH HYPOPITUITARISM

Abstract

Ectopic neurohypophysis (ENH) is a radiological finding often associated with growth hormone deficiency, either isolated or combined with other pituitary deficiencies. Little is known about the factors that promote complete migration of the neurohypophysis from the diencephalon into the sella turcica, posterior to the anterior pituitary, or the mechanism that leads to adenohypophyseal dysfunction in these cases. The hypothesis of a genetic cause for such morphological and functional changes of the pituitary has been strengthened by the discovery of several genes associated with this phenotype, such as HESX1, LHX4, OTX2, SOX3, GLI2, SHH, TGIF, PROKR2, FGFR1, ARNT2 and GPR161. However, only a minority of cases of hypopituitarism and ENH is due to mutations of these genes. Recently, we described the case of a patient with monosomy of the short arm of chromosome 18, which had the phenotype hypopituitarism/ENH. That index case suggested that one or more genes responsible for this phenotype could be located on this chromosomal region. In a literature review, two other patients with 18p monosomy and NHE/hypopituitarism had been previously described. A comparative analysis of their common missing chromosomal segments indicated that such gene(s) should be in the distal region 18p11.23. Therefore, the aim of this study is to screen molecular changes in the distal region to 18p 11.23 in patients with hypopituitarism and ENH, both microdeletions or insertions by MLPA (Multiplex-Ligation-dependent Probe Amplification) and point mutations by targeted new generation sequencing. (AU)