Novel HESX1 mutations associated with a life-threatening neonatal phenotype, pituitary aplasia, but normally located posterior pituitary and no optic nerve abnormalities

Context: Hesx1 is one of the earliest homeodomain transcription factors expressed during pituitary development. Very few HESX1 mutations have been identified in humans; although in those cases the disease phenotype shows considerable variability, all but one of the patients display an ectopic posterior pituitary and/or optic nerve abnormalities. Objective: The objectives of the study were to describe the complex phenotype associated with the panhypopituitarism of two unrelated Italian patients who, at birth, presented with hypoglycemic seizures and respiratory distress complicated by shock, in a familial context of neonatal death in one family and spontaneous miscarriage in both families and to identify the molecular basis of this unusual syndrome. Main Outcome Measures: Magnetic resonance imaging of the pituitary region, study of HESX1 gene and transcripts, and assessment of the ability of mutated HESX1 proteins to repress transcription were measured. Results: Magnetic resonance imaging examination showed an anterior pituitary aplasia in a flat sella turcica and a normally located posterior pituitary in both patients. A constellation of extrapituitary developmental defects were found in the two patients, but without any optic nerve abnormalities. Sequencing of HESX1 exons and their flanking intronic regions revealed two different homozygous mutations. A frameshift (c.449_450delAC) was identified in one case, whereas the other patient carried a splice defect (c.357 + 2T > C) confirmed by the study of HESX1 transcripts. If translated, these mutations would lead to the synthesis of truncated proteins partly or entirely lacking the homeodomain, with no transcriptional repression, as shown by their inability to inhibit PROP1 activity. Conclusions: These observations reveal two novel HESX1 mutations in a so-far-undescribed disease phenotype characterized by a life-threatening neonatal condition associated with anterior pituitary aplasia, in the absence of ectopic posterior pituitary and optic nerve abnormalities, two features classically associated with HESX1 defects.