ESPE Abstracts

Background: Two LIM homeodomain transcription factors, Lhx3 and Lhx4, are critical in the development of the nervous system and pituitary gland in mice. Lhx4 null mice die shortly after birth and have abnormal pituitary gland development. Recently, the first human homozygous LHX4 mutation was described, resulting in congenital hypopituitarism and neonatal death. Heterozygous LHX4 variants have been described and are linked to hypopituitarism but have variable penetrance.

Hypothesis: Haplo-insufficiency for LHX4 per se does not cause hypopituitarism; either LHX4 variants act in a dominant negative fashion or a second genetic/environmental abnormality is required to affect pituitary function.

Clinical case: The index case was born at term weighing 3.1 kg. She had neonatal pneumonia, and feeding problems and continued to have delayed milestones and learning difficulties. She also had day and night enuresis without evidence of diabetes insipidus. A CGH array showed a 2.2 Mb deletion of chromosome 1q25.2–1q25.3 which includes LHX4; the deletion was not present in the mother. Investigation showed normal pituitary function and a normal pituitary and brain on MRI. She grew along the 9–25 th centile with a midparental height on the 2 nd–9 th centile. She entered puberty at a normal age (9–10 years) although she had menarche at the age of 10.5 years. There was a family history of learning difficulties, deafness, renal abnormalities and anencephaly in three paternal cousins. The father is healthy. His genetic analysis is still pending.

Conclusion: Haplo-insufficiency of LHX4 in itself does not result in pituitary pathology. Redundancy or rescue by other transcription factors may be responsible for the absence of a pituitary phenotype in LHX4 dosage reduction. Heterozygous LHX4 mutations described in hypopituitarism may be part of a digenic or oligogenic cause of disease or act in a dominant negative fashion.