Endocrine Abstracts

Background: LHX4 encodes a member of the LIM-homeodomain transcription factor protein family that is required for development of the pituitary gland. To date, only incompletely penetrant heterozygous mutations in LHX4 have been described in patients with variable combined pituitary hormone deficiencies (CPHD).

Objective/hypothesis: To investigate a cohort of patients with congenital hypopituitarism for mutations in LHX4.

Method: We screened 150 patients with CPHD (the vast majority having an ectopic posterior pituitary (EPP)) using PCR and direct sequencing analysis. Upon identification of any variants, 100 ethnically-matched controls were screened and control databases (1000 genomes, dbSNP) consulted.

Results: We identified a novel homozygous missense mutation (c.377C>T, p.T126M) in two deceased male patients of Pakistani origin, born to non-consanguineous parents, with panhypopituitarism. The parents also had a daughter with a depressed nasal bridge and cleft palate. The second son had panhypopituitarism and was born small for gestational age with a micropenis, underdeveloped scrotum, and mid-facial hypoplasia. In spite of rapid commencement of hydrocortisone and thyroxine, all three children died within the first week of life. DNA analysis confirmed the presence of a homozygous p.T126M mutation, located in the LIM zinc-finger binding domain 2, predicted to alter protein–protein interaction. Additionally, we identified a novel heterozygous missense mutation (c.1009A>C, p.N337T) in a Caucasian female patient with isolated GHD (peak GH: 1.47 μg/l) learning difficulties, obesity and an EPP. The mutation is in the C-terminal domain, possibly affecting protein folding. Both mutations are located at highly conserved residues.

Functional studies are currently underway.

Conclusion: We report for the first time to our knowledge a novel homozygous mutation in LHX4 associated with a lethal phenotype; recessive mutations in LHX4 may be incompatible with life.