Combined pituitary hormone deficiency caused by a synonymous HESX1 gene mutation.

CONTEXT: Mutations in the HESX1 gene can give rise to complex phenotypes that involve variable pituitary hormone deficiencies and other developmental defects.

CASE DESCRIPTION: A 14 year old boy presented with short stature and delayed puberty and was diagnosed with GH deficiency, central hypothyroidism, hypogonadotropic hypogonadism, and secondary adrenal insufficiency. He had anterior pituitary hypoplasia, ectopic posterior pituitary and an interrupted pituitary stalk. Genetic studies uncovered a novel heterozygous variant in exon 2 of the HESX1 gene (c.219C>T; p.Ser73Ser). This single base change was predicted to be synonymous at the translational level but was shown to cause skipping of exon 2 in the RNA transcript.

CONCLUSIONS: This study of a patient with combined pituitary hormone deficiency revealed an unusual synonymous mutation of the HESX1 gene leading to abnormal RNA processing and underlines the importance of investigating silent variants that at first glance appear to be benign.