A homozygous splice site ROBO1 mutation in a patient with a novel syndrome with combined pituitary hormone deficiency.

The genetic causes of combined pituitary hormone deficiency remain elusive in most patients. Recently, incompletely penetrant heterozygous mutations in ROBO1 have been described in patients with pituitary stalk interruption syndrome. Herein, we identified a novel homozygous slice site mutation in ROBO1 (c.1342+1G>A) using a trio whole-exome sequencing strategy in a 5-year-old Japanese boy who had combined pituitary hormone deficiency, psychomotor developmental delay, severe intellectual disability, sensorineural hearing loss, strabismus, and characteristic facial features, including a broad forehead, micrognathia, and arched eyebrows. Magnetic resonance imaging delineated anterior pituitary hypoplasia, ectopic posterior pituitary, invisible pituitary stalk, thinning of the corpus callosum, and hypoplasia of the pons and midbrain. The phenotypically normal parents (first cousins) were heterozygous for the mutation. The results provide further evidence of ROBO1 being involved in the development of the pituitary gland. A recessive mutation of ROBO1 is a potential novel cause of a syndromic disorder associated with combined pituitary hormone deficiency.