Pituitary hypoplasia in patients with a mutation in the growth hormone-releasing hormone receptor gene

BACKGROUND AND PURPOSE: Several anatomic abnormalities of the pituitary gla nd have been described as occurring in association with congenital growth h ormone deficiency, including hypoplasia of the adenohypophysis, truncation of the pituitary stalk, and ectopia of the neurohypophysis. Their pathogene sis, however, is obscure. Normal pituitary development is dependent on the sequential expression of a series of ontogenetic factors. Growth hormone-re leasing hormone (GHRH) is known to stimulate somatotroph proliferation, and a dwarf mouse model with a mutant GHRH receptor, the "little mouse," has a small anterior pituitary due to hypoplasia of the somatotrophs. We recentl y described the human homolog of the little mouse (dwarfism of Sindh), caus ed by a homozygous nonsense mutation in the GHRH receptor gene in a Pakista ni kindred. We investigated MR imaging characteristics to gain information regarding the potential role of GHRH in human pituitary organogenesis, METHODS: MR images of the head were obtained of four affected male patients (age range, 22-29 years). Maximal anterior pituitary dimensions were deter mined from sagittal and coronal images, and pituitary volumes were estimate d from cubic and ellipsoid formulae. The measurements were compared with no rmative values matched for age and sex. RESULTS: The adenohypophysis was small in each of the four patients. The ma ximal height for the anterior pituitary was 3 mm in three patients and 2 mm in one (mean +/- SD, 2.75 +/- 0.5 mm), which is significantly (P < .001) l ess than the expected height of 5.6 +/- 1.0 mm for men in this age group. E stimates of anterior pituitary volume in the patients ranged from 75 to 124 mm(3) (104 +/- 21 mm(3)), which corresponds to 35% to 52% of the normal me an volume corrected for small head size (P < .005), No other cranial abnorm alities were identified. CONCLUSION: We describe significant hypoplasia of the adenohypophysis occur ring in four dwarfs with a nonsense mutation in the GHRH receptor. In addit ion to isolated growth hormone deficiency and severe dwarfism, affected pat ients have anterior pituitary hypoplasia, presumably due to somatotroph mal development. Resistance to GHRH explains the hypoplasia of the adenohypophy sis-a feature that contributes to growth hormone deficiency in this syndrom e. This is one of the few instances in which the molecular basis of pituita ry dysmorphogenesis has been identified.