Magnetic resonance imaging study of pituitary morphology in subjects homozygous and heterozygous for a null mutation of the GHRH receptor gene

Objective: Somatotrophs represent the majority of cells in the anterior pituitary, and their numeric reduction can cause anterior pituitary hypoplasia (APH). Small numbers of patients with familial isolated GH deficiency (IGHD) due to bi-allelic mutations in the GHRH receptor (GHRHR) gene (GHRHR) have been reported to have APH. We tested if APH was present in a large cohort of patients homozygous and heterozygous for a GHRHR mutation. Design: We studied pituitary morphology in adult and pediatric age subjects (8 years of age and older) belonging to a large extended Brazilian kindred with a high prevalence of IGHD due to a null GHRHR mutation. Methods: We performed brain magnetic resonance imaging (MRI) in 38 subjects, divided into four groups: group I: normal adults (five males, four females, age 38±11.7 years); group II: heterozygous adults (six males, seven females, age 42.23±8.8 years); group III: homozygous GH-naive affected adults (three males, five females, age 41.4±15.0 years); group IV: homozygous affected children (three males, five females, age 11.9±2.5 years). Results are expressed as means±S.D. Results: Pituitary height (mm) was not different between groups II and I (4.61±1.55 and 4.41±0.62 respectively), but it was significantly reduced in groups III (2.67±0.87, P < 0.001) and IV (2.87±0.79, P < 0.001) compared with group I. Pituitary volume (mm³) was normal in group II (417.12±140.86), but it was significantly reduced in groups in III and IV (124.06±64.27 and 155.68±39.79 respectively vs 414.56±71.57; both P < 0.001). The volume ratio (calculated by multiplying the pituitary volume by 1000 and dividing it by cranial volume) was significantly lower in the affected subjects (groups III and IV) (0.06±0.02) than in unaffected (groups I and II) (0.15±0.04; P < 0.0001), demonstrating that APH is not due to reduction of cranial volume. Conclusions: APH is present from childhood in patients homozygous for an inactivating GHRHR mutation, but it does not occur in heterozygous subjects. In our cohort, the presence of normal anterior pituitary size by MRI rules out homozygosity for a GHRHR mutation in subjects who are 8 years of age or older.