Congenital hypopituitarism: clinical, molecular and neuroradiological correlates

Objective Recent studies have suggested that mutations in genes encoding several hypothalamo-pituitary (H-P) transcription factors result in hypopituitarism [isolated GH deficiency (IGHD) and combined pituitary hormone deficiency (CPHD)], which may in turn be related to the neuroanatomy revealed by magnetic resonance (MR) imaging. Although studies have focused on patients with either optic nerve hypoplasia (ONH) or isolated hypopituitarism with normal optic nerves, few studies have compared the two groups. We aimed to relate the clinical phenotype of a large cohort (n = 170) of children with congenital hypopituitarism including septo-optic dysplasia (SOD) attending a single centre to the neuroradiological and genetic findings. Design Clinical, biochemical, MR imaging and molecular data were analysed retrospectively in 170 patients with or 'at-risk' (with ONH) of hypopituitarism to determine predictors of hypopituitarism. Results The presence of ONH was significantly associated with an absent septum pellucidum [odds ratio (OR) 31 center dot 5, 95% confidence intervals (CI) 7 center dot 3-136 center dot 6, P < 0 center dot 001], an abnormal corpus callosum (OR 10 center dot 5, 95% CI 3 center dot 8-28 center dot 6, P < 0 center dot 001) and stalk abnormalities (OR 2 center dot 3, 95% CI 1 center dot 2-4 center dot 2, P = 0 center dot 009). The risk of hypopituitarism was 27 center dot 2 times greater in patients with an undescended posterior pituitary (95% CI 3 center dot 6-205 center dot 1, P < 0 center dot 001). Anterior pituitary hypoplasia (OR 3 center dot 1, 95% CI 1 center dot 3-7 center dot 0, P = 0 center dot 006) and an absent pituitary stalk (P < 0 center dot 001) were also significantly associated with hypopituitarism. With respect to the type or severity of hypopituitarism, CPHD was more often associated with an abnormal corpus callosum (OR 6 center dot 1, 95% CI 1 center dot 4-27 center dot 4, P = 0 center dot 008) and stalk abnormalities (OR 2 center dot 8, 95% CI 1 center dot 3-6 center dot 1, P = 0 center dot 006). Male to female ratio was significantly greater in patients with normal optic nerves (3 center dot 3:1) as compared with those with ONH (1 center dot 2:1). The prevalence of diabetes insipidus, thyrotrophin and ACTH deficiencies was significantly greater in patients with ONH as compared with 'idiopathic' hypopituitarism. Mutations in pituitary transcription factors and genes regulating GH secretion were rare (5/170) in this cohort of patients with sporadic hypopituitarism. Conclusion Our data suggest that individuals presenting with ONH are at high risk for neuroradiologic and endocrine abnormalities. The neuroradiologic features are predictive not only of the presence, but also of the type, of hypopituitarism. The association of midline abnormalities with hypopituitarism in this cohort suggests a common developmental origin for these features, the aetiology of which remains unidentified in the majority of cases.