Mehta, A.; (2007) Phenotypic spectrum of patients with congenital disorders of the hypothalamo-pituitary axis. Doctoral thesis , University of London.

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Abstract

Mutations within the cascade of pituitary transcription factors that play a crucial role in its development and differentiation have improved our understanding of variable hypopituitarism in children. The diagnosis of hypopituitarism is problematic as it is dependent on a series of endocrine tests varying in sensitivity and specificity, compounded by evolving hormonal deficiencies. In order to test the hypothesis that human phenotypes are determined by the neuroanatomy which is further influenced by the position of the abnormal gene within the pituitary developmental cascade, clinical, biochemical, magnetic resonance MR imaging and molecular data were retrospectively analysed in subgroups from a cohort of 825 patients with variable hypothalamo-pituitary H-P abnormalities. The major aims were to determine abnormalities on MR imaging that help predict the spectrum of hypopituitarism, to assess if genotype determined phenotype and to ascertain the optimum test for diagnosis of hormone deficiency. Results showed good structure-function relationships within the H-P axis. Anterior pituitary hypoplasia and an undescended posterior pituitary were 6.7 and 33.1 times more prevalent in patients with hypopituitarism as compared with those without. These abnormalities were also significantly associated with endocrinopathies in patients with optic nerve hypoplasia. Within patients with hypopituitarism, midline forebrain defects MFD and pituitary stalk abnormalities were found to be significantly associated with combined pituitary hormone deficiency as opposed to isolated GH deficiency. GH was critical for early postnatal growth, which was also influenced by other pituitary hormones and MFD. Regular evaluation of serum thyroxine concentration best revealed TSH deficiency, as the TRH test was normal in 23% of patients with central hypothyroidism limiting its role as a diagnostic test. A combination of the short Synacthen test and 0800-hour serum Cortisol concentrations represented the optimal method of investigation for ACTH deficiency. The LHRH test in infancy needs careful interpretation, as responses were gender-specific with significantly exaggerated serum FSH concentrations in females. There was a poor genotype-phenotype correlation, particularly in patients with mutations in HESX1, PROP and SOX3, both within and between pedigrees, indicating a role for other genetic or environmental factors on phenotypic expression.

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