ESPE Abstracts (2019) 92 P1-104

Interesting Genotype-Phenotype Differences in Siblings with Familial Hypopituitarism and Pituitary Hypoplasia

Emma Thorley1, Lana Huang 1, Vijith Puthi2


1University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom. 2Peterborough City Hospital, Peterborough, United Kingdom


Context: The majority of congenital isolated growth hormone deficiency (IGHD) cases are idiopathic.Recent research has shed light on the genetic aetiologies of congenital hypopituitarism. HESX1 and GLI2 are two transcription factors, amongst a cascade of other transcription factors and signalling molecules, involved in the development of the pituitary gland. Mutations in both genes have been shown to cause congenital hypopituitarism with varying phenotypes.

Case: We report varying clinical presentations of IGHD in two siblings from a non-consanguineous family. The index case presented at 14 months with failure to thrive (FTT), underdeveloped genitalia, post axial polydactyly of his left foot, previous history of developmental dysplasia of hip and neonatal hypoglycaemia. He had significant mid-facial hypoplasia, prominent forehead and ears. He also has mild developmental delay and hearing impairment. The younger brother presented at 8 months with FTT and has milder phenotypic features of mid facial hypoplasia.

Both siblings have low IgF-1, IGHD, with MRI findings of severe pituitary hypoplasia and Chiari 1 malformation. The older sibling's genetic analysis revealed a pathogenic variant in paternally derived HESX1: c.475C>T, p. (Arg159Trp) and maternally derived GLI2 c.2671dupG, P. (Ala891Glys*140). The younger brother was found to have a maternally derived heterozygous GLI2 variant.

Both siblings have done exceedingly well on growth hormone therapy and have not have developed multiple pituitary hormone deficiency (MPHD).

Discussion: We present an interesting case of a double gene hit; with pathogenic mutations in HESX1 and GLI2, and explore the possibility of pituitary gene interactions in the phenotypic differences.

HESX1 mutations are typically associated with MPHD and septo-optic dysplasia (SOD). SOD is highly heterogeneous condition with multi-factorial aetiology, and HESX1 causes SOD by oligogenic interaction.

GLI2 mutations have been associated with holoprosencephaly (HPE) or HPE-like features with pituitary abnormalities and polydactyly. In the last decade, there is evidence gathering which suggests that pathogenic variants, especially loss of function (severe) variants, lead to mainly anterior pituitary hypoplasia, and less commonly posterior pituitary ectopy and post axial polydactyly. Two-thirds of individuals with loss of function variants in GLI2 (nonsense, frameshift canonical splice site variants) have both pituitary deficiency and polydactyly, whereas in those with milder missense variants, these features occur more rarely in combination. There is often wide phenotypic variability, even in the same family. Even the severe loss of function variants are often inherited from an unaffected normal parent suggesting variable penetrance and likely effects of other genes or environmental factors.

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