ESPE Abstracts

Background: Congenital panhypopituitarism is associated with a variety of gene mutations. Abnormalities in the Gli2 gene were only recently described to be associated with congenital panhypopituitarism (Franca et al. 2010). Gli2 is a gene that encodes a transcription factor downstream of the Sonic Hedgehog pathway – known to play an important role in morphogenesis during embryology.

Objective and hypotheses: Although Gli2 mutations were described to be related to holoprosencephaly, we like to present a family with pituitary hormone dysfunction and polydactyly.

Method: The index case was a girl admitted with extreme failure to thrive at the age of 6 weeks. The heel prick screening for congenital hypothyroidism was normal. She experienced hypoglycaemia and hyperbilirubinemia in the neonatal period. Hormonal testing and MRI investigations showed panhypopituitarism and an ectopic neurohypophysis. Her mother had isolated polydactyly. Family history showed that out of 26 family members of three generations, six persons had either panhypopituitarism, polydactyly or both. One person had cryptorchidism, choanal atresia and a single median incisor, besides panhypopituitarism and polydactyly.

Results: In all six affected family members the pathogenic frameshift mutation c.3676C>T (p.Arg1226X) in the Gli2 gene was found. This mutation leads to truncation of the Gli2 protein. Two family members also had a 80 kb deletion of chromosome 18q22.1 encompassing the CDH7-gene which is probably not related to the phenotype.

Conclusion: In this family the same Gli2 mutation is related either to a relatively mild phenotype of isolated polydactyly, or to a more severe phenotype consisting of pituitary dysfunction, in the absence of holoprosencephaly. Knowledge of the co-occurrence of polydactyly and panhypopituitarism with the same gene defect is important for clinicians because i) it provides a tool for early recognition of congenital panhypopituitarism and ii) it enables targeted genetic testing. Furthermore, these data confirm the role of Gli2 in the embryogenesis of both the extremities and the pituitary gland.