ESPE Abstracts

Objective: Glioblastoma 2 (encoded by GLI 2 gene), is an activating zinc-finger transcription factor, involved in the Sonic Hedgehog pathway and embryogenesis of diencephalon and distal extremities Heterozygous mutations of GLI2 gene cause a wide range of clinical phenotype known as holoprosencephaly and holoprosencephaly-like syndrome, pituitary insufficiency, mid-facial hypoplasia, and polydactyly. We, herein, report a novel heterozygous IVS11-2A>C(c.1957-2A>C) mutation in GLI2 gene with an extremely distinct phenotypical expression in two siblings and their father from an unrelated family.

Cases reports: The index case is a boy who was born after 40 weeks uneventful gestation via spontaneous vaginal delivery. His birth weight was 3700 gr. He has developed cholestasis on the first postnatal day. Etiological investigations including metabolic screening as well as liver "tru-cut" biopsy were normal. During follow-up, he presented with hypoglycaemia episodes. In physical examination he had postaxial polydactyly, mid-facial hypoplasia, high palatal arch, micropenis, bilateral cryptorchidism and a diagnosis of multiple pituitary hormone deficiency (MPHD; ACTH, TSH and GH) was considered. In pituitary MR imaging he had ectopic posterior pituitary with no other structural abnormality. An orchiopexy performed. Na-L-Thyroxin, hydrocortisone and GH replacement therapies commenced. At his recent follow up visit his height was 133.5 cm (-0,46), weight was 28.7kg (-0.51 SD) and body mass index was 16.1 kg/m2 (-0.4 SD). On physical examination, he had bilateral postaxial polydactyly, mid-facial hypoplasia, high palatal arch and moderate mental retardation. He was on antiepileptic therapy for focal epileptic seizures. In molecular genetics analysis, a novel heterozygous IVS11-2A>C (c.1957-2A>C) mutation detected in GLI2 gene. His father and 6 year-old brother also had the identical heterozygous mutation with an incomplete phenotypical expression. Of which both had only postaxial polydactyly with no any hormonal deficiency or additional clinical finding. The apparently healthy mother and 4 years-old sister were negative for the mutation.

Conclusion: Extrapituitary findings accompany MPHD may provide clues for the diagnosis of particular gene mutations such as GLI2, HESX1, LHX4, SOX3, and OTX2. Present novel heterozygous mutation detected in the GLI2 gene suggested an extremely variable clinical phenotype in individuals with identical mutation, even in those within the same family and incomplete penetrance of this gene mutations. Therefore, being aware of the association of extrapituitary manifestations like holoprosencephaly, ectopic posterior pituitary, polydactyly and midfacial hypoplasia with MPHD would provide a prompt diagnosis and proper management of cases with the GLI2 gene mutation.