Ectopic Posterior Pituitary, Polydactyly, Midfacial Hypoplasia and Multiple Pituitary Hormone Deficiency due to a Novel Heterozygous IVS11-2A>C(c.1957-2A>C) Mutation in the <i>GLI2</i> Gene

Abstract

A novel heterozygous IVS11-2A>C(c.1957-2A>C) mutation in the GLI2 gene is reported. There was an extremely distinct phenotypical expression in two siblings and their father. The index case was a boy who developed cholestasis and hypoglycaemia in the neonatal period. He had bilateral postaxial polydactyly, mid-facial hypoplasia, high palatal arch, micropenis, and bilateral cryptorchidism. Laboratory examination revealed a diagnosis of multiple pituitary hormone deficiency. There was severe anterior pituitary hypoplasia, absent pituitary stalk and ectopic posterior pituitary on magnetic resonance imaging which suggested pituitary stalk interruption syndrome with no other midline structural abnormality. Molecular genetic analysis revealed a novel heterozygous splicing IVS11-2A>C(c.1957-2A>C) mutation detected in the GLI2 gene. His father and a six-year-old brother with the identical mutation also had unilateral postaxial polydactyly and mid-facial hypoplasia although there was no pituitary hormone deficiency. This novel heterozygous GLI2 mutation detected appears to present with an extremely variable clinical phenotype, even in related individuals with an identical mutation, suggesting incomplete penetrance of this GLI2 mutation.

A case series of a mother and two daughters with a GLI2 gene deletion demonstrating variable expressivity and incomplete penetrance

“…Some of the most commonly reported characteristics, including anterior pituitary lobe hypoplasia, ectopic posterior pituitary lobe identified on MRI, the resulting pituitary deficiencies, postaxial polydactyly, and facial dysmorphisms, most commonly cleft lip and palate, were given their own column in order to facilitate comparing and contrasting the different families' characteristics. True holoprosencephaly was only identified in 2/37 patients and was the rarest characteristic identified on this review, although not all patients had imaging since it was obtained when clinically indicated in most cases Table 2 4‐7,10 . Over half (20/37) of the GLI2 gene mutation patients in this study were identified to have polydactyly, making it the most common characteristic 4‐7,10 …”

“…True holoprosencephaly was only identified in 2/37 patients and was the rarest characteristic identified on this review, although not all patients had imaging since it was obtained when clinically indicated in most cases Table 2 4‐7,10 . Over half (20/37) of the GLI2 gene mutation patients in this study were identified to have polydactyly, making it the most common characteristic 4‐7,10 …”

“…On examination of previously published families expressing an identical GLI2 mutation in the literature Table 1, the expression of the gene mutation varies widely among family members from normal phenotype to pituitary, facial, and limb abnormalities, confirming the pattern identified with the cases presented in this case series. [4][5][6][7]10 This case series and literature review support that patients with pathogenic variants of the GLI2 gene demonstrate autosomal dominant inheritance, variable expressivity, and incomplete penetrance. However, many of the parents in the literature did not receive brain imaging since it was not clinically indicated so it is possible that the findings noted are under-representative of the severity of the phenotypes.…”

“…True holoprosencephaly was only identified in 2/37 patients and was the rarest characteristic identified on this review, although not all patients had imaging since it was obtained when clinically indicated in most cases Table 2. [4][5][6][7]10 Over half (20/37) of the GLI2 gene mutation patients in this study were identified to have polydactyly, making it the most common characteristic. [4][5][6][7]10 The proband and her younger sister both presented with the classic dyad of Culler Jones, the mild presentation of GLI2 gene mutation characterized by GH deficiency and postaxial polydactyly, while their mother had postaxial polydactyly and otherwise asymptomatic for pituitary deficiencies.…”

“…However, many of the parents in the literature did not receive brain imaging since it was not clinically indicated so it is possible that the findings noted are under-representative of the severity of the phenotypes. [4][5][6][7]10 We recommend brain MRI imaging in such patients in order to better characterize pituitary deficiencies and associated hormonal deficiencies and to better inform possible clinical intervention.…”