De Novo GLI2 Missense Variant in a Child With Isolated Hypopituitarism and Craniofacial Anomalies: Expanding the Phenotypic Spectrum.

Abstract

Background: Culler-Jones syndrome (CJS) is an autosomal dominant disorder characterized by hypopituitarism, postaxial polydactyly, and craniofacial anomalies, associated with pathogenic GLI2 variants. Genotype-phenotype correlations suggest missense variants may present with isolated pituitary phenotypes.

Methods: We evaluated an 8-year-old boy referred for short stature, failure to thrive, and neurodevelopmental concerns. Clinical assessment, endocrine evaluation, imaging studies, and trio exome sequencing were performed.

Results: The patient exhibited growth hormone deficiency, dolichocephaly, midline diastema, lip and tongue ties, hypotonia, and ADHD. No polydactyly was noted. Trio exome sequencing revealed a de novo heterozygous likely pathogenic GLI2 variant (c.1496G>T; p.Arg499Leu) located within the DNA-binding zinc finger domain.

Conclusion: This case expands the phenotypic spectrum of GLI2-related disorders and reinforces that non-truncating GLI2 variants are often associated with isolated hypopituitarism and subtle craniofacial or neurodevelopmental features. Genomic testing should be considered in similar clinical presentations.