Reproductive Endocrinology

ORF09-05 - GLI2 Loss-of-Function Mutations Cause Idiopathic Hypogonadotropic Hypogonadism without Anterior Pituitary Hormone Deficits

Saturday, June 13, 2026

2:15 PM - 2:30 PM CT

Location: Room W185ABC

Oral Abstract Presenter(s)

Maria Stamou, MD, PhD

Instructor, Harvard Medical School
Massachusetts General Hospital
Boston, MA, United States

Co-Author(s)

RB

Ravikumar Balasubramanian, MBBS, PhD, FRCP Edin

Associate Professor of Medicine
The Massachusetts General Hospital
Boston, Massachusetts, United States

Co-Author(s)

LP

Lacey Plummer, MS

Massachusetts General Hospital
Boston, United States

Senior Author/Primary Investigator(s)

SS

Stephanie Seminara, MD

Mass Gen Hospital
Boston, Massachusetts, United States

Disclosure(s):

Maria Stamou, MD, PhD: No financial relationships to disclose

Ravikumar Balasubramanian, MBBS, PhD, FRCP Edin: No financial relationships to disclose

Introduction: Heterozygous loss-of-function (LoF) mutations in GLI2 are canonically associated with syndromic features characterized by congenital combined pituitary hormone deficiency (CPHD), polydactyly, holoprosencephaly and midfacial hypoplasia. While the developmental origin of Gonadotropin-Releasing Hormone (GnRH) neurons shares a genetic regulatory network with forebrain patterning, the role of GLI2 in human GnRH deficiency disorders (Kallmann Syndrome [KS] and normosmic Idiopathic Hypogonadotropic Hypgonadism [nIHH]) remains under-characterized. Previous studies have hinted at a genetic overlap, identifying GLI2 missense variants KS patients, often in digenic contexts, or noting KS as a rare sub-phenotype within large congenital hypopituitarism cohorts. However, definitive evidence linking GLI2 loss-of-function to primary hypothalamic GnRH pulse generator failure—distinct from secondary pituitary insufficiency—is lacking.

Methods: Whole exome sequencing from 1,309 IHH subjects (KS: 632; normosmic idiopathic hypogonadotropic hypogonadism [nIIHH]: 677) were reviewed for GLI2 rare sequence variants (RSVs) (stop, frameshift, essential splice and pathogenic missense mutations). Phenotypic charts were reviewed for genotype-phenotype correlations.

Results: We identified three novel, heterozygous truncating GLI2 mutations in three unrelated probands with IHH (2 males with KS; 1 female with normosmic IHH. All three stop mutations (p.Cys914Ter; p.Cys968Ter; p.Cys1110Ter) result in premature protein truncation, leading to the loss of the critical C-terminal transactivation domain required for sonic hedgehog (SHH) signal transduction. None of the subjects had other anterior pituitary hormone deficits. All probands failed to undergo spontaneous puberty. Detailed reproductive phenotypic evaluation the anosmic male subject harboring a de novo truncating variant revealed a severe neuroendocrine phenotype characterized by absent puberty, 1 ml testicular volume, and neuroendocrine profiling via overnight frequent blood sampling confirmed apulsatile Luteinizing Hormone (LH) secretion. Magnetic Resonance Imaging (MRI) of this subject displayed bilateral absence of the olfactory bulbs and a Rathke’s cleft cyst, without frank holoprosencephaly.

Discussion: While prior work extended the GLI2 phenotype to include KS within broad hypopituitary cohorts, our study demonstrates that GLI2 haploinsufficiency can selectively abolish the development of the olfactory-GnRH lineage without ventral forebrain defects or pan-hypopituitarism typically associated with the gene. The presence of truncating GLI2 mutations in isolated KS/IHH mandates that GLI2 be prioritized in reproductive genetic panels even in the absence of other pituitary or extra-pituitary features linked to GLI2 disorders.