Neuroendocrinology and Pituitary

MON-046 - A Novel ARX Mutation in A Congenital Hypogonadotropic Hypogonadism and Graves' Disease: A Case Report

Monday, June 15, 2026

9:00 AM - 2:00 PM CT

Location: ENDOExpo; Poster Floor

Submitting author(s)

PR

Prince Rastogi, DM ENDOCRINOLOGY

Senior Resident
ALL INDIA INSTITUTE OF MEDICAL SCIENCES JODHPUR INDIA
JODHPUR, Rajasthan, India

Abstract Poster Presenter(s)

PR

Prince Rastogi, DM ENDOCRINOLOGY

Senior Resident
ALL INDIA INSTITUTE OF MEDICAL SCIENCES JODHPUR INDIA
JODHPUR, Rajasthan, India

Senior Author/Primary Investigator(s)

RS

Ravindra Kumar Shukla, DM

AIIMS
jodhpur, Rajasthan, India

Introduction: Congenital hypogonadotropic hypogonadism (CHH) is a rare disease causing incomplete pubertal development and infertility due to deficient GnRH secretion or action. Its heterogeneity is associated with mutations affecting genes involved in pituitary development, neuronal migration, and GnRH signaling pathways. ARX (aristaless-related homeobox), a transcription factor gene located in the Xp21.3 region, is expressed mainly in cerebral cortex progenitor cells, olfactory bulb, pancreas, and testis, and is critical for early brain development and neuronal migration. ARX mutations are associated with a broad phenotypic spectrum ranging from severe neurodevelopmental disorders like Ohtahara syndrome, Proud syndrome, X linked Lissencephaly with abnormal genitalia (XLAG) to isolated intellectual disability. The objective of this report is to describe a case of CHH female caused by an ARX mutation coexisting with Graves’ disease. This mutation is novel in being associated with Kallmann Syndrome.

Case Report: A 28-year-old female presented with primary amenorrhea and poor breast development (Tanner Stage 2). She had a tall stature with eunuchoid proportions. Olfactory assessment had anosmia. For the last year, she developed features of hyperthyroidism and had a goiter grade 3. Investigations requested for the patient: LH 0.0 mIU/mL (1.9-12.5); FSH 0.17 mIU/mL (3.5-9.2); estradiol < 9 pg/mL (18-147); TSH 0.006 mIU/L (0.67 – 4.6), fT3 136.40 pg/mL (2.3-4.2), fT4 8.91 ng/dL (0.89-1.76), TSHR-Ab 34.49 IU/L ( < 1.22). Scintigraphy had diffuse toxic goiter, and BMD had low bone mass. Ultrasonography of the pelvis had infantile uterine proportions suggestive of long-standing hypoestrogenism. She had bilateral olfactory bulb agenesis, a hypoplastic left olfactory sulcus, and a small anterior pituitary gland on brain MRI. Exome Sequencing revealed a heterozygous c.469del in exon 2 of the ARX gene, likely pathogenic, resulting in a frameshift and premature truncation of the protein 11 amino acids downstream to codon 157. She was started on estradiol valerate and methimazole.

Conclusion: Clear genotype–phenotype associations in ARX-related disorders have yet to be established. This case highlights the broad clinical spectrum of ARX-associated disease and underscores that genes traditionally implicated in neurodevelopmental disorders can present with isolated CHH. It expands the current understanding of CHH and provides a basis for future research into the role of the ARX gene in reproductive endocrinology.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*