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.
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