Kallmann Syndrome: A Comprehensive Review of Pathophysiology, Clinical Manifestations, and Therapeutic Approaches

Abstract

Kallmann Syndrome (KS) is a rare genetic disorder characterized by hypogonadotropic hypogonadism (HH) and anosmia or hyposmia due to a defect in the migration of gonadotropin-releasing hormone (GnRH) neurons and olfactory nerve fibers during embryonic development. This syndrome, first described in the 20th century, encompasses a complex interplay of genetic mutations affecting neuronal migration and neuroendocrine regulation. The condition presents a broad spectrum of clinical manifestations, from delayed or absent puberty to infertility, and is frequently associated with additional non-reproductive anomalies, such as sensorineural hearing loss, renal agenesis, or cleft palate. The genetic heterogeneity of KS involves several implicated genes, including KAL1, FGFR1, PROKR2, and CHD7, among others. Diagnostic evaluation typically requires a multidisciplinary approach, integrating genetic testing, hormonal assessments, and neuroimaging to confirm the diagnosis and evaluate associated anomalies. Therapeutic strategies primarily focus on hormonal replacement therapy to induce and maintain secondary sexual characteristics and fertility treatment options for individuals seeking reproductive outcomes. Emerging treatments and the potential use of gene therapy are under investigation, offering new hope for targeted interventions. This review aims to provide a comprehensive overview of Kallmann Syndrome, highlighting its pathophysiology, clinical spectrum, diagnostic challenges, and evolving therapeutic landscape.