SAT-009 A Familial Case of Kallmann Syndrome in Costa Rica: Novel Variants in ANOS1 and Gnrhr Genes

Abstract Disclosure: J.E. Esquivel Vargas: None. A.L. Piedra Pacheco: None. L.F. Moya Porras: None. A.B. Santos Rojo: None. A. Hong Lo: None. L. Ulate Oviedo: None. Background: Kallmann Syndrome (KS) is a rare genetic disorder characterized by hypogonadotropic hypogonadism and anosmia or hyposmia, caused by defective migration of GnRH and olfactory neurons during embryogenesis. Its genetic heterogeneity includes mutations in more than 50 genes, with significant variability in clinical presentation. Clinical Case: This study presents a case series of nine patients from Costa Rica, all members of a multigenerational family with clinical signs consistent with KS. Genetic studies conducted by a third party identified two significant mutations: ANOS1 (c.78_108del, X-linked) and GNRHR (c.974del, autosomal recessive). A female carrier of both mutations exhibited no clinical symptoms, in accordance with the genetic pattern. Among the male family members, five carried the ANOS1 mutation alone, each with distinct clinical features. A 63-year-old man displayed a severe phenotype with anosmia, cryptorchidism, eunuchoid habitus, and delayed puberty. His testosterone was critically low at 14 ng/dL, with suppressed LH and FSH and osteopenia (T-score: -2.8). A 33-year-old male presented with cryptorchidism, anosmia, underdeveloped puberty, and testosterone at 76 ng/dL, also with low LH and FSH. A 26-year-old male exhibited mild hypogonadism and slight anosmia, with testosterone at 154 ng/dL and low gonadotropins. A 27-year-old male showed hypogonadism without anosmia, with testosterone at 253 ng/dL and suppressed LH and FSH. A 58-year-old male had no notable clinical features and a testosterone level of 22.8 ng/dL.Two family members carried both ANOS1 and GNRHR mutations. A 62-year-old male presented with anosmia, cryptorchidism, and hearing loss, with a testosterone level of 14 ng/dL and suppressed gonadotropins. A 53-year-old male displayed gynecoid fat distribution and gynecomastia without anosmia, with testosterone at 19 ng/dL and low gonadotropins.One family member was found with only the GNRHR mutation, a 60-year-old male who experienced normal puberty at age 15, had no anosmia, and maintained a testosterone level of 518 ng/dL and normal testicular volume.Males with ANOS1 mutations displayed variable phenotypes, all with hypogonadism and differing anosmia presentations. Isolated GNRHR mutations were associated with milder hypogonadism, while individuals with both mutations exhibited more severe phenotypes, suggesting digenic inheritance. Conclusion: This case series identifies two novel mutations in KS, contributing to the evidence of oligogenic inheritance. It highlights complex genotype-phenotype associations and uncommon clinical presentations, emphasizing their implications for clinical management and genetic counseling. Presentation: Saturday, July 12, 2025