9384 Two Siblings With Hypogonadotropic Hypogonadism As First Presentation Of The Severe Neuroendocrine Disorder Caused By RNF216

Abstract Disclosure: A.M. Rochtus: None. S. Vermeer: None. L. Antonio: None. Background: Biallelic mutations in RNF216 cause a syndrome characterized by hypogonadotropic hypogonadism, cerebellar ataxia, chorea and cognitive impairment, a combination first described over a century ago named Gordon Holmes syndrome (MIM 212840). Hypogonadotropic hypogonadism can be the initial manifestation of this severe neuroendocrine disorder. Case reportWe report two siblings born to consanguineous parents who were referred due to absent or delayed puberty progression. The elder sibling, a 17-year old male adolescent, presented with absence of secondary sexual characteristics and a high-pitched voice. He had normal cognitive development and no anosmia. Clinical examination revealed Tanner stage 1 and bilateral gynecomastia. Blood tests showed low levels of gonadotropins (LH < 0.3 IU/L [normal range: 1.7-8.6] and FSH < 0.3 IU/L [normal range: 1.2-7.7]) and low morning testosterone 11.4 ng/dL [normal range: 300-1000]. Examination of other pituitary hormones was normal. His 15-year old sister was referred due to primary amenorrhea. She had spontaneous thelarche and presented with Tanner stage 3. Blood examination revealed LH 1.1 IU/L, FSH 4.6 IU/L, and estradiol 2.5 ng/L [normal range: 15-350 ng/L]. Pituitary MRI was performed in the brother due to suspicion of Kallmann syndrome, revealing a normal anterior pituitary, hypoplastic posterior pituitary, and an extensive supratentorial leuko-encephalopathy. Whole-exome sequencing revealed a homozygous variant in RNF216 (c.1705_1710del, p.(Leu569_Ile570del)) (OMIM #212840) in both affected siblings. Further segregation analysis revealed that both parents were heterozygous carriers. RNF216 mutations cause a disorder characterized by combined neurodegeneration and reproductive dysfunction, with the majority of variants leading to amino-acid changes or truncation of the RBR domain or C-terminal extension, as observed in our family. ConclusionThis case report describes two siblings with absent or delayed puberty progression due to a homozygous novel RNF216 mutation. Further research is essential to elucidate the phenotypic variability present in patients with RNF216 mutations. Presentation: 6/1/2024