SAT-287 Hypogonadotropic Hypogonadism in RPL10 Mutation-Associated Syndromic Intellectual Disability

Background: A multitude of inactivating genetic mutations have been implicated in Idiopathic Hypogonadotropic Hypogonadism (IHH), either in Kallmann syndrome or in norm-osmic IHH. Over the last decade, a limited number of studies described variations in ribosomal protein L10 (RPL10) gene as a cause of X-linked syndromic intellectual disability; this was associated with a constellation of features, including: short stature, microcephaly, dysmorphic facies, intellectual disability, epilepsy. RPL10 gene is located on chromosome Xq28 in the region of G6PD and color vision genes. Literature review suggests that RPL10 is implicated in central nervous system (CNS) development and is identified as an X-linked autism-susceptibility gene. Clinical Case: Herein, we present an adolescent male who was found to be hemizygous for a novel missense variant, p.Asn73Ser (c.218A>G) in exon 5 of the RPL10 gene. He is also hemizygous for a novel missense variant p.Glu766Asp (c.2298G>T) in exon 19 of the CUL4B gene. Hemizygous mutations in CUL4B gene have been associated with X-linked intellectual disability with short stature, hypogonadotropic hypogonadism and abnormal gait. Patient has microcephaly, dysmorphic facial features, short stature and global developmental delays with profound intellectual disability. He is nonverbal, non-ambulatory and has bilateral sensorineural hearing loss, near blindness, seizure disorder, dystonia. At 16 years of age he developed neurologic complications: right side focal motor weakness, followed by left side weakness 4 months later. Subsequently, he developed central hypotonia with peripheral hypertonia. He developed primary acquired hypothyroidism with negative thyroid antibodies at age 15 years and also has hypogonadotropic hypogonadism. He became exclusively fed via G-tube due to aspiration pneumonia. Brain MRI showed subependymal heterotopia, thinning of the posterior corpus callosum, signal abnormality of the left hippocampus with mild volume loss of the right hippocampus; normal pituitary and pineal glands. This patient has 2 novel genetic mutations, both affecting central nervous system. Conclusion: This is the first description of IHH occurring in a patient with novel gene mutations of CUL4B and RPL10. While CUL4B gene mutations are known to be involved in CNS dysfunction, including IHH, it remains to be determined if mutations in RPL10 play a role in endocrinopathies of CNS origin.