Boucher Neuhäuser syndrome: cerebellar degeneration, chorioretinal dystrophy and hypogonadotropic hypogonadism - two novel cases and a review of 40 cases from the literature (P2.110)

Objective: The combination of progressive cerebellar degeneration, hypogonadotropic hypogonadism and chorioretinal dystrophy defines the rare Boucher-Neuhauser Syndrome (BNS), which has recently been linked to autosomal recessive mutations in the PNPLA6 gene in four index patients. Background: Here we present two novel index patients with BNS, providing both clinical information and genetic testing. In addition, the literature of previously published BNS cases is reviewed. Methods: Detailed neurological, ophthalmological and endocrinological assessment was performed in both index cases. A targeted high-throughput approach was used to search for PNPLA6 mutations. The spectrum of clinical presentations and phenotype evolution of BNS based on our two index cases and a MEDLINE search for publications related to BNS was then summarized. Results: We identified 4 recessive PNPLA6 mutations as the genetic cause in our two index cases, highlighting PNPLA6 as the major gene leading to BNS. The literature search identified 40 cases that fulfilled the clinical criteria for BNS. Both our two index patients and the previously published cases propose that the clinical presentation of BNS is variable regarding disease severity, age (range=1-40y) and clinical symptoms (cerebellar ataxia=38[percnt]; vision loss=36[percnt]; delayed puberty=26[percnt]) at disease onset. On brain MRI relatively selective atrophy of the superior and dorsal parts of the cerebellar vermis along with atrophy of the cerebellar hemispheres was found in a substantial fraction of BNS cases. Conclusions: Albeit defined clinically by the combination of spinocerebellar ataxia, chorioretinal degeneration and hypogonadotropic hypogonadism, BNS varies substantially in disease onset, clinical presentation and progression. Thus, a thorough assessment for ophthalmological, neurological and endocrinological changes in patients presenting with one of the key features is recommended. With PNPLA6 likely causing the large majority of BNS cases, future identification of the underlying gene defect will be facilitated. Disclosure: Dr. Tarnutzer has nothing to disclose. Dr. Gerth-Kahlert has nothing to disclose. Dr. Timmann-Braun has nothing to disclose. Dr. Chang has nothing to disclose. Dr. Harmuth has nothing to disclose. Dr. Bauer has nothing to disclose. Dr. Straumann has nothing to disclose. Dr. Synofzik has received personal compensation for activities with Actelion.