A novel mutation in RNF216 gene in a Turkish case with Gordon Holmes syndrome

Abstract

Background: Gordon Holmes syndrome (GHS) is a rare autosomal recessive disorder characterized by hypogonadotropic hypogonadism, cognitive decline, and cerebellar ataxia. Mutations in the Ring Finger Protein 216 (RNF216) gene have been known to be associated with GHS therewithal RNF216 mutations have been detected in cases with Huntington-like disease, 4H syndrome (hypodontia, hypomyelination, ataxia and hypogonadotropic hypogonadism), and congenital hypogonadotropic hypogonadism.

Case presentation: Here we report a novel homozygous frameshift mutation in RNF216 gene c.1860_1861dupCT (p.Cys621SerfsTer56) in a patient with hypogonadotropic hypogonadism, ataxia, and cognitive decline diagnosed with GHS also co-occurrence of parkinsonism and dystonia which was not reported before.

Conclusions: We report an extremely rare case of GHS. The core features of GHS are well defined, but genotype-phenotype correlations are still limited. To understand the pathophysiology of different phenotypes, the type and localization of novel mutations need to be defined, and the effect of these different variants on clinical features needs to be determined. Further studies should explain the factors of phenotypic variability present in GHS patients with RNF216 mutations.

Keywords: Cerebellar ataxia; Gordon Holmes syndrome; Hypogonadotropic hypogonadism; RNF216.

Fig. 1

MRI of the case in 2018 and 2022. According to 2018 (a, axial T2 and b, sagittal T1-weighted) MRI in 2022 (c axial, d sagittal T2-weighted) progression is seen in cerebellar, vermian and cerebral cortical atrophy. Mild atrophy in the mesencephalon has not progressed

Fig. 2

MRIs of the case in 2018 (a) and 2022 (b). Axial T2-weighted images show progression in periventricular confluent hyperintensities and cerebral cortical atrophy. Basal ganglia hyperintensities appear in 2022

Fig. 3

Pedigree of the family. The index case is marked with the arrow