Ataxia and Hypogonadotropic Hypogonadism with Intrafamilial Variability Caused by RNF216 Mutation

Abstract

Gordon Holmes syndrome (GHS) is a distinct phenotype of autosomal recessive cerebellar ataxia, characterized by ataxia, dementia, reproductive defects and hypogonadism; it has been recently found to be associated with RNF216 mutation. We performed whole-exome sequencing and filtered the resulting novel variants by the coordinates of the shared autozygome. We identified a novel splicing variant in RNF216 that is likely to abolish the canonical splice site at the junction of exon/intron 13 (NM_207111.3:c.2061G>A). We herein report two patients with GHS caused by a novel RNF216 mutation as the first follow up report on RNF216-related GHS, and show interfamilial variability of phenotype supporting the previously reported RNF216-related cases.

Keywords: Gordon Holmes; RNF216; cerebellar ataxia; hypogonadotropic hypogonadism.

Figure 1.

Family pedigree.

Figure 2.

Hand X-ray showed delayed bone growth. Patient 1: The chronological age of this patient is 20 years. The metacarpal heads and growth plates of the phalanges are not fused yet. The carpal bones are well ossified. The bone age of this patient is about 14 years to 15 years. Patient 2: The chronological age for the patient is 25 years. The growth plate of the distal radius and ulna are not fused yet where it normally starts at the age of 17 to 19 and maximally should be fused by the age of 20.

Figure 3.

Brain magnetic resonance imaging. Patient 1: mild cerebellar atrophy, mild cortical atrophy, significant bilateral confluent white matter abnormalities and partial empty sella with no mass lesions identified. Patient 2: significant cerebellum atrophy, mild cortical atrophy, mild white matter changes and normal pituitary gland.