Gordon Holmes syndrome due to compound heterozygosity of two new PNPLA6 variants – A diagnostic challenge

BACKGROUND: Gordon Holmes syndrome (GHS), characterized by cerebellar ataxia and hypogonadotropic hypogonadism (HH), has been related to recessive mutations in PNPLA6 gene. AIMS OF THE STUDY: Describe one Portuguese family with GHS due to compound heterozygosity of two new PNPLA6 variants. METHODS: Report on the clinical presentation, diagnostic and genetic workup to reach GHS diagnosis. RESULTS: The index case presented with slight cognitive impairment and primary amenorrhea, developed at the age of 25 a cerebellar syndrome. Her neurological exam revealed ataxia and mild extrapyramidal syndrome. She was born from non-consanguineous parents and had 8 siblings. Two of her sisters also had history of primary amenorrhea, tremor and ataxia. All 3 were diagnosed with HH and previous FMR1 gene screening on her sisters revealed a 51 CGGs allele. However, 2 normal-sized FMR1 alleles were identified on the proband thus excluding the FXTAS diagnosis in the family. Further PNPLA6 variant screening revealed 2 novel variants in compound heterozygosity [c.2404G > C]; [c.4081C > T], which co-segregated with the disease. CONCLUSIONS: This case shows how incomplete studies can be misleading, increases genetic knowledge of GHS and expands its clinical spectrum. The coexistence of a FMR1 intermediate allele in this family constituted an additional challenge in the etiological investigation.