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

摘要

BackgroundGordon Holmes syndrome (GHS), characterized by cerebellar ataxia and hypogonadotropic hypogonadism (HH), has been related to recessive mutations inPNPLA6gene.Aims of the studyDescribe one Portuguese family with GHS due to compound heterozygosity of two newPNPLA6variants.MethodsReport on the clinical presentation, diagnostic and genetic workup to reach GHS diagnosis.ResultsThe 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 previousFMR1gene screening on her sisters revealed a 51 CGGs allele. However, 2 normal-sizedFMR1alleles were identified on the proband thus excluding the FXTAS diagnosis in the family. FurtherPNPLA6variant screening revealed 2 novel variants in compound heterozygosity [c.2404G?>?C]; [c.4081C?>?T], which co-segregated with the disease.ConclusionsThis case shows how incomplete studies can be misleading, increases genetic knowledge of GHS and expands its clinical spectrum. The coexistence of aFMR1intermediate allele in this family constituted an additional challenge in the etiological investigation.