New observations on minifascicular neuropathy with sex-dependent gonadal dysgenesis: a case series with nerve ultrasound assessment

Background: Gonadal dysgenesis with minifascicular neuropathy (GDMN) is a rare autosomal recessive condition associated with biallelic DHH pathogenic variants. In 46, XY individuals, this disorder is characterized by an association of minifascicular neuropathy (MFN) and gonadal dysgenesis, while in 46, XX subjects only the neuropathic phenotype is present. Very few patients with GDMN have been reported so far. We describe four patients with MFN due to a novel DHH likely pathogenic homozygous variant and the results of nerve ultrasound assessment.

Methods: This retrospective observational study included 4 individuals from 2 unrelated Brazilian families evaluated for severe peripheral neuropathy. Genetic diagnosis was performed with a peripheral neuropathy next-generation sequencing (NGS) panel based on whole exome sequencing focused analysis that included a control SRY probe to confirm genetic sex. Clinical characterization, nerve conduction velocity studies, and high-resolution ultrasound nerve evaluation were performed in all subjects.

Results: Molecular analysis disclosed in all subjects the homozygous DHH variant p.(Leu335Pro). Patients had a striking phenotype, with marked trophic changes of extremities, sensory ataxia, and distal anesthesia due to a sensory-motor demyelinating polyneuropathy. One 46, XY phenotypically female individual had gonadal dysgenesis. High-resolution nerve ultrasound showed typical minifascicular formation and increased nerve area in at least one of the nerves assessed in all patients.

Conclusion: Gonadal dysgenesis with minifascicular neuropathy is a severe autosomal recessive neuropathy characterized by trophic alterations in limbs, sensory ataxia, and distal anesthesia. Nerve ultrasound studies are very suggestive of this condition and may help to avoid invasive nerve biopsies.