Convergent pathological and ultrasound features in hereditary syndromic and non‐syndromic minifascicular neuropathy related to DHH

Background: Minifascicular neuropathy (MN) is a rare, autosomal recessive disease with prominent structural changes of peripheral nerves. So far, it has been observed in females with a 46,XY karyotype and mutations of the Desert Hedgehog (DHH) gene, thus linking MN to gonadal dysgenesis (GD) and disorders of sex development (DSD). Methods and results: A 46,XX proband with normal female sex and gender development underwent clinical evaluations, nerve conduction studies and genetic screening for a severe motor-sensory neuropathy. Sural nerve biopsy revealed a profound disturbance of perineurium development with a thin and loose structure that hinted at MN. High-resolution ultrasound (HRUS) also disclosed diffuse changes of nerve echotexture that visibly correlated with the pathological features. After extensive genetic testing, a novel homozygous DHH null mutation (p.Ser185*) was identified in the proband and in her sister, who was affected by a similar motor-sensory neuropathy, but was eventually found to be a 46,XY patient according to a late diagnosis of DSD with complete GD. Interpretation: DHH should be considered as a possible cause of rare non-syndromic hereditary motor-sensory neuropathies, regardless of DSD. HRUS could effectively smooth the complex diagnostic workup as it demonstrated a high predictive power to detect MN, providing the same detailed correlations to the pathologic features of the nerve biopsy and Dhh-/- mice in both sisters. Hence, HRUS may assume a pivotal role in guiding molecular analysis in individuals with or without DSD.