A novel case of concurrent occurrence of demyelinating-polyneuropathy-causing PMP22 duplication and SOX10 gene mutation producing severe hypertrophic neuropathy

Abstract

Background: Hereditary motor and sensory neuropathy, also referred to as Charcot-Marie-Tooth disease (CMT), is most often caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. This duplication causes CMT type 1A (CMT1A). CMT1A rarely occurs in combination with other hereditary neuromuscular disorders. However, such rare genetic coincidences produce a severe phenotype and have been reported in terms of "double trouble" overlapping syndrome. Waardenburg syndrome (WS) is the most common form of a hereditary syndromic deafness. It is primarily characterized by pigmentation anomalies and classified into four major phenotypes. A mutation in the SRY sex determining region Y-box 10 (SOX10) gene causes WS type 2 or 4 and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease. We describe a 11-year-old boy with extreme hypertrophic neuropathy because of a combination of CMT1A and WS type 2. This is the first published case on the co-occurrence of CMT1A and WS type 2.

Case presentation: The 11-year-old boy presented with motor developmental delay and a deterioration in unstable walking at 6 years of age. In addition, he had congenital hearing loss and heterochromia iridis. The neurological examination revealed weakness in the distal limbs with pes cavus. He was diagnosed with CMT1A by the fluorescence in situ hybridization method. His paternal pedigree had a history of CMT1A. However, no family member had congenital hearing loss. His clinical manifestation was apparently severe than those of his relatives with CMT1A. In addition, a whole-body magnetic resonance neurography revealed an extreme enlargement of his systemic cranial and spinal nerves. Subsequently, a genetic analysis revealed a heterozygous frameshift mutation c.876delT (p.F292Lfs*19) in the SOX10 gene. He was eventually diagnosed with WS type 2.

Conclusions: We described a patient with a genetically confirmed overlapping diagnoses of CMT1A and WS type 2. The double trouble with the genes created a significant impact on the peripheral nerves system. Severe phenotype in the proband can be attributed to the cumulative effect of mutations in both PMP22 and SOX10 genes, responsible for demyelinating neuropathy.

Keywords: Charcot–Marie–tooth disease; Hypertrophic neuropathy; MR neurography; PMP22; SOX10; Waardenburg syndrome; Whole-body MRI.

Fig. 1

Pedigree chart. The proband, sister, and some of his paternal family members have similar symptoms of polyneuropathy with foot deformities. Only the proband has been diagnosed with congenital hearing loss and heterochromia iridis

Fig. 2

Magnetic resonance imaging of the cranial nerves. Sagittal (A-B), axial (C-E), and coronal (F-K) T2-weighted images reveal thickened cranial nerves except the olfactory and optic nerves. Abbreviations, III: oculomotor nerve, IV: trochlear nerve, V1: ophthalmic nerve, V2: maxillary nerve, V3: mandibular nerve, VI: abducens nerve, VII: facial nerve, VII: auditory nerve, IX: glossopharyngeal nerve, X: vagus nerve, XII: hypoglossal nerve, L: left, and P: Posterior

Fig. 3

Whole-body magnetic resonance neurography (WB-MRN) with short tau inversion recovery (STIR) sequences. WB-MRN by maximum intensity projection (A) and axial STIR images (B-I) demonstrate an extreme enlargement of the entire peripheral nervous system with some nodular changes. Abbreviations, BP: brachial plexus, IC: intercostal nerve, L: left, LSP: lumbosacral plexus, M: median nerve, P: peroneal nerve, R: radial nerve, S: sciatic nerve, and U: ulnar nerve

Fig. 4

Magnetic resonance imaging with short tau inversion recovery sequences in the proband’s sister with CMT1A. Coronal magnetic resonance neurography (A), and axial images (B-E) do not reveal an extreme nerve thickening, as observed in the proband

Fig. 5

A hypothetical pathophysiology of extreme hypertrophic neuropathy because of PMP22 and SOX10 gene mutations. The patient with CMT1A (B) has an additional copy of the PMP22 gene. The PMP 22 proteins are overexpressed in the Schwan cell and myelin layers, compared to healthy controls (A). Aberrant interaction between the SOX10 and PMP22 genes may cause an additional overexpression of the PMP22 protein in the proband (C)