An Unusual Cause of Peroneal Neuropathy

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We discuss the case of a teenage girl who presented with neurologic symptoms suggestive of a peripheral neuropathy, before the development of a central arteriovenous fistula. Electromyography and nerve conduction studies indicated peroneal motor neuropathy, but her comprehensive genetic study results were negative for common Charcot-Marie-Tooth mutations. After 2 years of stable symptoms, she presented with unilateral throbbing headache and tinnitus. Magnetic resonance angiography revealed a carotid cavernous fistula, which was confirmed with conventional angiography. A successful coil embolization of the fistula was performed. Whole exome sequencing demonstrated a de novo heterozygous c.3158G>A (p.G1056D) mutation in the COL31A gene, consistent with Ehlers-Danlos type IV. To our knowledge, this is the first reported case of isolated peroneal motor neuropathy in a patient with Ehlers-Danlos type IV. This case highlights the utility of whole exome sequencing in the diagnosis of patients with neurologic symptoms that do not fit a clear phenotype.

Introduction

Ehlers-Danlos syndrome encompasses a group of inherited connective tissue disorders, best known for joint hypermobility and skin hyperextensibility. These well-recognized signs are not as apparent in type IV, the vascular type. The clinical diagnosis of Ehlers-Danlos syndrome type IV (EDS4; OMIM1300500) is based on 4 clinical criteria, which include (1) thin, translucent skin, (2) easy bruising, (3) characteristic facial appearance (acrogeria), and (4) rupture of arteries, intestines, and uterus. EDS4 is estimated to represent 5%-10% of cases of Ehlers-Danlos.1 Perhaps because of this rarity, the diagnosis is often made only after serious vascular complications, which carry high morbidity and mortality.2, 3 Joint contractures, peripheral neuropathy, and other neurologic manifestations of EDS4 are described in rare individuals with this condition. Here, we discuss the case of a young girl who initially presented with neurologic symptoms suggestive of a peripheral neuropathy before the development of vascular complications associated with EDS4, including central arteriovenous fistula. Whole exome sequencing (WES) was performed, which excluded primary or concurrent neurologic disease and identified a novel mutation in COL3A1, consistent with the diagnosis of EDS4.

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Case Report

The patient initially presented at the age of 15 years with findings suggestive of bilateral peroneal motor neuropathy with pes equinus contractures and lower extremity muscle atrophy (Fig. 1). In addition, she had a history of easy bruising and bleeding along with poor wound healing. She additionally reported intermittent headaches characterized as mild migrainous headaches well controlled with amitriptyline. Physical examination revealed transparent skin with visible veins over her back and

Discussion

EDS4 is inherited in an autosomal-dominant fashion from mutations of the type III procollagen gene, COL3A1.2 Approximately 95% of the mutations result in the production of abnormal type III procollagen. There are 2 major mutation types: point mutations resulting in substitutions of glycine for another amino acid in the triple-helical domain and splice site mutations.1, 2, 4 Our patient had a novel point mutation resulting in the substitution of a glycine residue for aspartic acid in this

Conclusion

EDS4 is a form of Ehlers-Danlos disease that is associated with significant morbidity and mortality. Patients may first present to a neurologist׳s attention owing to vascular complications, involving the CNS. EDS4 may also have more indolent neurologic complications, which may be unrecognized when not associated with vascular findings. Prompt diagnosis can aid in rapid recognition of the potentially catastrophic complications and help delineate increased risks involved in surgical or

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