Charcot neuropathy (CN) is a known complication of diabetes. Zygodactyly is a congenital malformation causing cutaneous webbing of the second and third toes. We noticed patients with diabetes with CN frequently had zygodactyly. To determine the frequency of this, we examined a prospective series of 25 patients with CN and 29 patients without CN in a podiatry clinic. All had type 2 diabetes and peripheral neuropathy and were referred from diabetes or vascular departments sequentially. The patients with CN (both acute and chronic) had plain foot radiography (lateral, oblique, dorsoplantar weight-bearing views) with Lisfranc dislocation or disorganization or swelling consistent with a Charcot foot and confirmation with MRI. There was no finger syndactyly, facial dysmorphism, or genetic syndrome. Zygodactyly was present (skin webbing occurring from the first metatarsophalangeal joint distally) in 19 case subjects and one control subject (Fig. 1A–D). The χ2 statistic where the CN group had syndactyly (n = 19) or no syndactyly (n = 6) and patients without CN had syndactyly (n = 1) or no syndactyly (n = 28) was 30.3 (1 degree of freedom P <0.001).
There is a novel finding of zygodactyly and CN. There appears to be a significant difference between the CN and non-CN groups (one limitation is this cohort size is small), suggesting a common mechanism. Type A1 syndactyly is referred to as zygodactyly when affecting the second and third toes (and not the hands) and varies from unilateral minor impression of webbing to bilateral complete webbing and fusion of nails. To avoid any misinterpretation of results, it should be noted that all patients had webbing at least up to the first metatarsophalangeal joint (partial zygodactyly, including minor webbing of fourth and fifth toes [Fig. 1A]), and the majority had webbing distal to the first metatarsophalangeal joint (Fig. 1B) to complete syndactyly (full zygodactyly [Fig. 1C and D]) at the toenail. No association between diabetes, CN, and zygodactyly has been described together or with systemic diseases other than acute myeloid leukemia (1). Zygodactyly occurs in isolation and in over 300 rare genetic syndromes, none of which have both neuropathy and diabetes. An association between the osteoprotegerin (OPG) gene and diabetic CN suggests a genetic component in bone readsorption (2). The OPG ligand receptor RANKL has a role in tooth movement and apoptosis pathways and thus could cause syndactyly if apoptosis is incomplete. Connexin 43 mutations in oculodentodigital dysplasia (3) cause neuropathy and cutaneous syndactyly of fourth and fifth fingers, suggesting a link between slow nerve conduction and syndactyly. Neuroaxonal dystrophy and zygodactyly have been described together (4). Teratogenic causes of zygodactyly were noted in mice in 1929 by Bean (5), including radiation-induced mutagenesis. We can speculate on genetic causes and environmental or in utero causes, although we had no access to maternal history to determine whether there was any in utero exposure to any toxin or underlying medical condition in this study. There appears to be an association with zygodactyly and CN and diabetes, and further research should look at family history and potential genetic markers in a larger prospective cohort of patients in a wider ethnic group. Viewing online Internet photos of patients with CN confirms zygodactyly among different sexes and ethnicities.
The novel association of zygodactyly may act as a potential predictor of future CN and may allow clinical intervention and prevention options.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Author Contributions. D.O.M., G.P.A., and A.L. contributed data and reviewed the manuscript. P.J.M. wrote the main manuscript draft. G.P.A. and P.J.M. analyzed the data. All authors saw and approved the final manuscript. P.J.M. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.