Scleroderma, scleroedema, nephrogenic systemic fibrosis, eosinophilic fasciitis and pretibial and generalised myxoedema are included in the differential diagnosis (see Table 32.1). The presence of waxy papules giving the skin a cobblestone appearance helps to distinguish scleromyxoedema from scleroedema and scleroderma. Raynaud’s phenomenon, nailfold capillary abnormalities, telangiectases, calcinosis and positive antinuclear autoantibodies (ANA), often with defined specificity and nucleolar staining pattern by immunofluorescence, are typically present in systemic sclerosis but rare in scleromyxoedema (and the other differentials listed). Scleroedema occurs in children and adults and typically affects the upper back, neck and face. The skin induration is nonpitting and hard, and there is no sharp demarcation between the normal and affected skin. Diabetes (typically long-standing and insulin dependent), recent infection (particularly streptococcal) and IgG k paraproteinaemia are associated. Both scleroedema and scleromyxoedema may be associated with paraproteinaemia and with a plasma cell dyscrasia and less commonly with multiple myeloma [4]. NSF and eosinophilic fasciitis commonly involve the extremities and rarely the face. Normal renal function and absence of exposure to gadolinium-based contrast media exclude NSF. In eosinophilic fasciitis there is woody induration of the limbs, usually sparing the hands and feet. At sites of vessels, the overlying skin shows typical guttering. Marked peripheral eosinophilia commonly occurs. Normal thyroid function and absent thyroid autoantibodies exclude both generalised and pretibial myxoedema. A diagnostic skin biopsy, preferably a deep incisional ellipse, is essential. A diagnostic flow chart summarising the key clinical and investigational features that underpin the diagnosis of scleromyxoedema is shown in Fig. 32.3.