Disorders characterized by excessive mucin deposition, increased collagen production, or fibrocyte hyperplasia are historically categorized as mucinoses, sclerosing disorders, and fibrosing disorders, respectively. The fibroblast is central in each of these conditions. Thus, shifting our focus from the fibroblast product (mucin, collagen, and fibrosis) to the cell of origin, the fibroblast and the mechanisms that stimulate specific fibroblast activities will provide better understanding of the histopathogenesis of these diseases and also lays a foundation for the development of more effective treatments for these incapacitating conditions. In some disorders, a singular fibroblast activity predominates, such as excessive mucin or collagen production [pretibial myxedema (see Chapter 151) and sclerodermoid disorders respectively (see Chapter 157)]. In others, a combination of excessive mucin and collagen production is observed (scleredema) or excessive mucin production and fibroblast hyperplasia occurs [scleromyxedema and nephrogenic systemic fibrosis (see Chapter 150)].

Fibroblasts are derived from CD34-positive hematopoietic precursors that originate in the bone marrow and populate the skin during development and wound repair. The chief role of the skin fibroblast is to deposit collagen, elastin, and ground substance, the major constituents of the dermis and pannicular septae and the substrate to which the epidermis and skin appendages attach (see Chapter 63).

The stimuli that cause fibroblasts to overproduce mucin or collagen or to proliferate or aberrantly immigrate into skin are varied. Infectious triggers, inflammatory states, diabetes mellitus, drugs, genetic mutations, and toxins as well as specific mediators such as eicosanoids, growth factors, cytokines, immunoglobulin-paraproteins, and other circulating factors have been implicated, but the precise mechanisms that result in fibroblast pathology (fibropathy) are poorly characterized. Some of these stimuli may recruit bone-marrow-derived fibroblast precursors to the skin; others may act directly on fibroblasts already residing in the skin.

This chapter will discuss scleredema and scleromyxedema. Other diseases relevant to cutaneous fibroblasts are discussed elsewhere in this textbook and listed in Table 158-1.

Historical Aspects

Scleredema was described by Buschke in 19021 and is also designated as scleredema of Buschke and scleredema adultorum, although the latter is a misleading term because children or adolescents can develop the condition.

Epidemiology

Scleredema is rare, although the precise incidence and prevalence are unknown. Men and women are affected with equal frequency. More than half of cases of scleredema occur in childhood or adolescence, most commonly after an upper respiratory tract infection.2 Streptococcal infection is most commonly identified, but other infectious agents have also been implicated. Disease development in adulthood in association with adult-onset diabetes mellitus is the second most common presentation of scleredema. Uncommonly, scleredema occurs in association with paraproteinemia or multiple myeloma, and this association possibly is becoming more common as other causes diminish in frequency with better treatment and management of underlying disease.

Pathogenesis

Type 1 collagen and hyaluronate appear to be the major fibroblast products that are increased in scleredema-affected skin.3–5 The precise mechanism(s) for increased collagen and glycosaminoglycan production in scleredema is not known. Stimulation of fibroblasts by serum factors or immunoglobulin may be related to the pathogenesis of scleredema, particularly cases associated with infectious agents or a paraproteinemia. Serum from a patient with scleredema associated with paraproteinemia was able to increase collagen production by cultured fibroblasts in vitro.6 However, the factor(s) involved has not been elucidated. Other soluble circulating cytokines and small molecule mediators likely also play critical roles.

Clinical Findings

The clinical findings of scleredema are distinctive. An acute onset of nonpitting induration of neck, shoulders, and upper back skin may be followed by involvement of the face and arms. Characteristically, the affected skin appears smooth and waxy, with tense dermal induration and prominent follicular ostia, at times imparting a “peau d’orange” appearance (Fig. 158-1). In general, however, skin changes are better felt on palpation than seen. The skin of the upper trunk (especially the back) is a favored site for scleredema, but more widespread involvement may be observed. The affected and unaffected skin blend imperceptibly. Scleredema involving the esophagus, bone marrow, nerve, liver, or salivary glands has been described rarely.7,8 However, investigations to identify internal organ involvement by scleredema are infrequently pursued. Patients may report symptoms of restricted motion of joints, the tongue, or eyes, as well as weak or tender muscles.