Fiona M. Lewis There are several cutaneous manifestations of systemic disease, and indeed these can occasionally be the presenting feature. The vulva may be involved in many of these and can be a site of predilection in conditions such as Crohn’s disease. Intertriginous eruptions, which include the vulva, are a common feature in several metabolic and nutritional disorders. Recognition of these signs is important in earlier diagnosis of the underlying problem. Dermatomyositis is an inflammatory condition affecting the skin and muscles. A classic heliotrope rash on the face and neck is seen with Gottron’s papules on the dorsal fingers, together with a myopathy. It can be associated with an underlying malignancy in about 15%, and there is a subset of patients who are anti‐Jo‐1 positive and have interstitial lung disease. Vulval involvement is rare, and symptoms are non‐specific with itching [1] or chronic discharge and dyspareunia [2]. A reticulosarcoma of the vulva occurred in a patient with dermatomyositis who was on azathioprine, and it was felt that the immunosuppressive treatment was a factor in the malignancy [3]. Genital involvement in systemic or cutaneous lupus is uncommon. In a series of 121 patients with lupus erythematosus (LE), both male and female, 21% of those with systemic disease and 24% of those with chronic cutaneous disease had mucosal involvement (nose, eyes, mouth) [4]. No specific genital lesions were found in 48 female patients with systemic LE, although one had vaginal lesions possibly secondary to Sjögren’s syndrome. Vulval lesions were, however, found in 2 out of 42 women with chronic cutaneous LE. Of these two, one had erythema with ulceration and later scarring near the introitus; the other had erythema and white reticulate vulval lesions, with lichen planus‐like lesions in the mouth. The histology of LE and lichen planus can be similar, and it is possible that the features in this second case were due to lichen planus. The two conditions can also coexist, which makes it difficult to categorise at times. Vulval involvement in LE is rare but discoid LE has been reported [5, 6], and there is one case report of a patient with systemic LE who developed a plaque of cutaneous lupus on the left labium majus [7]. Sjögren’s syndrome is caused by lymphocytic infiltration of exocrine glands, predominantly the salivary and lacrimal glands. The disease is much more common in females, and the mean age of onset is 50–60 years. Many patients produce autoantibodies, particularly anti‐SS‐A (Ro) and SS‐B (La). The vaginal microbiome is similar to that of controls [8]. In typical Sjögren’s, there is dense lymphocytic infiltration of the glands. One study does suggest that this is also the case in the vulva [9], but this was probably the normal lymphoid associated tissue that is normally present [10]. Increased CD45+ cells have been seen in vaginal biopsies of patients with Sjögren’s [11]. The predominant symptoms are xerostomia and dry eyes (sicca syndrome), but most female patients also complain of genital symptoms. The predominant problem reported is that of vaginal dryness, and dyspareunia is common. In a case‐control study of 36 women with 43 controls, 61% of the patients with Sjögren’s syndrome described dyspareunia and 55% vaginal dryness, compared with 39% and 33% of controls, respectively [12]. This not surprisingly has an effect on sexual function, which is impaired in all aspects in patients compared to controls [13]. Pelvic floor dysfunction is also reported [14]. In a study of patients presenting with dyspareunia who also complained of musculoskeletal symptoms, 4 of the 11 were found to have primary Sjögren’s syndrome, and it was noted that the vaginal symptoms can predate ocular and oral symptoms by many months [15]. There is an increased incidence of lymphoma. Some patients will have extra‐glandular involvement such as vasculitis and cryoglobulinaemia. Most cases are associated with other autoimmune diseases, especially rheumatoid arthritis, systemic sclerosis, and LE. There are individual case reports of vaginal atresia [16] and vulval amyloidosis [17] occurring in association with Sjögren’s syndrome. Various disease‐modifying drugs have been tried with variable results. Rituximab has shown promise for the systemic features such as severe vasculitis. For the vulval and vaginal symptoms, regular emollients and lubricants are needed. Patient support groups British Sjögren’s Syndrome Association www.bssa.uk.net Sjögren’s Foundation www.sjogrens.org Last accessed October 2021. This is a distinctive eruption, which together with diabetes and weight loss, constitutes glucagonoma syndrome. This is linked to an alpha cell neuroendocrine tumour of the pancreatic islet cells, and the rash may be the presenting feature of the tumour [18]. The vulva is frequently involved as it particularly affects flexures. The cause of the rash is unknown. The high levels of glycogen are implicated as often the rash will resolve very quickly after tumour removal or reduction in glycogen levels with medical treatment. Another theory is that the gluconeogenesis and lipolysis in the liver leads to deficiencies of amino acids. These are not specific but show epidermal necrolysis and a mild lymphocytic dermal infiltrate. It is more common in females, and the peak presentation is between 40 and 50 years. The lesions are annular erythematous papules and plaques with superficial epithelial necrosis, presenting as erosions and sometimes bullae. They can heal at the edges to form a serpiginous pattern (Figure 32.1). Secondary infection is common. Other features include angular cheilitis, stomatitis, and nail changes. Patients frequently develop diabetes. Flexural psoriasis, bullous dermatoses, Hailey‐Hailey disease, and acrodermatitis enteropathica must be considered. Necrolytic migratory erythema is rarely reported without a glucagonoma, when it is termed pseudoglucagonoma. It can be associated with liver disease and malabsorption [18]. Surgical removal of the tumour usually leads to rapid improvement. The somatostatin analogues, particularly octreotide, are very helpful and can lead to rapid resolution of the cutaneous features [19]. Sunitinib and everolimus are biologic agents used in the treatment of pancreatic neuroendocrine tumours. Figure 32.1 Glucagonoma syndrome: scaly and moist serpiginous rash. This condition is related to zinc deficiency and can be genetic or more commonly acquired. The inherited form of acrodermatitis enteropathica is due to mutations in the SLC39A4 gene, which encodes for the Zip4 transporter protein [20]. Zinc is absorbed in the jejunum via the Zip4 transporter protein. Genetic mutations therefore reduce absorption. The acquired form can be due to malabsorption, poor nutrition, or gastric surgery. It is more common in premature babies due to increased demand and insufficient zinc stores. Drugs such as sodium valproate and penicillamine can also predispose to a low zinc level [21]. The histological features are similar to that seen in all deficiency dermatoses such as glucagonoma syndrome and pellagra. The characteristic feature is the necrotic change in keratinocytes with vacuolisation and balloon degeneration. The rash starts in early infancy. The lesions are red, eroded, and vesicopustular, affecting not only the anogenital area but also the peri‐oral area. A bullous variant is recognised [22]. Alopecia and diarrhoea are common features. In adults, the problem is usually acquired, but there can be a relapse of genetic disease in pregnancy [23]. The diagnosis is confirmed by a low serum zinc level. Zinc‐dependent enzymes such as alkaline phosphatase are also useful markers as these can be reduced. However, falsely low values may be found in hypoalbuminaemia. It must be distinguished from candidiasis, seborrhoeic dermatitis, flexural psoriasis, Hailey‐Hailey disease, and necrolytic migratory erythema. Similar eruptions are seen in other nutritional deficiencies (see below), and it is often helpful to check for these in patients with malnutrition or malabsorption. A rare differential diagnosis is Netherton’s syndrome. The genital lesions may be similar [24], but there are additional features of ichthyosis, atopy, and hair abnormalities. Secondary infection is a common problem especially if there are vesicles and blisters where the epidermal barrier is broken. Oral elemental zinc at a dose of 3 mg/kg/day is first‐line treatment and often leads to a rapid resolution. This will need to be lifelong therapy for the inherited types, but the duration of therapy in acquired disease depends on severity. Zinc levels should be monitored regularly. Several forms of this disease are now recognised. Most cases are linked to insulin resistance, either in isolation or as part of an insulin resistance syndrome. It can also be seen with obesity (previously termed pseudo‐acanthosis nigricans) and with gastrointestinal malignancy, especially gastric adenocarcinoma. Rarely, it is drug related. Some types of acanthosis nigricans associated with hypochondroplasia are linked to FGFR3 mutations [25]. The changes in the skin are thought to be related to circulating factors that increase the growth of keratinocytes and fibroblasts. In the benign forms, this may be insulin or insulin‐like growth factor, and in the malignant form, growth factors produced by the tumour. The histology shows hyperkeratosis and papillomatosis, some acanthosis, and pigmentation. Horny inclusions are sometimes present. The vulva is frequently involved [26] along with the neck, the mucosae, and flexures. The areas are dark, with a velvety surface (Figure 32.2) but can be warty with multiple skin tags on the surface. If the acanthosis nigricans is linked with an underlying malignancy, the onset is usually rapid and may be accompanied by tripe palms and lip involvement. Treatment is aimed at the underlying disease process. Hyperinsulinaemia should be corrected, and weight loss may be helpful. Multiple treatments have been tried, including topical keratolytics, oral retinoids, and surgical modalities [27]. Several other nutritional deficiencies including those of biotin, riboflavin, Vitamin B6 (pyridoxine), and essential fatty acids can all cause a flexural eruption [28] which is similar to that seen in acrodermatitis enteropathica. These problems can be inherited but are more commonly acquired and seen in patients with malabsorption, anorexia nervosa or bulimia, and after bariatric surgery. Figure 32.2 Acanthosis nigricans: velvety thickening on inner thighs. This is an uncommon problem where vascular calcification occurs, leading to exquisitely painful necrosis of the overlying skin.
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Conditions Associated with Systemic Disease
Vulval involvement in connective tissue disease
Dermatomyositis
Lupus erythematosus
Sjögren’s syndrome
Epidemiology
Pathophysiology
Histological features
Clinical features
Complications
Associated disease
Treatment
Resources
Vulval disorders associated with metabolic disturbances
Necrolytic migratory erythema (Glucagonoma syndrome)
Pathophysiology
Histological features
Clinical features
Differential diagnosis
Associated disease
Treatment
Acrodermatitis enteropathica
Genetics
Pathophysiology
Histological features
Clinical features
Investigations
Differential diagnosis
Complications
Treatment
Acanthosis nigricans
Genetics
Pathophysiology
Histological features
Clinical features
Treatment
Other nutritional deficiencies
Calciphylaxis
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