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Impact of Endocrine Disorders on Skin Disorders

  • Domenico BonamonteEmail author
  • Angela Filoni
Living reference work entry
Part of the Endocrinology book series (ENDOCR)

Abstract

Endocrine diseases may result in changes in cutaneous function and morphology, which cause various skin manifestations, including nonspecific or pathognomonic signs. As the cutaneous lesions can serve as a marker of endocrine disease and result in substantial morbidity, it is important for the clinician to be aware of their importance for a prompt and adequate diagnostic approach to the patients.

Some skin manifestations may be recognized clinically, but sometimes they need a histopathological confirm.

In this chapter, the various disorders of the hypothalamic-pituitary axis, thyroid gland, pancreas, adrenal gland, and androgen axis, as well as hereditary and neoplastic endocrine syndromes, will be outlined.

Keywords

Skin disease Dermatologic features Endocrine diseases Hormonal abnormalities Genetic syndromes Carney complex Autoimmune polyglandular syndromes Polyendocrine disorders Multiple endocrine neoplasia syndromes Hypogonadism Pheochromocytoma Addison’s disease Hyperandrogenism Cushing’s syndrome Parathyroid gland Hypoparathyroidism Hyperparathyroidism Adrenal glands Hyperadrenalism Graves’ disease Prolactinoma Hyperthyroidism Hypothyroidism Acromegaly Hypopituitarism Polycystic ovary Carcinoid syndrome Merkel cell carcinoma Neuroendocrine tumors Glucagonoma syndrome Autoimmune polyglandular syndromes 21-Hydroxylase deficiency 

Introduction

Dysregulation of endocrine hormones, as is seen in the many endocrinopathies, often results in clinically significant dermatologic disease. As these cutaneous lesions can serve as markers of endocrine disease, it is important for clinicians to be aware of their documented dermatologic manifestations. In this chapter, we outline various disorders of the hypothalamic-pituitary axis, thyroid gland, pancreas, adrenal gland, and androgen axis as well as hereditary endocrine syndromes.

Pituitary Gland

The hypothalamic releasing hormones (GH) reach the anterior pituitary gland by vascular route and stimulate the release of growth hormone, thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin and adrenocorticotropic hormone (ACTH).

Hypopituitarism

Usually, the clinical findings are the result of reduced production and release of several hormones, with consequent various signs of hypogonadism, hypothyroidism, and adrenal insufficiency.

Pallor of the skin with a yellowish tinge of the palms, soles, and nasolabial folds due to carotenemia and decreased melanocyte-stimulating hormones (MSH) production is a prominent feature. Lack of the normal pink color of the cheeks, earlobes, and palms also contributes to the pallor, but mucous membranes retain their normal hue in contrast with anemia. The decreased MSH production is also cause of generalized hypopigmentation, especially in the sexual areas. There is an increased sensitivity to sunlight and loss of pigmentation of traumatized skin. The texture of the skin is dry but smoother and softer than in primary hypothyroidism. Decreased gonadotrophin secretion results in loss of body hair, usually first involving the axillae. Beard growth slows but is not totally lost in adult males; scalp hair tends to be fine and dry. Thinness of the skin and subcutaneous tissues causes fine wrinkling around the eyes and mouth, suggesting premature aging. The face appears expressionless and puffy due to diminution of the facial skin folds. The activity of sebaceous and sweat glands is decreased. Onycholysis, longitudinal ridging, and brownish discoloration of the nail plate may be observed (Davidovici et al. 2008).

Hyperpituitarism

While most pituitary tumors are not functional, some produce increased levels of the various hormones, causing a variety of cutaneous findings.

Acromegaly

Acromegaly is a syndrome resulting from an excess of secretion of GH in adults, which in turn leads to exaggerated production of IGF-1 (Melmed 2006). Hypersecretion of GH and IGF-1 is responsible for the morphological changes in skin cells and adnexa.

The patients present soft tissue overgrowth, skin thickening, and cutaneous puffiness due to dermal glycosaminoglycan accumulation on the face, hands, and feet.

Facial thickening and edema commonly manifest as coarsening of the chin, nose, and supraorbital ridges as well as enlarged jaw (macrognathia), thick lips, macroglossia, macrocheilia, and gingival hyperplasia. In addition to a pronounced nasolabial groove, increased size, with redness, and wrinkling of the forehead can produce a melancholic expression; the unfortunate expression of a “basset hound look” is descriptive. Hypertrophy and folding of the scalp of older male patients give rise to a cerebriform or gyrate appearance leading to cutis verticis gyrata due to increase in dermal collagen and consequent buckling and coarse furrowing of the skin at the posterior neck and on the scalp (Diven et al. 1991).

Acromegaly can cause a disproportionate enlargement of fingertips, of hands, and of feet leading to a drumstick-like appearance (Kanaka-Gantenbein et al. 2016).

Multiple pigmented skin tags (acrochordons), which are usually correlated with insulin resistance and diabetes mellitus, are present in a large percentage of acromegalic patients. It is unclear whether their appearance is due to the excess of the GH/IGF-1 axis or it is the consequence of a metabolic dysregulation. Lentiginous spots and melanocytic nevi have also been reported, but there is little evidence to suggest a higher risk of malignant or benign skin neoplasia (Resende et al. 2012).

Acanthosis nigricans is a common skin manifestation in up to 30% of patients suffering from acromegaly; however, it must be consider its possible presence in a variety of other endocrine disorders as well. Elevated insulin levels may stimulate keratinocyte and dermal fibroblast proliferation via binding to the IGFR1, a tyrosine kinase receptor with a high similarity to the insulin receptor, resulting in the formation of plaque-like lesions that characterize the disorder. The skin becomes dark, soft, and velvet-like, with folds due to hyperkeratosis, papillomatosis, and slight acanthosis (Torley et al. 2002).

Acne is another skin manifestation caused by changes in the pilosebaceous unit under the effect of various hormones. Although not all patients develop acne or sebaceous cysts, oily skin with large pores seems to be a common manifestation (Borlu et al. 2012). Excess sweating is observed in 50–88% of patients, as a result of enhanced gland excretion rather than increased gland number. This may lead to abscess formation in the axillary and gluteal regions (Ben-Shlomo and Melmed 2006). Moreover, involvement of the hair and nails can result in hypertrichosis as well as platonychia (flat, broad nail), respectively. Alteration in skin pigment may present as diffuse hyperpigmentation in approximately 40% of patients.

Continuous treatment leads to significant reversal of soft tissue and bone expansion due to a decline in GH levels. Studies have shown that 18–24 months of medical therapy are associated with complete reversal of most clinical features in 50% of patients; hyperhidrosis, however, persists in the majority of cases. In addition, refractory cases of cutis verticis gyrata may be treated with scalp reduction procedures for cosmetic purposes.

McCune-Albright Syndrome

McCune-Albright syndrome is a rare disorder characterized by the association of precocious puberty (mostly in girls), polyostotic fibrous dysplasia, and café au lait pigmented skin lesions. Individuals with McCune-Albright are predisposed to develop a number of endocrine disorders including excessive GH production and consequently gigantism or acromegaly, depending on the age of the first manifestations. Irregular café au lait pigmentation (also termed as “Coast of Maine,” because of its jagged borderline) is usually present at birth or shortly thereafter. These lesions, present on the neck and buttocks, tend to both respect the midline and follow the developmental lines of Blaschko (Dumitrescu and Collins 2008).

Hyperprolactinemia

The clinical manifestations of hyperprolactinemia depend upon the hormone level, the sex of the patient, and the individual sensitivity to the lactogenic and mammotropic effects of the hormone. In women, hyperprolactinemia results in the so-called galactorrhea-amenorrhea syndrome. In men, galactorrhea can occur, but impotence and loss of libido are more frequent complaints. The skin becomes thickened and coarse. Pores on the face enlarge, and there is excessive oiliness; typical acne vulgaris and seborrhea may develop. In children, the straight hairline is molded to conform to the adult configuration (calvities frontalis adolescentium).

Elevated prolactin levels may cause hyperandrogenism due to the enhanced end-organ response to normal androgen levels, resulting in androgenetic alopecia (Fig. 1. Androgenetic alopecia) caused by vellus transformation of scalp hairs, which corresponds to hair follicle miniaturization by repeated hair cycles with shortened anagen phase. In males, androgenetic alopecia is characterized by a distinct pattern of androgen-dependent progressive hair loss from the scalp (male-pattern alopecia) that starts with a bitemporal recession of the frontal hair line and follows by a thinning of the frontal and vertex scalp areas. The process may lead to complete baldness of the top of the scalp. Women present with a diffuse reduction in hair density over the frontal and vertex areas, but parietal and occipital regions may also be involved. Histopathologically, androgenetic alopecia is characterized by progressive diminution of follicular size. Hirsutism (increase in androgen-dependent terminal hair) occurs on the extremities, the anterior chest, the abdomen, the lower back, and in the beard area. Acanthosis nigricans is also present. There was a report of three women with plaque-type psoriasis, in which the increase in severity and extent of the skin disease correlated with the development of a prolactin-secretory pituitary gland microadenoma (Regana and Millet 2000).
Fig. 1

Androgenetic alopecia of a young girl (female pattern hair loss) with development of a diffuse bald area

Prolactinoma

In women, prolactinoma is detected fairly early because of consequent amenorrhea, infertility, and often galactorrhea. In addition, elevated prolactin levels can cause hyperandrogenism, producing androgenetic alopecia and hirsutism. In men, the changes are more subtle, but include impotence, infertility, gynecomastia, and galactorrhea. The eruption of cherry angiomas has been described with prolactinoma.

Thyroid Gland

Thyroid hormones potentiate both alpha- and beta-adrenergic receptors in multiple tissues throughout the body with consequent clinical responses including increased body temperature, hyperhidrosis, and warm moist skin (Safer 2011).

Congenital Hypothyroidism

Congenital hypothyroidism, a condition caused by thyroid hormone deficiency in fetal life, commonly manifests as intellectual disability. In addition, these individuals may develop myxedema, orbital hypertelorism, protruding abdomen with associated umbilical hernia, acral swelling, a clavicular fat pad, and slow-growing nails.

Hypothyroidism

Individuals with acquired hypothyroidism often present with cold, mottled, and dry skin covered with fine scales, notably on the extensor sides of extremities (Heymann 1992).

The skin tends to be pale both because of the dermal mucopolysaccharides and dermal water content. The most striking effect is the lack of facial expression. The tongue is thickened and enlarged, often interfering with articulate speech. The diffuse puffiness is secondary to increased deposits of mucin in the skin, known as myxedema. Myxedema is a consequence of the storage of large amounts of proteoglycans, which are also responsible for the yellowish color of the skin. The affliction most commonly affects palms, soles, and nasolabial folds; a lack of scleral involvement can differentiate the clinical manifestations of carotenemia from jaundice (Krause 2006). After substitution of the thyroid hormones, the pathologic proteoglycan deposits are quickly mobilized again. In addition, excess carotene, due to reduced hepatic conversion of beta-carotene to vitamin A, can deposit in the stratum corneum and manifest as a yellowing of the skin.

Hypothyroid patients may sometimes suffer Candida folliculitis. Wound healing is decelerated.

In addition, patients often have rough and brittle hair at least partly due to reduced sebum secretion; diffuse, partial alopecia, often including genital and beard hair and loss of the lateral third of the eyebrow (madarosis), has been described in up to 50% of patients. In case of sudden hypothyroidism, telogen effluvium may result. Similarly, nails may be thickened, brittle, and slow growing.

Asteatotic eczema, acquired ichthyosis, and palmoplantar keratoderma are also observed.

Lastly, autoimmune conditions can be observed, such as dermatitis herpetiformis, alopecia areata (Fig. 2. Alopecia areata), vitiligo (Fig. 3. Vitiligo), and autoimmune urticaria.
Fig. 2

Alopecia areata, circular areas of alopecia in a child

Fig. 3

Vitiligo lesions of elbows and knees of a young boy; some repigmentation is evident on the knees

Hyperthyroidism

In hyperthyroidism, which may result from autochthone hyperfunction of the gland or from increased stimulation by pituitary TSH, the skin is warm, tender, and wet with a soft turgor as in infantile skin. Common cutaneous manifestations include flushing of the face, often with striking erythema and hyperhidrosis of the palms and soles. The epidermis is thin but not atrophic. Clinically, the hair in thyrotoxicosis is often fine and soft with a downy texture; a diffuse alopecia areata may also be observed, clinically characterized by sudden onset of patches of hair loss. It may undergo spontaneous remission or exacerbations, sometimes evolving into hair loss of the entire scalp (alopecia totalis) and body hair (alopecia universalis) (Demirkesen 2015).

Nails are often described as soft and shiny. Onycholysis (the separation of the distal nail plate from the bed) is a common occurrence. The proximal portion of the nail plate presents with a pink color, while the distal portion appears white in color. The resulting upturned nail plate, often referred to as “plummer’s nail,” involves more often the fourth fingernail. Less common cutaneous manifestations include generalized pruritus, eczematous dermatitis, chronic urticaria, and dermographism (Jabbour 2003).

Graves’ Disease

The most common cause of hyperthyroidism is the Graves’ disease, characterized by autoimmune thyroid disease often in association with exophthalmos, pretibial myxedema, and acropachy. The phenomenon occurs in 4% of individuals; the hands, face, and pretibial and periorbital areas are most commonly affected resulting in a non-pitting edema.

The skin is dry, cool, and atrophic as consequence of decreased vascular flow and decreased reaction to heat. The eyes can appear puffy or swollen, the outer third of the eyebrow can be lost, and ptosis can occur due to decreased sympathetic stimulation. Additional features of myxedema include broadening of the nose, thickening of the lips, and macroglossia. Facial expression may be blunted which can limit others’ abilities to interpret emotion.

Thyroid acropachy, a rare manifestation of Graves’ disease (0.1–1%), is characterized by the triad of digital clubbing, acral swelling, and diaphyseal proliferation of the periosteum in acral and distal long bones. Also, the mucous membranes become dry, while the tongue is fissured.

Both vitiligo and alopecia areata are present with an incidence of about 5%. Rarely, immunobullous disorders have been reported (Leonhardt and Heymann 2002), such as pemphigus foliaceus, pemphigus vulgaris, bullous pemphigoid, herpes gestationis, and dermatitis herpetiformis.

Prevention is by efficient and timely management of thyroid dysfunction, and avoidance of trauma, tobacco use, and factors causing stasis in the lower extremity such as obesity. The standard management of dermopathy includes local or intralesional corticosteroids (Lan et al. 2015).

Parathyroid Gland

Hypoparathyroidism

Hypoparathyroidism may cause skin changes somewhat similar to those of hypothyroidism – the skin may be dry, keratotic, and puffy, with rough-fragile hair. Nails are brittle and ridged, with cracking at the free margin, or crumbling of the distal nail plate.

Chronic mucocutaneous candidiasis, especially of the nails and oral mucosa, may occur in conjunction with hypoparathyroidism, but it is not a feature of post-thyroidectomy iatrogenic hypoparathyroidism. Hypocalcemia secondary to hypoparathyroidism may induce the von Zumbusch-type pustular psoriasis. Correction of the hypocalcemia usually results in clearing of the skin manifestations. Extensive calcification of the skin and subcutaneous tissue has been reported in a neonate with congenital hypoparathyroidism.

Hyperparathyroidism

Skin changes are not a particular feature of hyperparathyroidism, although subcutaneous calcification may occur (especially in hyperparathyroidism secondary to renal failure) (Marx 2000).

Calcinosis cutis arises in the setting of abnormal calcium or phosphate metabolism and has been observed in primary or secondary hyperparathyroidism, paraneoplastic hypercalcemia, and hypervitaminosis D. Calcinosis cutis presents with firm, white dermal papules, nodules, plaques, or subcutaneous nodules typically at periarticular sites (Oh et al. 1999). Lesions tend to resolve spontaneously when calcium and phosphate levels normalize.

Calciphylaxis is usually associated with secondary or tertiary hyperparathyroidism. Clinically, it begins as violaceous, mottled patches and plaques that resemble livedo reticularis. Occasionally, bullae are present. Lesions progress to painful, necrotic, indurated plaques and nodules that evolve to nonhealing ulcers covered with thick black eschars. Lesions most often involve the lower extremities and, less commonly, the upper extremities and trunk. It can also manifest as gangrene of the fingers, toes, or penis.

Another sign that can be found in hyperparathyroidism is “Jellinek sign” that refers to darkening of the eyelids.

Adrenal Glands

Hyperadrenalism

Dermatologistsare intimately familiar with the effects of excess amount of glucocorticosteroids because of the frequent occurrence of iatrogenic Cushing’s syndrome in patients with corticosteroid-dependent disorders.

Systemically applied corticosteroids at a dose above the daily production of endogenous cortisol (more than 20 mg) usually lead to a clinical picture identical to that of endogenous hypersecretion. The clinical appearance is indistinguishable without data of the medical history.

Following long-term application of topical glucocorticosteroids leads to striae distensae, thinning of the skin, telangiectasias, and a rosacea-like dermatitis of the face. These side effects are more pronounced on the face, since the glucocorticoids increase the degradation of collagen and elastic fibers induced by sunlight: the aging skin is thus at higher risk than young skin. Novel steroids such as budesonide, mometasone furoate, prednicarbate, 17,21-hydrocortisone-aceponate and hydrocortisone 17-butyrate-21-propionate, methylprednisolone aceponate, and fluticasone propionate all have a good anti-inflammatory effect and lesser side effects (Brazzini and Pimpinelli 2002).

Cushing’s Syndrome

Chronic glucocorticoid excess may occur due to increased secretion of adrenocorticotrophic hormone (ACTH, corticotrophin), usually from the pituitary, due to glucocorticoid hypersecretion of adrenal origin (ACTH-independent) or due to exogenous administration of glucocorticoids. The cutaneous manifestations are quite similar whether caused by endogenous or iatrogenic hypercorticism, although there are additional effects mediated by androgens in patients with adrenal disease.

A fine “cigarette paper” wrinkling is found on the dorsum of the hand and the elbow due to skin atrophy. The skin becomes fragile and can peel off when removing an adhesive tape (Liddle’s sign). Poikiloderma-like changes have also been reported. As the body’s mass redistributes and enlarges, the fragile skin stretches, and subcutaneous blood vessels become more easily visible, appearing as purple and large (>1 cm in diameter) striae (Fig. 4. Striae). They differ from the commonly found striae of adolescence, pregnancy, and obesity with respect to their inordinate depth and breadth and intense color (Hanley et al. 2016).
Fig. 4

Typical purple and large striae of Cushing’s syndrome

Facial acne (Fig. 5. Acne) and hirsutism are attributed to increased adrenal androgen and/or cortisol secretion (Stratakis 2016).
Fig. 5

Severe acne with papules, pustules, and nodules

Erythematous, monomorphic papules or small pustules distributed along the upper trunk, proximal upper extremities, neck, and face may be observed. Women and prepubertal children with Cushing’s syndrome typically have fine downy facial lanugo hair and, in addition to acne and hirsutism, may also have temporal scalp hair regression. Acanthosis nigricans (Fig. 6. Acanthosis nigricans) manifests with velvety, hyperpigmented, and thickened plaques occurring most often at the nape of the neck and the axilla, often associated with insulin resistance. Patients are predisposed to fungal overgrowth with pityrosporum yeast resulting in pityriasis versicolor (Fig. 7. Pityriasis versicolor) and folliculitis as well as dermatophyte infections of the body, hands, feet, and nails due to cortisol-induced immune suppression and glucose intolerance (Leventhal and Braverman 2016). Other nonspecific cutaneous conditions, such as virilism and dyspigmentation, may be observed.
Fig. 6

Acanthosis nigricans of the neck of a young girl

Fig. 7

Pityriasis versicolor, hypopigmented variant on the trunk

Deposition of adipose tissue in characteristic locations contributes to the Cushingoid appearance: cheeks (“moon facies”), dorsocervical fat pad (“buffalo hump”), supraclavicular fat pad (thick, short neck), and behind the orbit (exophthalmos). Furthermore, loss of subcutaneous tissue can cause easy bruising and delayed wound healing.

Other than striae, the majority of dermatologic manifestations resolve after therapy targeted at excess cortisol production.

Although management of striae generally yields unsatisfactory results, in many cases, they become less noticeable over time. In addition, some reports suggest the efficacy of topical tretinoin cream, acid peels, and topical hyaluronic acid preparations; other treatment modalities include laser therapy, intense pulsed light, and microdermabrasion.

Pseudo-Cushing’s Disease

A clinical and biochemical mimic of Cushing’s disease has been described in alcoholics. The biochemical parameters are not as severe as seen in true disease, and the condition can resolve on alcohol abstinence.

Addison’s Disease

Addison’s disease is the consequence of the hyposecretion of glucocorticoids (adrenal insufficiency) as result of primary insufficiency of the adrenal gland following inflammation or autoimmune diseases. The typical skin manifestation is a generalized bronze hyperpigmentation, result of increased melanin production; it is observed in almost all adult patients and 67% of pediatric patients. The hyperpigmentation is typically diffuse and is most intense on areas exposed to light. It is also accentuated in the flexures, at sites of pressure and friction, and in the creases of palms and soles. Normally pigmented areas, such as the nipples and genital skin, darken (Kendereski et al. 1999). Mucous membrane lesions are usually spots or patches rather than diffuse pigmentation, and the oral pigmentation may persist after glucocorticoid replacement therapy. Scar permanent pigmentation occurs in scars acquired during adrenal insufficiency, while scars that precede the disorder or occur during therapy are unaffected. In addition, patients may notice darkening of existing nevi (Sünkel et al. 2001). The hairs become darker, and nails show dark bands. Aside from changes in pigment, women with Addison’s disease may experience a loss of axillary and pubic hair, due to adrenal androgen production.

Rarely, the skin pigmentation is absent and patients in Addisonian crisis presented with “white” disease.

Pheochromocytoma

Skin findings are minimal and may include hyperhidrosis and facial pallor. The features of Raynaud’s phenomenon are occasionally triggered or worsened.

Hypogonadism

In case of hypogonadism already present by prepubertal age, no pubertal signs occur during growth. In men, the aging skin remains thin and smooth and the pores small, in particular apparent on the face. The periocular wrinkles are notably small and crinkling. Beard and other terminal hairs (axillae, pubes) are lacking. The reduction of scalp hair is delayed. The normal decline of testosterone levels in the aging male is associated with a thinning of the skin that is dry and atrophic and loses elasticity. The terminal hairs do not regress, but turn gray. In men supplemented with testosterone, the signs appear to a lesser extent. A special kind of hypogonadism is Klinefelter’s syndrome, based on disomy of the X chromosome (47, XXY). Patients tend to develop androgen deficiency at an earlier age and have a higher risk of developing connective tissue diseases, thrombophilia, and osteoporosis (Kasten et al. 2005).

Excessive Androgen Production

The adrenal gland can produce excessive amounts of androgens. The main adrenal processes involved are secretory tumors in adults and congenital adrenal hyperplasia in children. In adults, the tumors, both adenomas and carcinomas, have abnormal production pathways so that androgens may be overproduced. In infants, there may be enzymatic defects, usually 21-hydroxylase deficiency, so that glucocorticosteroids are not produced, ACTH levels increase, and the androgen precursors occurring along the synthetic pathway before the step involving the enzymatic defect are overproduced. Depending on the defect, the problem may appear in infancy or later on, even in adult life. Functional adrenal tumors can also be observed in children.

The main clinical findings in women include acne, hirsutism, cliteromegaly, frontal baldness, deepened voice, and amenorrhea. In men, there may be decreased testicular volume. In childhood, girls experience masculinization (pseudohermaphroditism), while boys show signs of precocious puberty.

Polycystic Ovarian Syndrome (PCOS)

PCOS is linked to several cutaneous features. It is the most common cause of hirsutism, which is defined as excess terminal hair growth in a male-pattern distribution including the beard area (face and neck), back, chest, and lower abdomen (Blank et al. 2008). Hyperandrogenism contributes to this clinical presentation by increasing the circumference of hair fibers and prolonging the anagen phase of hair growth in the beard, axillary, and pubic regions. However, androgen levels do not correlate directly with the quantity of hair growth. Acne vulgaris is an additional manifestation (Yildiz 2006). Consideration for androgen excess should be given in case of moderate-to-severe acne, particularly when acne appears resistant to conventional therapies or recurrent after treatment with isotretinoin. Virilization can be another consequence of androgen excess and is characterized by deepening of the voice, muscle hypertrophy, reduction in breast size, clitoromegaly, and androgenetic alopecia. Individuals with androgenetic alopecia often notice a gradual thinning of the hair of the vertex and upper biparietal region of the scalp with preservation of the anterior hair line. The normal ratio of terminal to vellus hairs should be at least 2:1, but in androgenetic alopecia, there are an increased number of vellus hairs (Herskovitz and Tosti 2013). Other common findings include acanthosis nigricans – due to insulin resistance and hyperinsulinism – as well as seborrheic dermatitis.

The treatment of hirsutism and acne with anti-androgen therapy (spironolactone) may be effective. Additional treatment for hirsutism includes laser hair removal. Treatment options for androgenetic alopecia in females include topical minoxidil and spironolactone (Cause et al. 2017).

Pancreas

Diabetes Mellitus (DM)

Skin findings may be the first sign of diabetes, providing clues to current and past metabolic status. Recognition of cutaneous markers enables earlier diagnosis and treatment, improving the overall prognosis. According to various studies, 30% to 91% of diabetic patients experience at least one dermatologic complication (Mahmood et al. 2005). Many skin manifestations disproportionately affect patients with type 1 or type 2 DM.

The acute and chronic dermatological manifestations can be divided in specific and nonspecific disorders.

Necrobiosis Lipoidica Diabeticorum

Necrobiosis lipoidica diabeticorum (NLD) is a chronic, necrotizing, and granulomatous skin disease occurring primarily in individuals with diabetes. The affliction manifests with dark red papules that gradually evolve and enlarge, giving rise to atrophic skin.

Solitary or multiple lesions are most commonly distributed bilaterally on the lower extremities, particularly the pretibial areas, but may occur on the face, trunk, and upper extremities as well. Distinctive necrobiosis surrounded by palisading granulomas is seen on histopathology. NLD can be asymptomatic or painful and/or pruritic, especially when ulcerated. Ulceration occurs in approximately 35% of lesions, either spontaneously or secondary to trauma. Ulcerative lesions may be complicated by secondary infection and, rarely, by development of squamous cell carcinoma.

New lesions of NLD may be observed as a Koebner phenomenon.

Necrobiosis lipoidica appears in 0.3–1.6% of diabetic patients with a predisposition for those who are insulin dependent. In pediatric patients, the diagnosis of NLD portends a greater risk of developing diabetic nephropathy and retinopathy. It is stated that approximately 75% of patients with necrobiosis lipoidica have or will develop DM. In patients with type 1 diabetes, necrobiosis lipoidica arise at an earlier mean age than those with type 2 diabetes (Van Hattem et al. 2008).

Although the pathogenesis of NLD is not known, it is suggested that an antibody-mediated vasculitis with secondary collagen degeneration is the main cause of the disorder.

There is no satisfactory universal approach to treatment. Both topical and intralesional corticosteroids have shown efficacy. Caution should be taken as corticosteroids can worsen the atrophic epidermis or ulcerated lesions; calcineurin inhibitors, compression therapy, and psoralen with PUVA are the most frequently used modalities (Erfurt-Berge et al. 2012). No single drug has shown consistent efficacy, and regardless of the modality, NLD lesions tend to relapse on cessation of therapy.

Granuloma Annulare

Granuloma annulare (GA) is a rare, benign, and self-limited dermatitis of the pretibial regions and the extensor surfaces of the limbs. The cutaneous lesions are similar to those of NLD, but without causing atrophy of the epidermis. The lesions begin as firm, skin-colored dermal papules, which expand gradually in a centrifugal way. The format is annular, with a central hyperpigmentation, and sometimes the papules are frankly erythematous, becoming erythematous-brownish posteriorly. Individual lesions gradually expand and centrally involute, forming annular rings with raised borders. The papules of annular shape grow slowly and can measure from 0.5 to 5.0 cm (Dabski and Winkelmann 1989) (Fig. 8. Granuloma Annulare).
Fig. 8

Granuloma annulare. Annular pink to pink-brown plaques, the dorsal aspect of the hand is a common location

The most commonly affected areas are those exposed to trauma, such as backs of the hands and feet, fingers, elbow, arms, and legs; sometimes the scalp may be affected. Although the association of GA with diabetes is controversial, generalized lesions are mostly considered to be among the cutaneous manifestations of DM (Ahmed and Goldstein 2006). Generalized granuloma annulare initially appears as multiple, small, firm, skin-colored, or red dermal papules that tend to be symmetrically distributed on the distal extremities and sun-exposed areas of the trunk (Muhlbauer 1980). It is curious that up to 33% of cases of generalized GA are atypical presentations with nonannular, mostly coalescing papules. In most cases the plaques are asymptomatic, but may present mild and occasional itching or a burning sensation.

The histopathology shows lymphohistiocytic granulomatous inflammation of the dermis and collagen degeneration. Colloidal iron stain reveals abundant deposition of mucin. The presence of mucin and the absence of increased plasma cells help to histologically distinguish GA from NLD.

The duration of the disease is highly variable. Many lesions disappear spontaneously, without scarring, but they can last for months to years. Disappeared lesions have about 40% chance to reappear.

Granuloma annulare has a poor therapeutic response; the available options include high-dose topical steroids, intralesional injection of corticosteroids, PUVA, cryotherapy, or drugs such as niacinamide, infliximab, dapsone, and topical calcineurin inhibitors (Sahin et al. 2006). Oral isotretinoin can be effective in symptomatic patients, and the improvement of lesions occurs in 90% of those with decreased itching and erythema.

Diabetic Bullae

Diabetic bullae (DB), or bullosis diabeticorum, is a rare, noninflammatory, bullous disorder characterized by large, clear, and tense noninflammatory blisters that develop or occur with no preceding trauma on normal-appearing skin. The bullae are painless and predominantly occur on the lower extremities, especially on the feet and soles, but can also affect back and side of the hands and the arms. The diameter of the blisters varies between 0.5 and 5 cm; they are often bilateral, with an inflammatory base, and contain a clear, sterile, nonserous content. The blisters evolve rapidly (as quickly as 15 min has been reported), are usually painless and non-pruritic, and disappear spontaneously without scarring in 2–5 weeks (Larsen et al. 2008).

Even though uncommon, DB can be considered a distinct marker of DM and manifest in patients with long history of diabetes or with complications such as nephropathy or neuropathy, although there are reports of concomitant appearance to the initial presentation of DM. A combination of angiopathy and neuropathy may play a role in the physiopathology of BD (Levy and Zeichner 2012).

There are no specific tests for DB. The diagnosis is based on characteristic findings, clinical course, and the exclusion of other bullous disorders, such as drug eruption, immunobullous disease, and porphyria cutanea tarda. Histologic examination may aid diagnosis: the blisters manifest in three different types based on the level of cleavage. The most common type shows an subepidermal cleavage at the level of the lamina lucida without acantholysis, which appear and disappear spontaneously without scarring (Sehgal et al. 2011). The second type is rarer and involves lesions that may be hemorrhagic including resolution with scars and atrophy. The cleavage plane is below the dermoepidermal junction, with destruction of anchoring fibrils. A third described type consists of multiple blisters associated with sun exposure and markedly tanned skin. It affects the feet, legs, and arms and must be distinguished from porphyria cutanea tarda.

Treatment of DB is focused on skin protection and preventing secondary infection (Lipsky et al. 2000). Immediate regulation of the blood glucose level has been recommended as a result of the finding that hypoglycemic episodes often precede eruptions.

Scleredema Diabeticorum

Scleredema diabeticorum (SD), or diabetic scleredema, is a rare chronic connective tissue disorder primarily associated with type 2 diabetes. It presents as painless, non-pitting swelling that starts on the lateral and posterior neck and may spread to the anterior neck, shoulders, face, and upper torso (Martin et al. 2011).

The involved skin is hard, thick, and indurated, sometimes erythematous. There is a peau d’orange appearance of the skin with decreased sensitivity to pain and touch. The disease is usually asymptomatic, but pain may be present in severe cases.

SD shows a slowly progressive course. The skin sclerosis may reduce joint flexibility in the case of finger involvement. Huntley’s papules (aggregated small erythematous papules) may be present.

It is observed in 2.5–14% of patients with poorly controlled diabetes; it is more common in adult patients with diabetes, while only rarely is reported in children (Wilson and Newmark 1995).

It is most likely to develop in adults with long-standing diabetes and with poor glycemic control. Unequivocal diagnosis of scleredema by histologic examination requires a full thickness excisional biopsy to examine the dermis. The microscopic findings reveal a markedly thickened reticular dermis, thick collagen bundles, and mild infiltrate of mucin in the deeper dermis. Both edema and sclerosis are notably absent. The diagnosis is usually based on history and physical examination. Although the clinical presentations are indistinguishable, scleredema of Buschke occurs in children after a viral or bacterial upper respiratory infection and self-resolves in months. There is no highly effective treatment for SD: phototherapy (especially by the use of UVA1), physiotherapy, and systemic therapy with penicillin are some options. Other recommended therapies include strict glycemic control with an insulin pump, potent topical and intralesional steroids, penicillamine, intralesional insulin, low-dose methotrexate, prostaglandin E1, and pentoxifylline (Ikeda et al. 1998). Despite the different therapy modalities, SD remains a frequently therapy-resistant disease. Although strict glycemic control does not show consistent therapeutic benefit, it is proposed to be an effective preventive measure.

Cutaneous Infections

Diabetes causes several changes in immunologic system, but especially the decrease in leukocyte chemotaxis and phagocytosis leads to a significant deficiency of immune response that favors infections (Geerlings and Hoepelman 1999). Diabetic neuropathy and angiopathy play an important role in the infection, and mechanical trauma painless and unrecognized may facilitate microbial entry. Cutaneous infections of the skin (i.e., staphylococcal pyodermas, candidiasis (Fig. 9. Candida infection), erythrasma, and dermatophyte infections) may run an unusually prolonged or recurrent course. The most common fungal infections are candidiasis, especially vulvovaginal, balanopreputial, and angular stomatitis. Other common superficial mycoses are extensive pityriasis versicolor and dermatophytoses (e.g., tinea corporis) (Fig. 10. Tinea corporis), which are associated to microangiopathy and poor glycemic control. Rarely deep or systemic mycotic infections in diabetics include nocardiosis, cryptococcosis, and zygomycoses (mainly mucormycosis).
Fig. 9

Candida infection. An acute infection. The fringe of scale is present on the opposing borders. There are numerous satellite pustules beyond the intertriginous area

Fig. 10

Tinea corporis with a ringworm pattern (red and scaly borders, with lighter central area)

Bacterial infections may be varied and severe as those caused by Staphylococcus or Pseudomonas. The infection may be mild or severe and may manifest as abscesses or carbuncles. Recurrent erysipelas may also occur, with bullous and necrotizing lesions.

A high serum glucose level predisposes patients to these afflictions. About half of patients present an infectious episode in the course of their disease (Lima et al. 2017). Many studies have shown that the incidence of infection correlates with mean blood glucose levels (Perez and Kohn 1994). Skin infections may even be the presenting feature of diabetes. The best preventive measure for all skin infections in diabetes is optimal glycemic control beginning as early as possible.

The Diabetic Foot

Diabetic foot ulcers are one of the most common and serious complications of diabetes; they affect 15% of all diabetic patients and result in a high financial burden (Boulton et al. 2005). The lifetime risk to a person with diabetes for developing a foot ulcer could be as high as 25% (Singh et al. 2005), and the primary factors in the development of the lesions are vascular insufficiency and peripheral neuropathy. In the USA, the diabetic foot is responsible for 70% of lower limb amputations annually (Ngo et al. 2005).

Classically, the so-called diabetic foot is a chronic ulcer that evolves after trauma or over a callus caused by changes in points with altered sensitivity due to neuropathy (60–70%). A much smaller proportion is linked to peripheral vascular ischemia (about 15%). The causes can coexist, and about 25% of diabetics may present foot ulcers during the development of the disease (Fig. 11. Diabetic foot). Ulcers are difficult to heal due to the underlying immunosuppression of the disease, hyperkeratotic borders, and sometimes ischemia. The treatment is performed according to the etiology. If the pulses are palpable, energetic therapeutic measures such as the debridement and dressing usually heal the wound in few weeks. On the other hand, no measures are effective in the presence of ischemia, and surgical revascularization is crucial to the treatment. Secondary infections and osteomyelitis are factors that complicate the approach, and systemic antibiotics should be evaluated in all cases (Ahmad 2016).
Fig. 11

Diabetic ulcer of the right foot

Acanthosis Nigricans

Acanthosis (“acantho” meaning thorn) nigricans (black) (AN), described as a diffuse, velvety thickening and hyperpigmentation of the skin, has been associated with diabetes. It has a strong tendency to involve the axillae, neck, inframammary and inguinal folds, and perineum.

AN has also been observed in obesity and polycystic ovary syndrome and may manifest as a paraneoplastic syndrome in gastrointestinal malignancies (Kutlubay et al. 2015). It is due to the hyperactivity of different growth factors.

AN may precede type 2 diabetes mellitus; the prevalence increases with age (Barbato et al. 2012). In diabetic patients, there is a statistically significant correlation of increasing severity of acanthosis nigricans with increasing BMI.

The association with obesity is presumably via insulin resistance and enhanced production of IGF-1 and IGF-2. Lesions are gray-brown to black and rough, have thickened plaques and prominent skin lines, and occur most commonly in flexural areas (axillae, back and sides of neck, inguinal creases, inframammary). Also, palms and soles show hyperplasia of the relief as “tripe palms.” Histologically, there are hyperkeratosis, epidermal papillomatosis, and increased numbers of melanocytes. Acanthosis nigricans is frequently asymptomatic, but patients may present with lesions that are painful, disfiguring, malodorous, or macerated.

Although no effective treatment exists, weight loss often leads to improved appearance of this finding. Retinoids (topical or systemic) and keratolytic agents (salicylic acid, lactic acid, urea) may also aid in management of the disease (Parex 1994). Treatment of the underlying disease (obesity, diabetes mellitus, intestinal tumor) is essential.

Diabetic Dermopathy

Diabetic dermopathy is the most common dermatologic marker of DM, affecting up to 70% of adult patients. It is generally agreed that four or more shin spots increase the probability that diabetes is present, warranting an evaluation (Yosipovitch et al. 1998). Although it is commonly seen in adults, it can occasionally manifest in children.

Diabetic dermopathy is characterized by the eruption of multiple asymptomatic, irregularly shaped, dull red to pink papules or plaques predominantly on the pretibial skin bilaterally but also occurring on the forearms, thighs, and lateral malleoli.

One to 2 weeks after they appear, these lesions evolve to well-circumscribed, atrophic, brown macules often with fine scale. New lesions may emerge, and older ones resolve spontaneously leaving slightly depressed, hyperpigmented areas. It is a dynamic process with lesions of varied stages present at the same time. Shin spots may occasionally be complicated by ulceration.

Diabetic dermopathy is a clinical diagnosis. Because the histopathology is relatively nonspecific, skin biopsy is best avoided.

The cause of shin spots is unknown. Attempts to explain the pathogenesis have centered on trauma and on microangiopathy with associated capillary changes.

No medical intervention is necessary aside from appropriate wound care to accelerate healing and prevent infection (Verrotti et al. 1995).

Acquired Perforating Dermatoses

Acquired perforating dermatoses comprise a group of chronic skin disorders defined histologically by transepidermal perforation and elimination of a connective tissue component of the dermis. The acquired perforating dermatosis group is almost exclusively associated with chronic renal failure, diabetes, and/or hemodialysis (often related to diabetic nephropathy).

Although rare, the clinical picture is typical with pruritic, erythematous, and umbilicated hyperkeratotic papules, or nodules with adherent crusts are found sometimes in a linear fashion (Wagner and Sachse 2013).

The eruption is found primarily on the extremities and trunk, less often on the head. The papules are distributed in a distinctive serpiginous pattern. Acquired perforating dermatoses undergo koebnerization (the development of lesions at sites of trauma) and are typically exacerbated by excoriation. The pathogenesis is poorly understood. It remains unknown whether the primary abnormality occurs in the dermis or epidermis and whether the pruritus is an underlying cause or a resultant effect of the skin condition. Acquired perforating dermatoses in the setting of diabetes are relatively unresponsive to therapy. By avoiding trauma to the area, lesions may resolve slowly. Therefore, symptomatic relief of pruritus is a core treatment strategy.

Therapy with topical and oral retinoids or corticosteroids has been described; intralesional triamcinolone can also be used. Varying beneficial effects are reported with PUVA, UVB phototherapy, antibiotics (doxycycline), oral antihistamine, cryotherapy, and renal transplantation.

Eruptive Xanthomatosis

Xanthomas are yellow-tan-orange papules, plaques, and patches, often appearing on the palms and elbows and along tendons, as a Koebner phenomenon on pressure points. They arise suddenly in groups of multiple yellow papules, 1–4 mm in diameter.

Eruptive xanthomas typically appear in association with chylomicronemia and hypertriglyceridemia (greater than 700 mg/dL), which is common in DM.

Approximately one-third of all diabetic patients have serum lipoprotein abnormalities caused by insulinopenia. The histopathology shows an accumulation of lipid-laden histiocytic foam cells with a mixed infiltrate of lymphocytes and neutrophils in the dermis. The diagnosis of eruptive xanthomatosis should prompt further investigation and treatment of hyperglycemia.

Lesions may resolve after hyperlipidemia is controlled. Statins or fibrates can supplement treatment as tolerated.

Vitiligo

Vitiligo is an acquired, chronic, depigmenting disorder of the skin characterized by well-demarcated macules due to selectively destroyed melanocytes. The cause of vitiligo is still debated, but either a loss of cutaneous melanocytes or a loss of melanocyte function is believed to occur, and this likely involves cell-mediated autoimmunity.

It often affects extremities, face, and neck as well as trunk, in a symmetrical distribution, and is easy to diagnose. It is a highly prevalent skin alteration with a prevalence of 2–10% in type 1 diabetes patients, occurring spontaneously with progressive course.

Recent progress in the understanding of immune pathomechanisms opens interesting perspectives for innovative treatment strategies.

Acrochordons (Skin Tags)

About 70% of patients with skin tags have diabetes. These benign, asymptomatic, exophytic growths are observed usually on the eyelids, neck, axillae, groin, and other skin folds. They may be flesh-colored or, less often, hyperpigmented and can range from small papules to pedunculated polyps, typically 1–6 mm diameter, with smooth or irregular surfaces (Crook 2000). Hyperproliferation of keratinocytes due to hyperglycemia and insulin stimulation may stimulate skin tags. Most of the fibroma is asymptomatic and no therapy is necessary; however, many patients want them to be removed as they may cause skin irritation and are disturbing.

Yellow Skin and Nails

Yellowish skin and nails are described with increased frequency among individuals with diabetes compared with the general population. This finding is asymptomatic and considered benign, but the exact cause has not been elucidated. The best explanation for diabetic yellow skin is likely a discoloration caused by certain end products associated with nonenzymatic glycosylation of dermal collagen (Hoerer et al. 1975). There is no treatment for this phenomenon.

The increased frequency of yellow nails among diabetic patients may be at least partially attributable to an increased prevalence of onychomycosis.

Generalized Pruritus

Chronic pruritus is a common skin manifestation of diabetes. It is often associated with xerosis cutis. About 3–49% of people with diabetes have itching, considerably impairing their quality of life. The generalized itching may occur in clinically inconspicuous dry skin or be associated with erythematous papules or with prurigo nodularis (Ko et al. 2013).

Poor microcirculation and hypohidrosis causing xerosis were proposed as explanations. Pruritus vulvae was the only type of localized pruritus seen more frequently in patients with diabetes; it is most frequently caused by an infectious process, particularly induced by Candida. Therefore, exogenous diabetic drug therapy and pathogens may explain the increased frequency of pruritus in diabetes (Feingold and Elias 1987).

Therapy includes normalizing glucose levels accompanied by basic skin care with emollients. However, in some cases of prurigo nodularis, these measures will not be sufficient, and topical corticosteroids, intralesionally injected corticosteroids, or topical capsaicin will be needed (Lee and Shumack 2005).

Ichthyosiform Skin

An ichthyosiform aspect may arise from changes of the skin in diabetes; it appears frequently in young subjects with insulinodependent diabetes and is associated with microangiopathy and duration of disease.

Keratosis pilaris can also be observed, and both appear to be associated with skin xerosis present in these patients.

Lichen Planus

Around 1/4 of lichen planus patients have diabetes (Seyhan et al. 2007). The clinical findings show the typical pruritic polygonal erythematous papules with white striae (Wickham striae), characteristically located on ankles and wrists (Fig. 12. Lichen planus), with optional involvement of the mucosa. Lichen planus belongs to the skin diseases that may be provoked mechanically, also known as Koebner phenomenon, which is also observed in psoriasis.
Fig. 12

Lichen planus. Violaceous papules on the forearm

Moreover a significantly higher prevalence of oral lichen planus is reported in type 1 DM, compared to type 2 and a control population.

A large number of therapies are available to treat lichen planus. Topical corticosteroids, topical calcineurin inhibitors, phototherapy, systemic retinoids, systemic corticosteroids, methotrexate, hydroxychloroquine, or dapsone can be used.

Rubeosis Faciei

Rubeosis is a vascular erythema on the face and neck present in up to 60% of patients with diabetes, probably linked to the loss of the vasoconstrictor tone. It tends to be more easily appreciated in Fitzpatrick skin types 1 and 2 because increased melanin can obscure the coloration. It usually reflects poor glycemic control and is associated to peripheral neuropathy. In these patients, hyperglycemia can lead to a change in the microcirculation. It becomes clinically evident by facial venous dilatation. Although rubeosis is a benign condition, it may serve as a clue to the more menacing internal processes of microangiopathy secondary to suboptimal glycemic control; therefore it is prudent to assess patients for other microangiopathies such as retinopathy and nephropathy. Treatment consists in diabetic control and avoidance of alcohol, caffeine, and other vasodilators.

Palmar Erythema

Palmar erythema is believed to be a microvascular complication of both types 1 and 2 diabetes mellitus. It consists in a symmetric, asymptomatic, and slightly warm erythema most frequently limited to the thenar and hypothenar eminences. This form of palmar erythema differs from normal physiologic mottling that involves the entire palm elicited by factors such as atmospheric temperature, emotional state, elevation of the hand, and pressure on the palm. Like rubeosis faciei and yellow skin, diabetic palmar erythema is benign yet may signify an underlying process that calls for therapy.

Nail Bed Erythema

Erythema of the proximal nail fold is another reddish color change of diabetic skin; it has been attributed to dilatation of the superficial vascular plexus presenting as periungual telangiectasias (visibly dilated capillaries around the nail bed). Although classically associated with scleroderma and dermatomyositis, periungual telangiectasias are frequently observed among diabetic patients, again representing underlying diabetic microangiopathy. The periungual capillaries of diabetic patients with this isolated venous portion congestion differ morphologically from those changes seen in connective tissue diseases, where the capillary loops are markedly blunted and attenuated. Although it is usually asymptomatic, nail bed erythema in diabetic patients often presents with associated cuticle changes and tenderness of the fingertip. Nail bed erythema should not be confused with paronychia, which is caused by bacterial or fungal infection.

Pigmented Purpura

Pigmented purpura coexists with diabetic dermopathy (pigmented pretibial patches, shin spots) in about 50% of cases. The affliction, also called pigmented purpuric dermatoses, includes a heterogeneous group of uncommon, idiopathic, and progressive skin conditions causing patches of orange to brown, nonblanching pigmentation speckled with 0.3–1.0 cm so-called cayenne pepper spots. These asymptomatic lesions are distributed mainly over the lower extremities, especially the pretibial leg, with occasional involvement of the ankles and dorsa of the feet, and are caused by erythrocyte extravasation from the superficial venous plexus. The deposition of hemosiderin released from red blood cells is responsible for the characteristic color. Pigmented purpura occurs most commonly in elderly diabetic patients, often precipitated by congestive heart failure and, therefore, presenting with lower extremity edema. Of the six recognized clinical variants of pigmented purpura, the most common is progressive pigmented dermatosis or Schamberg’s disease (Ratnam et al. 1991). In the absence of diabetic dermopathy, pigmented purpura is not considered a marker for diabetes.

Cutaneous Reactions to Diabetic Treatment

Adverse Skin Reactions to Insulin

Insulin itself may cause side effects to the skin. Itching, edema, stinging, pain, or warmth and redness may interest the injection site. Systemic manifestations may involve urticaria and angioedema as well as palmar and plantar pruritus and disseminated itching and flushing (Heinzerling et al. 2008). Frequently lipoatrophy and lipohypertrophy are observed. Lipohypertrophy is the most frequent local reaction of subcutaneous insulin treatment and affects approximately 27% of people with diabetes; lipoatrophy is characterized by atrophy of subcutaneous adipose tissue at the insulin injection site (Richardson and Kerr 2003).

The risk of local bacterial infections is positively correlated to the number of daily insulin injections, while it is less uncommon in patients using insulin pumps. Rapidly resorbed insulins may decrease the risk, but a regular change of the injection site is mandatory.

The advent of recombinant insulin preparations has largely done away with once common insulin allergies (Ferringer and Miller 2002). Insulin allergy concerns less than 1% of patients using injectable insulin. Delayed hypersensitivity reactions are the most common type of allergic reaction, but immediate, local, or generalized and biphasic reactions also occur. Treatment options include antihistamines, the addition of steroid to insulin, desensitization therapy, rotating the injection site, or discontinuation of therapy. Anaphylaxis is an extremely rare adverse reaction.

Oral Hypoglycemic Agents

Oral antidiabetics have been reported to cause systemic reactions, such as erythema multiforme, leukocytoclastic vasculitis, allergic drug eruptions, and photosensitivity (Wiwanitkit 2011). It is estimated that 1–5% of patients treated with a first-generation sulfonylurea, such as chlorpropamide or tolbutamide, experience a cutaneous reaction (most often a maculopapular eruption) within the first 2 months of therapy. These drugs have been identified as causes of lichenoid or psoriasiform drug eruptions by some authors (Noakes 2003). Chlorpropamide causes an alcohol flush reaction, characterized by generalized warmth, erythema, headache, and tachycardia, in 10–30% of patients; the reaction begins about 15 min after consumption of alcohol and lasts for an hour. Discontinuation of the drugs usually leads to prompt resolution of the rash. On rare occasions, drug-associated pemphigus vulgaris has also been attributed to sulfonylurea therapy (Paterson et al. 1993).

The most common cutaneous reactions to second-generation sulfonylureas, such as glipizide and glimepiride, include photosensitivity, urticaria, and pruritus. Metformin has been reported to cause a psoriasiform drug eruption, erythema multiforme, and leukocytoclastic vasculitis. Acarbose acts by inhibiting the α-glucosidase enzymes and has been reported as a possible trigger of erythema multiforme exudativum and generalized exanthematous pustulosis (Wu et al. 2008).

Polyendocrine Disorders

Multiple Endocrine Neoplasia (Men) Syndromes

MEN syndromes represent a spectrum of autosomal dominant disorders that include benign and malignant neoplasms of multiple endocrine tissues. Variable endocrine involvement leads to a vast range of clinical presentations, with cutaneous features often contributing to the identification of these disorders.

Angiofibromas are the most common cutaneous manifestation of MEN1, with one study finding facial angiofibromas in 88% of individuals. These lesions appear as flesh-colored, pink, or red papules with a smooth and shiny surface; they have a predilection for the upper lip, as opposed to the nasolabial folds as seen in tuberous sclerosis.

Other common dermatologic findings include truncal collagenomas, lipomas, café au lait macules, confetti-like hypopigmented macules, and multiple gingival papules (Fuleihan and Rubeiz 2006).

Although only occurring in 3% of patients with MEN1, glucagonoma is associated with a distinct cutaneous manifestation termed necrolytic migratory erythema. Often in occasion of new-onset diabetes mellitus, necrolytic migratory erythema initially presents as erythema of the groin and perineum and can eventually spread to the extremities and perioral region. The areas of erythema often progress to vesicles and bullae before a final crusting stage (de Laat et al. 2016).

The most significant dermatologic manifestation of MEN2A is lichen amyloidosis. This pruriginous condition has a predilection for the extensor surfaces of the upper back and extremities. Lesions appear as gray-to-brown, hyperkeratotic papules that may evolve into larger plaques.

In MEN2B, patients may develop, by the fifth year of life, numerous superficial neuromas which appear as whitish-to-pink sessile papules distributed on the lips, tongue, buccal mucosa, gingiva, palate, and pharynx. The anterior one-third of the tongue is most likely to be involved and demonstrates clear-to-pink papules. Signs of eyelid or conjunctival involvement include a thickened eyelid margin as well as disorganized eyelashes. Patients have a characteristic facies of thickened and slightly everted lips and eyelids with a rubbery to bumpy appearance. They can also have a “marfanoid body habitus” (long, slender extremities with sparsity of fat and muscle, laxity of joints, and pectus excavatum).

Lastly, patients with MEN2B are found to have café au lait macules at an increased incidence (Darling et al. 1997).

For patients with benign skin tumors (angiofibromas, lipomas, and collagenomas), surgical excision can be employed. In addition, topical rapamycin and laser therapy, used alone or concomitantly, can reduce the size and number of angiofibromas. There is no reported definitive therapy for lichen amyloidosis; however, a variety of case reports have successfully used multiple treatment approaches including retinoids, corticosteroids, laser therapy, and phototherapy.

Autoimmune Polyglandular Syndromes

Autoimmune polyglandular syndromes (APS) are a heterogeneous group of immune-mediated disorders characterized by insufficiency of at least two endocrine organs. Chronic mucocutaneous candidiasis is observed in the majority of patients with APS I and typically presents prior to the associated endocrinologic features. It refers to the presence of frequent or persistent fungal infections of the mucous membranes, skin, and nails. Oral candidiasis peaks in incidence within the first 2 years of life and tends to follow a chronic course. Cutaneous candidal infections may result in angular cheilitis, scalp infection, intertrigo, and diaper or perianal candidiasis. Lastly, fungal infection of the nails leads to discoloration and thickening as well as paronychia (inflammation of the periungual skin). Other dermatologic associations with APS I include alopecia areata and vitiligo, which affect approximately 30% and <10% of patients, respectively. Cutaneous features of Addison’s disease and epidermolysis bullosa acquisita have also been reported in type 1 syndrome (Burke et al. 1986). Patients with APS II and III may also present with vitiligo and alopecia areata, albeit less frequently. The clinical presentation of patients with APS I may be impacted by the presence of hypoparathyroidism as well. In this condition, the skin is typically dry, scaly, and hyperkeratotic. In addition, observation may reveal opaque, brittle nails with longitudinal grooves as well as sparse hair. In addition to management of endocrine abnormalities, treatment of the cutaneous features of APS employs the use of antifungal agents.

Genetic Syndromes

Carney Complex

The characteristic cutaneous manifestations of Carney complex are spotty skin pigmentation (lentigines) most often found around the lips; on the eyelids, canthi, and the conjunctivae; the ears; and the genital area and present by the time of puberty. Mucocutaneous myxomas, which are derived from effects on fibroblasts, tend to develop within the first two decades of life, are generally asymptomatic sessile or pedunculated pink papules, and are distributed on the eyelids, nipples, buttocks, external ear, tongue, palate, and perineums (Saggini and Brandi 2011).

Patients may develop multiple blue nevi (including the epithelioid histologic subtype characteristic of this condition) which have a predilection for acral skin, the buttocks, and the head.

Nevi may be present at birth, but develop at the time of puberty. Less frequently, skin lesions such as café au lait macules, lentigines, pilonidal sinus, multiple skin tags, lipomas, hyperpigmentation, as well as depigmented macules, white patches of the skin due to depigmentation, can also be observed. Finally, skin atrophy, stretch marks, folliculitis, and hirsutism may be present in the Cushing’s syndrome (Horvath and Stratakis 2009).

21-Hydroxylase Deficiency

Of greater relevance to dermatologists (as it is common) is the less severe, late-onset form of congenital adrenal hyperplasia; prenatal virilization does not occur. The milder enzyme deficiency was termed nonclassical 21-hydroxylase deficiency in 1979 and was later found to be the most common autosomal recessive disorder in humans. Similar to classical congenital adrenal hyperplasia, nonclassical 21-hydroxylase deficiency may cause premature development of pubic hair, advanced bone age, accelerated linear growth velocity, and diminished final height in both males and females. Severe cystic acne has also been attributed to nonclassical congenital adrenal hyperplasia. Women may present with symptoms of androgen excess, including hirsutism, temporal baldness, and infertility. Polycystic ovary syndrome may also be seen in these patients. In males, early beard growth, acne, and growth spurt may prompt the diagnosis of 21-hydroxylase deficiency.

Neuroendocrine Tumors

Glucagonoma Syndrome

Glucagonoma syndrome is a rare disease resulting from a nearly always malignant pancreatic tumor. The distinctive skin lesions of necrolytic migratory erythema are situated mainly on the face in perioral and perinasal distribution, perineum, genitalia, shins, ankles, and feet. Typically, the lesions present as patches of intense erythema that may be angular, annular, or irregular in outline followed by the development of flaccid vesicles and bullae with subsequent denudation of the skin, with crusting and fissuring. They begin as erythematous papules or plaques. Central clearing then occurs, leaving bronze-colored, indurated areas centrally, with blistering, crusting, and scaling at the borders. The cutaneous eruptions occur mainly in the groin, extremities, thighs, buttocks, and perineum. Affected areas are often pruritic and painful. Necrolytic migratory erythema may be complicated by secondary cutaneous infections with yeast such as Candida albicans or bacteria such as Staphylococcus aureus. Skin biopsies obtained from the edge of the lesions reveal superficial necrolysis, with separation of the outer layers of the epidermis, and perivascular infiltration with lymphocytes and histiocytes. In addition, patients may develop glossitis (red, shiny smooth tongue), angular cheilitis, anemia, venous thromboses, and alopecia. Therapy consists in surgical removal of the pancreatic tumor; a near-complete resolution of the skin disease is seen often only 1 week after surgery.

Carcinoid Syndrome

Most carcinoid tumors originate from the small intestine; they can spread to large parts of the intestinum, the stomach, and the bronchus and may metastasize to the lymph nodes and liver. The skin presents with a pellagra-like appearance lesions with pigmentation and hyperkeratosis on legs and arms. Others cutaneous features include exuberant and transient bright red flushing initially on the face, neck, and upper chest; on repeated episodes, it may involve the entire torso and extremities. The typical flush begins suddenly and lasts 20–30 s. Patients may complain of sensations of heat, stiffness, and paresthesias during the attacks. Finally, after prolonged and repeated attacks, a permanent cyanotic flush of the face with telangiectasias resembling rosacea may develop. Patients may also develop niacin deficiency, hypoproteinemia, and scleroderma-like features without Raynaud’s phenomenon (Bell et al. 2005).

Merkel Cell Carcinoma

Merkel cell carcinoma is a rare and aggressive neuroendocrine tumor which occurs most commonly in the elderly and in sun-exposed skin, giving rise to metastasis in the lymph nodes and distant organs in most cases. Merkel cell polyomavirus is thought to be a major contributor to the pathogenesis of the malignancy; however, the exact mechanism of tumorigenesis is unclear and is likely multifactorial. There are several postulated mechanisms, including integration of viral DNA, expression of T-antigen and evasion of host immune response under the influence of exposure to ultraviolet radiation. Clinically, Merkel cell carcinoma occurs on the head and neck, with predilection for the eyelids and periorbital skin as well as extremities. The tumor may present with various skin manifestations but typically develops as a small, less than 2 cm painless, violaceous papule, plaque, cyst, or infiltrative nodule. The lesion may expand slowly or rapidly. Giant variants, mucosal involvement, ulceration, and multiple tumors are less commonly observed. Histopathology shows a tumor of small blue cells with hyperchromatic nuclei and scant cytoplasm, which frequently extends into the subcutaneous fat.

Treatment includes surgery with reconstruction associated with radiotherapy and/or chemotherapy for advanced stages including widespread metastases (Daoud et al. 2013).

Summary

Cutaneous lesions can serve as a marker of endocrine disease; it is important for the clinician to be aware of their importance for a prompt and adequate diagnostic approach to the patients.

A common feature of these conditions is the secretion of hormones or bioactive substances which produce both widespread multisystem effects and prominent cutaneous signs.

In this chapter, the main skin diseases having an endocrinological basis are described. These include cutaneous features of diabetes mellitus, diseases due to alterations of corticosteroid and androgen metabolism, diseases due to dysfunctions of growth hormone secretion, diseases due to dysfunctions of the thyroid gland, paraneoplastic syndromes, and genetic syndromes including dermatological and endocrine symptoms.

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Section of Dermatology, Department of Biomedical Science and Human OncologyUniversity of BariBariItaly

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