Accessory tragi are usually found as solitary, dome-shaped papules and nodules, present at birth, usually in the preauricular region but sometimes in the neck, anterior to the sternomastoid muscle.1.^{2.3. and 4.} The cervical lesions have been regarded by some as a discrete but closely related entity, also of branchial origin: ⁵ they have been reported as cervical auricles, ‘wattles’, and congenital cartilaginous rests.^{6.7. and 8.}

Accessory tragi may be multiple, including a linear arrangement, ⁹ and sometimes bilateral. ¹⁰ Rarely, they are associated with other syndromes of the first branchial arch, such as hemifacial microsomia (oculo-auriculo-vertebral spectrum (OAVS) or Goldenhar’s syndrome (OMIM 164210)), in which a myriad of congenital anomalies have been described.^{9. and 11.} In one recent case a deletion in the region of 22q11.2 has led to speculation that this is a candidate gene for the syndrome. ¹² It is currently thought that the gene maps to 14q32. Clinically, accessory tragi, including the lower cervical variants, are usually diagnosed as skin tags.

Polythelia, as the presence of supernumerary nipples is sometimes called, is a developmental abnormality found in approximately 1% of the population. ¹⁷ Much less common is polymastia, the term used to describe the presence of two or more breasts. This rare phenomenon occurs mostly in the axilla, but other sites have been recorded.^{18. and 19.} Polymastia refers to the presence of nipple, areola, and glandular tissue and if areola is not present, the term supernumerary glandular tissue is more appropriate.^{20. and 21.} There is a predilection for females in both supernumerary nipple and polymastia. Familial cases of supernumerary nipple have been recorded. ²² The supernumerary structure is usually a solitary, asymptomatic, slightly pigmented, nodular lesion, often with a small, central, nipple-like elevation. It may occur anywhere along the pathway of the embryonic milk line, particularly on the anterior aspect of the chest or the upper abdomen. Rarely, it is outside this line.^{23. and 24.} Clinically, it resembles a nevus or fibroma. There is said to be an increased incidence of renal abnormalities in patients with a supernumerary nipple, ¹⁸ although recent studies have failed to confirm this association.^{25.26.27. and 28.} Rarely, a small patch of hairs may be the only marker of underlying accessory breast tissue (‘polythelia pilosa’). ²⁹ Accessory breast tissue is rarely seen in a Becker’s nevus. ³⁰

Dermoscopy of one case showed a central white area, central streak, and a very faint pigmented network at the periphery. ³¹

Accessory scrotum is the presence of scrotal skin outside of its normal location, but without testicular tissue. It is usually found in the perineal or inguinal region. ³³ A normal scrotum is also present. An accessory scrotum has been reported in a patient with a Becker’s nevus (see p. 294).

Agenesis of the scrotum is an exceedingly rare event. ³⁴

There are isolated reports of the occurrence in the skin of ectopic tissue. Most cases represent embryological vestiges, but trauma (surgery or a gun-shot injury) is the explanation for splenic tissue in the subcutaneous tissues of the abdomen.^{35.36. and 37.} Ectopic bowel mucosa may follow congenital eversion or implantation after an –ostomy involving bowel. ³⁸ Rarely, nephrogenic rests are found in the lumbosacral region, either with or without associated spinal dysraphism. ³⁹

Other ectopic tissues reported in the skin have included thymus, ⁴⁰ respiratory mucosa, salivary gland, ⁴¹ thyroid, ⁴² brain, thymus, ⁴³ and pancreas. There is one report of a subcutaneous thymoma, but it probably spread from its more usual location. ⁴⁴ Ectopic nail (onychoheterotopia) is a rare condition in which nail-like tissue occurs in a location other than the nail bed.^{45. and 46.} Fewer than 50 cases have been recorded. It may be congenital or acquired, the latter usually following acute trauma or repeated minor injuries to the nail unit.^{45. and 46.}

Cheilitis glandularis is a chronic inflammatory disorder affecting mucous glands and ducts of the lower lip. It appears to be a heterogeneous entity, which has been attributed in the past to hyperplasia of labial salivary glands.^{47.48. and 49.} However, a critical review of reported cases does not support this explanation⁵⁰ except in a few cases. ⁵¹ It has been suggested that the condition includes cases of factitious cheilitis,^{52.53. and 54.} premature and exaggerated actinic cheilitis, and cases with a coexisting atopic diathesis in which mouth breathing may play a role. ⁵⁰ A case has been reported of cheilitis glandularis superimposed on oral lichen planus. ⁵⁵ It has also been reported in albinos. ⁵⁶ It should be noted that only mild swelling of the lip is needed to produce eversion, which in itself exaggerates the appearance of swelling. ⁵⁰

The patients present with macrocheilia, usually confined to the lower lip. ⁵⁷ There is often crusting and fissuring with a mucoid discharge. Salivary duct orifices may be prominent. Clinically, the lesions need to be distinguished from plasma cell cheilitis, ⁵⁸ cheilitis granulomatosis (Melkersson–Rosenthal syndrome – see p. 188), and Ascher’s syndrome, in which there is acute swelling of the lip and eyelids (usually the upper) resulting from edema, inflammation, and a possible increase in size of labial and lacrimal glands respectively.^{48.59.60.61. and 62.}

Squamous cell carcinoma may sometimes supervene, further evidence that many cases have an actinic etiology.^{47.49. and 63.}

Treatment involves elimination of aggravating factors, reinstating oral hygiene, and the use of lip balms and sunscreens. Topical or intralesional corticosteroids, antibiotics, topical 5-fluorouracil cream, cryotherapy, and surgical excision have all been used. In the patient referred to above with concurrent oral lichen planus, treatment with topical tacrolimus and pimecrolimus was successful. ⁵⁵

The omphalomesenteric duct normally becomes obliterated early in embryonic life but remnants may persist, producing an enteric fistula, an umbilical sinus, a subcutaneous cyst, or an umbilical polyp.^{66. and 67.} The latter presents as a bright red polyp or fleshy nodule, 0.5–2 cm in diameter; ⁶⁸ it may discharge a mucoid secretion. A distinctive umbilical polyp, devoid of any epithelial component, and termed a fibrous umbilical polyp is discussed further below.

Urachal anomalies usually present at or shortly after birth. ⁶⁴ They may present as periumbilical dermatitis. ⁶⁹ A patent urachus will result in the passage of urine from the umbilicus. Urachal sinuses and deeper cysts result from partial obliteration of the urachus, with small persistent areas. ⁷⁰

Other lesions presenting at the umbilicus include endometriosis (see p. 455), primary⁷¹ and secondary tumors (see p. 928), ⁷² and inflammatory granulomas. ⁷³ The granulomas result from inflammatory changes associated with persistent epithelialized tracts or simply from accumulation of debris in a deep umbilicus with resulting ulceration and inflammation. ⁶⁴ Sometimes a pilonidal sinus is present. ⁷⁴

The fibrous umbilical polyp appears to be a distinctive lesion of early childhood with an uncertain pathogenesis. ⁷⁵ It has a marked predilection for boys. A series of 19 cases from one institution suggests that it is not rare. They ranged in size from 0.4 to 1.2 cm in diameter.

Relapsing polychondritis is a rare multisystem disorder of unknown etiology manifesting with recurrent inflammation of the cartilaginous tissues of different organs, particularly the ear, but also the nasal septum and tracheobronchial cartilage.^{78.79.80.81. and 82.} A frequent presentation is with tenderness and reddening of one or both ears resembling an infectious cellulitis.^{83.84. and 85.} Onset is usually in middle age. Pediatric cases are uncommon. ⁸⁶ Other manifestations include polyarthritis, ocular inflammation, audiovestibular damage, cardiac lesions, and a vasculitis.^{78.87. and 88.} Relapsing polychondritis has been reported in association with psoriasis, ⁸⁹ aseptic abscesses, ⁹⁰ myelodysplastic syndromes,^{91. and 92.} malignant lymphoma,^{93. and 94.} acute febrile neutrophilic dermatosis (Sweet’s syndrome), ⁹⁵ human immunodeficiency virus infection, ⁹⁶ and, in one case, pseudocyst of the auricle. ⁹⁷ Its association with Behçet’s disease has been called ‘MAGIC syndrome’ (mouth and genital ulcers with inflamed cartilage). ⁹⁸ Relapsing polychondritis needs to be distinguished from Wegener’s granulomatosis. ⁹⁹ The course of the disease is variable, but there is usually progressive destruction of cartilage, with consequent deformities. Death ensues in up to 25% of patients as a result of respiratory and cardiovascular complications.

There are pointers to an immunological pathogenesis. These include the detection of cell-mediated immunity to cartilage, the presence of antibodies to type II collagen, ¹⁰⁰ and the demonstration by direct immunofluorescence of immunoglobulins and C3 in the chondrofibrous junction and around chondrocytes.^{97. and 101.} A case thought to have been precipitated by the use of the drug goserelin (Zoladex) for the treatment of prostatic adenocarcinoma has been reported. ¹⁰²

Colchicine,^{103. and 104.} dapsone,^{105. and 106.} and corticosteroids have been used in the management.

Acanthosis nigricans is a cutaneous manifestation of a diverse group of diseases which include internal cancers and various endocrine and congenital syndromes (Table 19.1).^{109.110.111. and 112.} It may occur as an inherited disorder and in association with Down syndrome. ¹¹³ It may also be related to the ingestion of certain drugs. In all these circumstances, acanthosis nigricans presents as symmetrical, pigmented, velvety plaques and verrucous excrescences confined usually to the flexural areas of the body, particularly the axillae.^{109. and 110.} It may also involve the back of the neck, the periumbilical and anogenital regions, and the face.^{114.115. and 116.} Rarely, there is generalized involvement of the skin.^{117.118.119. and 120.} The oral mucosa, particularly that of the lips and tongue, is affected also in 25% or more of cases. ¹²¹ Involvement of the esophagus has been reported. ¹²² Hyperkeratotic lesions may develop on the palms, soles, and knuckles.^{123.124. and 125.} Such cases should be distinguished from the condition called acral acanthotic anomaly or acral acanthosis nigricans in which velvety, hyperpigmented plaques occur on the elbows, knees, knuckles, and the dorsal surfaces of both feet in individuals with a dark complexion. ^{126. and 127.}

The paraneoplastic type of acanthosis nigricans is a rare manifestation of an internal cancer, usually an adenocarcinoma of the stomach or other part of the alimentary tract.128.^{129.130.131.132.133. and 134.} Lymphomas, ¹³⁵ renal carcinoma, ¹³⁶ endometrioid carcinoma of the parametrium, ¹³⁷ lung carcinoma, ¹³⁸ bladder carcinoma, ¹³⁹ liver tumors, ¹⁴⁰ and squamous cell carcinomas¹⁴¹ are occasionally associated. Acanthosis nigricans may precede or follow the diagnosis of the cancer but in most instances the two are diagnosed simultaneously.^{129.137. and 142.} The sign of Leser–Trélat, another paraneoplastic phenomenon, may occur in association with acanthosis nigricans. ¹³⁴ Florid cutaneous papillomatosis may also accompany this variant of acanthosis nigricans. ¹⁴³ There are some reports of the reversibility of the skin lesions upon removal or treatment of the accompanying malignant disease.^{129. and 142.}

The various endocrine disorders and congenital syndromes which may be complicated by acanthosis nigricans appear to have in common a resistance of the tissues to the action of insulin;^{112.144.145.146.147.148.149.150.151. and 152.} hyperinsulinemia may be present.^{153. and 154.} Insulin resistance is present in the case of lipoatrophy (lipodystrophy),^{155.156.157.158. and 159.} the Prader–Willi syndrome, ¹⁶⁰ leprechaunism, ¹⁵⁶ pineal hyperplasia, and the so-called ‘type A and B insulin resistance syndromes’ (Rabson–Mendenhall syndrome – OMIM 262190).^{144.145.161.162. and 163.} Obesity is often present.^{164. and 165.} Acanthosis nigricans has been found in 19%, 23%, and 4% of African American, Hispanic, and non-Hispanic white youth, respectively, who have a body mass index ≥98th percentile. ¹⁶⁶ Alterations in leptin levels have also been implicated.^{126. and 159.} A combination of acanthosis nigricans and insulin resistance is found in approximately 5% of hyperandrogenic females, often in association with polycystic ovaries.^{145.148.167. and 168.} Acanthosis nigricans localized to a plaque of scleredema has been reported in a diabetic patient. ¹⁶⁹ Its occurrence in pregnancy, not complicated by diabetes mellitus, is difficult to explain. ¹⁷⁰

Onset of the rare familial cases is in early childhood.^{171.172. and 173.} There may be accentuation of symptoms at puberty. This variant is inherited as an autosomal dominant trait, although there may be variable phenotypic expression. ¹⁷¹ The association of acanthosis nigricans with ectodermal dysplasia has been called Lelis’ syndrome (OMIM 608290). ¹⁷⁴ Other syndromes associated with acanthosis nigricans include the severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN syndrome – OMIM 187600), and Crouzon syndrome with acanthosis nigricans (OMIM 612247). They result from mutations in the fibroblast growth factor receptor 3 (FGFR3) gene on chromosome 4p16.3.^{175. and 176.} Sometimes familial acanthosis nigricans occurs with mutations in this gene, but there are no associated dysmorphic features. ¹⁷⁷ Rare cases, distributed along Blaschko’s lines, have variously been called nevoid acanthosis nigricans or epidermal nevus of the acanthosis nigricans type. ¹⁷⁸ In a series of four cases, the presence of typical acanthosis nigricans elsewhere in one case suggests the possibility that the unilateral component along Blaschko’s line may be an example of type 2 mosaicism. ¹⁷⁹ Of further interest is the finding that a large proportion of epidermal nevi are caused by mutations in the gene controlling activating fibroblast growth factor receptor 3 (FGFR3) in the epidermis, ¹⁸⁰ a finding also made in some cases of acanthosis nigricans (see above) and in some seborrheic keratoses. ¹⁸¹

Drugs that have been incriminated in the causation of acanthosis nigricans include somatotropin, ¹⁸² corticosteroids, ¹⁸³ niacin (nicotinic acid),^{184. and 185.} oral contraceptives, diethylstilbestrol (stilbestrol), the folic acid antagonist triazinate, ¹⁸⁶ gemfibrozil, amprenavir, ¹⁸⁷ palifermin, ¹⁸⁸ and methyltestosterone. ¹⁸⁹ Acanthosis nigricans-like lesions have developed in ichthyotic skin following the topical application of fusidic acid. ¹⁹⁰ Its occurrence at the site of repeated insulin injections is rare. ¹⁹¹

The molecular basis of acanthosis nigricans is becoming increasingly clearer; it appears to represent an abnormal epidermal proliferation in response to various factors.^{158. and 192.} Members of the tyrosine kinase receptor (TKR) superfamily, including epidermal growth factor receptor (EGFR), insulin growth factor receptor 1 (IGFR1), and fibroblast growth factor receptors (FGFRs), particularly FGFR3, are some of the factors involved. ¹⁹² They have both mitogenic and antiapoptotic effects on keratinocytes. In the case of the paraneoplastic group, the factor may be a tumor-produced peptide, such as epidermal growth factor (EGF) or transforming growth factor (TGF-α),^{138. and 193.} while in the group related to tissue insulin resistance, the tissue growth factors include insulin itself, which may be increased in some of these conditions.^{148.158. and 194.} Alterations in insulin growth factor receptors also occur. ¹⁹² The characteristic flexural localization remains an enigma. The rare keratins, 18 and 19, have been reported in basal keratinocytes in acanthosis nigricans. ¹⁹⁵

Confluent and reticulated papillomatosis (of Gougerot and Carteaud) is a rare form of papillomatosis characterized by the development of asymptomatic, small red to brown, slightly verrucous papules with a tendency to central confluence and a reticulate pattern peripherally.^{197.198.199. and 200.} Uncommonly the lesions are non-pigmented with a fine white scale. ²⁰¹ Pruritus has been reported. ²⁰² It involves particularly the upper part of the chest and the intermammary region and back; the neck, chin, upper parts of the arms, and the axillae may also be involved. It has a predilection for younger individuals, with the mean age of onset 15 years in one series of 39 patients. ²⁰³ Familial occurrence has been documented.^{204.205. and 206.}

It has been regarded as a variant of acanthosis nigricans, as a genodermatosis, as an unusual response to ultraviolet light²⁰⁷ or to Pityrosporum orbiculare infection,^{208.209.210. and 211.} and as a result of some unidentified endocrine imbalance.^{197. and 212.} In 2005, a previously unknown Dietzia strain (an actinomycete) was isolated from the skin scrapings of a case. ²¹³ This remains to be confirmed. Its coexistence with acanthosis nigricans has been reported. ²¹⁴

Response to calcipotriene (calcipotriol)^{215. and 216.} and retinoids^{217. and 218.} favors the theory that it is an abnormality of keratinization. On the other hand, response to various antibiotics, particularly minocycline, has also been reported.^{203.219.220.221.222.223.224.225.226. and 227.} Minocycline is now the treatment of choice. It has also been successfully treated with topical mupirocin ointment. ²²⁸

Acrokeratosis paraneoplastica (Bazex’s syndrome) is a rare paraneoplastic dermatosis associated with cancers which are usually supradiaphragmatic^{234.235.236.237.238. and 239.} in origin, although tumors at other sites have also been incriminated.^{240. and 241.} Sarcomas and lymphomas have also been implicated in the etiology.^{242. and 243.} It commences with violaceous erythema and psoriasiform scaling on the hands and feet with later extension to the ears and nose.244. ^{and 245.} Violaceous keratoderma of the hands and feet develops, and ill-defined psoriasiform lesions eventually form at other sites on the arms and legs. ²³⁵ Bullous lesions are rare. ²⁴⁶ These changes in the skin usually precede the onset of symptoms related to the associated cancer.^{247.248. and 249.} Removal of the neoplasm leads to a remission of the condition in 95% of cases and recurrence triggers a relapse. ²⁴³ This syndrome has been reported in association with acquired ichthyosis, another paraneoplastic disorder. ²⁵⁰ The pathogenesis of the condition is unknown, although transforming growth factor-α, produced by tumor cells, may play a role. ²⁵⁰

Erythroderma (exfoliative dermatitis) is a cutaneous reaction pattern that can occur in a wide variety of benign and malignant diseases.^{16.253.254. and 255.} It is uncommon, with an incidence of 1–2 per 100 000 of the population.^{253. and 256.} Clinically, it is characterized by erythema and exfoliation which involve all or most of the skin surface. ²⁵⁴ Distressing pruritus is often present. ²⁵³ Other clinical features include fever, malaise, keratoderma, alopecia, and a mild, generalized lymphadenopathy. Laboratory findings include blood eosinophilia, elevated levels of IgE and, in some, a polyclonal gammopathy.^{253. and 257.} The mean age at onset is approximately 60 years, although cases in infancy, often associated with ichthyosiform dermatoses (see p. 251) or immunodeficiency, have been reported.^{258.259.260.261. and 262.} Omenn’s syndrome (OMIM 603554) combines erythroderma and combined immunodeficiency. ²⁶³ There is a male predominance, particularly in the idiopathic group (see below).

Erythroderma is most often seen as an exacerbation of a pre-existing dermatological condition but it may also be drug related or be associated with cutaneous T-cell lymphoma or some other malignant tumors. Approximately 15% of cases are idiopathic (Table 19.2). In one retrospective study, 62.5% were related to an underlying dermatosis, 16% were due to drug reactions, and 12.5% to cutaneous T-cell lymphoma. ²⁶⁴ In a more recent study, there was a pre-existing dermatosis in 74.4%, 14.6% were idiopathic, and drugs and malignancy each accounted for 5.5% of cases. ²⁶⁵

A pre-existing dermatosis is present in more than 50% of cases. ²⁵⁶ Psoriasis is the most common of these.^{266.267. and 268.} Various factors, including the use of systemic steroid therapy or retinoids, have been incriminated in precipitating an erythrodermic crisis in psoriasis.266. ^{and 269.} Other underlying dermatoses include atopic dermatitis, seborrheic dermatitis, allergic contact dermatitis, photosensitivity syndromes, ²⁷⁰ pityriasis rubra pilaris and, rarely, stasis dermatitis, dermatophytosis, pemphigus foliaceus, and even bullous pemphigoid.^{265.271.272.273. and 274.} In some countries, there is a significant association with HIV infection; ²⁷⁵ in contrast, pulmonary tuberculosis is a very rare association. ²⁷⁶

Drug-induced cases may follow topical sensitization to neomycin, ethylenediamine, or clioquinol (Vioform). ²⁷⁷ Usually, erythroderma follows the ingestion of a drug such as phenytoin, penicillin, isoniazid, trimethoprim and sulfonamides, antimalarials, ²⁷⁸ thiazide diuretics, gold, chlorpromazine, calcium carbimide (cyanamide), ²⁷⁹ nifedipine, ²⁸⁰ roxatidine, ²⁸¹ escitalopram, ²⁸² imatinib, ²⁸³ or allopurinol.^{271. and 284.} There are a few case reports of erythroderma following the use of certain non-steroidal anti-inflammatory drugs such as sulindac, meclofenamate sodium, and phenylbutazone. ²⁸⁵ One case followed the use of beta-blocker eye drops (timolol maleate) ²⁸⁶ and, another, the use of hypericum (St John’s wort). ²⁸⁷ The use of recombinant cytokine therapy may precipitate erythroderma (see p. 521).^{288. and 289.} Drug-related cases usually have a rapid onset and relatively quick resolution over 2–6 weeks, in contrast to the more prolonged course of the idiopathic and lymphoma-related cases. ²⁷¹

Approximately 10% of cases are associated with a cutaneous T-cell lymphoma, in the form of the Sézary syndrome or erythrodermic mycosis fungoides. ²⁹⁰ The erythroderma may precede or occur concurrently with the diagnosis of the cancer.^{254. and 291.} Uncommonly, erythroderma is associated with an extracutaneous lymphoma or some other tumor.^{292. and 293.}

The idiopathic group, also known as ‘the red man syndrome’, is associated more often with keratoderma and dermatopathic lymphadenitis than the other groups. ²⁹⁴ It is also more likely to persist than some of the other types. Some cases may progress to mycosis fungoides after many years.^{294. and 295.}

The pathogenetic mechanisms involved in erythroderma are not known. The erythema results from vascular dilatation and proliferation and it has been suggested that interactions between lymphocytes and endothelium may play a role. ²⁹⁶ Circulating adhesion molecules are detectable in erythroderma but their values are not of differential diagnostic use. ²⁹⁷ A lymphocytopenia involving CD4⁺ T cells is sometimes found, probably a consequence of the sequestration of these cells in the skin. ²⁹⁸

Papuloerythroderma of Ofuji is a rare entity, first reported from Japan, featuring widespread erythematous, flat-topped papules with a striking sparing of body folds (the so-called ‘deck-chair’ sign).^{309.310.311. and 312.} Eosinophilia and lymphopenia are sometimes present. It occurs most commonly in elderly males. It is often associated with underlying lymphoma or cancer.^{313.314. and 315.} It has developed in patients with atopic erythroderma, ³¹⁶ HIV infection, ³¹⁷ hepatitis C infection, ³¹⁸ and in one with biliary sepsis. ³¹⁹ Aspirin and furosemide (frusemide) have also been suggested as precipitants.^{320. and 321.} Papuloerythroderma appears to be a distinct clinical entity, but its etiology is unknown. It has been suggested recently that it may be an early variant of mycosis fungoides.^{322.323.324.325.326. and 327.} Most cases run a chronic course. Several treatment regimens have been used with varying success. ³²⁸

Scalp dysesthesia is characterized by symptoms of burning, stinging, or itching, which is often associated with psychological stress. The author has received biopsies (all normal) from at least 10 cases, and coined the term ‘burning scalp syndrome’. Sometimes telogen effluvium may accompany this condition. Patients have benefited from low-dose antidepressants. ³²⁹

Cutaneous and soft tissue emphysema is rarely encountered in clinical dermatology. ³³⁰ It may follow head and neck surgery, including various dental treatments, trauma, cutaneous cryotherapy,^{331. and 332.} intermittent positive pressure ventilation, and lung disease associated with alveolar rupture. ³³⁰ It is usually confined to the cervicofacial region but involvement of the elbow region has been described. ³³³ Clinically it is most often confused with angioedema. ³³⁰ It resolves in a few days.