45.1 CHAPTER 45 Disorders of Connective Tissue N.P. Burrows1 & C.R. Lovell2 1Department of Dermatology, Addenbrooke’s Hospital, Cambridge, UK 2Kinghorn Dermatology Unit, Royal United Hospital, Bath, UK Cutaneous atrophy, 45.2 Osteogenesis imperfecta (OI), 45.40 Keloids and hypertrophic scars, 45.54 Generalized cutaneous atrophy, 45.2 Pachydermoperiostosis, 45.41 Premature ageing syndromes, 45.56 Localized cutaneous atrophy, 45.6 Relapsing polychondritis, 45.42 Pangeria, 45.57 Poikiloderma, 45.13 Fibromatoses, 45.44 Progeria, 45.58 Disorders of elastic fi bres, 45.14 Palmar fi bromatosis, 45.45 Acrogeria, 45.59 Lax skin, 45.14 Camptodactyly, 45.46 Laboratory studies, 45.60 Generalized cutis laxa, 45.14 Plantar fi bromatosis, 45.47 Other associated conditions, 45.60 Anetoderma, 45.17 Penile fi bromatosis, 45.47 Perforating dermatoses, 45.63 Other localized forms of elastolysis, 45.19 Knuckle pads, 45.48 Acquired reactive perforating dermatosis, 45.63 Pseudoxanthoma elasticum, 45.21 Pachydermodactyly, 45.48 Perforating disease due to exogenous agents, 45.64 Acquired PXE-like syndromes, 45.24 Juvenile fi bromatoses, 45.49 Reactive perforating collagenosis, 45.64 Linear focal elastosis, 45.25 Other benign fi brous cutaneous nodules, 45.50 Verrucous perforating collagenoma, 45.65 Actinic elastosis, 45.26 Infantile stiff-skin syndromes, 45.50 Elastosis perforans serpiginosa, 45.65 Digital papular calcifi c elastosis, 45.28 Systemic hyalinosis, 45.50 Miscellaneous disorders, 45.66 Actinic granuloma, 45.28 Winchester’s syndrome, 45.50 Colloid milium, 45.66 Elastofi broma, 45.29 Congenital fascial dystrophy, 45.50 White fi brous papulosis of the neck, 45.67 Elastoderma, 45.29 Restrictive dermopathy, 45.51 Papular elastorrhexis, 45.68 Marfan’s syndrome (MFS), 45.30 Other causes of diffuse fi brosis, 45.51 Progressive osseous heteroplasia, 45.68 Disorders of collagen, 45.31 Environmental and drug-induced scleroderma, 45.51 Fascial hernias of the legs, 45.68 Ehlers–Danlos syndrome, 45.31 Nephrogenic systemic fi brosis, 45.53 Constricting bands of the extremities, 45.69 Occipital horn syndrome, 45.39 GEMSS syndrome, 45.53 Heberden’s and Bouchard’s nodes, 45.70 Prolidase defi ciency, 45.39 POEMS syndrome, 45.54 Introduction temic sclerosis and dermatomyositis. Both genetic and acquired The connective tissue of the normal skin is discussed in Chapter 3. factors (including the possibility of infective agents) may play Diseases that predominantly affect the cutaneous connective some part in producing these conditions, which are fully dis- tissue (collagen, elastin and ground substance) can be divided into cussed in Chapter 51. three main groups [1,2]: The attempt to classify the pathological changes according to 1 Genetic abnormalities that affect connective tissue formation whether ground substance, collagen, elastin or cellular compo- or metabolism. Examples include Ehlers–Danlos syndrome nents are mainly or wholly involved is not always easy, and may (EDS) (which affects collagen), pseudoxanthoma elasticum have been inaccurate in the past. (PXE) (elastic tissue) and the mucopolysaccharidoses (ground In this chapter, some of the genetic and acquired diseases that substance). affect mainly collagen or elastin are discussed. Disorders of the 2 Acquired metabolic or degenerative disorders, such as scurvy ground substance are discussed elsewhere (see myxoedema, cuta- and solar elastosis, which are liable to affect people with no neous mucinosis and mucopolysaccharidoses). genetic defect if the environmental cause is present. There are, in addition, many other disorders, including 3 Infl ammatory ‘collagen vascular’ or ‘connective tissue’ diseases, developmental defects, reactive or scarring conditions and which damage connective tissue as a result of complex immu- benign or malignant neoplasms, that may involve the connective nological reactions involving autogenous antigens. This group tissue. includes systemic lupus erythematosus, rheumatic fever, sys- References 1 Christiano AM, Uitto J. Molecular pathology of the elastic fi bers. J Invest Dermatol 1994; 103: S53–7. Rook’s Textbook of Dermatology, 8th edition. Edited by DA Burns, 2 Prockop DJ, Kivirikko KI. Collagens: molecular biology, diseases, and potentials SM Breathnach, NH Cox and CEM Griffi ths. © 2010 Blackwell Publishing Ltd. for therapy. Annu Rev Biochem 1995; 64: 403–34. 45.2 Chapter 45: Disorders of Connective Tissue Cutaneous atrophy Wrinkles can be classifi ed into three morphological types [6]: 1 Crinkles. This is a very fi ne wrinkling which occurs in aged Atrophy of the skin is a term that is applied to the clinical changes skin, even in areas protected from sunlight. These fi ne wrinkles produced by a decrease in the dermal connective tissue. It is char- disappear when the skin is slightly stretched. They are caused acterized by thinning and loss of elasticity. The skin usually by deterioration of elastin, especially the vertical subepidermal appears smooth and fi nely wrinkled, and it feels soft and dry. fi ne elastic fi bres which keep the epidermis in tight apposition Veins or other subcutaneous structures may be unduly conspicu- to the dermis [7,8]. Ultrastructural studies have shown that ous. There is often associated loss of hair follicles, and telangiec- even in normal people the elastic fi bres begin to deteriorate from tasia may also be present, due to the loss of connective tissue the age of 30 years onwards, regardless of the amount of sun support of the capillaries. There may or may not be an associated exposure, although sunlight undoubtedly increases the damage atrophy of the epidermis. [9]. Crinkles are seen in a marked form in mid-dermal elastoly- Atrophy of the skin occurs in varying degree in a large number sis (see below). of skin conditions, and the underlying histological changes are 2 Glyphic wrinkles. These creases are an accentuation of the also variable, because the several components of the connective normal skin markings. They occur on skin which has been tissue may be involved to a different degree. Atrophy that includes prematurely aged by elastotic degeneration caused by sunlight, subcutaneous tissue or even deeper structures is referred to as for example on the sides and back of the neck (see actinic panatrophy. elastosis). The main causes of cutaneous atrophy are as follows. 3 Linear furrows. These are long, straight or slightly curved 1 Generalized cutaneous thinning: grooves that are usually seen on the faces of elderly people. (a) ageing They include the horizontal frown lines along the forehead, the (b) rheumatoid disease ‘crows’ feet’ radiating from the lateral canthus of the eye and (c) glucocorticoids (exogenous or endogenous) the creases from the nose to the corners of the mouth. 2 Poikiloderma The facial skin has a remarkably complex and dense intrader- 3 Atrophic scars (striae) mal elastic tissue mesh. This sheath of elastin is unique to the face, 4 Anetoderma (see p. 45.17) not being found in such complexity elsewhere. In youth, the linear 5 Chronic atrophic acrodermatitis (borreliosis) furrows caused by facial muscle contraction disappear due to 6 Follicular atrophoderma elastic recoil, but in older people they become permanent. There 7 Vermiculate atrophoderma is some controversy regarding the histology of these linear furrows. 8 Atrophoderma of Pasini and Pierini (probably morphoea) Several groups have claimed that the linear wrinkles cannot be 9 Atrophic naevi distinguished by light or electron microscopy from the surround- 10 Panatrophy: ing skin, and Kligman et al. [6] claim the furrow is merely a con- (a) local panatrophy fi gurational change, like the crease in an old glove. Tsuji et al. [8], (b) facial hemiatrophy. however, claim that the upper dermis in the furrow shows less elastotic change than the surrounding skin. Other authors [9,10], on the other hand, claim that the trabeculae of the retinacula cutis Generalized cutaneous atrophy (which anchors the dermis to the underlying fascia) are broader The skin becomes increasingly thin and atrophic in elderly people, and much shorter underneath the wrinkles than in the surround- and both the epidermis and the dermis are affected [1] (see Chapter ing skin. The hypertrophy of these subcutaneous septa is probably 8 for further details). As a result, the aged skin becomes fragile, related to repetitive mechanical stimuli generated by the facial translucent, lax and wrinkled, with a tendency to easy bruising. muscles over the years. Intrinsic ageing of skin may be compounded by environmental Wrinkles are a characteristic feature of photodamaged skin factors, such as chronic sun exposure and smoking. Dermal thick- (Chapter 29). Cigarette smoking is also a potent, independent ness is considerably decreased in the elderly [1]. Wound healing cause of wrinkling. The so-called ‘cigarette face’ is characterized is delayed in the elderly because of a decrease in the numbers and by pale, grey, wrinkled skin with rather gaunt features, so that synthetic capability of fi broblasts [2]. With increasing age, both heavy smokers can often be recognized from their facial appear- keratinocytes and fi broblasts show a decreased response to various ance alone. Heavy smokers are fi ve times more likely to be wrin- growth factors [3]. kled than non-smokers of the same age, and cigarette smoking probably has at least as much effect on facial wrinkles as sun Ageing and wrinkles exposure [11,12]. The pathogenesis of these deleterious effects Wrinkles may be defi ned as creases or furrows in the skin surface. on facial skin is unknown, but causative factors might include They are generally distinguished from the lax pendulous folds of ischaemia due to the vasoconstriction induced by nicotine or skin which occur in conditions such as PXE and cutis laxa, but the sympathetic nerve stimulation, decreased tissue oxygenation, distinction is somewhat arbitrary, because loss of dermal elastic increased tissue carboxyhaemoglobin, increased platelet aggrega- tissue is common to all these conditions. Deepening of the furrows tion, decreased prostacyclin formation and reduced collagen occurs with advancing age [4]. Histologically, there is epidermal deposition [12].