Before discussing the disorders of collagen in the skin, a brief account will be given of the composition, types, and metabolism of collagen.

Although the various disorders of connective tissue have been assigned to a particular chapter of this volume on the basis of which element is most affected, it must be emphasized that an alteration in one component of connective tissue may influence the synthesis, deposition, and structure of other components. ¹⁶ For instance, alterations in the elastic tissue and proteoglycan composition of the dermis may be found in some of the primary disorders of collagen.

The following categories will be considered, although it is acknowledged that the allocation of some of the disorders to a particular section is somewhat arbitrary:

It should be noted that diseases such as systemic lupus erythematosus and polyarteritis nodosa, which have been regarded in the past as ‘collagen diseases’, are not included in this chapter as they are not disorders of collagen in the strict sense. They are discussed with their appropriate tissue reaction pattern.

Morphea is the commonest form of scleroderma. Usually it presents on the trunk or extremities as one or several indurated plaques with an ivory center and a violaceous border (the ‘lilac ring’). Lesions confined to the breast have been reported. ²⁷ Irregular areas of hyperpigmentation or hypopigmentation may be present within the lesion. ²⁸ Other clinical forms include guttate, generalized, subcutaneous, keloidal, and bullous types.^{22.29.30. and 31.} Occasionally, more than one type is present in the same individual.

Guttate morphea consists of small, pale, slightly indurated lesions on the upper part of the trunk which may resemble lichen sclerosus et atrophicus. ³² In the rare generalized morphea there are large plaque-like lesions, often with vague symmetry, involving the trunk and extremities. ³³ Atrophy and fibrosis of the deep tissues may lead to crippling deformities. Ulceration and calcification may also develop in some of the lesions. ³²Disabling pansclerotic morphea is an aggressive variant of the generalized type and is of early onset.^{34. and 35.} Lesions may develop in adult life.^{36. and 37.} Lesions may extend circumferentially on an extremity leading to massive pansclerosis and atrophy.^{32. and 38.} Peripheral eosinophilia and mild non-progressive visceral changes are sometimes present in this variant. ³⁵ Cutaneous squamous cell carcinoma is a rare complication of long-standing lesions.^{39. and 40.}Subcutaneous (deep) morphea (morphea profunda) consists of one or more ill-defined, deep sclerotic plaques on the abdomen, sacral area, or extremities; its progression is slow and usually relentless.^{41.42.43.44. and 45.} Solitary lesions may not progress. ⁴⁶ Rarely, the lesions have a linear arrangement. ⁴⁷ Deep morphea has developed at the site of a previous vaccination. ⁴⁸Keloidal (nodular) morphea may be part of this spectrum, although the nodules may also be in the dermis, clinically resembling a keloid.^{22.49.50.51. and 52.} Nodules are a rare finding in systemic and linear scleroderma.^{53.54.55.56.57. and 58.}Bullous lesions may rarely complicate both localized and systemic scleroderma.^{29. and 59.} They may present initially as acquired unilateral edema. ⁶⁰ In some cases, bullous morphea represents the secondary appearance of bullous lichen sclerosus et atrophicus on a lesion of morphea.^{61. and 62.}Superficial morphea is a recently described variant that differs in its clinical and histological presentation from classic morphea. ⁶³ There is minimal to no induration of patches that are hypo- or hyperpigmented. ⁶³ Males are uncommonly affected. ⁶⁴ There are no associated symptoms. It has been suggested that superficial morphea is atrophoderma of Pasini–Pierini.^{65. and 66.}

Lesions of morphea may coexist with lichen sclerosus et atrophicus (see p. 316) ⁶⁷ and there are isolated reports of localized sclerodermatous lesions occurring in association with elastosis perforans serpiginosa (‘perforating morphea’), ⁶⁸ granuloma annulare, ⁶⁹ Hashimoto’s thyroiditis, ⁷⁰ multiple myeloma, ⁷¹ a herpes zoster scar, ⁷² xanthomatosis, ⁷³ a congenital hypopigmented plaque of unknown type, ⁷⁴ discoid lupus erythematosus, ⁷⁵ subacute lupus erythematosus, ⁷⁶ and the presence of the so-called ‘lupus anticoagulant’ (see p. 201). ⁷⁷ Generalized morphea has been reported in a patient with Felty’s syndrome. ⁷⁸ Bronchiolitis obliterans developed in another patient. ⁷⁹

The etiology of morphea is controversial. Antibodies and lymphoproliferative responses⁸⁰ to Borrelia burgdorferi, the cause of Lyme disease, have been detected in a significant number of patients with morphea in Austria and some other parts of Europe.^{81.82. and 83.} Spirochetes have been demonstrated in tissue sections in some cases using a modified silver stain, ⁸⁴ an avidin-biotin immunoperoxidase system^{85. and 86.} or techniques using the polymerase chain reaction (PCR).^{87. and 88.} Organisms have also been detected by focus-floating microscopy. ⁸⁹ However, these findings have not been confirmed in most other countries^{90.91. and 92.} and this leads to the view that in most instances there is no association between B. burgdorferi infection and morphea.^{93.94.95.96.97.98. and 99.} Another explanation is that certain genotypes of Borrelia found only in parts of Europe and Japan are responsible, as is the situation with lichen sclerosus et atrophicus. ¹⁰⁰ However, this explanation is not confirmed by a recent study from Germany which found no evidence of Borrelia by PCR in lesional skin of 33 patients with morphea. ¹⁰¹ It has also been suggested that a new spirochetal agent unrelated to B. burgdorferi may be the causative agent in some countries. ¹⁰² The increased collagen synthesis by fibroblasts in morphea may result from lymphokines released by the inflammatory cell infiltrate. ¹⁰³ Transforming growth factor β (TGF-β) is increased in lesional skin. ¹⁰⁴ Serum levels of procollagen type I carboxyterminal propeptide are increased in patients with localized and systemic scleroderma. ¹⁰⁵ Insulin-like growth factor (IGF)-I, which is a profibrotic compound, is increased in lesional and non-lesional skin of patients with morphea. ¹⁰⁶ Features of autoimmunity are also present in localized scleroderma, with a high percentage of patients having antinucleosome and antihistone antibodies.^{107.108.109. and 110.} Anti-agalactosyl antibodies are present in about 20% of patients, and they can be an indicator of disease severity. ¹¹¹ Antinuclear antibodies are uncommon except in the linear form; ²⁶ antibodies to single-stranded DNA are sometimes present, particularly in generalized morphea.^{112. and 113.} Rheumatoid factor is present in about 20% of cases.^{114. and 115.} Increased levels of circulating ICAM-1 are present; the levels correlate with the number of lesions and the area involved. ¹¹⁶ Whereas TGF-β is known as a profibrotic cytokine which may have a role in the pathogenesis of scleroderma, decorin reduces TGF-β levels and has antifibrotic properties. Decorin levels are increased in the early stages of scleroderma, particularly the systemic form. ¹¹⁷

Morphea has developed, in a few instances, at the site of previous radiotherapy (radiation port scleroderma).^{118.119.120.121. and 122.} There is a marked up-regulation of collagen synthesis following radiotherapy. ¹²³ Morphea has also been reported in a patient taking the semisynthetic ergot alkaloid bromocriptine, a drug that has been associated with pulmonary fibrosis. ¹²⁴ It has followed the use of balicatib, a cathepsin K inhibitor. ¹²⁵ It has also developed adjacent to the site of a leaking silicone-gel breast implant, ¹²⁶ as a tattoo reaction, ¹²⁷ and in areas of chronic venous insufficiency. ¹²⁸

Therapy using various PUVA-related protocols has been used with some success.^{129. and 130.} It has been used with oral retinoids. ¹³¹ UVA1 phototherapy is also an effective therapy.^{132. and 133.} Low-dose UVA1 phototherapy can also be given with calcipotriol ointment. ¹³⁴ Calcipotriol can also be used with corticosteroids. ¹³⁵ The effects of UVA are mainly restricted to the epidermis and dermis, restricting its use in deep forms of the disease. Photodynamic therapy has also been trialed for the treatment of morphea. ¹³⁶ Corticosteroids remain the initial treatment of choice for localized lesions. ¹³⁷ Pulsed high-dose corticosteroids, with low-dose methotrexate, have been given to treat severe cases of localized scleroderma.^{138. and 139.} The combination of systemic immunosuppression and PUVA therapy has been used to treat progressive diffuse morphea. ¹⁴⁰

Linear scleroderma is a variant of localized scleroderma in which sclerotic areas of skin develop in a linear pattern.^{141. and 142.} It is the second most common form of localized scleroderma after morphea. ¹⁴³ It may occur on the head, trunk, or extremities; on the limbs it may extend the full length, leading to contractures of the joints that it crosses. ¹⁴⁴ Muscle calcification is extremely rare. ¹⁴⁵ A familial case has been recorded. ¹⁴⁶

Linear scleroderma involving the frontoparietal area is referred to as en coup de sabre from its supposed likeness to the scar of a saber cut.^{147.148.149.150. and 151.} Central nervous system and ophthalmic involvement are rare. ¹⁵² This variant, which is more likely to be bilateral than the other forms of linear scleroderma,^{153. and 154.} may be associated with various degrees of facial hemiatrophy (Parry–Romberg syndrome).^{155.156. and 157.} A study from Mexico City in 2002 found that it was possible to distinguish scleroderma en coup de sabre (SCS) from progressive facial hemiatrophy (Parry–Romberg syndrome). ¹⁵⁸ Whereas cutaneous sclerosis was present in 8 of 13 patients with SCS, it was absent in all 9 patients with facial hemiatrophy. Cutaneous hyperpigmentation and alopecia were also more common in patients with SCS.^{158. and 159.} The more frequent clinical features in facial hemiatrophy were total hemifacial involvement and ocular changes. ¹⁵⁸ A retrospective study of 54 patients from the Mayo Clinic, reported in 2007, found 26 patients with SCS, 13 with Parry–Romberg syndrome, and 15 with both diseases. Bilateral disease was present in four patients. In addition to the association between this syndrome and SCS,^{160. and 161.} other associations of Parry–Romberg syndrome have included borreliosis, ¹⁶² anti-double-stranded DNA antibodies, ¹⁶³ and neurological involvement. ¹⁶⁰ Rarely, linear scleroderma has been observed overlying the sclerosing bone dystrophy known as melorheostosis,^{164. and 165.} or in association with hypertrichosis^{166. and 167.} or systemic lupus erythematosus. ¹⁶⁸ Osteolysis with subsequent fractures is a rare occurrence. ¹⁶⁹ In many cases the lesions appear to have followed Blaschko’s lines.^{58.170.171. and 172.} The simultaneous occurrence of linear scleroderma and homolateral segmental vitiligo has been reported. ¹⁷³

The onset of linear scleroderma is sometimes abrupt and occasionally follows trauma. ¹⁴¹ Its mean duration is longer than that of plaque-type morphea and it is less likely to resolve as completely. Disease activity is mirrored by the titer of antihistone autoantibodies, which decrease with disease resolution. ¹⁷⁴

Topical calcipotriol, combined with PUVA therapy, have been used to treat SCS. ¹⁵¹ UVA1 phototherapy can also be used for various sclerotic skin diseases. ¹⁷⁵

The diffuse form accounts for 20–40% of cases of systemic scleroderma. There is usually truncal and acral skin involvement of abrupt onset, associated with the appearance of Raynaud’s phenomenon and constitutional symptoms. ¹⁹⁷ Synovitis is common. Other features include esophageal hypomotility and strictures, rectal prolapse, sigmoid volvulus, nodular regenerative hyperplasia of the liver, primary biliary cirrhosis, idiopathic pulmonary fibrosis, pulmonary hypertension, Sjögren’s disease, thrombosis of major vessels,^{200. and 201.} intrauterine fetal death, ²⁰² and renal failure. ¹⁹⁷ Neurotropic ulceration secondary to peripheral neuropathy is a rare occurrence. ²⁰³ Left ventricular non-compaction, myopathy, and polyneuropathy were associated with cutaneous sclerosis in one case. ²⁰⁴

The limited variant of systemic scleroderma typically affects older women. Raynaud’s phenomenon often precedes the onset of cutaneous thickening, which is usually limited to the digits. ²⁰⁵ Hair loss and anhidrosis are present in affected areas. Facial telangiectasia and cutaneous calcification often develop and there is an increased incidence of late-onset pulmonary hypertension. Anticentromere antibodies are present in up to 70–80% of patients.^{206.207.208.209.210. and 211.}

Limited systemic scleroderma includes the condition referred to as the CREST syndrome,^{212. and 213.} which derives its name from the clinical features of calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia. ²¹⁴ Not all of these features are invariably present, leading to suggestions that this term should be dropped in favor of the term ‘limited systemic scleroderma’. ²⁰ Another variant combines Raynaud’s phenomenon, anticentromere antibodies, and digital necrosis without sclerodactyly. ²¹⁵ Glomerulonephritis is a rare association. ²¹⁶ A patient with localized systemic scleroderma developed abrupt thickening and induration of the skin following an episode of borreliosis. This component of her illness resolved after specific antibiotic therapy for the Borrelia infection. ²¹⁷ Limited systemic sclerosis has been reported in association with discoid lupus erythematosus in two Japanese patients with anticentromere antibodies. ²¹⁸

Pigmentary changes may be found in both the diffuse and the limited forms of systemic scleroderma. ²¹⁹ They may take the form of vitiligo-like areas with perifollicular and sometimes supravascular sparing, diffuse hyperpigmentation with accentuation in sun-exposed areas, or pigmentary changes in areas of sclerosis.^{220. and 221.} Reticulate hyperpigmentation is another variant. ²²² Livedo reticularis and livedoid vasculitis with ulcers occur uncommonly. ²⁰¹ Macrovascular involvement as detected by arteriography is not rare in patients with digital ulceration or gangrene. ²²³

Other clinical features of systemic scleroderma include a weak association with certain HLA antigen types, particularly DR5 and DR1, ²²⁴ and rare familial cases.^{225.226. and 227.} Antinuclear antibodies are present in almost all patients, usually with a speckled or nucleolar pattern.^{208.228.229. and 230.} Further characterization of these antibodies is possible now that specific nuclear macromolecules have been identified. ²⁰⁸ Autoantibodies to the Fc receptor are present in about 50% of cases, ²³¹ while antibodies to Scl-70 (antitopoisomerase) are present in approximately 30% of patients.^{197.232. and 233.} Patients with these ANA antibodies are more susceptible to vascular disease and pulmonary fibrosis. ²³⁴ A patient with systemic lupus erythematosus and topoisomerase I antibody has been reported. ²³⁵ A subset of patients with lupus-like features has anticardiolipin antibodies. ²³⁶ These antibodies may have a role in the genesis of vascular involvement related to systemic scleroderma. ²³⁷ Antibodies to the cytoplasmic antigen Ro/SSA are present in approximately one-third of cases. ²³⁸ Antineutrophil cytoplasmic antibodies of perinuclear type (p-ANCA) are present in a small number of patients. ²³⁹ Systemic angiitis has been reported as a rare complication of systemic sclerosis, but the p-ANCA status has been reported in only one of these cases.^{239. and 240.} The serum levels of various enzymes and substrates involved in the sclerotic process have been used as an indicator of disease activity. They include xylosyltransferase (involved in proteoglycan metabolism),^{241. and 242.} tissue inhibitors of metalloproteinase-2, ²⁴³ matrix metalloproteinase-9, ²⁴⁴ soluble vascular adhesion molecule 1 and E-selectin, ²⁴⁵ type I collagen degradation products, ²⁴⁶ and hyaluronan. ²⁴⁷

Collagenomas (connective tissue nevi of collagen type) are rare hamartomas of the skin in which there is an increase in dermal collagen. They usually present as asymptomatic, firm, flesh-colored plaques and nodules, 0.5–5.0 cm in diameter, on the trunk and upper part of the arms. ⁶⁶¹ The ear, ⁶⁶⁴ sole of the foot,^{665. and 666.} and vulva⁶⁶⁷ are rare sites of involvement. There may be several lesions⁶⁶⁸ or up to a hundred or more, with an onset in adolescence.^{669. and 670.} Rapidly growing (eruptive) collagenomas have been reported in the multiple endocrine neoplasia type I syndrome, ⁶⁷¹ and in pregnancy. ⁶⁷² Eruptive collagenomas have also been reported as the only lesion.^{673. and 674.} Uncommonly, they occur in a zosteriform or linear distribution.^{675.676.677.678.679.680. and 681.} A family history is sometimes present (familial cutaneous collagenoma) and in these cases there is autosomal dominant inheritance.^{669.682.683.684. and 685.} Familial cutaneous collagenomas (OMIM 115250) result from a mutation in the LEMD3 gene, as seen in the Buschke–Ollendorff syndrome.^{686. and 687.}

Associated clinical features include a cardiomyopathy, ⁶⁶¹ Down syndrome,^{688.689. and 690.} and occult spinal dysraphism. ⁶⁹¹ Uncommonly, the connective tissue nevi associated with the Buschke–Ollendorff syndrome (see p. 334) are of collagenous composition rather than of the usual elastic tissue type.^{692.693.694. and 695.} A connective tissue nevus of collagen type has been reported in association with pseudo-Hurler polydystrophy (mucolipidosis III), ⁶⁹⁶ and in Proteus syndrome, in which the nevi are often acral, sometimes of the plantar cerebriform type.^{697.698. and 699.} Plantar collagenomas can occur in the absence of the Proteus syndrome. ⁷⁰⁰

Solitary collagenomas are sometimes quite large, as seen with the cerebriform or ‘paving stone’ variants on the sole of the foot.^{701. and 702.} Sometimes a connective tissue nevus is associated with cutis verticis gyrata, a descriptive term for a condition of the scalp in which deep furrows and convolutions are present. The folds of skin may, however, have normal morphology.^{703. and 704.} Other pathological associations of cutis verticis gyrata include lymphedema, ⁷⁰⁵ mental retardation, ⁷⁰⁶ adipocyte proliferation, acromegaly, ⁷⁰⁷ misuse of anabolic substances, ⁷⁰⁸ myxedema, Noonan syndrome,^{706. and 709.} tumors, and the insulin resistance syndrome. ⁷¹⁰ Cutis gyrata, usually on the scalp, can be seen in the Beare–Stevenson syndrome (OMIM 123790) characterized by mutations in the transmembrane region of fibroblast growth factor receptor (FGFR)-2 located at chromosome 10q26. Acanthosis nigricans, skin tags, and anogenital anomalies are other features of this syndrome. ⁷¹¹ There is a reduction in expression of tuberin in connective tissue nevi associated with the tuberous sclerosis complex. ⁷¹²

Collagenomas must be distinguished from sclerotic fibromas (see p. 815) which present as tumor-like nodules. They have a characteristic histological appearance with dense collagen bundles, often in a storiform arrangement. Athlete’s nodules are related to, but different from, collagenomas. One such example is the dermal nodule found in the sacrococcygeal region of bicycle riders. ⁷¹³

The shagreen patch is a distinct clinical variant of collagenoma, found exclusively in those with tuberous sclerosis. It consists of a slightly elevated, flesh-colored plaque of variable size, usually on the lower part of the trunk. ⁷¹⁹ It has the appearance of untanned leather. Smaller ‘goose flesh’ papules may form as satellite lesions.