Volume 70 August 1977
567
Section of Dermatology President M Feiwel FRCP
Meeting 21 October 1976
Cases Pseudoxanthoma Elasticum and Acrosclerosis J D Wilkinson MRCP (for R P R Dawber MRCP and T J Ryan FRCP) (Department oJ Dermatology, Slade Hospital, OxJord, OX3 7JH)
BH, woman aged 35 History: Bilateral Raynaud's phenomenon present for 5 years. Recurrent infarction and infection of finger tips had led to necrosis and resorption of the distal phalanges of both index fingers. General health was good. There were no gastrointestinal symptoms or shortness of breath. Referral was due to increasing stiffness of fingers and vasospasm that now occurred in both summer
Fig 1 Hands showing typicalftatures oj acroscierosis
and winter. The patient had not regarded any of her other skin changes as abnormal. She was not on any medication but smoked fifteen cigarettes a day. Family history. There was a family history of Raynaud's phenomenon and lax joints. Relatives were examined but did not reveal any evidence of pseudoxanthoma elasticum, systemic sclerosis or any other 'collagen' disease. On examination: Typical changes of acrosclerosis were present on the hands (Fig 1) with spindle shaped fingers showing scarring, pulp atrophy and Raynaud's phenomenon. There were dilated nailfold capillaries and the skin of the hands was stiff and immobile. 'Matt-like' telangiectasia was present on the face, hands, neck and lips.
Proc. roy. Soc. Med. Volume 70 August 1977
568
Fig
2
X-ray of hands showing pulp atrophy of soft tissue
No evidence
and terminal
phalangeal resorption.
calcification
Mild but characteristic changes of pseudoxanthoma elasticum were present in the axillx, groins, antecubital fosse and around the neck. The affected skin was soft with a reticulate pattern of yellowish papules. In the axillx the skin appeared lax and wrinkled. General examination was normal. Blood pressure was 140/85 mm Hg. The patient was shortsighted but no other abnormality was found on
ophthalmic investigation.
Investigations: Routine investigations were normal and did not reveal any evidence of systemic involvement. X-ray of hands (Fig 2) showed terminal phalangeal resorption of both index fingers but no soft tissue calcification. Specific investigations did not reveal any abnormality in renal, gastrointestinal or cardiovascular function. Lung function tests showed only marginally decreased carbon monoxide perfusion. Antinuclear factor was negative.
Fig 3A, scanning electron microscopy oj normal dermal collagen bundles. x 5000. B, disrupted and tangledfibres seen in pseudoxanthoma elasticum. x 5000
Section of Dermatology
Histology was consistent with pseudoxanthoma elasticum showing a relatively acellular dermis with indistinct bands of collagen of variable thickness. The elastic fibres were fragmented and curled. Occasional calcified particles were seen. Discussion
The coexistence of any two rare disorders may, of course, be entirely fortuitous. Pai & Zak (1970), however, reported a similar case of pseudoxanthoma elasticum, systemic sclerosis and perforating elastomas. Pseudoxanthoma elasticum has also been reported in association with Paget's disease and Marfan's syndrome (Rook et al. 1972). Pope (1974) has recently subdivided pseudoxanthoma elasticum on genetic and clinical grounds. The recessive type 2 pseudoxanthoma elasticum is a rare generalized cutaneous form without systemic involvement while dominant type 1, recessive type 1 and dominant type 2 varieties differ in the severity of their cardiovascular and ophthalmic complications. Our patient would appear to be the usual sporadic or recessive type 1 case. She does not yet appear to have developed any of the systemic complications of either pseudoxanthoma elasticum or acrosclerosis. Gastrointestinal bleeding is, however, the most common complication in this group. Considerable attention has been given to the structure of elastic fibres in pseudoxanthoma elasticum but scanning electron microscopy (Dawber & Shuster 1971) suggests that the collagen bundles in the mid and lower dermis are also disrupted (Fig 3A, B). Instead of the well ordered wavy collagen bundles of normal skin, the middle and lower dermis in pseudoxanthoma elasticum shows an irregular network of tangled, curled and branching fibres. This change may well be the morphological result of biochemical abnormalities in skin collagen. The association of pseudoxanthoma elasticum with other connective tissue disorders may therefore be due to an underlying defect in collagen
569
Table 1 Types of collagen (Martin et al. 1975)
Collagen type
Chain composition al (I)2a2
II III
al z1
IV
(11)3 (111)3 a, (IV)3
Site Skin, bone, tendon blood vessel
Cartilage
Skin, blood vessel,
gut Basement membrane
the genetics of pseudoxanthoma elasticum could be relevant. Four genetically distinct collagen types are recognized. (Martin et al. 1975: see Table 1). Type I and III collagens are especially important constituents of skin blood vessel and gut, the former also comprising bone collagen. Specific collagenous abnormalities have recently been described in four of the seven Ehlers Danlos variants (Pinnel et al. 1972, Lichtenstein et al. 1973, Pope et al. 1975, Di Ferrante et al. 1975) and the lethal autosomal recessive form of osteogenesis imperfecta (Penttinen et al. 1975). Ehlers Danlos IV specifically lacks type III collagen which results in abnormally fragile skin, arteries and gut (Figs 1 & 2). Immunofluorescent techniques have shown
cotanno typ II petd.(epoue]omPp
a
biosynthesis. REFERENCES Dawber R P R & Shuster S
(1971) British Journal of Dermatology 84, 130 Pai S H & Zak F G (1970) Dermatologica 140, 54 Pope F M
(1974) Archives of Dermatology 110, 209
1977 b n r).
Dr F M Pope (Clinical Research Centre, Division of Cell Pathology, Watford Road, Harrow): The observation of Dawber & Shuster (1971) of reduced collagen fibres in the mid and lower dermis of pseudoxanthoma elasticum patients may have important implications. Recent advances in collagen biochemistry and observations upon
Fig, I From left to right: skin peptides from Ehlers Danlos IV patient; purified al (III) CB8 peptide; skin peptides from normal patient. The Ehlers Danlos I Vpatient contains no type IIIlpeptide. (Reproducedfjrom Pope et al. 1977, by kind permission)
Proc. roy. Soc. Med. Volume 70 August 1977
570
TYPE I
30,000
20,000 0L
_ A
10,000 -1 0,000
10
30 20 FRACTION NUMBER
40
50
Fig 2 Procollagen peaks isolated by diethylaminoethyl chromatographyfrom cultured fibroblasts. Note absent type Ill procollagen peak in Ehlers Danlos IVfibroblasts. (Reproducedfrom Pope et al. 1975, by kind permission) type III collagen to be localized subintimally and type I collagen within the media of arteries (Gay et al. 1975). Four distinct genetic types of pseudoxanthoma elasticum are recognized, two autosomal dominant and two recessive (Pope 1974a, b), which vary in clinical severity. Some have severe vascular complications and others show loose-jointedness, hyperextensible skin and blue sclerm, reminiscent of other inherited defects of connective tissue. Type I or III collagen abnormalities in such patients are certainly possible, and different forms of pseudoxanthoma elasticum may show different biochemical differences. The observations of Dawber & Shuster suggest that such studies may prove fruitful. REFERENCES Dawber R P R & Shuster S (1971) British Journal of Dermatology 84, 130 Di Ferrante N, Leachman R D, Angelini P, Dunnell P V, Francis G & Almazan A (1975) Connective Tissue Research 3, 49-53 Gay S, Balleisin L, Remberger K, Feitzek P P, Adelmann B C & Kuhn K (1975) Klinische Wochenschrift 53, 599-902 Lichtenstein J R, Martin G R, Kuhn L D, Byers B H & McKusick V A (1973) Science 182, 298-299 Martin G R, Lichtenstein J R, McKusick V A, Penttinen R, Rowe D W, Pope F M & Sussman M D (1975) Birth Defects Series 11, No. 6, 11-13 Penfttnen R P, Lichtenstein J R, Martin G R & McKusick V A (1975) Proceedings of the National Academy of Sciences of the USA 72, 586-589 Pinnel S R, Krane S M, Kenzora J C & Glimcher M J (1972) New England Journal of Medicine 286, 913-920 Pope F M (1 974a) Journal of Medical Genetics 11, 152-157 (1974b) Archives of Dermatology 100, 209-211 Pope F M, Martin G R, Lichtenstein J R, Penttinen R, Gesson B, Rowe D W & McKusick V A (1975) Proceedings of the National Academy of Sciences of the
USA 72, 1314-1317
Pope F M, Martin G R & McKusick V A (1977) Journal of Medical Genetics 14, 200-204 Rook A, Wilkinson D S & Ebling F J G (1972) Textbook of Dermatology. 2nd ed. Blackwell, Oxford; p 1486
The following cases were also presented: Atrophoderma of Pasini and Pierini Dr 0 S Manocha (for Dr H W Chadfield) (The Royal Hospital Wolverhampton) Peniciliamine Induced Bullous Eruption Dr R A Marsden, Dr R P R Dawber and Dr T J Ryan (Slade Hospital, Oxford) Mycosis Fungoides and Hodgkin's Disease Dr J D Wilkinson (for Dr R E Bowers and Dr T J Ryan) (Slade Hospital, Oxford) Extramedullary Plasmacytoma Dr C D Calnan (St John's Hospitalfor Diseases of the Skin, London WC2H 7BJ) Juvenile Pemphigoid Dr R A Marsden and Dr T J Ryan (Slade Hospital, Oxford) Cutis Marmorata Telangiectatica Congenita Dr T J Ryan (Slade Hospital, Oxford)
567
Section of Dermatology President M Feiwel FRCP
Meeting 21 October 1976
Cases Pseudoxanthoma Elasticum and Acrosclerosis J D Wilkinson MRCP (for R P R Dawber MRCP and T J Ryan FRCP) (Department oJ Dermatology, Slade Hospital, OxJord, OX3 7JH)
BH, woman aged 35 History: Bilateral Raynaud's phenomenon present for 5 years. Recurrent infarction and infection of finger tips had led to necrosis and resorption of the distal phalanges of both index fingers. General health was good. There were no gastrointestinal symptoms or shortness of breath. Referral was due to increasing stiffness of fingers and vasospasm that now occurred in both summer
Fig 1 Hands showing typicalftatures oj acroscierosis
and winter. The patient had not regarded any of her other skin changes as abnormal. She was not on any medication but smoked fifteen cigarettes a day. Family history. There was a family history of Raynaud's phenomenon and lax joints. Relatives were examined but did not reveal any evidence of pseudoxanthoma elasticum, systemic sclerosis or any other 'collagen' disease. On examination: Typical changes of acrosclerosis were present on the hands (Fig 1) with spindle shaped fingers showing scarring, pulp atrophy and Raynaud's phenomenon. There were dilated nailfold capillaries and the skin of the hands was stiff and immobile. 'Matt-like' telangiectasia was present on the face, hands, neck and lips.
Proc. roy. Soc. Med. Volume 70 August 1977
568
Fig
2
X-ray of hands showing pulp atrophy of soft tissue
No evidence
and terminal
phalangeal resorption.
calcification
Mild but characteristic changes of pseudoxanthoma elasticum were present in the axillx, groins, antecubital fosse and around the neck. The affected skin was soft with a reticulate pattern of yellowish papules. In the axillx the skin appeared lax and wrinkled. General examination was normal. Blood pressure was 140/85 mm Hg. The patient was shortsighted but no other abnormality was found on
ophthalmic investigation.
Investigations: Routine investigations were normal and did not reveal any evidence of systemic involvement. X-ray of hands (Fig 2) showed terminal phalangeal resorption of both index fingers but no soft tissue calcification. Specific investigations did not reveal any abnormality in renal, gastrointestinal or cardiovascular function. Lung function tests showed only marginally decreased carbon monoxide perfusion. Antinuclear factor was negative.
Fig 3A, scanning electron microscopy oj normal dermal collagen bundles. x 5000. B, disrupted and tangledfibres seen in pseudoxanthoma elasticum. x 5000
Section of Dermatology
Histology was consistent with pseudoxanthoma elasticum showing a relatively acellular dermis with indistinct bands of collagen of variable thickness. The elastic fibres were fragmented and curled. Occasional calcified particles were seen. Discussion
The coexistence of any two rare disorders may, of course, be entirely fortuitous. Pai & Zak (1970), however, reported a similar case of pseudoxanthoma elasticum, systemic sclerosis and perforating elastomas. Pseudoxanthoma elasticum has also been reported in association with Paget's disease and Marfan's syndrome (Rook et al. 1972). Pope (1974) has recently subdivided pseudoxanthoma elasticum on genetic and clinical grounds. The recessive type 2 pseudoxanthoma elasticum is a rare generalized cutaneous form without systemic involvement while dominant type 1, recessive type 1 and dominant type 2 varieties differ in the severity of their cardiovascular and ophthalmic complications. Our patient would appear to be the usual sporadic or recessive type 1 case. She does not yet appear to have developed any of the systemic complications of either pseudoxanthoma elasticum or acrosclerosis. Gastrointestinal bleeding is, however, the most common complication in this group. Considerable attention has been given to the structure of elastic fibres in pseudoxanthoma elasticum but scanning electron microscopy (Dawber & Shuster 1971) suggests that the collagen bundles in the mid and lower dermis are also disrupted (Fig 3A, B). Instead of the well ordered wavy collagen bundles of normal skin, the middle and lower dermis in pseudoxanthoma elasticum shows an irregular network of tangled, curled and branching fibres. This change may well be the morphological result of biochemical abnormalities in skin collagen. The association of pseudoxanthoma elasticum with other connective tissue disorders may therefore be due to an underlying defect in collagen
569
Table 1 Types of collagen (Martin et al. 1975)
Collagen type
Chain composition al (I)2a2
II III
al z1
IV
(11)3 (111)3 a, (IV)3
Site Skin, bone, tendon blood vessel
Cartilage
Skin, blood vessel,
gut Basement membrane
the genetics of pseudoxanthoma elasticum could be relevant. Four genetically distinct collagen types are recognized. (Martin et al. 1975: see Table 1). Type I and III collagens are especially important constituents of skin blood vessel and gut, the former also comprising bone collagen. Specific collagenous abnormalities have recently been described in four of the seven Ehlers Danlos variants (Pinnel et al. 1972, Lichtenstein et al. 1973, Pope et al. 1975, Di Ferrante et al. 1975) and the lethal autosomal recessive form of osteogenesis imperfecta (Penttinen et al. 1975). Ehlers Danlos IV specifically lacks type III collagen which results in abnormally fragile skin, arteries and gut (Figs 1 & 2). Immunofluorescent techniques have shown
cotanno typ II petd.(epoue]omPp
a
biosynthesis. REFERENCES Dawber R P R & Shuster S
(1971) British Journal of Dermatology 84, 130 Pai S H & Zak F G (1970) Dermatologica 140, 54 Pope F M
(1974) Archives of Dermatology 110, 209
1977 b n r).
Dr F M Pope (Clinical Research Centre, Division of Cell Pathology, Watford Road, Harrow): The observation of Dawber & Shuster (1971) of reduced collagen fibres in the mid and lower dermis of pseudoxanthoma elasticum patients may have important implications. Recent advances in collagen biochemistry and observations upon
Fig, I From left to right: skin peptides from Ehlers Danlos IV patient; purified al (III) CB8 peptide; skin peptides from normal patient. The Ehlers Danlos I Vpatient contains no type IIIlpeptide. (Reproducedfjrom Pope et al. 1977, by kind permission)
Proc. roy. Soc. Med. Volume 70 August 1977
570
TYPE I
30,000
20,000 0L
_ A
10,000 -1 0,000
10
30 20 FRACTION NUMBER
40
50
Fig 2 Procollagen peaks isolated by diethylaminoethyl chromatographyfrom cultured fibroblasts. Note absent type Ill procollagen peak in Ehlers Danlos IVfibroblasts. (Reproducedfrom Pope et al. 1975, by kind permission) type III collagen to be localized subintimally and type I collagen within the media of arteries (Gay et al. 1975). Four distinct genetic types of pseudoxanthoma elasticum are recognized, two autosomal dominant and two recessive (Pope 1974a, b), which vary in clinical severity. Some have severe vascular complications and others show loose-jointedness, hyperextensible skin and blue sclerm, reminiscent of other inherited defects of connective tissue. Type I or III collagen abnormalities in such patients are certainly possible, and different forms of pseudoxanthoma elasticum may show different biochemical differences. The observations of Dawber & Shuster suggest that such studies may prove fruitful. REFERENCES Dawber R P R & Shuster S (1971) British Journal of Dermatology 84, 130 Di Ferrante N, Leachman R D, Angelini P, Dunnell P V, Francis G & Almazan A (1975) Connective Tissue Research 3, 49-53 Gay S, Balleisin L, Remberger K, Feitzek P P, Adelmann B C & Kuhn K (1975) Klinische Wochenschrift 53, 599-902 Lichtenstein J R, Martin G R, Kuhn L D, Byers B H & McKusick V A (1973) Science 182, 298-299 Martin G R, Lichtenstein J R, McKusick V A, Penttinen R, Rowe D W, Pope F M & Sussman M D (1975) Birth Defects Series 11, No. 6, 11-13 Penfttnen R P, Lichtenstein J R, Martin G R & McKusick V A (1975) Proceedings of the National Academy of Sciences of the USA 72, 586-589 Pinnel S R, Krane S M, Kenzora J C & Glimcher M J (1972) New England Journal of Medicine 286, 913-920 Pope F M (1 974a) Journal of Medical Genetics 11, 152-157 (1974b) Archives of Dermatology 100, 209-211 Pope F M, Martin G R, Lichtenstein J R, Penttinen R, Gesson B, Rowe D W & McKusick V A (1975) Proceedings of the National Academy of Sciences of the
USA 72, 1314-1317
Pope F M, Martin G R & McKusick V A (1977) Journal of Medical Genetics 14, 200-204 Rook A, Wilkinson D S & Ebling F J G (1972) Textbook of Dermatology. 2nd ed. Blackwell, Oxford; p 1486
The following cases were also presented: Atrophoderma of Pasini and Pierini Dr 0 S Manocha (for Dr H W Chadfield) (The Royal Hospital Wolverhampton) Peniciliamine Induced Bullous Eruption Dr R A Marsden, Dr R P R Dawber and Dr T J Ryan (Slade Hospital, Oxford) Mycosis Fungoides and Hodgkin's Disease Dr J D Wilkinson (for Dr R E Bowers and Dr T J Ryan) (Slade Hospital, Oxford) Extramedullary Plasmacytoma Dr C D Calnan (St John's Hospitalfor Diseases of the Skin, London WC2H 7BJ) Juvenile Pemphigoid Dr R A Marsden and Dr T J Ryan (Slade Hospital, Oxford) Cutis Marmorata Telangiectatica Congenita Dr T J Ryan (Slade Hospital, Oxford)
