CASE REPORT
DOI 10.1111/j.1365-2133.2006.07473.x
Poikiloderma, tendon contracture and pulmonary fibrosis: a new autosomal dominant syndrome? N.P. Khumalo, K. Pillay,* P. Beighton, H. Wainwright,* B. Walker,à N. Saxe, B.M. Mayosi§ and E.D. Batemanà Divisions of Dermatology, §Cardiology and àPulmonology, Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa Divisions of *Anatomical Pathology and Human Genetics, Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
Summary Correspondence N.P. Khumalo. E-mail:
[email protected]
Accepted for publication 17 April 2006
Key words fibrosis, genetic, poikiloderma, pulmonary, skin, tendon
Conflicts of interest None declared.
Members of two generations of a South African family have a unique syndrome comprising poikiloderma, tendon contractures and progressive pulmonary fibrosis. The condition is clinically important as the skin changes, which involve the face, have considerable cosmetic impact, while lung involvement is potentially lethal in adulthood. Skin manifestations which facilitate diagnosis include facial telangiectasia, mottled hypo- and hyperpigmentation, papules and epidermal atrophy. The scalp, facial and body hair are fine and scanty. The tendon contractures lead to progressive digital flexion deformities and abnormalities of the ankles and feet, with disturbance of gait. Pulmonary involvement manifests as progressive dyspnoea. Pedigree data are compatible with an autosomal dominant mode of transmission. Poikiloderma of Weary is characterized by linear sclerotic and fibrous bands and not tendon contractures and is not associated with potentially lethal pulmonary fibrosis. Rather than name this disorder a variant of Weary syndrome, it might be prudent to use as an umbrella title one composed by Weary himself: ‘hereditary sclerosing poikiloderma’ (HSP), under which variants such as HSP Weary type, HSP with cardiac involvement (aortic stenosis described as inconsistently associated with Weary syndrome) and HSP with tendon/ pulmonary involvement (current family) may be classified. The manifestations in this family differ from other poikilodermata and, to the best of our knowledge, have not been previously documented.
The hereditary poikilodermas are a group of conditions which are characterized by mottled pigmentation, telangiectasia and epidermal atrophy. The eponymous Weary form of sclerosing poikiloderma, the Rothmund–Thomson syndrome and the Werner syndrome are well-documented disorders in this category. We have investigated a South African family in which persons in two generations had poikiloderma, tendon contractures and progressive pulmonary fibrosis. The disorder appears to be a unique autosomal dominant entity. In order to establish syndromic status, our observations are described, depicted and discussed in this article.
Case report A 26-year-old woman (II:5) gave a history of heat intolerance and skin lesions on the face since early childhood. At the age
of 9 years she developed Achilles tendon contractures, which were treated by bilateral tendon lengthening at the age of 14 years (Fig. 1). Clinically, she had telangiectasia, mottled hyper- and hypopigmentation, papules and epidermal atrophy on the cheeks and face (Fig. 2a). She had fine scalp hair, thin eyebrows and used a tattoo to improve her appearance (Fig. 2b). There was virtually no hair on her arms and legs, which also showed variable pigmentation, and minimal freckling was evident on the trunk. Her feet were small (South African/European shoe size 35) and she had atrophy of both thenar and hypothenar eminences (Fig. 3a). She was unable to extend her fingers fully, due to sclerosis of the digits (Fig. 3b), but no Raynaud phenomenon was present. Her teeth and nails were normal. Two attempts by experienced laboratory staff to collect sweat resulted in an insufficient amount of sweat for chemical analysis. This hypohidrosis, taken together with her sparse hair,
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Fig 1. Surgical scars secondary to Achilles tendon lengthening.
suggested ectodermal dysplasia. She had a history of childhood asthma and cigarette smoking (10 per day for 10 years), allergic rhinitis and salicylate hypersensitivity, and skin prick tests to several aeroallergens were positive. Pulmonary evaluation revealed restrictive impairment of lung function [forced vital capacity (FVC) 78% of predicted and forced expiratory volume in 1 s (FEV1)/FVC% ¼ 86%] with impaired diffusing capacity for carbon monoxide [carbon monoxide single breath method (DLCOSB) 67% of predicted]. However, no lung abnormality was evident on examination, and chest X-ray was normal. Tests for antinuclear antibodies and rheumatoid factor were negative and serum angiotensin-converting enzyme was normal. Her father (I:2) and brother (II:3), who had previously been examined by one of us (E.D.B.), had similar skin and skeletal abnormalities and had died of diffuse interstitial pulmonary fibrosis at the age of 56 and 30 years, respectively. The latter had a history of tendon-lengthening surgery on both feet by the age of 5 years, and presented at age 28 years with progressive breathlessness and dry cough of 15 months’ duration, clubbing of fingers and toes, extensive ‘Velcro’-type crackles over mid and lower lung fields bilaterally, and respiratory failure. He had a history of smoking 20 cigarettes per day for 10 years but no history of respiratory allergies. Bronchoalveolar lavage (BAL) confirmed increased proportions of
Fig 2. Patient II:5. (a) Telangiectasias on the cheeks, and mottled (hyper-, hypo- and normal) pigmentation, papules and epidermal atrophy on the cheeks and face. (b) Fine scalp hair, and thin eyebrows (she used a tattoo to improve appearance).
neutrophils (13%) and eosinophils (4%) in BAL fluid, and transbronchial biopsy confirmed mild interstitial inflammation and fibrosis compatible with usual interstitial pneumonia. At presentation his FVC and FEV1 were 34% and 37% of predicted, respectively (FEV1/FVC% ¼ 90%) and diffusing capacity was 34% of predicted. He deteriorated rapidly despite high-dose oral corticosteroid treatment. At postmortem he was found to have tendon contractures, thin tapered limbs with short nails and clubbing, truncal obesity and encasement of the mediastinal and abdominal organs by excess fat. The skin showed scleroderma-like change with replacement of the adnexal structures by fibrosis (Fig. 4a). Microscopy of the skin also revealed elastic tissue degeneration with the formation of elastic globes in the papillary dermis (Fig. 4b). There was extensive diffuse interstitial 2006 The Authors
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while her brother (II:1) is unaffected. Neither of the marriages was consanguineous, the two wives were unrelated and no other family members have the condition. The pedigree is shown in Figure 6.
Discussion
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Fig 3. Patient II:5. (a) Atrophy of both thenar and hypothenar eminences. (b) Inability to extend the fingers fully, due to sclerosis.
fibrosis of the lungs with abnormal airspace formation consistent with usual interstitial pneumonia (Fig. 4c). Fibrosis of the oesophagus and mediastinal lymph nodes was also present. Other findings were medial mucinous degeneration (Fig. 4d) of the arteries with associated elastic degeneration and medial calcification of the splenic and anterior descending coronary artery. There was also extensive fatty infiltration of the pancreas and peripheral skeletal muscle (Fig. 4e). A surviving brother (II:4) who, at 5 years older than the proband, is aged 31 years, has similar skin and limb changes and heat intolerance but does not have features of tendon involvement. He has well-developed chest muscles as a result of body-building but slight tapering of the arms persists (Fig. 5). Chest examination, X-ray and tests of lung function (FVC 91% of predicted, FEV1/FVC% ¼ 76% and DLCOSB ¼ 88% of predicted) were normal apart from mild cardiomegaly. Echocardiography confirmed left ventricular hypertrophy, thought to be the result of hypertension and a rigorous daily exercise routine. Renal function and serum angiotensinconverting enzyme level were normal, and antinuclear antibody and rheumatoid factor were negative. A half sister from her father’s previous marriage (II:2) is reported by family members to have similar skin changes,
The major manifestations of the condition in the affected family are poikiloderma, tendon contractures and progressive pulmonary fibrosis, together with degenerative changes in other organs. The involvement of two generations, with apparent male to male transmission and affected males and females, is strongly suggestive of autosomal dominant transmission, with variable phenotypic expression. The differential diagnosis of the condition in the South African family includes the ectodermal dysplasias. It is very likely, however, that the heat intolerance, reduced sweating and thin hair, which are reminiscent of hypohidrotic ectodermal dysplasia, are secondary to adnexal fibrosis. Moreover, poikiloderma is not a feature of ectodermal dysplasia syndromes. The clinical features in this family resemble the Weary form of hereditary sclerosing poikiloderma. This autosomal dominant condition is characterized by generalized poikiloderma, sclerosis of palms and soles, linear hyperkeratotic and sclerotic bands, digital clubbing and tissue calcinosis.1 Inconsistent manifestations in the two affected families reported by these authors include noncalcified aortic stenosis without heart failure and duodenal ulcer. In a further report, Grau Salvat et al.2 documented a woman aged 67 years who had progressive poikiloderma from the age of 4 years, papules on the neck (similar to those on the South African patients’ faces) and digital sclerosis with Raynaud phenomenon. Echocardiographic studies revealed severe aortic stenosis. Her mother and three brothers had similarly affected skin. Two of her brothers had died at the ages of 54 and 66 years as a result of aortic valvular heart disease. Autoimmune serology was negative in this family.2 The potentially lethal pulmonary fibrosis which was a significant feature in the South African family has not been described in Weary syndrome. Further, none of the affected members of the South African family had cutaneous fibrous bands or valvular heart disease. Although the surviving brother does have radiological evidence of cardiomegaly, this is probably related to athleticism, body-building and early-onset hypertension. The authors are of the opinion that our family does not have Weary syndrome and it is also highly unlikely that lung involvement is segregating as a separate entity in this family as pulmonary fibrosis did not occur in family members who did not have poikiloderma. Moreover, the use of eponyms may not be as consistent as clinically descriptive classifications, as evidenced by past nosological confusion concerning the Weary–Kindler syndrome.3 We suggest, for future classification, the adoption of the umbrella name ‘hereditary sclerosing poikiloderma’ under which Weary syndrome1 and its ‘inconsistent findings’ can each be subclassified as ‘associated with valvular heart disease’,2 ‘associated with
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Fig 4. (a) Replacement of skin adnexal structures by fibrosis (haematoxylin and eosin; original magnification ·25). (b) Elastic globes in the papillary dermis (elastin–van Gieson; original magnification ·100). (c) Extensive fibrosis of the lungs with smooth muscle metaplasia and abnormal airspace formation (haematoxylin and eosin; original magnification ·25). (d) Medial mucinous degeneration of the aorta; increased mucopolysaccharides highlighted on the Alcian blue stain (original magnification ·25). (e) Fatty infiltration of skeletal muscle (haematoxylin and eosin; original magnification ·40).
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tendon contracture/lung fibrosis’ (the current condition) and other future variants. The Rothmund–Thomson syndrome (MIM 268400) enters into the differential diagnosis, but differs by virtue of a depressed nasal bridge, juvenile cataracts and hypogonadism.4 Similarly, the Werner form of poikiloderma (MIM 277700) is characterized by premature ageing, scleroderma, cataract and premature arteriosclerosis.5 There is neither tendon nor pulmonary involvement in either of these disorders and both are autosomal recessive traits. The X-linked reticulate pigmentary disorder with systemic manifestations (MIM 301220) has some clinical resemblance but lacks telangiectases and can also be readily differentiated from our family by virtue of the mode of inheritance.6 It is possible that this condition is primarily an autosomal dominant connective tissue disorder, which induces a vasculopathy with secondary fibrosis (in various tissues including the skin and fatal lung fibrosis), elastic tissue degeneration in the skin and fatty infiltration of muscles. Thus far, however, serological screening for autoimmunity has proved negative, and the phenotype does not conform to any recognized pattern of collagen vascular disease, including scleroderma. The prominence of fibrosis in this condition suggests that the primary defect might be in the regulation of fibrogenesis
involving abnormalities of both collagen and elastin. Abnormalities that develop shortly after birth, resulting in defective growth of limbs and skin, in which the dermis appears to be secondarily involved, point to the focus being on connective tissue. Abnormalities of genes for growth factor-like transforming growth factor b1 (TGFb1) are potential candidates for this disorder. Transgenic mice that overexpress a constitutively active human TGFb1 develop multiorgan fibrosis, suggesting a link between TGFb1 expression and fibrotic disease.7 Furthermore, TGFb and other genes involved in extracellular matrix homeostasis have been implicated in scleroderma lung fibrosis.8 Other candidates would be the Rothmund–Thomson RECQL4 gene on chromosome 8q24.3 and the Werner RECQL2 gene on chromosome 8p22–p12, although these are less likely because of the mode of transmission.4,9 Genes responsible for Werner and Rothman–Thompson syndromes have been identified as homologues of Escherichia coli RecQ, which encodes a DNA helicase that unwinds double-stranded DNA into singlestranded DNAs. These observations may have a bearing on the pathogenesis of the present disorder. Recognition and characterization of the determinant gene would establish the autonomous syndromic status of the disorder, which we propose should be classified under ‘hereditary sclerosing poikilodermas’ and not Weary syndrome. 2006 The Authors
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Acknowledgments N.P.K. thanks Professor R. Happle for helpful comments on the abstract version of this work. P.B. is grateful to the SA National Research Foundation and the MRC for support.
References
Fig 5. Patient II:4. Well-developed chest muscles; less developed arms.
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I:2
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1 Weary PE, Hsu YT, Richardson DR et al. Hereditary sclerosing poikiloderma. Report of two families with an unusual and distinctive genodermatosis. Arch Dermatol 1969; 100:413–22. 2 Grau Salvat C, Pont V, Cors JR, Aliaga A. Hereditary sclerosing poikiloderma of Weary: report of a new case. Br J Dermatol 1999; 140:366–8. 3 Wiebe CB, Silver JG, Larjava HS. Early-onset periodontitis associated with Weary–Kindler syndrome: a case report. J Periodontol 1996; 67:1004–10. 4 Wang LL, Levy ML, Lewis RA et al. Clinical manifestations in a cohort of 41 Rothmund–Thomson syndrome patients. Am J Med Genet 2001; 102:11–17. 5 Meisslitzer C, Ruppitsch W, Weirich-Schwaiger H et al. Werner syndrome: characterization of mutations in the WRN gene in an affected family. Eur J Hum Genet 1997; 5:364–70. 6 Anderson RC, Zinn AR, Kim J, Carder KR. X-linked reticulate pigmentary disorder with systemic manifestations: report of a third family and literature review. Pediatr Dermatol 2005; 22:122–6. 7 Clouthier DE, Comerford SA, Hammer RE. Hepatic fibrosis, glomerulosclerosis, and lipodystrophy-like PEPCK-TGF-beta-1 transgenic mice. J Clin Invest 1997; 100:2697–713. 8 Grutters JC, du Bois RM. Genetics of fibrosing lung diseases. Eur Respir J 2005; 25:915–27. 9 Yu C-E, Oshima J, Wijsman EM et al. Werner’s Syndrome Collaborative Group: mutations in the consensus helicase domains of the Werner syndrome gene. Am J Med Genet 1997; 60:330–41.
II : 5
Fig 6. Pedigree of the family with poikiloderma, tendon contractures and pulmonary fibrosis, showing pedigree numbers by generation and person number (i.e. I:1–II:5). Males are indicated by squares, females by circles. Affected individuals have filled-in symbols, and deceased individuals are crossed. The index case (II:5) has two siblings, father and half-sister affected, consistent with autosomal dominant inheritance.
Further study of the molecular basis for this potentially lethal autosomal dominant condition may provide valuable insights into the causes and mechanisms of more common and debilitating fibrotic diseases, particularly those affecting the lung and skin.
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