AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

Cutis laxa (CL) is a rare, inherited or acquired connective tissue disorder in which the skin becomes inelastic and hangs loosely in folds. The clinical presentation and the mode of inheritance show considerable heterogeneity. Autosomal dominant, autosomal recessive, and X-linked recessive patterns have been noted in inherited forms. Recently, a serine to proline amino acid substitution in the fibulin 5 (FBLN5) gene has been associated with problems in normal elastogenesis, resulting in a recessive form of CL in humans.¹ The X-linked form is currently classified in the group of copper transport diseases. The precise cause is unknown, but it may be due to abnormal elastin metabolism resulting in markedly reduced dermal elastin content.

In both the inherited type and the acquired type, the internal organs are frequently involved. CL may be preceded by an inflammatory rash, or it may develop spontaneously.

Pathophysiology

CL is characterized by degenerative changes in the elastic fibers resulting in loose, pendulous skin. The skin is sagging, redundant, and stretchable, with reduced elastic recoil.

In most cases of CL, the biochemical and molecular basis of the skin changes are unclear. However, the histopathologic analysis of the skin in several patients reveals alterations in the quantity or the morphology of elastin in which fragmentation or a loss of elastic fibers is present. Additionally, evidence of abnormal cross-linking of elastin exists in some patients with CL.

Recent studies have shown that several factors, such as copper deficiency, lysyl oxidase, elastases, and elastase inhibitors, contribute to abnormal elastin degradation.² Lysyl oxidase, a copper-dependent enzyme, is important in the synthesis and cross-linking of elastin and collagen. Therefore, low levels of serum copper could lead to diminished elastin synthesis. However, only a few patients with CL have demonstrated low serum copper levels. Defective copper utilization may also lead to decreased activity of elastase inhibitor alpha-1 antitrypsin, resulting in destruction of elastic fibers.

Cultured dermal fibroblasts from patients with CL have shown increased elastolytic activity compared with healthy skin, and elastolysis has been suggested to result from increased elastase activity.

Inflammatory cells or their mediators might damage elastic fibers. Polymorphonuclear leukocytes and macrophages release elastases, which could damage elastic fibers with subsequent phagocytosis.

Excessive loss of cutaneous elastin in one patient with CL appeared to be related to the combined effects of low lysyl oxidase activity with high levels of cathepsin G, an elastolytic protease.

However, variations in the morphology of the elastic fibers among skin samples from individuals with CL suggest that the biochemical basis of the disorder may be heterogeneous. Indeed, CL could result from mutations that affect the synthesis, the stabilization, or the degradation of elastic fibers.

Frequency

United States

Congenital forms of CL are more common than acquired disease. The recessively inherited form is most frequent and most severe.

Mortality/Morbidity

• The autosomal dominant form of CL has a benign course; primarily, skin involvement is present, with few, if any systemic complications, and a normal life expectancy.
• The autosomal recessive form is often associated with severe internal complications, such as genitourinary and gastrointestinal diverticula, diaphragmatic hernia, and emphysema leading to cor pulmonale and death in the first few years of life.
• Approximately one half of the cases of acquired CL are associated with a preceding inflammatory eruption, such as urticaria, eczema, erythema multiforme, or vesicular eruption, as well as reactions to penicillin or other drugs. Patients with Wilson disease are at particular risk because of the elastolytic effects caused by long-term, high doses of the copper chelation agent penicillamine.³ The postinflammatory form of acquired CL is typified by intense, episodic cutaneous inflammation and recurrent erythematous plaques. Systemic manifestations, such as fever, malaise, and leukocytosis, often accompany the inflammation. The cutaneous laxity that follows is limited to areas of previous inflammation.
• The X-linked recessive variant of CL is rare, with skin laxity and skeletal and genitourinary tract abnormalities. X-linked CL is identical to Ehlers-Danlos syndrome type IX, and both conditions are now known as occipital horn syndrome.

Race

CL affects persons of all races.

Sex

CL affects men and women equally.

Age

The autosomal dominant form has a later onset than the autosomal recessive form. Acquired CL may develop at any age, but it often begins in adulthood.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Patients complain of progressive laxity and sagging of the skin as they notice the development of loose, wrinkled skin.
• A history of an inflammatory process involving the skin preceding the development of loose folds of skin may be present.
• Patients may have a family history of a skin disorder.
• A history of prior penicillin or penicillamine use may be present.
• Urticarial lesions preceding acquired CL have been reported in association with alpha-1 antitrypsin deficiency. Acquired CL can also occur in association with complement deficiency (C3 and C4), systemic lupus erythematosus, sarcoidosis,⁴ multiple myeloma,^{5, 6, 7} and systemic amyloidosis.⁸ More recently, a case of CL has been associated with immunoglobulin G (IgG)–4 heavy-chain deposition disease of the kidneys.⁹

Physical

• Skin - Primary lesion
• • The skin is loose, inelastic, and hangs in folds.
  • Loose, pendulous skin gives the appearance of aging; therefore, patients appear much older than their actual age.
  • The skin demonstrates decreased elastic recoil on stretching.
  • Skin fragility, easy bruisability, and poor wound healing are not associated with CL.
• Skin - Distribution
• • Any portion of the body may be affected; however, the loose appearance is most prominent around the eyes, the face, the neck, the shoulders, and the thighs.
  • In many cases of acquired CL, involvement of the face and the neck occurs first and progresses in a cephalocaudal fashion.
• Gastrointestinal tract: Diverticula of the small and large bowels may be present; rectal prolapse may occur.
• Pulmonary: Bronchiectasis, emphysema, and cor pulmonale may be present. In acquired CL, pulmonary involvement typically manifests as emphysema due to the loss of the elastin support network and is the most common cause of death in these patients.
• Cardiovascular: Cardiomegaly, congestive heart failure, murmurs, cor pulmonale, and aortic aneurysms may occur. Severe aortic disease may be present as a result of aortic vessel medial degeneration and extracellular elastin deposits lacking microfibrillar elements.
• Skeletal: Dislocation of the hips; osteoporosis; and other skeletal abnormalities, such as growth retardation, delayed fontanelle closure, and ligamentous laxity, may be present.
• Other: Umbilical, inguinal, and hiatal hernias may occur.

Causes

• The underlying cause of CL is unknown and probably variable. Most hypotheses suggest possible mechanisms for the reduction of elastic fibers in CL. Those most often reported in literature are as follows:
• • Abnormal copper metabolism/copper deficiency
  • Decreased serum elastase inhibitor level
  • Low lysyl oxidase activity
  • Increased elastase activity
  • Postinflammatory elastolysis
  • Immune-mediated mechanism
  • Decreased elastin gene expression

DIFFERENTIALS

Section 4 of 11  

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• Follow-up
• Miscellaneous
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Other Problems to be Considered

Costello syndrome
Granulomatous slack skin (variant of cutaneous T-cell lymphoma)
Marfan syndrome
Mid-dermal elastolysis¹⁰
Wrinkly skin syndrome¹¹

WORKUP

Section 5 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Although no routine laboratory findings are present in CL, a CBC may reveal normochromic, normocytic anemia, while total protein and beta-2 microglobulin levels may be elevated.
• Serum protein electrophoresis and quantitative immunoglobulins can be performed to assess for myeloma.
• Direct immunofluorescence studies for IgG, immunoglobulin A (IgA), immunoglobulin M (IgM), C3, C1q, and fibrin may be performed to assess for related conditions, such as lupus erythematosus.
• Serum copper, zinc, ceruloplasmin, alpha-1 antitrypsin, C4, rapid plasma reagent, and antinuclear antibody levels can be measured.
• Serum and urine elastin peptide levels may be elevated.

Imaging Studies

• An echocardiogram may be obtained.
• A chest radiograph can be obtained to help check for pulmonary involvement.

Other Tests

• Pulmonary function tests may be performed

Procedures

• A skin biopsy and/or a bone marrow biopsy may be performed.

Histologic Findings

No specific histologic abnormality is seen on routine stains with hematoxylin and eosin. On elastic fiber stains, all types of CL show a reduction in the number of elastic fibers throughout the dermis, with remaining fibers being shortened, clumped, granular, or fragmented. In severe cases, no elastic fibers may be present, but only fine, dustlike particles scattered throughout the dermis can be seen. In cases preceded by an inflammatory eruption, such as urticaria or vesicles, the inflammatory infiltrate may be mononuclear (lymphocytes and histiocytes) or mixed, containing neutrophils. When vesicles are present, they are subepidermal, with papillary collections of neutrophils and eosinophils mimicking dermatitis herpetiformis.

Involved visceral organs show granular changes in the elastic fibers similar to those seen in the skin. Collagen abnormalities have also been described but are ultrastructurally nonspecific.

Electron microscopic examination reveals degenerative changes in the elastic fibers, which are variable from case to case. However, the most significant finding is the presence of electron-dense amorphous or granular aggregates that are irregularly distributed in the vicinity of the elastic fibers.

TREATMENT

Section 6 of 11  

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• Clinical
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• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• No treatment exists to prevent disease progression, although dapsone can be used acutely to control swelling in persons with acquired CL.
• Penicillamine and doxycycline are ineffective.

Surgical Care

• Surgical correction of redundant skin folds, prolapses, or hernias may be undertaken. However, surgery often produces only temporary benefit.
• Botulinum toxin injections are being considered for improving the aged appearance and facial defects seen in persons with CL.¹²

Consultations

• Consult a dermatologist for evaluation of the underlying cause of CL.
• Consult an internal medicine specialist for evaluation of the underlying cause of CL and internal organ involvement.
• CL increases the risk for aortic aneurysm; therefore, regular cardiac monitoring is recommended to avert a potentially fatal aortic rupture.

MEDICATION

Section 7 of 11  

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The goals of pharmacotherapy are to eradicate the infection, to reduce morbidity, and to prevent complications.

Drug Category: Antibiotics

These agents may be useful to control the acute phase.

FOLLOW-UP

Section 8 of 11  

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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Deterrence/Prevention

• Discontinuation of cigarette smoking is beneficial to prevent the progression of pulmonary disease.

Complications

• The most serious complication, which may be life threatening, is cor pulmonale resulting from severe progressive pulmonary emphysema.
• In the autosomal dominant form, few, if any, systemic complications occur.
• Severe internal complications of the autosomal recessive form include genitourinary and gastrointestinal diverticula, diaphragmatic hernia, and emphysema leading to cor pulmonale and death in the first few years of life.
• In acquired CL, visceral involvement is common and has occurred in all reported patients with onset of acquired disease after the age of 20 years. This may involve the lungs, the gastrointestinal tract, the heart, and the urogenital system with breakdown of elastic fibers and loss of tissue support.

Prognosis

• The lifespan of some patients with CL may not be significantly decreased. Patients with the autosomal dominant form have a normal life expectancy.

MISCELLANEOUS

Section 9 of 11  

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• Clinical
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• Miscellaneous
• Multimedia
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Medical/Legal Pitfalls

• Failure to rule out significant underlying diseases

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Prominent skin laxity and wrinkling on the back.
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Media type:  Photo

Media file 2:  Marked diminution of elastic fibers in the lower dermis (Verhoeff-van Gieson stain). Courtesy of Dr F. Abreo.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
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• Miscellaneous
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• References

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7. Gupta A, Helm TN. Acquired cutis laxa associated with multiple myeloma. Cutis. Feb 2002;69(2):114-8. [Medline].
8. Newton JA, McKee PH, Black MM. Cutis laxa associated with amyloidosis. Clin Exp Dermatol. Jan 1986;11(1):87-91. [Medline].
9. Tan S, Pon K, Bargman J, Ghazarian D. Generalized cutis laxa associated with heavy chain deposition disease. J Cutan Med Surg. Sep-Oct 2003;7(5):390-4. [Medline].
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11. Gupta N, Phadke SR. Cutis laxa type II and wrinkly skin syndrome: distinct phenotypes. Pediatr Dermatol. May-Jun 2006;23(3):225-30. [Medline].
12. Tamura BM, Lourenço LM, Platt A, Pertel P, Santos LF, Levites J. Cutis laxa: Improvement of facial aesthetics by using botulinum toxin. Dermatol Surg. Dec 2004;30(12 Pt 2):1518-20. [Medline].
13. Boente MC, Winik BC, Asial RA. Wrinkly skin syndrome: ultrastructural alterations of the elastic fibers. Pediatr Dermatol. Mar-Apr 1999;16(2):113-7. [Medline].
14. Bouloc A, Godeau G, Zeller J, Wechsler J, Revuz J, Cosnes A. Increased fibroblast elastase activity in acquired cutis laxa. Dermatology. 1999;198(4):346-50. [Medline].
15. Chartier S, Faucher L, Tousignant J, Rochette L. Acquired cutis laxa associated with cutaneous angiocentric T-cell lymphoma. Int J Dermatol. Oct 1997;36(10):772-6. [Medline].
16. Debelle L, Tamburro AM. Elastin: molecular description and function. Int J Biochem Cell Biol. Feb 1999;31(2):261-72. [Medline].
17. Fornieri C, Quaglino D, Lungarella G, Cavarra E, Tiozzo R, Giro MG, et al. Elastin production and degradation in cutis laxa acquisita. J Invest Dermatol. Oct 1994;103(4):583-8. [Medline].
18. George S, Jacob M, Pulimood S, Chandi SM. Cutis laxa. Clin Exp Dermatol. Sep 1998;23(5):211-3. [Medline].
19. Greaney MJ, Richards AB. Bilateral orbital fat prolapse in cutis laxa. Br J Ophthalmol. Jun 1998;82(6):713-4. [Medline].
20. Hatamochi A, Kuroda K, Shinkai H, Kohma H, Oishi Y, Inoue S. Regulation of matrix metalloproteinase (MMP) expression in cutis laxa fibroblasts: upregulation of MMP-1, MMP-3 and MMP-9 genes but not of the MMP-2 gene. Br J Dermatol. May 1998;138(5):757-62. [Medline].
21. Kumar S, Sehgal VN, Sharma RC. Common genodermatoses. Int J Dermatol. Oct 1996;35(10):685-94. [Medline].
22. Martín L, Requena L, Yus ES, Furio V, Fariña MC. Acrolocalized acquired cutis laxa. Br J Dermatol. May 1996;134(5):973-6. [Medline].
23. Nahas FX, Sterman S, Gemperli R, Ferreira MC. The role of plastic surgery in congenital cutis laxa: a 10-year follow-up. Plast Reconstr Surg. Sep 1999;104(4):1174-8; discussion 1179. [Medline].
24. Nikko A, Dunnigan M, Black A, Cockerell CJ. Acquired cutis laxa associated with a plasma cell dyscrasia. Am J Dermatopathol. Oct 1996;18(5):533-7. [Medline].
25. Ozkan S, Fetil E, Günes AT, Bozkurt E, Sahin T, Erkizan V, et al. Cutis laxa acquisita: is there any association with Borrelia burgdorferi?. Eur J Dermatol. Oct-Nov 1999;9(7):561-4. [Medline].
26. Robertson SP, Bankier A. Sotos syndrome and cutis laxa. J Med Genet. Jan 1999;36(1):51-6. [Medline].
27. Sephel GC, Byers PH, Holbrook KA, Davidson JM. Heterogeneity of elastin expression in cutis laxa fibroblast strains. J Invest Dermatol. Jul 1989;93(1):147-53. [Medline].
28. Szabo Z, Crepeau MW, Mitchell AL, Stephan MJ, Puntel RA, Yin Loke K, et al. Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene. J Med Genet. Mar 2006;43(3):255-8. [Medline].
29. Tassabehji M, Metcalfe K, Hurst J, Ashcroft GS, Kielty C, Wilmot C, et al. An elastin gene mutation producing abnormal tropoelastin and abnormal elastic fibres in a patient with autosomal dominant cutis laxa. Hum Mol Genet. Jun 1998;7(6):1021-8. [Medline].
30. Uenishi T, Uchiyama M, Sugiura H, Danno K. Pseudoxanthoma elasticum with generalized cutaneous laxity. Arch Dermatol. May 1997;133(5):664-6. [Medline].
31. Uitto J, Ryhänen L, Abraham PA, Perejda AJ. Elastin in diseases. J Invest Dermatol. Jul 1982;79 Suppl 1:160s-168s. [Medline].
32. Zlotogora J. Wrinkly skin syndrome and the syndrome of cutis laxa with growth and developmental delay represent the same disorder. Am J Med Genet. Jul 16 1999;85(2):194. [Medline].

Article Last Updated: Nov 26, 2007