Cutis Laxa (Elastolysis) 

Updated: Apr 13, 2017
Author: Marc Zachary Handler, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Cutis laxa (CL), or elastolysis, is a rare, inherited or acquired connective-tissue disorder in which the skin becomes inelastic and hangs loosely in folds. Patients develop a prematurely aged appearance.[1] 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. 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 cutis laxa (elastolysis) in humans.[2] Autosomal recessive cutis laxa is a genetically heterogeneous condition.[3] A combined disorder of N- and O-linked glycosylation has been described in children with congenital cutis laxa in association with severe central nervous system involvement, brain migration defects, seizures, and hearing loss.

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. Autosomal dominant congenital cutis laxa (ADCL) is genetically heterogeneous and shows clinical variability. Mutations in the elastin gene (ELN) have been described.[4, 5]

In both the inherited type and the acquired type, the internal organs are frequently involved. Cutis laxa (elastolysis) may be preceded by an inflammatory rash, such as urticaria,[1] or it may develop spontaneously.

Pathophysiology

Cutis laxa (elastolysis) 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. The cutaneous findings of cutis laxa may be striking, but the elastic fiber network is even more important for pulmonary and cardiovascular function.[6]

In most cases of cutis laxa (elastolysis), 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 cutis laxa (elastolysis).

Studies have shown that several factors, such as copper deficiency, lysyl oxidase, elastases, and elastase inhibitors, contribute to abnormal elastin degradation.[7] 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 cutis laxa (elastolysis) 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 cutis laxa (elastolysis) 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 cutis laxa (elastolysis) 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 cutis laxa (elastolysis) suggest that the biochemical basis of the disorder may be heterogeneous. Indeed, cutis laxa (elastolysis) could result from mutations that affect the synthesis, the stabilization, or the degradation of elastic fibers.

Epidemiology

Frequency

Cutis laxa (elastolysis) is rare. Congenital forms of cutis laxa (elastolysis) are more common than acquired disease. The recessively inherited form is most frequent and most severe. Autosomal dominant forms also exist.

Race

Cutis laxa (elastolysis) affects persons of all races.

Sex

Cutis laxa (elastolysis) affects men and women equally.

Age

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

Prognosis

The lifespan of some patients with cutis laxa (elastolysis) may not be significantly decreased. Patients with the autosomal dominant form have a normal life expectancy. The autosomal dominant form of cutis laxa (elastolysis) 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.[8, 9]  

Approximately one half of the cases of acquired cutis laxa (elastolysis) 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.[10] 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.[11] The postinflammatory form of acquired cutis laxa (elastolysis) 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.

Acquired cutis laxa is a rare cutaneous manifestation of hematologic malignancy, particularly plasma cell dyscrasias, including multiple myeloma, monoclonal gammopathy of undetermined significance, and heavy-chain deposition disease.[12, 13, 14] A case report of γ heavy-chain deposition disease with acquired cutis laxa and hypocomplementemia demonstrated the deposition of γ heavy chain and complement components C1q and C3 on the surfaces of dermal elastic fibers, indicating complement fixation by the deposited heavy chains. A mechanism of elastic tissue destruction by complement fixation with resultant activation of the complement cascade ultimately causing elastolysis was suggested.

The X-linked recessive variant of cutis laxa (elastolysis) is rare, with skin laxity and skeletal and genitourinary tract abnormalities. X-linked cutis laxa (elastolysis) is identical to Ehlers-Danlos syndrome type IX, and both conditions are now known as occipital horn syndrome.

Hypothyroidism owing to isolated thyrotropin deficiency has been reported in a newborn with the autosomal recessive form of congenital cutis laxa.[15]

In rare cases, cutis laxa (elastolysis) is associated with congenital hemolytic anemia of unknown origin and early-onset pulmonary emphysema.[16]

Gastrointestinal manifestations include diverticulosis and, rarely, hypertrophic pyloric stenosis[17] and recurrent ileus.[18]

 

Presentation

History

Patients report progressive laxity and sagging of the skin as they notice the development of loose, wrinkled skin. Note the image below.

Prominent skin laxity and wrinkling on the back. Prominent skin laxity and wrinkling on the back.

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 cutis laxa (elastolysis) have been reported in association with alpha-1 antitrypsin deficiency. Acquired cutis laxa (elastolysis) can also occur in association with complement deficiency (C3 and C4), systemic lupus erythematosus, sarcoidosis,[19] multiple myeloma,[20, 21, 22] , systemic amyloidosis,[23] and immunoglobulin G (IgG)–4 heavy-chain deposition disease of the kidneys.[24]

Physical Examination

Physical findings may include the following:

  • 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 cutis laxa (elastolysis). Down-slanting palpebral fissures and a long philtrum are indicative of autosomal recessive cutis laxa type 2A.[25]

  • 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 cutis laxa (elastolysis), involvement of the face and the neck occurs first and progresses in a cephalocaudal fashion. Patients have a prematurely aged appearance.

  • 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 cutis laxa (elastolysis), 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.[26]

  • Skeletal: Osteoporosis and other skeletal abnormalities, such as growth retardation, delayed fontanelle closure, and ligamentous laxity, may be present. Frontal bossing and thin triangular faces have been reported in autosomal recessive cutis laxa type 2A patients. Flat feet is a common finding as well, along with hypotonia and congenital hip dislocation.[25]

  • Other: Umbilical, inguinal, and hiatal hernias may occur.

Causes

The underlying cause of cutis laxa (elastolysis) is unknown and probably variable. Most hypotheses suggest possible mechanisms for the reduction of elastic fibers in cutis laxa (elastolysis). 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

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 cutis laxa (elastolysis), 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.

 

DDx

Diagnostic Considerations

Also consider the following:

  • Costello syndrome
  • Geroderma osteodysplasticum hereditaria [27]
  • Granulomatous slack skin (variant of cutaneous T-cell lymphoma)
  • Marfan syndrome
  • Mid-dermal elastolysis [28]
  • Periorbital changes secondary to topical bimatoprost [29]
  • Wrinkly skin syndrome [30]

Differential Diagnoses

 

Workup

Laboratory Studies

Although no routine laboratory findings are present in cutis laxa (elastolysis), a CBC count 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.

Thyroid function tests may be considered in newborns with cutis laxa.

Direct mutation analysis may be performed to specifically differentiate forms of cutis laxa.[31]

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 cutis laxa (elastolysis) 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.[32]

Note the image below.

Marked diminution of elastic fibers in the lower d Marked diminution of elastic fibers in the lower dermis (Verhoeff-van Gieson stain). Courtesy of Dr F. Abreo.

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

Medical Care

No treatment exists to prevent disease progression, although dapsone can be used acutely to control swelling in persons with acquired cutis laxa (elastolysis), consistent with the suspected role of neutrophil elastase. Penicillamine and doxycycline are ineffective.

Cutis Laxa Internationale is an international support group for patients with cutis laxa (elastolysis).

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 cutis laxa (elastolysis).[33]

Consultations

Consult a dermatologist for evaluation of the underlying cause of cutis laxa (elastolysis).

Consult an internal medicine specialist for evaluation of the underlying cause of cutis laxa (elastolysis) and internal organ involvement.

Cutis laxa (elastolysis) increases the risk for aortic aneurysm; therefore, regular cardiac monitoring is recommended to avert a potentially fatal aortic rupture.

Affected individuals may require a consultation with a pulmonologist.

Consultation with a geneticist is suggested, particularly for patients presenting in childhood.

Prevention

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

 

Medication

Medication Summary

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

Antibiotics

Class Summary

These agents may be useful to control the acute phase.

Dapsone (Avlosulfon)

Dapsone is bactericidal and bacteriostatic against mycobacteria; the mechanism of action is similar to that of sulfonamides, with which competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth. The anti-inflammatory mechanism of action may be related to inhibition of halide-myeloperoxidase system of neutrophils.