Continuing Education Activity

Cutis laxa (CL) is a group of rare diseases of connective tissue characterized by redundant skin with loss of elasticity and premature aging. Heritable forms have variable transmissions and clinical expressions. Three major groups are individualized based on the mode of inheritance: autosomal dominant CL, autosomal recessive CL, and X-linked recessive CL. Acquired forms are more frequent and characterized by a later onset. This activity reviews the workup of cutis laxa and describes the role of health professionals working together to manage this condition.

Objectives:

• Describe the histopathophysiology of cutis laxa.
• Outline the presentation of cutis laxa.
• Summarize the treatment of cutis laxa.
• Summarize the workup of cutis laxa and describes the role of health professionals working together to manage this condition.

Introduction

Cutis laxa (CL) is a group of rare diseases of connective tissue characterized by redundant skin with loss of elasticity and premature aging.[1] Heritable forms have variable transmissions and clinical expressions. Three major groups are individualized based on the mode of inheritance: autosomal dominant CL, autosomal recessive CL, and X-linked recessive CL. Acquired forms are more frequent and characterized by a later onset. The histopathologic findings include sparse and fragmented elastic fibers. In all cases, mutations lead to abnormal proteins that disrupt the architecture of elastic fibers.

Etiology

The etiology involves a disorder of the elastic fiber network. The disease can affect the skin as well as the internal organs. Autosomal dominant CL has been associated with mutations of the elastin gene resulting in quantitative or qualitative abnormalities in this protein.[2] X-linked CL is associated with gene mutations ATPA7 and abnormalities of copper transport.[3] The autosomal recessive CL is very heterogeneous with 2 types characterized as 1 and 2 having different extracutaneous involvement. Type 1 is associated with mutations in the gene encoding fibulin 5.[4] Type 2 is associated with mutations in the lysyl oxidase gene. Acquired cutis laxa can follow the beginning of an inflammatory condition, which increases the degradation of elastic fibers.

Epidemiology

No precise estimate of the disease’s prevalence is available. Inherited forms are rare. They appear either at birth or in early childhood. Acquired forms have a later onset, generally in adulthood. No racial or ethnic predilection has been reported.

Histopathology

The histological examination shows a decrease in elastic fibers density, which are sparse and fragmented. Fiber density may be normal in autosomal dominant form with a later onset. Giant cells may be seen phagocyting elastic fibers. The acquired forms are associated with an inflammatory infiltrate.[5] The structure of the elastic fiber is irregularly fragmented when examined by electron microscopy with an accumulation of granular materials. The microfibrils are reduced in the superficial dermis. In some cases, alterations in collagen fibers may accompany elastic fibers abnormalities.

History and Physical

All forms of CL have loose and sagging skin with reduced elasticity and resilience in common. This clinical aspect is sufficiently characteristic to make the diagnosis. The skin is diffusely flaccid and redundant, especially in the face. The laxity usually progresses over time. It realizes a prematurely old and sad aspect. However, in all cases, it is the severity of the visceral disorders which conditions the prognosis of CL. For the autosomal dominant CL, cutaneous manifestations are quite late. Visceral involvement is absent or benign. It includes pulmonary lesions (emphysema, bronchiectasis, stenosis of the pulmonary artery), digestive hernias, and genital prolapse. The life expectancy of these patients is considered roughly the same as the general population, even if cases of aneurysms or aortic ruptures and severe pulmonary emphysema have been reported. Differential diagnosis with acquired CL can be difficult. X-linked CL is identical to Ehlers-Danlos syndrome Type IX and considered a variant of Menkes disease with a good prognosis. In addition to cutaneous manifestations, there are facial and thoracic dysmorphism, exostoses, sinuous carotids, intracranial arterial stenoses, stenosis, and genitourinary tract diverticula,[6] articular hyperlaxity. The intelligence quotient is low.

Autosomal recessive CL type one is probably the most severe form of CL. Cutaneous involvement occurs early in life. It is usually associated with intrauterine retarded growth, facial dysmorphism, thoracic and spinal deformities, as well as mental retardation. Severity is related to the fatal pulmonary involvement (early emphysema, pneumothorax), digestive and urological involvement (hernias, diverticula), or vascular involvement (sinuous and ectatic arteries). For autosomal recessive CL type two, cutaneous lesions usually respect the face and involve the palms and the plants. They are associated with delayed growth,[7] mental retardation, a facial dysmorphism, ligament hyperlaxity, and a dislocation of the hips. The similarity with the "wrinkled skin syndrome" is discussed.[8][9] Acquired forms of CL are more frequent. They can be either generalized or localized.[10] The generalized form occurs after a post-inflammatory skin disorder. It frequently develops in adults. The skin becomes chalazodermic, conferring an aged and flaccid appearance to all skin coating. Simultaneously, respiratory failure develops, induced by the elastolysis in the bronchioloalveolar tract. This generalized elastolysis, occurring in post-inflammatory conditions, has a poor prognosis. Its causes remain mostly unknown. Some cases have been described after drug eruption, amyloidosis type AL, still disease, or infectious disease.[11] Localized forms involve the extremities. They may be associated with rheumatoid polyarthritis, syphilis, myeloma, sarcoidosis. An acral variant with the involvement of the face and extremities has been reported.[12]

Evaluation

If the diagnosis is easy to suspect, the confirmation and the determination of the transmission mode for inherited forms is difficult and must be entrusted to an interprofessional team familiar with this type of pathology. A cutaneous biopsy is not mandatory for the diagnosis. A molecular diagnosis is in the domain of research. It is not always feasible, but can, in some informative families, allow antenatal diagnosis. Searching for visceral complications is systematic and regular.

Treatment / Management

There is no specific treatment for CL or preventing the progression of the disease. Skin manifestations do not tend to improve spontaneously. They can be treated by plastic surgery, which provides significant improvement, whatever the associated extracutaneous manifestations. Interventions are usually not complicated because of the absence of disorders concerning cicatrization, hemostasis, or dermal fragility, contrasting with Ehlers-Danlos syndromes. However, their results are transient, and relapse is the rule. Botulinum toxin has been used for acquired forms and localized ones. The involvement of other internal organs requires an interprofessional approach.

Differential Diagnosis

The differential diagnosis includes normal skin aging, pseudoxanthoma elasticum, and pseudoxanthoma elasticum-like disorder with multiple coagulation factors deficiency, in which the skin can be loose and sagging.[13] Mid-dermal elastolysis is an acquired disorder characterized by circumscribed or diffuse areas of fine wrinkling, most often in sun-exposed sites on the upper trunk, lateral neck, and upper arms.[14] The “Michelin tire baby” phenotype of congenital circumferential skin creases on the extremities may be reminiscent of CL, but the folds reflect excess tissue rather than cutaneous laxity.

Prognosis

Patients with only cutaneous involvement have a good prognosis, and life expectancy is usually normal. Internal organs involvement, especially pulmonary impairment, is associated with poor prognosis. Autosomal recessive CL is the most severe form.

Enhancing Healthcare Team Outcomes

Therapeutic management must be part of an interprofessional approach. The dermatologist is usually the primary care physician, who makes the diagnosis. Dermatology nurses and nurse practitioners monitor patients, provide education to patients and their families, and inform the team about changes in status. After that, depending on the type of CL, the mode of transmission and the clinical examination data, the patient will be referred to other specialists for somatic examination and searching other associated visceral manifestations. The patient should be regularly followed-up.