Cutis Laxa

Etiology

The etiology of cutis laxa involves a disorder of the elastic fiber network, impacting both the skin and internal organs. Autosomal dominant cutis laxa has been associated with mutations of the elastin gene, resulting in quantitative or qualitative abnormalities in this protein.[2] X-linked cutis laxa is associated with gene mutations in ATPA7, impacting copper transport abnormalities.[3] Autosomal recessive cutis laxa exhibits high heterogeneity, with 2 types—type 1 and type 2—featuring distinct extracutaneous involvement. Type 1 correlates with mutations in the gene encoding fibulin-5,[4] whereas type 2 is associated with mutations in the lysyl oxidase gene. Acquired cutis laxa can develop after the onset of an inflammatory condition, which accelerates the degradation of elastic fibers.

Epidemiology

Currently, a precise estimate of the prevalence of cutis laxa is unavailable. This condition may manifest either at birth or in early childhood. Inherited forms of cutis laxa are rare, whereas acquired forms typically emerge later in adulthood. No specific racial or ethnic predisposition has been reported for the condition.

Pathophysiology

The biochemical basis of cutis laxa is likely heterogeneous, stemming from mutations that impact the synthesis, stabilization, or degradation of elastic fibers. Research indicates that various factors, including copper deficiency, lysyl oxidase, elastases, and elastase inhibitors, contribute to the degradation of abnormal elastic fibers.

Lysyl oxidase, an enzyme dependent on copper, is crucial in synthesizing and cross-linking elastin and collagen. Consequently, reduced serum copper levels could potentially diminish elastin synthesis. However, it is worth noting that only a minority of patients with cutis laxa exhibit low serum copper levels. Furthermore, faulty copper utilization may decrease the activity of elastase inhibitors (alpha-1 antitrypsin), thereby destroying elastic fibers.

Cultured dermal fibroblasts from patients with cutis laxa have demonstrated increased elastolytic activity compared with healthy skin, suggesting that increased elastase activity may contribute to elastolysis. Inflammatory cells or their mediators may also play a role in damaging elastic fibers. Polymorphonuclear leukocytes and macrophages release elastases, which could lead to elastic fiber damage followed by phagocytosis.[5] However, the observed variations in elastic fiber morphology among skin samples from individuals with cutis laxa indicate the heterogeneous nature of the molecular basis underlying this disorder.

Histopathology

Histopathological examination reveals affected tissues with sparse and fragmented elastic fibers, which are attributed to mutations causing abnormal proteins that disrupt the structure of elastic fibers in affected tissues. Fiber density may remain normal in cases of the autosomal dominant form with a later onset. Giant cells may also be observed phagocytizing elastic fibers. In acquired forms, an inflammatory infiltrate is often associated.[6] Under electron microscopy, the elastic fiber structure appears irregularly fragmented, with an accumulation of granular materials. In addition, microfibrils are diminished in the superficial dermis. In certain instances, alterations in collagen fibers may accompany abnormalities in elastic fibers.

History and Physical

All forms of cutis laxa share a common feature of loose and sagging skin with reduced elasticity and resilience. This clinical aspect is distinctive enough to facilitate diagnosis. The skin exhibits diffuse flaccidity and redundancy, particularly noticeable on the face. Over time, laxity typically worsens, resulting in a prematurely aged appearance. However, it is the severity of the associated visceral disorders that ultimately determines the prognosis of cutis laxa in all cases.

Autosomal Dominant Cutis Laxa

In autosomal dominant cutis laxa, cutaneous manifestations typically manifest relatively late. Visceral involvement is either absent or benign and includes pulmonary lesions, including emphysema, bronchiectasis, and stenosis of the pulmonary artery, digestive hernias, and genital prolapse. Generally, the life expectancy of patients with autosomal dominant cutis laxa is comparable to that of the general population, although instances of aneurysms, aortic ruptures, and severe pulmonary emphysema have been reported. Differential diagnosis with acquired cutis laxa can be challenging.

X-linked Recessive Cutis Laxa

X-linked cutis laxa is identical to Ehlers-Danlos syndrome type IX and is considered a variant of Menkes disease with a favorable prognosis. In addition to cutaneous manifestations, individuals may exhibit facial and thoracic dysmorphism, exostoses, sinuous carotids, intracranial arterial stenoses, genitourinary tract diverticula,[7] and articular hyperlaxity. The intelligence quotient tends to be low in affected individuals.

Autosomal Recessive Cutis Laxa Type 1

Autosomal recessive cutis laxa type 1 is probably the most severe form of cutis laxa, with cutaneous involvement occurring early in life. This type often correlates with intrauterine growth retardation, facial dysmorphism, thoracic and spinal deformities, and mental retardation. Severity is often associated with fatal pulmonary complications such as early emphysema and pneumothorax, as well as digestive and urological involvement, including hernias and diverticula, and vascular complications involving sinuous and ectatic arteries.

Autosomal Recessive Cutis Laxa Type 2

In autosomal recessive cutis laxa type 2, cutaneous lesions typically spare the face but affect the hands and feet. These lesions are often accompanied by delayed growth,[8] mental retardation, facial dysmorphism, ligament hyperlaxity, and a dislocation of the hips.[9][10] Acquired forms of cutis laxa are more common and can manifest as either generalized or localized.[11] The generalized form occurs after an inflammatory skin disorder and frequently develops in adults. The skin becomes chalazodermic, conferring an aged and flaccid appearance to all skin coating.

Simultaneously, respiratory failure may develop due to elastolysis in the bronchioloalveolar tract. This generalized elastolysis, which occurs in postinflammatory conditions, typically carries a poor prognosis, and its causes largely remain unknown. Instances have been documented following drug eruptions, amyloidosis, and Still disease.[12] Localized forms primarily affect the extremities and may be associated with rheumatoid polyarthritis, syphilis, myeloma, and sarcoidosis. In addition, an acral variant involving the face and extremities has been reported.[13]

Evaluation

Although the diagnosis of cutis laxa may be readily suspected, confirming it and determining the mode of transmission for inherited forms can be challenging and should be managed by an interprofessional team experienced in this pathology. A cutaneous biopsy is not obligatory for diagnosis, and molecular diagnosis remains primarily in the realm of research. Although not always feasible, it may enable antenatal diagnosis in some informative families. The assessment for visceral complications should be conducted systematically in a step-wise manner.

Treatment / Management

Currently, a specific treatment that prevents the progression or cure of cutis laxa does not exist. Skin manifestations typically do not improve spontaneously; however, plastic surgery can offer significant improvement, regardless of associated extracutaneous manifestations. Surgical interventions are generally uncomplicated due to the absence of issues regarding wound healing, hemostasis, or dermal fragility, which contrasts with Ehlers-Danlos syndrome. Nevertheless, outcomes are often temporary, with relapse being common. The involvement of other internal organs necessitates an interprofessional approach to comprehensive management of the condition.

Although cosmetic surgery is considered the most effective treatment for cutis laxa, caution should be exercised due to the high likelihood of recurrence post-surgery, especially in patients with concomitant systemic diseases. Therefore, a comprehensive multistep diagnosis and treatment plan should be implemented for all individuals with cutis laxa.

Preoperatively, patients must complete relevant examinations, including abdominal and cardiac ultrasounds, to exclude surgical contraindications. Subsequently, psychological counseling, including the risks of surgery and the high possibility of recurrence, might be of great benefit to the patients. Postoperative care should include scar creams and pressure masks to reduce scar hyperplasia.

Laser therapy with a 10,600-nm carbon dioxide fractional laser system has proven effective in improving skin texture.[14] In cutis laxa, the potential mechanism of laser therapy is related to the regeneration of elastic fibers. Thus, the combined treatment of surgery and laser application is postulated to improve the long-term results of therapy. Botulinum toxin may represent an additional, less invasive resource to improve facial defects in these patients, especially in the acquired forms and localized ones.[15](B3)

Differential Diagnosis

The differential diagnoses of cutis laxa include:

• Normal skin aging: The signs of normal skin aging include fine lines and wrinkles, loss of elasticity, thinning of the skin, dryness, uneven pigmentation, such as age spots, and increased susceptibility to bruising.

• Pseudoxanthoma elasticum: An inherited disorder caused by mutations in the ABCC6 transporter gene, impacting connective tissue in various body parts. This condition leads to the mineralization of elastic tissue, characterized by changes in the skin, eyes, cardiovascular system, and gastrointestinal system. Individuals with pseudoxanthoma elasticum may exhibit excess, wrinkled skin. Unlike individuals with cutis laxa, the affected skin in pseudoxanthoma elasticum tends to be hyperelastic, and loose joints are also common. Onset can occur from early childhood to adulthood.

• Pseudoxanthoma elasticum–like disorder: This condition is associated with multiple coagulation factor deficiencies, wherein the skin may also display laxity and sagging.[16] 

• Mid-dermal elastolysis: This is an acquired disorder characterized by circumscribed or diffuse areas of fine wrinkling, commonly observed in sun-exposed areas such as the upper trunk, lateral neck, and upper arms.[17] 

• The "Michelin tire baby" phenotype: The Michelin tire baby phenotype, characterized by congenital circumferential skin creases on the extremities, may resemble cutis laxa, but these folds are due to excess tissue rather than cutaneous laxity.

• Ehlers-Danlos syndrome: Ehlers-Danlos syndrome is a group of genetic connective tissue disorders characterized by skin hyperextensibility, tissue fragility, and joint hypermobility. Patients with Ehlers-Danlos syndrome often have poor skin healing, making them unsuitable candidates for plastic surgery. Unlike cutis laxa, where the skin is loose and recovers slowly from distension, the skin in Ehlers-Danlos syndrome is hyperextensible and quickly recovers from distension. This clinical difference aids in distinguishing between the two conditions. Additionally, in the skin pathology of Ehlers-Danlos syndrome patients, collagen fibers appear loose and disordered, whereas, in cutis laxa, collagen fibers typically appear normal, serving as a diagnostic criterion.[1]

• Hutchinson-Gilford progeria syndrome: This syndrome is also known as progeria and is a rare and fatal disease characterized by accelerated aging from early childhood, with individuals typically succumbing to myocardial infarction or stroke in the second decade of life.[18][19] This degenerative disorder is caused by a pathogenic mutation of the LMNA gene on chromosome 1q.[20] Patients with progeria exhibit a distinctive facial appearance, including micrognathia, prominent eyes, circumoral cyanosis, alopecia, and prominent scalp veins. Additionally, they present sclerotic skin changes and a reduced range of joint motion, features that help distinguish it from cutis laxa in clinical appearance.

Prognosis

Cutis laxa patients with only cutaneous involvement have a good prognosis, and life expectancy is usually normal. Internal organ involvement, especially pulmonary impairment, is associated with poor prognosis. Autosomal recessive cutis laxa is the most severe form.

Complications

In the autosomal dominant form, systemic complications are rare. However, the autosomal recessive form can present severe internal complications, including genitourinary and gastrointestinal diverticula, diaphragmatic hernia, and emphysema, leading to cor pulmonale and death within the first few years of life. Acquired cutis laxa often involves visceral manifestations, which have been observed in all reported patients with disease onset after the age of 20. These manifestations may entail the breakdown of elastic fibers and loss of tissue support in the lungs, gastrointestinal tract, heart, and urogenital system.