Practice Essentials
Cutis laxa, 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.
Autosomal recessive cutis laxa (ARCL) is a genetically heterogeneous condition. [2] ARCL has several subtypes:
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FBLN4 ( EFEMP2)-related cutis laxa (ARCL1B) is often characterized by accompanying severe cardiovascular symptoms include arterial stenosis, tortuosity, and aneurysms along with skeletal malformations, retrogenia, high-arched palate, and orbital hypertelorism. Severe forms of ARCL 1B can be responsible for morbidity in neonates, but the condition can also manifest in milder forms. [4]
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ATP6V0A2-related cutis laxa (ARCL2A) is a defect of N- and O-linked glycosylation. [6] The condition produces the characteristic loose skin of cutis laxa, but this feature often improves as the patient ages. Additionally, ARCL 2A patients typically have hip dysplasia present at birth, enlarged anterior fontanel, myopia, developmental delay, seizure disorders, and hernias. [4, 7]
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PYCR1-related cutis laxa (ARCL2B) causes symptoms of developmental delay, growth delay, microcephaly, progeroid features, protruding auricles, and skeletal abnormalities. [4]
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ARCL3A or De Barsy syndrome A is caused by ALDH18A1 mutations. The condition is characterized by delayed growth, ocular cataracts, cognitive impairment, loose skin, and joint hypermobility. Patients may also have amino acid synthesis issues and hyperammonemia. [4]
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ARCL3B or De Barsy syndrome B is caused by mutations in PYCR1. It produces identical symptoms to ARCL3A. [4]
Gerodermia osteodysplasticum is an autosomal recessive disorder attributed to mutations in GORAB (SCYL1BP1). [8] This condition occurs in infants and young children and is characterized by loose skin, micrognathia, hip dysplasia, dwarfism, and osteoporosis. However, gerodermia osteodysplasticum does not typically cause cardiopulmonary symptoms. [4]
Macrocephaly, alopecia, cutis laxa, and scoliosis (MACS) syndrome is also autosomal recessive. Other symptoms include short stature, pes planus, and joint hypermobility. [4]
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) and fibulin 5 (FBLN5) gene have been described. [9, 10, 4]
In both the inherited type and the acquired type, the internal organs are frequently involved. Cutis laxa may be preceded by an inflammatory rash, such as urticaria, [1] or it may develop spontaneously.
Acquired cutis laxa type II, also called Marshall syndrome, has been reported as secondary to Sweet syndrome (acute febrile neutrophilic dermatosis) in a child. [11]
Treatment
No treatment exists to prevent disease progression, although dapsone can be used acutely to control swelling in persons with acquired cutis laxa, consistent with the suspected role of neutrophil elastase. Penicillamine and doxycycline are ineffective.
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. [12]
Patient education
Cutis Laxa Internationale is an international support group for patients with cutis laxa. Genetic counseling is recommend for cutis laxa patients and their families.
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. [13]
In most cases of cutis laxa, 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.
Studies have shown that several factors, such as copper deficiency, lysyl oxidase, elastases, and elastase inhibitors, contribute to abnormal elastin degradation. [14] 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 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 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 a single patient with cutis laxa 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 suggest that the biochemical basis of the disorder may be heterogeneous. Indeed, cutis laxa could result from mutations that affect the synthesis, the stabilization, or the degradation of elastic fibers.
Epidemiology
Cutis laxa (elastolysis) is rare. Congenital forms of cutis laxa are more common than acquired disease. The recessively inherited form is most frequent and most severe. Autosomal dominant forms also exist.
Cutis laxa affects persons of all races and affects men and women equally. The autosomal dominant form has a later onset than the autosomal recessive form. Acquired cutis laxa 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 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. [15, 16]
Approximately one half of the cases of acquired cutis laxa 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. [17] 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. [18] The postinflammatory form of acquired cutis laxa 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. [19, 20, 21] 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 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. [22]
In rare cases, cutis laxa is associated with congenital hemolytic anemia of unknown origin and early-onset pulmonary emphysema. [23]
Gastrointestinal manifestations include diverticulosis and, rarely, hypertrophic pyloric stenosis [24] and recurrent ileus. [25]
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Prominent skin laxity and wrinkling on the back.
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Marked diminution of elastic fibers in the lower dermis (Verhoeff-van Gieson stain). Courtesy of Dr F. Abreo.
