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Cutis Laxa

Generalized Dermatochalasia

Cutis laxa refers to loose or wrinkled skin and is the most striking symptom of a variety of inherited and acquired connective tissue disorders.


Presentation

ADCL, ARCL, XRCL and acquired CL are associated with different symptoms. For clinical purposes, ARCL related to mutations in genes FBLN5, EFEMP2 and LTBP4 are referred to as type 1 disorders. ARCL related to defects of genes ATP6V0A2 and PYCR1 correspond to type 2 disorders.

All forms of CL share the symptom of excess, loose and wrinkled skin. Most forms of CL are not associated with an augmented vulnerability, though. In individuals who inherited gene mutations triggering CL, redundant skin may be recognized at birth or become visible within the first year of life. Faces of these children appear like those of old people and are marked by baggy eye sacks, sagging checks and drooping mouth angles. Furthermore, loose skin is readily apparent at neck, abdomen, hands and feet.

Additional symptoms largely depend on the type of CL.

ADCL

ADCL is generally less severe than both types of ARCL. Dermatological alterations dominate over internal organ involvement. An increased risk for bronchiectasis, pulmonary emphysema, aortic aneurysm as well as umbilical and inguinal hernias exists [1].

ARCL - type 1

This is the most severe form of CL. It is potentially lethal. Patients who survive show lung emphysema, cor pulmonale, diaphragmatic defects, diaphragmatic hernia, arterial malformations, aneurysm, diverticuli along the gastrointestinal and urinary tracts, umbilical and inguinal hernias, retarded growth and instability of the joints [11] [12].

ARCL - type 2

Skeletal anomalies dominate the clinical picture of this disease. Both osseous and articular structures are affected and patients may present with deformities, instable joints, premature loss of teeth and delayed closure of cranial sutures and fontanels.

XRCL

Patients suffering from XRCL present similarly to those diagnosed with ARCL - type 2.

Acquired CL

Acquired CL usually manifests in adulthood. It is often referred to as post-inflammatory CL and, according to current knowledge, may follow any disease associated with high fever or severe inflammation. Little is known about the pathophysiological mechanisms triggering this disorder and thus, it may only be speculated about which diseases can and which can't provoke CL.

In about 50% of patients developing acquired CL, a prodromal stage marked by fever, malaise, angioedema and rash may precede CL. The latter mainly manifest in face and neck regions. Loose skin formation typically starts here, too, and spreads over the body. It may be restricted to face, neck and/or trunk or become generalized. In most cases, CL is limited to previously inflamed areas of skin.

Plethora
  • Acquired CL is often described as post-inflammatory CL and has been related to a plethora of diseases, e.g., penicillin allergy, myeloma, lymphoma, syphilis, borreliosis, toxocariasis, onchocerciasis, rheumatoid arthritis, systemic lupus erythematosus[symptoma.com]
High Fever
  • It is often referred to as post-inflammatory CL and, according to current knowledge, may follow any disease associated with high fever or severe inflammation.[symptoma.com]
Wheelchair Bound
Premature Loss of Teeth
  • Both osseous and articular structures are affected and patients may present with deformities, instable joints, premature loss of teeth and delayed closure of cranial sutures and fontanels.[symptoma.com]
Severe Brachydactyly
  • Severe brachydactyly and a unique facial appearance with prominent eyes distinguish LMS in the early stages from other forms of cutis laxa [ Sousa et al 2014 ].[ncbi.nlm.nih.gov]
Hypomimia
  • Affected individuals have a common facial gestalt with triangular face, hypomimia, large everted ears, and a cutis laxa more pronounced in extremities. About 95% of affected individuals have intellectual disability.[ncbi.nlm.nih.gov]
Cerebellar Sign
  • Neurologic regression (with or without seizures) can include spasticity and cerebellar signs and symptoms (ataxia, slurred speech). Some adolescents become wheelchair bound.[ncbi.nlm.nih.gov]
Renal Injury
  • In γ-HCDD, extrarenal manifestations such as cutis laxa may precede renal injury and are precious tools for an early diagnosis, which is crucial to avoid progression of irreversible renal and elastic tissue damage.[ncbi.nlm.nih.gov]

Workup

CL diagnosis is generally based on the patient's family's medical history and clinical examination. The former may hint at a particular type of heritable CL, but spontaneous mutations have repeatedly been described and heritable CL can't be ruled out because no such cases have been observed in relatives. Genetic testing may be carried out to identify the precise mutation and this information is important for prognosis and life expectancy. A significant share of patients does not present mutations of any of those genes known to be involved in CL pathophysiology, though. Histopathological analysis of skin biopsies is generally not necessary but may reveal the above described changes in elastic fiber quantity and quality. If laboratory analyses of blood samples are carried out, the most common findings are elevated serum levels of elastin-derived peptides, hyperproteinemia and normochromic, normocytic anemia.

Such alterations may also be detected in blood samples of adult patients tentatively diagnosed with acquired CL. Here, a more thorough workup is recommended to associate dermatological findings with possibly underlying diseases. Further laboratory analyses and diagnostic imaging are first-line diagnostic tools to detect autoimmune disorders, hematopoietic malignancies, rheumatoid arthritis and other pathologies.

If diagnosis of CL is confirmed, sonographic and radiographic examination of thorax and abdomen as well as pulmonary function tests should be realized to assess cardiac and pulmonary involvement. Such examinations should be repeated at regular intervals.

Normocytic Anemia
  • If laboratory analyses of blood samples are carried out, the most common findings are elevated serum levels of elastin-derived peptides, hyperproteinemia and normochromic, normocytic anemia.[symptoma.com]

Treatment

Treatment of CL is supportive and should be adjusted to the patient's individual dermatological and systemic complications of the disease.

According to the patient's individual risk for cardiaovascular and pulmonary complications, drug therapy may serve to prevent or delay formation of aortic aneurysm and pulmonary impairment. Beta-sympatholytic agents are often administered to this end.

Surgical interventions may be indicated to treat aortic aneurysm, diaphragmatic, umbilical or inguinal hernia, diverticuli of gastrointestinal or urinary tract and skeletal malformation. Excess skin is generally more of a cosmetic problem and may be resected. Also, injections of botulinum neurotoxin have been reported to improve the appearance of skin [13]. However, long-term resolution cannot be guaranteed with either of the aforementioned interventions and relapses are frequent.

Patients and their families may benefit from psychological support.

Prognosis

Prognosis varies largely between distinct forms of CL. ADCL are usually associated with a better outcome than ARCL, life expectancy is approaching that of healthy individuals. Morbidity mainly results from cutaneous alterations. ARCL related to mutations of genes FBLN5, EFEMP2 and LTBP4 are generally lethal within early childhood. Most of these patients die from cardiovascular or respiratory failure.

Prognosis for patients suffering from acquired CL depends on the underlying disease and is worst for those cases associated with malignancies.

Etiology

In general, inherited and acquired forms of CL may be distinguished. With regards to those cases triggered by genetic disorders, mutations inherited with autosomal dominant, autosomal recessive and X-linked recessive traits have been described and corresponding forms of CL are accordingly designated ADCL, ARCL and XRCL.

ADCL have been related to mutations of the ELN and FBLN5 genes that encode for tropoelastin and extracellular matrix protein fibulin-5, which is important for elastogenesis, respectively [3]. ELN is located at position 7q11.23, FBLN5 at position 14q32.12.

Similarly, gene defects of ELN and FBLN5 genes may be inherited with an autosomal recessive trait. Further forms of ARCL relate to mutations of the following genes:

  • EFEMP2, a gene encoding for extracellular matrix protein fibulin-4, which is not only needed for elastogenesis but also for collagen synthesis - thus, EFEMP2-related ARCL is more severe than FBLN5-related ARCL [4]; gene EFEMP2 is located at position 11q13.1
  • LTBP4, whose gene product interacts with fibulin-5 to regulate elastic fiber assembly [5]; it can be found at position 19q13.2
  • ATP6V0A, encoding for proton pump involved in Golgi function [6]; ubicated at position 12q24.31
  • PYCR1, a gene that encodes for an enzyme which catalyzes proline biosynthesis and thereby contributes to supply of components for elastin and collagen [7]; it is located at position 17q25.3
  • ADLH18A1, whose gene product participates in ornithine, citrulline, arginine, and proline biosynthesis [8]; the gene is ubicated at 10q24.1

XRCL are triggered by missense mutations in gene ATP7A, which encodes for a copper-transporting ATPase. This particular type of CL was formerly classified as Ehlers Danlos syndrome type 9 and is better known as occipital horn syndrome.

Patients may suffer also from additional gene defects. Those individuals diagnosed with De Barsy syndrome, for instance, show PYCR1 mutations that do, however, not account for all symptoms. The term cutis laxa syndrome has been proposed to describe CL with severe nervous system involvement [9]. Geroderma osteodysplasticum, Menkes disease and RIN2 syndrome are further examples for complex syndromes that comprise CL.

Acquired CL is often described as post-inflammatory CL and has been related to a plethora of diseases, e.g., penicillin allergy, myeloma, lymphoma, syphilis, borreliosis, toxocariasis, onchocerciasis, rheumatoid arthritis, systemic lupus erythematosus, celiac disease and others [1].

Of note, some patients neither present gene defects in any of the aforementioned genes nor have a medical history that would explain acquired CL. While these cases may be deemed idiopathic, unknown genetic disorders or triggers most likely account for them.

Epidemiology

CL is a rare disease. The overall incidence doesn't seem to surpass 1 per 1,000,000 births. Presumably, inheritable forms are more common than the acquired type of the disease. With regards to genetic disorders causing CL, de novo mutations seem to account for a major share of cases. Some specific genetic defects have only been described in a handful of cases.

CL due to genetic defects is usually diagnosed in neonates or infants while acquired CL typically manifests in adulthood. XRCL is more common in females than in males.

Sex distribution
Age distribution

Pathophysiology

Fibroblasts and smooth muscle cells synthesize soluble tropoelastin. Copper-dependent lysyl oxidase subsequently oxidize, as their name indicates, lysyl residues of tropoelastin which results in cross-linking of these molecules and formation of insoluble elastin. Elastin and microfibrils are finally assembled to form elastic fibers.For some types of CL, the precise point of disturbance of elastogenesis can be named: ELN encodes for tropoelastin itself. The respective mutation renders tropoelastin less likely to bind to fibrillin, a microfibrillar protein. Mutations of FBLN5, EFEMP2 and LTBP4 encode for fibulin-5, fibulin-4 or an associated protein and these molecules introduce tropoelastin to microfibrils. Therefore, the protein network building elastic fibers cannot be established. Copper transport deficiencies may lead to decreased activity of lysyl oxidase and diminished cross-linking. This pathogenetic mechanism accounts for symptoms of XRCL and ATP7A mutation [10].

Symptoms associated with distinct forms of CL thus result from impairment of elastogenesis and, in more severe cases, collagen synthesis. This may affect both quantity and morphology of connective tissue fibers in skin, arteries, lungs and other tissues. The most noticeable consequence of such a connective tissue disorder is excess, sagging skin with increased resilience but less flexibility. Histopathologic analyses of skin biopsies submitted to elastic fiber stains usually reveal sparse, fragmented or granular elastic fibers within the reticular dermis.  No specific finding allows assignment to a particular form of CL, though. But because alterations are not limited to the skin, CL patients have a very high risk of aortic aneurysm and pulmonary emphysema.

Prevention

Although no specific measures can be recommended to prevent the onset of CL, general life style decisions may help to slow down progress of lung and skin damage. In this context, smoking and excess exposure to sunlight should be avoided.

Patients diagnosed with CL who wish to procreate may benefit from genetic counseling.

Summary

Cutis laxa (CL) is a descriptive term that refers to loose or wrinkled skin, which can even be a physiological condition: Cutis laxa senilis describes characteristic changes of skin appearance and composition in the elderly. And in fact, patients who are diagnosed with pathological CL may seem to have aged prematurely but don't suffer from progeria. This article will focus on pathological CL.

CL may be provoked by dominant, recessive, autosomal or X-linked genetic disorders, although symptoms do not necessarily manifest at birth. They may develop in the course of the first year of life. CL may also be acquired. Medication, hematopoietic malignancies, bacterial and parasitic infections, autoimmune disorders and other entities have all been related to CL [1]. In any case, CL results from connective tissue disorders, mainly from disturbances of elastogenesis. Elastin conveys elasticity not only to the skin, but also to other organs that continuously expand and contract. Arteries and lungs are often mentioned as examples, but tendons, ligaments, elastic cartilage, uterus and many other tissues also contain elastic fibers. Thus, excess, wrinkled and hypoelastic skin may be the most striking symptom of CL, but affected individuals often suffer from systemic involvement [2]. Morbidity and mortality principally result from cardiovascular and pulmonary complications.

Patient Information

Cutis laxa (CL) is a rare disease characterized by excess, wrinkled and less elastic skin that gives the impression of premature aging. However, CL is a connective tissue disorder and as such, is not restricted to the skin. Internal organs are frequently involved, too.

Causes

There are distinct types of CL that all share the striking symptom of redundant, wrinkled skin. Most cases result from genetic disorders, i.e., patients either inherited gene defects from their parents or any gene involved in connective tissue synthesis has mutated spontaneously. Here, symptoms are either recognizable at birth or develop during early childhood.

If CL is diagnosed in adults, the disease is usually acquired. Although pathophysiological mechanisms are not yet understood, it seems administration of certain drugs, infectious diseases, cancer and autoimmune disorders may trigger this form of CL.

Symptoms

Elastogenesis is the medical term for the biosynthesis of elastin and elastic fibers. These fibers convey resilience and elasticity to skin, arteries, lungs, tendons, ligaments and a variety of other tissues that are constantly submitted to expansion and contraction. Because most of the above mentioned gene mutations affect those genes required for elastogenesis, CL patients present lower quantity and quality of elastic fibers in these tissues and develop symptoms accordingly:

Of note, an individual suffering from a specific type of CL will usually not present all these symptoms. Rash and inflammation of the skin, for instance, is typical for acquired CL but does generally not occur in any inheritable form.

Diagnosis

CL diagnosis is based on the patient's family's medical history and clinical examination. If CL has not been diagnosed in this particular family before, genetic screens may be carried out to identify the precise mutation causing the disease. This particularly applies to neonates and infants manifesting symptoms of CL.

In contrast, adults are more often diagnosed with acquired CL and laboratory analyses of blood and urine samples as well as diagnostic imaging are generally applied to detect any underlying disease that triggered CL.

Regular follow-ups are necessary to assess the condition of internal organs and allow an early detection of exacerbation.

Treatment

There is no causative treatment for CL. Medication may be described to prevent or delay the onset of cardiovascular and pulmonary complications, e.g., aortic aneurysm and pulmonary emphysema. Surgical interventions may be required to treat these and other pathologies of internal organs. Hernias, diverticuli of gastrointestinal and urinary tract, and skeletal malformations, for instance, either indicate or may improve after surgical repair. Excess, loose skin may be resected or toned injecting botulinum neurotoxin.

References

Article

  1. Berk DR, Bentley DD, Bayliss SJ, Lind A, Urban Z. Cutis laxa: a review. J Am Acad Dermatol. 2012; 66(5):842 e841-817.
  2. Tofolean DE, Mazilu L, Staniceanu F, et al. Clinical presentation of a patient with cutis laxa with systemic involvement: a case report. Rom J Morphol Embryol. 2015; 56(3):1205-1210.
  3. Graul-Neumann LM, Hausser I, Essayie M, Rauch A, Kraus C. Highly variable cutis laxa resulting from a dominant splicing mutation of the elastin gene. Am J Med Genet A. 2008; 146A(8):977-983.
  4. Papke CL, Tsunezumi J, Ringuette LJ, et al. Loss of fibulin-4 disrupts collagen synthesis and maturation: implications for pathology resulting from EFEMP2 mutations. Hum Mol Genet. 2015; 24(20):5867-5879.
  5. Noda K, Dabovic B, Takagi K, et al. Latent TGF-beta binding protein 4 promotes elastic fiber assembly by interacting with fibulin-5. Proc Natl Acad Sci U S A. 2013; 110(8):2852-2857.
  6. Kornak U, Reynders E, Dimopoulou A, et al. Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2. Nat Genet. 2008; 40(1):32-34.
  7. Guernsey DL, Jiang H, Evans SC, et al. Mutation in pyrroline-5-carboxylate reductase 1 gene in families with cutis laxa type 2. Am J Hum Genet. 2009; 85(1):120-129.
  8. Nozaki F, Kusunoki T, Okamoto N, et al. ALDH18A1-related cutis laxa syndrome with cyclic vomiting. Brain Dev. 2016.
  9. Morava E, Lefeber DJ, Urban Z, et al. Defining the phenotype in an autosomal recessive cutis laxa syndrome with a combined congenital defect of glycosylation. Eur J Hum Genet. 2008; 16(1):28-35.
  10. Dagenais SL, Adam AN, Innis JW, Glover TW. A novel frameshift mutation in exon 23 of ATP7A (MNK) results in occipital horn syndrome and not in Menkes disease. Am J Hum Genet. 2001; 69(2):420-427.
  11. Loeys B, Van Maldergem L, Mortier G, et al. Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum Mol Genet. 2002; 11(18):2113-2118.
  12. Alehossein M, Pourgholami M, Kamrani K, Soltani M, Yazdi A, Salamati P. Radiologic findings in cutis laxa syndrome and unusual association with hypertrophic pyloric stenosis. Iran J Radiol. 2013; 10(2):94-98.
  13. Tamura BM, Lourenco LM, Platt A, Pertel P, Santos LF, Levites J. Cutis laxa: Improvement of facial aesthetics by using botulinum toxin. Dermatol Surg. 2004; 30(12 Pt 2):1518-1520.

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Last updated: 2019-07-11 22:36