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Lymphedema-Distichiasis Syndrome

NORD is very grateful to David A. Stevenson, MD, Assistant Professor, and Amy Calhoun, MD, Fellow, University of Utah, Department of Pediatrics, Division of Medical Genetics, for assistance in the preparation of this report.

Synonyms of Lymphedema-Distichiasis Syndrome

  • lymphedema with distichiasis

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Lymphedema-distichiasis syndrome is a rare genetic multisystem disorder characterized by swelling of the legs because of fluid accumulation and the development of extra eyelashes (distichiasis). Distichiasis may range from a few extra lashes to a full set of extra eyelashes. Swelling most often affects both legs (bilateral) and usually occurs around puberty. Additional anomalies sometimes associated with this disorder include early onset varicose veins, droopy eyelids (ptosis), cardiac (heart) defects, cleft palate, , cysts on the spinal cord, abnormal heart rhythm, and abnormal curvature of the spine (scoliosis). Lymphedema-distichiasis syndrome is caused by mutations of the FOXC2 gene and is inherited as an autosomal dominant trait.

Symptoms

The symptoms of lymphedema-distichiasis vary greatly from case to case even among members of the same family. The most common finding is the extra row of eyelashes (distichiasis). Most patients also develop swelling (edema) or puffiness of the legs because of the accumulation of protein-rich fluid (lymph) in the soft layers of tissue under the skin.

The severity of lymphedema (swelling due to the accumulation of lymph fluid) varies, but usually involves only the legs. In most cases, both legs are affected (bilateral). In some cases, swelling may cause tightness, discomfort and unusual tingling sensations (paresthesias) in the affected areas. Typically, lymphedema develops around puberty, although it can develop as early as before the person is born or in adulthood.

Males develop lymphedema at an earlier age than females and are more likely to develop cellulitis. Cellulitis is a bacterial infection that is often associated with lymphedema. Cellulitis is characterized by swollen, reddened skin that may feel warm and tender.

Distichiasis may range from a few extra lashes to a full set of extra eyelashes. This can be very hard to see and is often missed by routine examination. Associated eye abnormalities may occur including an abnormal sensitivity to light (photophobia), inflammation of the delicate membrane that lines the inside of the eyelids (conjunctivitis), irritation of the curved transparent outer layer of fibrous tissue covering the eyeball (cornea), and the development of a small tender bump on the eyelid (stye). Drooping or sagging of the eyelids (ptosis) may also occur.

Many individuals with lymphedema-distichiasis syndrome develop varicose veins, a condition marked by twisted, widened and enlarged veins just below the surface of the skin. In some cases, varicose veins may precede the development of lymphedema. In individuals with lymphedema-distichiasis, varicose veins develop at a much younger age and with greater frequency than in the general population.

Congenital heart disease has been reported in some individuals with of lymphedema-distichiasis syndrome, especially a condition known as tetralogy of Fallot. Tetralogy of Fallot consists of a combination of four different heart defects: a ventricular septal defect; obstructed outflow of blood from the right ventricle to the lungs (pulmonary stenosis); a displaced aorta, which causes blood to flow into the aorta from both the right and left ventricles; and the abnormal enlargement of the right ventricle. This combination of abnormalities typically leads to poor blood flow to the lungs and poor blood oxygenation. The symptoms tend to worsen with time if this remains untreated and can be life-threatening.

In some cases, irregular heartbeats (arrhythmias) may develop.

In rare cases, additional abnormalities have been reported to occur in association with lymphedema-distichiasis syndrome including crossed eyes (strabismus), incomplete closure of the roof of the mouth (cleft palate), side-to-side curvature of the spine (scoliosis), webbing of the neck, and cysts on the outermost layer of the membranes (meninges) that cover the spinal cord (spinal extradural cysts). Very rarely, patients may have total body swelling prior to birth (hydrops fetalis). Also very rarely, patients may have breathing problems due to abnormal lymph flow in their lungs.

Causes

Lymphedema-distichiasis syndrome is an autosomal dominant genetic disorder. Genetic disorders are caused by abnormalities in the DNA carried in each cell in the body. DNA is packaged into chromosomes. Human body cells normally have 46 chromosomes. Each chromosome is paired and numbered 1through 22. The sex chromosomes are designated X and Y. Males have one X and one Y and females have a pair of X's. One member of each pair comes from a person's mother and the other from his or her father. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 16q24.3" refers to band 24.3 on the long arm of chromosome 16. The numbered bands specify the location of numerous genes that are present on each chromosome. Because of the pairing of chromosomes, there are two copies of most of the genes in a human's body.

In dominant genetic disorders, the disorder occurs even though only one of the two copies of the gene is changed. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Investigators have determined that lymphedema-distichiasis syndrome occurs due to changers or disruptions (mutations) in the forkhead family transcription factor (FOXC2) gene located on the long arm (q) of chromosome 16 (16q24.3). It is currently unknown exactly how mutations in this gene lead to the symptoms of lymphedema-distichiasis syndrome.
Lymphedema is caused by the accumulation of protein-rich fluid (lymph) in areas of the body, typically due to dysfunction or abnormality of the lymphatic system. The lymphatic system is a circulatory network of vessels, ducts, and nodes that filter and distribute lymph and blood cells throughout the body. In lymphedema-distichiasis syndrome it is possible that the lymphedema develops due to obstruction, malformation, underdevelopment (hypoplasia), or improper function of various lymphatic vessels. One group of researchers, Mellor et al., showed that the venous valves failed in both the superficial and deep veins in the lower limbs of individuals with FOXC2 mutations suggesting that the FOXC2 gene is important for the normal development and maintenance of venous and lymphatic valves. Their group also showed that lymph vessel function in people with lymphedema distichiasis syndrome was negatively affected by gravity, possibly explaining why the legs are primarily affected when the gene change (mutation) is present in every cell in the body.

Affected Populations

Lymphedema-distichiasis affects males and females in equal numbers. Lymphedema develops in males at an earlier age than females. The prevalence of this disorder in the general population is unknown. Lymphedema-distichiasis syndrome may go undiagnosed making it difficult to determine its true frequency in the general population.

Related Disorders

Symptoms of the following disorders can be similar to those of lymphedema-distichiasis. Comparisons may be useful for a differential diagnosis.

The hereditary lymphedemas are the disorders most commonly confused with lymphedema-distichiasis syndrome. The disorder which is most similar is hereditary lymphedema type II or Meige syndrome. Persons with Meige syndrome have pubertal onset of lymphedema (swelling due to accumulation of tissue fluid) this is not typically associated with other symptoms or malformations. This disorder is autosomal dominant, but the gene is not known.

Hereditary lymphedema type IA, also known as Milroy disease, typically presents much earlier than lymphedema-distichiasis or Meige. Most patients have lower limb lymphedema at birth or in the first year of life. This disorder is also autosomal dominant and is caused by mutations in the FLT4 or VEGFR3 gene.

Hypotrichosis-lymphedema-telangiectasia syndrome is another disorder associated with lower limb lymphedema. The lymphedema typically occurs in childhood. This is associated with loss of hair and telangiectasias which are most commonly seen on the palms of the hands. It is caused by mutations in SOX18 and can be either autosomal dominant or autosomal recessive.

Yellow nail syndrome typically presents much later in life than lymphedema-distichiasis, Milroy, Meige, or hypotrichosis-lymphedema-telangiectasia. It is a rare disorder characterized by yellow, thickened, and curved nails with almost complete stoppage of nail growth. Loss of the strip of hardened skin at the base and sides of a fingernail (cuticles) may also occur. Separation of the nails from the nail bed (onycholysis) may cause the nails to fall out. Yellow nail syndrome is usually associated with the presence of fluid in the lungs (plural effusion) and swelling of the arms and legs (lymphedema). Other respiratory problems may occur such as chronic inflammation of the bronchi and bronchioles (bronchiectasis), chronic bronchitis, and/or ongoing inflammation of the membranes that line the sinus cavities (sinusitis). Lymphedema usually occurs around puberty. Yellow nail syndrome occurs, in some cases, because of mutations to the FOXC2 gene and is inherited as an autosomal dominant trait. (For more information on this disorder, choose "Yellow Nail" as your search term in the Rare Disease Database.)

None of the above disorders have distichiasis.

Standard Therapies

Diagnosis
A diagnosis of lymphedema-distichiasis syndrome is primarily made based upon a thorough clinical evaluation, a detailed patient history, and the identification of characteristic findings (i.e., primary lymphedema, distichiasis). FOXC2 molecular testing is available clinically to help confirm a diagnosis. A variety of specialized tests may be performed to determine the extent of the disorder. Such tests include lymphoscintigraphy or an echocardiogram. During lymphoscintigraphy, a substance known as a contrast medium is injected into a lymphatic vessel (usually in a hand or foot). A series of x-rays are taken that show the medium as it moves through the lymphatic vessels giving physicians a picture of the health and structure of the lymphatic vessels. During an echocardiogram, reflected sounds waves are used to create an image of the heart, which can reveal congenital heart defects potentially associated with lymphedema-distichiasis syndrome.

Treatment
The treatment of lymphedema-distichiasis syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment is aimed at reducing swelling and preventing infection. Complete decongestive therapy (CDT) is a form of treatment in which specialized massage techniques are coupled with therapeutic bandaging, meticulous skin care, exercise, and the use of well-fitted compression garments such as fitted stockings. Antibiotics may be used to treat recurrent infections such as cellulitis or as a preventive (prophylactic) measure in individuals with recurrent infections.

Distichiasis may be managed with lubrication or plucking (epilation). More definitive treatments for distichiasis include cryotherapy, electrolysis, or lid splitting. Cryotherapy is the application of extreme cold to destroy diseased tissue. Electrolysis uses a short-wave radio frequency to destroy the extra eyelashes. Lip splitting is a surgical procedure in which the eyelid is split open to expose the root (follicle) of the eyelashes. Each extra eyelash is then removed (excised). In some cases, cryotherapy or electrolysis is used in conjunction with lid splitting.

In some cases, surgery may be performed to treat other abnormalities such as ptosis or cleft palate. Individuals with heart abnormalities may be monitored regularly.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Organizations related to Lymphedema-Distichiasis Syndrome

References

JOURNAL ARTICLES
de Bruyn G, Casaer A, Devolder K, et al. Hydrops fetalis and pulmonary lymphangiectasia due to FOXC2 mutation: an autosomal dominant hereditary lymphedema syndrome with variable expression. Eur J Pediatr. 2012;171(3):447-50.

Mellor RH, Tate N, Stanton AWB, Hubert C, Maekinen T, Smith A, Burnand K, Jeffery S, Levick JR, Mortimer PS; Mutations in FOXC2 in humans (lymphedema distichiasis syndrome) cause lymphatic dysfunction on dependency. J Vasc Res. 2011; 44:381-4.

Shimoda H, Bernas MJ, Witte MH. Dysmorphogenesis of lymph nodes in foxc2 haploinsufficient mice. Histochem Cell Biol. 2011;135(6):603-13.

Sanches-Carpintero R, Dominguez P, Nunez MT, Patino-Garcia A, Spinal extradural arachnoid cysts in lymphedema-distichiasis syndrome. Genet Med. 2010; 12: 532-5.

Connell F, Brice G, Jeffery S, Keely V, Mortimper P, Mansur S. A new classification system for primary lymphatic dysplasias based on phenotype. Clin Genet. 2010; 77:438-452.

Connell F, Brice G, Mortimer P. Phenotypic characterization of primary lymphedema. Ann NY Acad Sci. 2008;1131:140-6.

Mellor RH, Brice G, Stanton AW, French J, Smith A, Jeffery S, Levick JR, Burnand KG, Mortimer PS; Lymphoedema Research Consortium. Mutations in FOXC2 are strongly associated with primary valve failure in veins of the lower limb. Circulation. 2007;115:1912-20.

Berry FB, Tamimi Y, Carle MV, Lehmann OJ, Walter MA. The establishment of a predictive mutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis. Hum Mol Genet. 2005;14:2619-27.

Kriederman BM, Myloyde TL, Witte MH, et al., FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome. Hum Mol Genet. 2003;12:1179-85.

Brice GW, Mansour S, Bell R, et al., Analysis of phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. J Med Genet. 2002;39:478-83.

Erickson RP, Dagenais SL, Caulder MS, et al., Clinical heterogeneity in lymphoedema-distichiasis syndrome with FOXC2 truncating mutations. J Med Genet. 2001;38:761-6.

Fang J, Dagenais SL, Erickson RP, et al., Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Med Genet. 2000;67:1382-8.

Mangion J, Rahman N, Mansour S, et al., A gene for lymphedema-distichiasis maps to 16q24.3. Am J Hum Genet. 1999;65:427-32.

INTERNET
Mansour S, Brice GW, Jeffery S, Mortimer P. (Updated August 2, 2007). Lymphedema-Distichiasis Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2012. Available at http://www.genetests.org. Accessed March 2, 2012.

Brice GW, Mansour S, Ostergaard P, Connell F, Jeffery S, Mortimer P. (Updated July 23, 2009). Milroy Disease. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2012. Available at http://www.genetests.org. Accessed March 2, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Lymphedema, Hereditary, II. Entry No: 153200. Last Edited June 10, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 2, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Lymphedema, Hereditary, IA. Entry No: 153100. Last Edited July 13, 2010. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 2, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Lymphedema-Distichiasis Syndrome. Entry No: 153400. Last Edited July 10, 2008. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 2, 2012.

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Report last updated: 2012/03/19 00:00:00 GMT+0

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