Clinical Diagnosis

The clinical diagnosis of lymphedema-distichiasis syndrome is based on the presence of the following:

• Primary lymphedema (chronic swelling of the extremities caused by an intrinsic dysfunction of the lymphatic vessels)

• Distichiasis (aberrant, extra eyelashes arising from the meibomian glands)

Molecular Genetic Testing

Gene. FOXC2 is the only gene in which mutations are known to cause lymphedema-distichiasis syndrome [Fang et al 2000].

Evidence for locus heterogeneity. Four affected families with no mutation identified in FOXC2 have been reported. Brice et al [2002] reported one out of 18 families in whom linkage was compatible with the FOXC2 locus but no mutation was identified. Finegold et al [2001] reported three small families out of 14 with no identifiable mutation; however, no linkage data were available. A duplication of a region 5’ to FOXC2 has been shown in an isolated case with lymphedema distichiasis and no FOXC2 mutation [Witte et al 2009]. It is not known if the duplication has a causative effect.

Clinical testing

Table 1. Summary Molecular Genetic Testing Used in Lymphedema-Distichiasis Syndrome

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Gene and Test Method 1	Test Availability
FOXC2	Sequence analysis	Sequence variants 2	~95%	Clinical
	Deletion / duplication analysis 3	Exonic or whole-gene deletions / duplications	Unknown; none reported 4

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. See CMA.

4. No deletions or duplications involving FOXC2 have been reported to cause lymphedema-distichiasis syndrome. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband

• Physical examination for the cardinal findings of lymphedema and distichiasis

• Molecular genetic testing of FOXC2

Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with FOXC2 mutations. However, a recent twin study suggested a link between FOXC2 and early onset of varicose veins [Ng et al 2005].

Natural History

The most common findings in lymphedema-distichiasis syndrome are lower-limb lymphedema and distichiasis.

Lymphedema is present in most individuals with lymphedema-distichiasis syndrome. It typically appears in late childhood or puberty (age range: 7-40 years) [Erickson et al 2001, Brice et al 2002], although congenital onset has been reported [Finegold et al 2001; Brice, unpublished observations].

Lymphedema is confined to the lower limbs, is often asymmetric, and can be unilateral. The severity of the lymphedema varies within families. Males develop edema at a significantly earlier age and have more problems with cellulitis than females. Sixty-five percent of males in one series complained of recurrent cellulitis in the edematous leg, compared to 25% of females [Brice et al 2002].

Primary lymphedema is usually associated with hypoplasia or aplasia of the lymphatic vessels. However, individuals with lymphedema-distichiasis syndrome have an increased number of lymphatic vessels and inguinal lymph nodes [Dale 1987, Brice 2003]. Although present, the lymphatic vessels do not appear to function properly.

Isotope lymphoscintigraphy can be used to demonstrate that the swelling is caused by lymphedema. Radioactive colloid is injected into the toe web spaces and uptake in the ilioinguinal nodes is measured at intervals. Low uptake can be demonstrated in most affected individuals in association with dermal backflow, indicating lymph reflux into the lower limbs. This technique replaces lymphangiography (x-ray after injection of dye into the lymphatic vessels in the foot).

Distichiasis describes the presence of aberrant eyelashes arising from the meibomian glands on the inner aspects of the inferior and superior eyelids. These range from a full set of extra eyelashes to a single hair. Distichiasis is observed in 94% of individuals with lymphedema-distichiasis syndrome [Brice et al 2002]. Although distichiasis may be present at birth, it may not be recognized until early childhood.

About 75% of affected individuals have ocular problems related to distichiasis including corneal irritation, recurrent conjunctivitis, and photophobia. About 25% of individuals have no symptoms from distichiasis and are thus not aware of it. Therefore, any individual with primary lymphedema of the lower limbs should be examined carefully for the presence of distichiasis.

Finegold et al [2001] described one family with a FOXC2 mutation with lymphedema only; however, only three individuals were affected and it is not known whether they were examined by slit lamp for evidence of distichiasis, which can sometimes be very subtle. In a study of 23 probands reported to have Meige disease (see Differential Diagnosis) only one was found to have a mutation in FOXC2. More extensive examination of the individuals in this family revealed that although the proband did not have distichiasis, four affected relatives had evidence of distichiasis on slit-lamp examination [Rezaie et al 2008].

In one family, distichiasis was associated with a mutation in FOXC2 but none of the affected individuals had evidence of lymphedema. The two affected individuals in the family were the 13-year-old proband (who could still develop lymphedema at a later date) and her father [Brooks et al 2003].

Varicose veins. The incidence of varicose veins is much higher (and onset earlier) in individuals with lymphedema-distichiasis syndrome than in the general population. About 50% of individuals with lymphedema-distichiasis syndrome have clinically evident varicose veins [Brice et al 2002]. In one family, light-reflective rheography and Doppler studies showed bilateral incompetence at the sapheno-femoral junction and long saphenous vein, which were presumed to be congenital abnormalities affecting both deep and superficial veins [Rosbotham et al 2000]. Ongoing studies of venous abnormalities suggest that they are present in all individuals with FOXC2 mutations [Mellor et al 2007].

Ptosis. Approximately 30% of individuals with lymphedema-distichiasis syndrome have unilateral or bilateral congenital ptosis of variable severity.

Congenital heart disease occurs in 7% of individuals with lymphedema-distichiasis syndrome. Structural abnormalities include ventricular septal defect, atrial septal defect, patent ductus arteriosis, and tetralogy of Fallot. Cardiac arrhythmia, most commonly sinus bradycardia, may also occur.

Cleft palate. About 4% of individuals have cleft palate with or without Pierre-Robin sequence.

Other findings. Other abnormalities include scoliosis, spinal extradural cysts [Kanaan et al 2006], neck webbing, uterine and renal anomalies, strabismus, and synophrys. Neonatal chylothorax has been reported in one case in association with congenital heart disease [Chen et al 1996]. One paper suggested an association with yellow nails, but discolored nails are a common feature of chronic lymphedema regardless of cause.

Genotype-Phenotype Correlations

No genotype-phenotype correlation for the major clinical signs has been reported; however, a preliminary study suggested that asymptomatic anomalies of the anterior chamber of the eye are more extensive if the mutation is in the forkhead domain rather than in other regions of the gene [Lehmann et al 2003].

Penetrance

Approximately 80% of individuals with lymphedema-distichiasis syndrome have lymphedema by early adulthood (age 30 years), although a few individuals may develop lymphedema later.

Approximately 94% of affected individuals have distichiasis. In all families reported with mutations in FOXC2, at least one individual has had distichiasis.

Anticipation

No evidence of anticipation has been reported.

Nomenclature

Lymphedema and ptosis, once described as a separate entity, is thought to be the same as lymphedema-distichiasis syndrome [Finegold et al 2001].

Prevalence

The prevalence of lymphedema-distichiasis syndrome is not known; it is a well-recognized cause of autosomal dominant primary lymphedema.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with lymphedema-distichiasis syndrome, the following evaluations are recommended:

• Referral to an ophthalmologist (preferably one familiar with distichiasis) for slit-lamp examination, as the extra lashes may be subtle and easily missed on clinical examination

• Physical examination to document the presence of manifestations and identify evidence of cellulitis

• Isotope lymphoscintigraphy to confirm underlying abnormality of the lymphatics as the cause of the edema

• Physical examination of the heart and possible echocardiography if murmur or arrhythmia is identified

• Medical genetics consultation

Treatment of Manifestations

The following are appropriate:

• Conservative management of symptomatic distichiasis with lubrication or epilation (plucking), or more definitive management with cryotherapy, electrolysis, or lid splitting [O'Donnell & Collin 1993]. Recurrence is possible even with more definitive treatment.

• Referral to a lymphedema therapist for management of edema (fitting hosiery, massage). Although the edema cannot be cured, some improvement may be possible with the use of carefully fitted hosiery and/or bandaging, which may reduce the size of the swelling as well as the discomfort associated with it.

• Surgery for ptosis if clinically indicated (e.g., obscured vision, cosmetic appearance)

• Referral to neurosurgery for individuals with symptomatic spinal cysts (i.e., any neurologic signs or symptoms especially in the lower limbs)

• Conservative management of varicose veins if possible, as surgery could aggravate the edema and increase the risk of infection or cellulitis

• Standard treatment for scoliosis

Prevention of Primary Manifestations

The implementation of hosiery prior to the development of lymphedema may be beneficial in reducing the extent of edema [P Mortimer, personal communication].

Prevention of Secondary Complications

The following are appropriate:

• Prevention of secondary cellulitis in areas with lymphedema, particularly as cellulitis may aggravate the degree of edema. Prophylactic antibiotics (e.g., penicillin V 500 mg daily) are recommended for recurrent cellulitis.

• Prompt treatment of early cellulitis with appropriate antibiotics (See the British Lymphology Society Consensus Statement for information on appropriate antibiotics.) It may be necessary to give the first few doses intravenously if there is severe systemic upset.

• Prevention of foot infections, particularly athlete's foot/infected eczema by treatment with appropriate creams/ointments

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Edema may be exacerbated during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Diuretics are not effective in the treatment of lymphedema.

Cosmetic surgery is often associated with disappointing results.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Lymphedema-distichiasis syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with lymphedema-distichiasis syndrome have an affected parent.

• A proband with lymphedema-distichiasis syndrome may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is about 25% [Brice et al 2002].

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include slit-lamp examination for distichiasis and clinical examination for lymphedema. Lymphoscintigraphy may be helpful [Rosbotham et al 2000].

Note: Although most individuals diagnosed with lymphedema-distichiasis syndrome have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members as a result of variable expressivity.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.

• If a parent of the proband is affected, the risk to the sibs is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

• If a disease-causing mutation cannot be detected in DNA extracted from leukocytes of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with lymphedema-distichiasis syndrome has a 50% chance of inheriting the mutation. Disease severity cannot be accurately predicted and is variable even within the same family.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible in the US (availability may vary by country) by analysis of DNA extracted from fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or amniocentesis usually performed at approximately 15 to 18 weeks' gestation. The disease-causing mutation of an affected family member must be identified before prenatal testing can be performed. Although available, prenatal diagnosis for lymphedema-distichiasis syndrome is rarely requested.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasonography. Fetal echocardiography at 16 to 20 weeks' gestation is recommended because of the increased risk for congenital heart disease. Because of the increased risk for cleft palate, additional fetal scans may be warranted during pregnancy as some instances of cleft palate may be detected.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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22. Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G, Woollard WJ, Dafou D, Kilo T, Smithson S, Lunt P, Murday VA, Hodgson S, Keenan R, Pilz DT, Martinez-Corral I, Makinen T, Mortimer PS, Jeffery S, Trembath RC, Mansour S. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet. 2011;43:929–31. [PubMed: 21892158]
23. Ostergaard P, Simpson MA, Mendola A, Vasudevan P, Connell FC, van Impel A, Moore AT, Loeys BL, Ghalamkarpour A, Onoufriadis A, Martinez-Corral I, Devery S, Leroy JG, van Laer L, Singer A, Bialer MG, McEntagart M, Quarrell O, Brice G, Trembath RC, Schulte-Merker S, Makinen T, Vikkula M, Mortimer PS, Mansour S, Jeffery S. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy. Am J Hum Genet. 2012;90:356–62. [PMC free article: PMC3276660] [PubMed: 22284827]
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Revision History

• 24 May 2012 (me) Comprehensive update posted live

• 2 August 2007 (me) Comprehensive update posted to live Web site

• 4 January 2007 (sm) Revision: FOXC2 mutations and Meige disease

• 16 June 2006 (cd) Revision: prenatal testing clinically available

• 6 March 2006 (cd) Revision: FOXC2 testing clinically available

• 29 March 2005 (me) Review posted to live Web site

• 13 September 2004 (sm) Original submission