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Lymphedema-Distichiasis Syndrome

Synonym: Lymphedema with Distichiasis

, FRCP, , RGN, BSc (Hons), , PhD, and , MD, FRCP.

Author Information

Initial Posting: ; Last Update: May 24, 2012.


Clinical characteristics.

Lymphedema-distichiasis syndrome is characterized by lower-limb lymphedema and distichiasis (aberrant eyelashes ranging from a full set of extra eyelashes to a single hair). Lymphedema typically appears in late childhood or puberty, is confined to the lower limbs, and is often asymmetric; severity varies within families. Males develop edema at an earlier age and have more problems with cellulitis than females. Distichiasis, which may be present at birth, is observed in 94% of affected individuals. About 75% of affected individuals have ocular findings including corneal irritation, recurrent conjunctivitis, and photophobia; other common findings include varicose veins, congenital heart disease, and ptosis. About 25% of individuals are asymptomatic.


The diagnosis of lymphedema-distichiasis syndrome is made clinically based on the presence of primary lymphedema and distichiasis. FOXC2 is the only gene in which pathogenic variants are known to cause lymphedema-distichiasis syndrome.


Treatment of manifestations: Lubrication, plucking, cryotherapy, electrolysis, or lid splitting for treatment of distichiasis; fitted stockings and bandages to improve swelling and discomfort associated with edema.

Prevention of primary manifestations: The implementation of hosiery prior to the development of lymphedema may be beneficial in reducing the extent of edema.

Prevention of secondary complications: To prevent secondary cellulitis treat athlete's foot and other infections promptly; treat early cellulitis with antibiotics.

Other: Diuretics are not effective in the treatment of lymphedema.

Genetic counseling.

Lymphedema-distichiasis syndrome is inherited in an autosomal dominant manner. Approximately 75% of affected individuals have an affected parent; about 25% have de novo pathogenic variants. Each child of an individual with lymphedema-distichiasis syndrome has a 50% chance of inheriting the pathogenic variant. Disease severity cannot be predicted and is variable even within the same family. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in an affected family member; however, it is rarely requested. Fetal echocardiography is recommended because of the increased risk for congenital heart disease.


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 pathogenic variants are known to cause lymphedema-distichiasis syndrome [Fang et al 2000].

Evidence for locus heterogeneity. Four affected families with no pathogenic variant 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 pathogenic variant was identified. Finegold et al [2001] reported three small families out of 14 with no identifiable pathogenic variant; 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 pathogenic variant [Witte et al 2009]. It is not known if the duplication has a causative effect.

Table 1.

Molecular Genetic Testing Used in Lymphedema-Distichiasis Syndrome

Gene 1Test MethodPathogenic Variants Detected 2Variant Detection Frequency by Gene & Test Method 3
FOXC2Sequence analysis 4Sequence variants~95%
Deletion/duplication analysis 5Exon or whole-gene deletions/duplicationsUnknown; none reported 6

See Molecular Genetics for information on allelic variants.


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


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Testing that identifies exon or whole-gene 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.


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.)

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 pathogenic variant in the family.

Clinical Characteristics

Clinical Description

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 pathogenic variant 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 pathogenic variant 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 pathogenic variant 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 pathogenic variants [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 pathogenic variant is in the forkhead domain rather than in other regions of the gene [Lehmann et al 2003].


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 pathogenic variants in FOXC2, at least one individual has had distichiasis.


No evidence of anticipation has been reported.


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


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

Differential Diagnosis

Lymphedema. The presence of lymphatic vessels in lymphedema-distichiasis syndrome contrasts with other causes of primary lymphedema including Milroy disease and Meige disease, which show aplasia or hypoplasia of the lymphatic vessels.

  • In Milroy disease, lymphedema is usually present at birth and very rarely presents later. Distichiasis is not present. Milroy disease results from mutation of FLT4 (VEGFR3), encoding vascular endothelial growth factor receptor 3 [Irrthum et al 2000, Karkkainen et al 2000]. Inheritance is autosomal dominant.
  • Meige disease presents with primary lymphedema at puberty. Distichiasis is not observed. Meige disease predominantly affects women; inheritance is autosomal dominant. The gene(s) in which mutation is causative have not yet been confirmed.
  • Hypotrichosis-lymphedema-telangiectasia syndrome is the association of childhood-onset lymphedema in the lower limbs, loss of hair, and telangiectasia, particularly in the palms. Inheritance is either autosomal dominant or autosomal recessive. Pathogenic variants in SOX18 are causative [Irrthum et al 2003].
  • Lymphedema microcephaly is the association of congenital onset lymphedema with the presence of a small head circumference. Pathogenic variants in KIF11 have been found to be responsible for some cases of this condition [Ostergaard et al 2012].
  • Lymphedema with yellow nails (yellow nail syndrome, YNS) often presents after age 50 years. The nails in YNS are very slow growing, with transverse over-curvature and hardening of the nail plate. The nail changes are different from the typically discolored nails that are often associated with chronic lymphedema. Inheritance is said to be autosomal dominant; however, most cases are simplex (i.e., a single occurrence in a family) [Hoque et al 2007].
  • Emberger syndrome is the association of lower limb and genital lymphedema with myelodysplasia. Pathogenic variants in the transcription factor gene GATA2 are responsible for a proportion of cases [Ostergaard et al 2011].


  • Blepharocheilodontic syndrome is the association of lagophthalmos (inability to fully close eyes), cleft lip and palate, atrial septal defect, and oligodontia. Distichiasis is a feature; lymphedema is not observed.
  • Only one family has been reported with isolated distichiasis (i.e., absence of other malformations and/or lymphedema) [Brooks et al 2003]. Familial distichiasis has been described (OMIM 126300), but may not represent a separate genetic disorder. Others have noted individuals with "distichiasis only" in the context of a family in which both lymphedema and distichiasis were present [Falls & Kertesz 1964].
  • Distichiasis should also be clinically distinguished from trichiasis, a more common condition in which lashes arise normally from the anterior lamella of the eyelids but are misdirected. The misdirected lashes can cause symptoms similar to distichiasis (e.g., corneal irritation and photophobia).


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
  • Consultation with a clinical geneticist and/or genetic counselor

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. 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 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.


Diuretics are not effective in the treatment of lymphedema.

Cosmetic surgery is often associated with disappointing results.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants is about 25% [Brice et al 2002].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant 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 pathogenic variant cannot be detected in DNA extracted from leukocytes of either parent, two possible explanations are germline mosaicism in a parent or 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 pathogenic variant. 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 pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the pathogenic variant has been detected in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis are possible. Prenatal diagnosis for lymphedema-distichiasis syndrome is rarely requested.

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.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Lymphoedema Support Network (LSN)
    St. Luke's Crypt
    Sydney Street
    London SW3 6NH
    United Kingdom
    Phone: 020 7351 4480 (Information and Support); 020 7351 0990 (Administration)
    Fax: 020 7349 9809
  • National Lymphedema Network (NLN)
    116 New Montgomery Street
    Suite 235
    San Francisco CA 94105
    Phone: 800-541-3259 (toll-free); 415-908-3681
    Fax: 415-908-3813
  • Medline Plus
  • Lymphedema Family Study
    University of Pittsburgh, Department of Human Genetics
    A300 Crabtree Hall, GSPH
    Pittsburgh PA 15261
    Phone: 800-263-2152 (toll-free); 412-624-4659

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Lymphedema-Distichiasis Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
FOXC216q24​.1Forkhead box protein C2FOXC2 databaseFOXC2FOXC2

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Lymphedema-Distichiasis Syndrome (View All in OMIM)


Gene structure. FOXC2 (NM_005251.2) comprises a single 1.5-kb exon. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Benign variants reported in the 5' region of the gene include -512C>T [Ridderstråle et al 2002] and -350G>T [Osawa et al 2003], and in the 3' region, 1548C>T and 1702C>T [Kovacs et al 2003]. 1761G>A has been identified [Sholto-Douglas-Vernon et al 2005].

Pathogenic variants. Information on at least 35 different insertions and deletions situated throughout the gene has been published to date. More than 90% of pathogenic variants are small deletions or insertions. No whole-gene deletions have been reported.

The region 900-920 bp appears to be a "hot spot" for pathogenic variants, possibly because of the presence of a repeated GCCGCCGC element [Jeffery, unpublished data]. Several nonsense variants have been reported, as well as four missense variants: p.Ser125Leu [Bell et al 2001], p.Arg121His [Brice et al 2002], p.Trp116Arg, and p.Ser235Ile [Sholto-Douglas-Vernon et al 2005]. The first three are presumed to be disease-causing; the status of p.Ser235Ile is unknown.

Table 2.

FOXC2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.

Note: FOXC2 pathogenic variants analogous to p.Ser125Leu and p.Arg121His inactivate FOXC1 [Saleem et al 2003]. Pathogenic variants in FOXC1 give rise to Axenfeld-Rieger anomaly and congenital glaucoma.

A recent report has suggested that missense changes outside the forkhead domain can produce increased transactivational activity, which appears to be associated with a hypoplastic pattern on lymphoscintigraphy. None of the four patients with such pathogenic variants had distichiasis. [van Steensel et al 2009].

Normal gene product. Because the gene has no introns, no isomers exist. The normal product is active as a transcriptional regulator during embryonic development and is also expressed in white adipose tissue in adults and in human adult lymphatics [Petrova et al 2004].

Abnormal gene product. The assumed mechanism of pathogenesis is haploinsufficiency. It is not clear whether the frameshift pathogenic variants produce a protein product with novel amino acids or whether the mRNA or proteins are degraded.


Literature Cited

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Chapter Notes

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
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