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Lymphedema Distichiasis

Lymphedema distichiasis is commonly referred to as the "double row of eye lashes" expression of hereditary lymphedema. The gene FOXC2 mututation is involved with this symptom.

Cause: Mutation of FOXC2

Distichiasis-Lymphedema Syndrome is a rare inherited disorder characterized by the presence of extra eyelashes (distichiasis) and swelling of the arms and legs (lymphedema). Swelling of the legs, especially below the knees, and eye irritation are common in people with this disorder. Occasionally, cysts on the spine (epidural) and other abnormalities of the spinal column may also occur. Distichiasis-Lymphedema Syndrome is inherited as an autosomal dominant genetic trait. (1)


Gene Map Locus: 16q24.3

Genetics: Mutation in the forkhead family transcription factor gene MFH1 (FOX2; 602402). Related disorders with overlapping features include hereditary lymphedema II. (Meige Syndrome); lymphedema with ptosis and lymphedema with yellow nail syndrome.

Description: Expressed as the characteristic "double-row" of eye lashes. Usually not detected or observed until a compilcation such as corneal irritation or ulceration brings it to the attention of the patient or physician.

Related genetic features (lymphedema): Cardiac defects, cleft-palate, spinal extradural cysts and photofobia.


Lymphedema distichiasis

G. Brice and A. Child
Department of Cardiological Science
St. Georges Hospital Medical School, London

The features of this condition are lymphedema of pubertal onset, preceded by the development of extra lashes arising from the meibomian gland openings. These can vary from a full extra set of lashes to the odd extra lash. They are normally soft and pale but often cause corneal irritation. Cases of apparently severe distichiasis in which patients have been unaware of the extra lashes have been reported (Kremer et al. 1986, Mangion et al. 1999) underlining the need for ocular examination in all patients in which there is a family history of distichiasis or lymphedema. Equally, patients referred with distichiasis alone should be examined for limb swelling and a family history sought. In our series of 10 families ascertained via an ophthalmic department there are no families with distichiasis alone. In most cases the extra lashes are clearly visible and slit lamp examination is not required to confirm the diagnosis. Treatment is by epilation, cryotherapy or lid splitting surgery (Shammas et al. 1979, Temple & Collin 1994).

Lymphedema distichiasis is typically associated with the uncommon lymphangiographic finding of hyperplasia, in which there are numerous dilated lymphatic vessels in the legs (Dale 1987). In addition it is often associated with other congenital abnormalities such as heart defects, cleft palate, ptosis and vertebral anomalies (Temple & Collin 1994).

Mangion et al. (1999) published linkage to chromosome 16q24.3 in three families with lymphedema distichiasis. The addition of further individuals from the largest of three families subsequently reduced the critical interval from 16cM to 2Mb. Eight further lymphoedema-distichiasis families were also consistent with linkage to the same 2Mb region (Bell et al. 2000). Recently, the FOXC2 (MFH-1) transcription factor gene was found to harbour mutations in families affected by lymphedema distichiasis. One nonsense mutation and one four base paid duplication were found in unrelated patients (Fang et al. 2000). Subsequently, our group has located 14 FOXC2 mutations in distichiasis families, 13 of which were insertions or deletions. Mutation sites are scattered throughout the gene but no apparent genotype-phenotype correlation was evident (Bell et al., submitted for publication). Further work will be carried out to determine the effect of the mutations on protein function.





Alternative titles; symbols



A number sign (#) is used with this entry because of evidence that the lymphedema-distichiasis syndrome is caused by mutation in the forkhead family transcription factor gene MFH1 (FOXC2; 602402). Allelic disorders with overlapping features include hereditary lymphedema type II, or Meige syndrome (153200), lymphedema and ptosis (153000), and lymphedema and yellow nail syndrome (153300). 30 MEDLINE Neighbors


Lymphedema-distichiasis is an autosomal dominant disorder that classically presents as lymphedema of the limbs and double rows of eyelashes (distichiasis). Irritation of the cornea, with corneal ulceration in some cases, brings the patients to the attention of ophthalmologists. Other complications may include cardiac defects, cleft palate, spinal extradural cysts, and photophobia (Fang et al., 2000). 30 MEDLINE Neighbors


The first description of the combination of lymphedema and distichiasis was reported by Neel and Schull (1954). Falls and Kertesz (1964) reported 4 sibs with bilateral lymphedema of the legs and distichiasis. One of the 4 had striking webbed neck, whereas 2 were thought to have mild webbing. Several of the affected persons complained of photophobia and had partial ectropion of the lateral third of the lower lids, giving them a wide-eyed appearance. The father and one of his brothers reportedly had lymphedema, distichiasis, and webbed neck, and the paternal grandmother had lymphedema. An affected paternal uncle died of metastatic fibrosarcoma originating in an edematous leg. 30 MEDLINE Neighbors

Chynn (1967) saw these features in combination with spinal extradural cyst (271100) in 2, and perhaps 3, black sibs. Spinal changes were present but asymptomatic in the affected father, daughter, and son described by Robinow et al. (1970). Hoover (1971) studied a family with the lymphedema-distichiasis syndrome in 3 generations. 30 MEDLINE Neighbors

Dale (1987) noted that 'bilateral hypoplasia' lymphedema is an uncommon form of lymphedema in which lymphography shows abundant, dilated lymphatics occurring in both lower limbs, and the thoracic duct is either absent, obstructed, or deformed. Further, he noted that this form of lymphedema is often associated with other congenital malformations, including distichiasis and congenital heart disease. In a survey of 725 patients with primary lymphedema treated at St. Thomas' Hospital, Dale (1987) found 5 with distichiasis, all of whom showed bilateral hyperplasia. Of 475 patients investigated by lymphography, only 30 (6%) had bilateral hyperplasia. Of these, 11 (36%) had a positive family history, and 3 had both distichiasis and bilateral hyperplasia. Further examination of these affected families showed a variable phenotype, in that some members had both lymphedema and distichiasis, whereas others had only lymphedema. Kolin et al. (1991) described 2 cases of distichiasis, one in association with familial and congenital lymphedema with hypoplasia of lymphatics (suggesting Milroy disease), and the second in association with pubertal onset of lymphedema. 30 MEDLINE Neighbors

Johnson et al. (1999) described this syndrome in a 14-year-old African American girl who presented with a 3-month history of nonpitting edema beginning on the left distal leg and progressing to both lower extremities and extending to the thigh. She had had surgery for dual-chamber pacemaker placement for symptomatic bradycardia due to Mobitz type I secondary atrioventricular block and correction of supracardiac total anomalous pulmonary venous connection and patent ductus arteriosus (see 607411). The family history was notable for a maternal grandmother and a great-grandmother with lymphedema and congenital heart disease; the medical condition of the mother of the proband was unknown. Ophthalmic examination showed a bilateral double row of eyelashes without corneal abrasion. 30 MEDLINE Neighbors

Brice et al. (2002) described in detail the clinical findings in 74 affected subjects from 18 families, as well as 6 isolated cases, with the lymphedema-distichiasis syndrome. All patients had mutations in the FOXC2 gene, except 2 affected brothers who showed linkage to the FOXC2 gene. Fifty-seven of the 74 patients had clinical evidence of lymphedema, with the onset in males (9 to 11 years) significantly earlier than the onset in females (14 to 20 years), but penetrance appeared complete in both sexes by the age of 40 years. The lymphedema was usually bilateral and asymmetric. Lymphoscintigram in 9 patients showed abnormally low uptake of radioactive colloid in inguinal nodes, increased number of lymph conducting pathways, and lymph reflux. Distichiasis occurred in 94% of patients, 74% of whom had complications, including corneal irritation, photophobia, conjunctivitis, and styes. Ptosis was noted in 31%, congenital heart disease in 6.8%, and cleft palate in 4%. No patients had spinal extradural cysts. Varicose veins, present in 49%, were notable for early onset and increased prevalence compared to the general population, and Brice et al. (2002) emphasized the link between the lymphatic and vascular systems being affected. There were no apparent genotype/phenotype correlations. 30 MEDLINE Neighbors


In 3 families with lymphedema-distichiasis, Mangion et al. (1999) found linkage to 16q24.3. Subsequent analysis of the region for recombinants placed the locus between D16S422 and D16S3074, a distance of approximately 16 cM.

Erickson et al. (1995) described neonatal lymphedema, similar to that seen in Turner syndrome, associated with a Y;16 translocation in a male infant. They were not able to find a candidate gene on the Y chromosome to account for the lymphedema and turned their attention to the breakpoint in chromosome 16 at 16q24.3. When the lymphedema-distichiasis syndrome was mapped to a 16-cM region on distal chromosome 16, they determined that the breakpoint in the Y;16 translocation was within this region and narrowed the region to a 20-kb segment. 30 MEDLINE Neighbors


In 2 families with autosomal dominant lymphedema-distichiasis syndrome, Fang et al. (2000) identified inactivating mutations in the FOXC2 gene: a nonsense mutation (602402.0001) and a frameshift mutation (602402.0002),

Erickson et al. (2001) described truncating mutations in the FOXC2 gene in 9 families with lymphedema-distichiasis syndrome, 6 of which had not previously been reported.


Corbett et al. (1982); Pap et al. (1980); Schwartz et al. (1980)


1. Brice, G.; Mansour, S.; Bell, R.; Collin, J. R. O.; Child, A. H.; Brady, A. F.; Sarfarazi, M.; Burnand, K. G.; Jeffery, S.; Mortimer, P.; Murday, V. A. :
Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. J. Med. Genet. 39: 478-483, 2002.
PubMed ID : 12114478
2. Chynn, K.-Y. :
Congenital spinal extradural cyst in two siblings. Am. J. Roentgen. 101: 204-215, 1967.
3. Corbett, C. R. R.; Dale, R. F.; Coltart, D. J.; Kinmonth, J. B. :
Congenital heart disease in patients with primary lymphoedemas. Lymphology 15: 85-90, 1982.
PubMed ID : 7144249
4. Dale, R. F. :
Primary lymphoedema when found with distichiasis is of the type defined as bilateral hyperplasia by lymphography. J. Med. Genet. 24: 170-171, 1987.
PubMed ID : 3573000
5. Erickson, R. P.; Dagenais, S. L.; Caulder, M. S.; Downs, C. A.; Herman, G.; Jones, M. C.; Kerstjens-Frederikse, W. S.; Lidral, A. C.; McDonald, M.; Nelson, C. C.; Witte, M.; Glover, T. W. :
Clinical heterogeneity in lymphoedema-distichiasis with FOXC2 truncating mutations. J. Med. Genet. 38: 761-766, 2001.
PubMed ID : 11694548
6. Erickson, R. P.; Hudgins, L.; Stone, J. F.; Schmidt, S.; Wilke, C.; Glover, T. W. :
A 'balanced' Y;16 translocation associated with Turner-like neonatal lymphedema suggests the location of a potential anti-Turner gene on the Y chromosome. Cytogenet. Cell Genet. 71: 163-167, 1995.
PubMed ID : 7656589
7. Falls, H. F.; Kertesz, E. D. :
A new syndrome combining pterygium colli with developmental anomalies of the eyelids and lymphatics of the lower extremities. Trans. Am. Ophthal. Soc. 62: 248-275, 1964.
PubMed ID : 14269895
8. Fang, J.; Dagenais, S. L.; Erickson, R. P.; Arlt, M. F.; Glynn, M. W.; Gorski, J. L.; Seaver, L. H.; Glover, T. W. :
Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am. J. Hum. Genet. 67: 1382-1388, 2000. Note: Erratum: Am. J. Hum. Genet. 68: 818 only, 2001.
PubMed ID : 11078474
9. Hoover, R. E. :
Personal Communication. Baltimore, Md., 1971.
10. Johnson, S. M.; Kincannon, J. M.; Horn, T. D. :
Lymphedema-distichiasis syndrome: report of a case and review. (Letter) Arch. Derm. 135: 347-348, 1999.
PubMed ID : 10086462
11. Kolin, T.; Johns, K. J.; Wadlington, W. B.; Butler, M. G.; Sunalp, M. A.; Wright, K. W. :
Hereditary lymphedema and distichiasis. Arch. Ophthal. 109: 980-981, 1991.
PubMed ID : 2064580
12. Mangion, J.; Rahman, N.; Mansour, S.; Brice, G.; Rosbotham, J.; Child, A. H.; Murday, V. A.; Mortimer, P. S.; Barfoot, R.; Sigurdsson, A.; Edkins, S.; Sarfarazi, M.; Burnand, K.; Evans, A. L.; Nunan, T. O.; Stratton, M. R.; Jeffery, S. :
A gene for lymphedema-distichiasis maps to 16q24.3. Am. J. Hum. Genet. 65: 427-432, 1999.
PubMed ID : 10417285
13. Neel, J. V.; Schull, W. J. :
Human Heredity. Chicago: Univ. of Chicago Press (pub.) 1954. Pp. 50-51.
14. Pap, Z.; Biro, T.; Szabo, L.; Papp, Z. :
Syndrome of lymphoedema and distichiasis. Hum. Genet. 53: 309-310, 1980.
PubMed ID : 7372334
15. Robinow, M.; Johnson, G. F.; Verhagen, A. D. :
Distichiasis-lymphedema: a hereditary syndrome of multiple congenital defects. Am. J. Dis. Child. 119: 343-347, 1970.
PubMed ID : 5434594
16. Schwartz, J. F.; O'Brien, M. S.; Hoffman, J. C., Jr. :
Hereditary spinal arachnoid cysts, distichiasis, and lymphedema. Ann. Neurol. 7: 340-343, 1980.
PubMed ID : 7377759


Cassandra L. Kniffin - reorganized : 11/19/2003
Cassandra L. Kniffin - updated : 11/12/2003
Michael J. Wright - updated : 10/22/2002
Victor A. McKusick - updated : 12/12/2000
Victor A. McKusick - updated : 1/11/2000
Victor A. McKusick - updated : 6/3/1999


Lymphedema-Distichiasis Syndrome

Sahar Mansour, FRCP
Glen W Brice, RGN BSc (Hons)
Steve Jeffery, PhD
Peter Mortimer, MD, FRCP
Last Update:
2 August 2007

Initial Posting:
29 March 2005


Disease 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.

Diagnosis/testing.  The diagnosis of lymphedema-distichiasis syndrome is made clinically and is based on the presence of primary lymphedema and distichiasis. FOXC2 is the only gene known to be associated with lymphedema-distichiasis syndrome. Molecular genetic testing of the FOXC2 gene is clinically available.

Management.   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 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 mutations. Each child of an individual with lymphedema-distichiasis syndrome has a 50% chance of inheriting the mutation. Disease severity cannot be predicted and is variable even within the same family. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation has been identified in an affected family member; however, it is rarely requested. Fetal echocardiography is recommended because of the increased risk of congenital heart disease.


Clinical Diagnosis

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

Molecular Genetic Testing

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. —ED.

Gene.   FOXC2 is the only gene known to be associated with lymphedema-distichiasis syndrome [ Fang et al 2000].

Other loci.  Four affected families with no mutation identified in FOXC2 have been reported. Brice et al ( 2002) reported one family out of 18 families and six simplex cases (i.e., single occurrences of lymphedema-distichiasis syndrome in a family) 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.

Clinical testing

Research testing.  For those in whom no mutation is detected in the coding region by sequence analysis, the 5' and 3' regions of the FOXC2 gene can be sequenced and analyzed. Detection rate for coding region mutations should be 100%, other than laboratory error.

Clinical Description

Natural History

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

Lymphedema.  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.  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 no comment was made as to whether they were examined by slit lamp for evidence of distichiasis. Sometimes the distichiasis can 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, personal communication].

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

Varicose veins.  The incidenceof 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 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.  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 only in association with congenital heart disease [ Chen et al 1996]. One paper suggested an association with yellow nails, but discolored nails are often a 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].


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

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


No evidence of anticipation has been reported.


Lymphedema and ptosis, described as a separate entity in OMIM (153000), is thought to be the same as lymphedema-distichiasis syndrome [ Finegold et al 2001].


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

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

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



Evaluations Following Initial Diagnosis

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

Treatment of Manifestations

Prevention of Secondary Complications


Diuretics are not effective in the treatment of lymphedema.

Cosmetic surgery is often associated with disappointing results.

Genetics clinics are a source of 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.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

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 the variable expressivity.

Sibs of a proband

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 upon the genetic status of the proband's parents. If a parent is found to be affected, his or her family members are at risk.

Related Genetic Counseling Issues

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.

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 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.

DNA banking.  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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

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 about ten to 12 weeks' gestation or amniocentesis usually performed at about 15-18 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.

Molecular Genetics of Lymphedema-Distichiasis Syndrome
Gene Symbol
Chromosomal Locus
Protein Name
Forkhead box protein C2
Genomic Databases for Lymphedema-Distichiasis Syndrome
Gene Symbol
Entrez Gene

Normal allelic variants: The FOXC2 gene is composed of a 1.5-kb single exon. SNPs reported in the 5' region of the gene include -512C>T [ Ridderstrale 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].

Pathologic allelic variants: Information on at least 35 different insertions and deletions situated throughout the gene has been published to date. The region 900-920 bp appears to be a "hot spot" for mutations, possibly because of the presence of a repeated GCCGCCGC element [Jeffery, unpublished data]. Several nonsense mutations have been reported, as well as four missense mutations: p.Ser125Leu [ Bell et al 2001], p.Arg121His [ Brice et al 2002], p.Trp116Ala, and p.Ser235Ile [ Sholto-Douglas-Vernon et al 2005]. The first three are presumed to be causative; the status of p.Ser235Ile is unknown.

Mutations in FOXC1 give rise to Axenfeld-Rieger anomaly and congenital glaucoma. Mutations analogous to p.Ser125Leu and p.Arg121His in FOXC2 have been shown to inactivate FOXC1 [ Saleem et al 2003].

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 method of pathogenesis is haploinsufficiency. It is not clear whether the frameshift mutations produce a protein product with novel amino acids or whether the mRNA or proteins are degraded.


Spinal extradural arachnoid cysts in lymphedema-distichiasis syndrome.

Genet Med. 2010 Jun 8.

Sánchez-Carpintero R, Dominguez P, Núñez MT, Patiño-García A.

From the 1Department of Pediatrics, Pediatric Neurology Unit; 2Department of Radiology, Neuroradiology Unit; and 3Department of Pediatrics, Laboratory of Pediatrics, University Clinic of Navarra, Pamplona, Spain.


PURPOSE:: Lymphedema-distichiasis syndrome is characterized by the presence of lower limb lymphedema and supernumerary eyelashes arising from the Meibomian glands. Spinal extradural arachnoid cysts have been observed in some families but their true frequency is unknown. The aim of this study is to determine the frequency of spinal extradural arachnoid cysts in lymphedema distichiasis syndrome. 

METHODS:: We collected clinical information from all 45 living members of a complete family of 48 members and performed molecular analysis of the FOXC2 gene in 30 individuals. We obtained spinal magnetic resonance imaging from all family members with a FOXC2 gene mutation. 

RESULTS:: Twelve family members carried a mutation in the FOXC2 gene and had clinical features of lymphedema-distichiasis syndrome. Of these, 58% (seven individuals) had extradural arachnoid cysts.

DISCUSSION:: We suggest that a follow-up protocol for lymphedema-distichiasis syndrome families should include spinal magnetic resonance imaging for all affected members so that the timing of surgery for removal of these cysts can be optimized.



A case of lymphedema-distichiasis syndrome carrying a new de novo frameshift FOXC2 mutation.

Ophthalmic Genet. 2010 Ju

Fabretto A, Shardlow A, Faletra F, Lepore L, Hladnik U, Gasparini P.

Institute of Child and Maternal Health Burlo Garofolo, Genetics, Trieste, Italy.


PURPOSE: Lymphedema-Distichiasis (LD, OMIM 153400) is an autosomal dominant disorder with variable expression. The mutated gene implicated is FOXC2, which encodes for a forkhead transcription factor involved in the development of the lymphatic and vascular system. LD is characterized by late childhood or pubertal onset lymphedema of the limbs and distichiasis. Other associations have been reported, including congenital heart disease, ptosis, scoliosis. 

CONCLUSIONS: Here we describe a case of LD carrying a de novo frameshift mutation of FOXC2 who presented a prepubertal onset of lower limbs lymphedema and mild distichiasis associated with other anomalies such as webbing neck and ptosis.

Full text aqvailable at Informa Healthcare


Mutations in FOXC2 in humans (lymphoedema distichiasis syndrome) cause lymphatic dysfunction on dependency.

J Vasc Res. 2011

Mellor RH, Tate N, Stanton AW, Hubert C, Mäkinen T, Smith A, Burnand KG, Jeffery S, Levick JR, Mortimer PS.


Cardiac and Vascular Sciences (Dermatology), St. George's, University of London, London, UK.



Human lymphoedema distichiasis syndrome (LDS) results from germline mutations in transcription factor FOXC2. In a mouse model, lack of lymphatic and venous valves is observed plus abnormal smooth muscle cell recruitment to initial lymphatics. We investigated the mechanism of lymphoedema in humans with FOXC2 mutations, specifically the effect of gravitational forces on dermal lymphatic function.


We performed (1) quantitative fluorescence microlymphangiography (FML) on the skin of the forearm (non-swollen region) at heart level, and the foot (swollen region) below heart level (dependent) and then at heart level, and (2) immunohistochemical staining of microlymphatics in forearm and foot skin biopsies, using antibodies to podoplanin, LYVE-1 and smooth muscle actin.


FML revealed a marked reduction in fluid uptake by initial lymphatics in the LDS foot during dependency, yet normal uptake (similar to controls) in the same foot at heart level and in LDS forearms. In control subjects, dependency did not impair initial lymphatic filling. Immunohistochemical microlymphatic density in forearm and foot did not differ between LDS and controls.


FOXC2 mutations cause a functional failure of dermal initial lymphatics during gravitational stress (dependency), but not hypoplasia. The results reveal a pathophysiological mechanism contributing to swelling in LDS.


Dysmorphogenesis of lymph nodes in Foxc2 haploinsufficient mice.

 June 2011 



Different lymphscintigraphic patterns in patients with lymphedema distichiasis.

June 10, 2011
Sutkowska E, Bator A, Trompeta K, Szuba A.


Department and Clinic of Orthopaedic and Traumatologic Surgery, Wroclaw Medical University, Wroclaw, Poland.


Mutation of the transcription factor FOXC2 gene has been identified as the cause of lymphedema-distichiasis syndrome (LD). Subjects with LD usually present with lower extremity lymphedema and distichiasis--an additional row of eyelashes. Typically, lymphscintigrams of patients with LD show good transport of the radiotracer from the feet to the inguinal lymph nodes accompanied by reflux of tracer to the skin of the lower extremities ("dermal backflow"). We have examined two patients with LD syndrome and were able to demonstrate two different distinct lymphscintigraphic patterns: lymphatic hyperplasia with reflux and obstructive.


External Links


A Novel Missense mutation and two microearrangements in the FOXC2 gene of three famillies with lymphedema-distichiasis syndrome.

Mar 2010



Lymphedema-distichiasos syndrome without FOXC2 mutation: evidence for chromoaomw 16 duplication upstream of FOXC2

Dec 2009



Rare association of immunoglobulin A nephropathy and lymphedema-distichiasis syndrome

Mar 2010



Spinal extradural arachnoid cysts associated with distichiasis and lymphedema

Am J Med Genet A. 2007 Apr

Wiley InterScience


Lymphoedema-distichiasis and FOXC2: unreported mutations, de novo mutation estimate, families without coding mutations.

Hum Genet. 2005 Jul

Springer Link


Lymphedema distichiasis(1)


Lymphedema distichiasis syndrome and FOXC2 gene mutation



Author: Soheila Rostami, MD, Oculoplastic Fellow, Clinical Instructor, Department of Ophthalmology, University of Maryland

Soheila Rostami, MD, is a member of the following medical societies: American Academy of Ophthalmology, and American Medical Association


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