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.
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; symbolsLYMPHEDEMA WITH DISTICHIASIS Gene map locus 16q24.3
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).
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).
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.
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.
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.
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.
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.
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.
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.
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
Sahar Mansour, FRCP
Glen W Brice, RGN BSc (Hons)
Steve Jeffery, PhD
Peter Mortimer, MD, FRCP
2 August 2007
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.
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)
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.
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.
Sequence analysis of the entire coding region detects mutations in about 95% of individuals with lymphedema-distichiasis syndrome. Over 90% of mutations are small deletions or insertions. Four possible missense mutations (one of which has uncertain pathogenesis) and a small number of nonsense mutations have been reported. No entire gene deletions have been reported.
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.
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.
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.
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.
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.
Meige disease presents with primary lymphedema at puberty. Distichiasis is not observed. Meige disease predominantly affects women, but inheritance is autosomal dominant. The causative gene(s) has/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. Mutations in SOX18 are causative [ Irrthum et al 2003].
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].
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.
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
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 regarding management of edema (fitting stockings, massage). Although the edema cannot be cured, some improvement may be possible with the use of carefully fitted stockings 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 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
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 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.
Lymphedema-distichiasis syndrome is inherited in an autosomal dominant manner.
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.
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.
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.
Forkhead box protein C2
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.
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.
Genet Med. 2010 Jun 8.
A case of lymphedema-distichiasis syndrome carrying a new de novo frameshift FOXC2 mutation.
Ophthalmic Genet. 2010 Ju
Institute of Child and Maternal Health Burlo Garofolo, Genetics, Trieste, Italy. firstname.lastname@example.org
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
J Vasc Res. 2011
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.Karger
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.
A Novel Missense mutation and two microearrangements in the FOXC2 gene of three famillies with lymphedema-distichiasis syndrome.
Lymphedema-distichiasos syndrome without FOXC2 mutation: evidence for chromoaomw 16 duplication upstream of FOXC2
Rare association of immunoglobulin A nephropathy and lymphedema-distichiasis syndrome
Spinal extradural arachnoid cysts associated with distichiasis and lymphedema
Am J Med Genet A. 2007 Apr
Lymphoedema-distichiasis and FOXC2: unreported mutations, de novo mutation estimate, families without coding mutations.
Hum Genet. 2005 Jul
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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to Treat a Lymphedema Wound
Infections Associated with Lymphedema
para-aortic lymph node dissection (EPLND)
Axillary node biopsy
Small Needle Biopsy -
Fine Needle Aspiration
Lymphedema Gene FOXC2
Lymphedema Gene VEGFC
Lymphedema Gene SOX18
Home page: Lymphedema People
Page Updated: Nov. 28, 2011