Lymphedema-Distichiasis Syndrome

A number sign (#) is used with this entry because of evidence that the lymphedema-distichiasis syndrome (LPHDST) is caused by heterozygous mutation in the FOXC2 gene (602402) on chromosome 16q24.

See also lymphatic malformation-5 (LMPHM5; 153200) and lymphedema and yellow nail syndrome (153300), which show phenotypic overlap.

Description

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, varicose veins, ptosis, cleft palate, spinal extradural cysts, and photophobia (Fang et al., 2000; Brice et al., 2002).

Clinical Features

In a family reported by Bloom (1941), lymphedema of the legs occurred in 5 generations; six affected persons in 3 consecutive generations also had ptosis.

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. Falls and Kertesz (1964) made brief reference to a second family in which the male proband had ptosis and lymphedema and the father ptosis.

Chynn (1967) reported lymphedema and distichiasis with spinal extradural cyst (SEDAC) in 2 black sibs, aged 12 and 10 at the time of diagnosis. Progressive weakness in the legs was the main symptom. Another sib had lymphedema and distichiasis and may have had SEDAC. Bergland (1968) reported 3 of 4 sibs affected in the pedigree reported by Chynn (1967). 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. Cilluffo et al. (1981) noted that spinal extradural cysts are often arachnoid diverticula.

Dale (1987) noted that 'bilateral hyperplasia' 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.

Finegold et al. (2001) studied 11 families with lymphedema and mutations in the FOXC2 gene. Broad phenotypic heterogeneity was observed within the families, as well as overlapping phenotypically defined lymphedema syndromes: Meige lymphedema (LMPHM5; 153200), lymphedema-distichiasis syndrome, and yellow nail syndrome (153300), but not Milroy disease (LMPHM1; 153100). The authors stated that the phenotypic classification of autosomal dominant lymphedema did not appear to reflect the underlying genetic causation of these disorders.

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. Five patients had renal abnormalities, including nephritis, duplex kidney, and recurrent infections. Varicose veins were present in 49% and 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.

Patil et al. (2004) noted that distichiasis is the most consistent feature of lymphedema-distichiasis syndrome and made observations on distichiasis without lymphedema.

Yildirim-Toruner et al. (2004) reported a German-Irish family in which 6 affected members spanning 3 generations had lymphedema-distichiasis syndrome. Four of the affected members also had renal disease, and 3 had type II diabetes mellitus (see 125853), features not usually seen in lymphedema-distichiasis syndrome. The oldest affected member of the family was 73 years old at the time of report and was on chronic renal dialysis. One of her sons, aged 45 years, had developed proteinuria at age 32 years. Renal biopsy showed chronic sclerosing glomerulopathy and chronic tubulointerstitial nephritis. One member of the family underwent renal transplantation and, shortly thereafter, pancreatic transplantation, both with excellent results. She was 36 years old at the time of report and had distichiasis but no lymphedema.

Yabuki et al. (2007) reported a Japanese family in which 10 members had variable manifestations of lymphedema-distichiasis syndrome. Spinal extradural arachnoid cysts (SEDAC) were found in 7 patients, of whom 4 had distichiasis. Two patients had isolated distichiasis, and 1 had lymphedema and distichiasis. Only 1 individual had all 3 features. Inheritance was clearly autosomal dominant. Although genetic analysis of the FOXC2 gene was not performed, the clinical features were suggestive of the diagnosis and indicated that SEDAC may be a common component.

Kumar et al. (2007) reported a 3-generation family from Jordan in which 12 members had lymphedema-distichiasis; 10 were alive at the time of the study, including a pair of affected identical twins who were discordant for the phenotype, as only 1 had lymphedema and varicose veins at age 28 years. The findings suggested that phenotypic variation in the disorder is not always due to modifying genes. All affected individuals had distichiasis, 5 had lymphedema, 4 had varicose veins, and 3 had cleft palate.

Mellor et al. (2007) examined the venous system of the leg with Duplex ultrasound in 18 FOXC2 mutation-positive individuals, including 3 without lymphedema, from 7 families with lymphedema-distichiasis syndrome previously reported by Bell et al. (2001) and Brice et al. (2002). All 18 had superficial venous reflux in the great saphenous vein, compared to only 1 of 12 controls (10 of whom were mutation-negative family members). Deep venous reflux was also recorded in 14 of the 18 mutation-positive individuals, including all 3 mutation carriers without lymphedema, compared to only 1 of 12 controls.

Rezaie et al. (2008) disputed the clinical diagnoses of some of the patients reported by Finegold et al. (2001). In particular, 10 of the 11 families reported by Finegold et al. (2001) had distichiasis, consistent with the lymphedema-distichiasis syndrome. The last family was not reported to have either yellow nails or distichiasis, but Rezaie et al. (2008) emphasized that the detection of distichiasis is often difficult to confirm and cannot be assumed to be absent from patient self-reports. In addition, Rezaie et al. (2008) did not identify mutations in the FOXC2 gene in 22 unrelated probands with Meige disease, i.e., lymphedema without distichiasis. One additional proband was found to carry a FOXC2 mutation, but detailed ophthalmologic examination revealed accessory eyelashes in him and his affected family members, thus confirming the diagnosis of lymphedema-distichiasis. The authors also noted that ptosis is a variable feature of the lymphedema-distichiasis syndrome, occurring in about 30% of patients, and suggested that lymphedema and ptosis alone do not comprise a distinct syndrome; rather, those patients likely also have distichiasis.

From a cohort of 288 patients with primary noncongenital lymphedema, van Steensel et al. (2009) reported 11 probands who were heterozygous for mutations in the FOXC2 gene. Seven of the probands had a positive family history for lymphedema, but family members were not available for study. All 11 patients had venous insufficiency, which affected the deep system in 8. Only 2 patients were reported to have distichiasis, but the authors noted that it is a feature that can be quite subtle and might have been missed. Lymphoscintigraphy performed in 1 patient with a gain-of-function missense mutation (see 602402.0016) showed minimal uptake (0.5% on the right and 1.7% on the left), indicating lack of transport consistent with lymphatic hypoplasia.

De Niear et al. (2018) reported a 3-generation family with lymphedema-distichiasis. The proband was a 4-year-old boy who presented with distichiasis and photophobia, eye rubbing, and squinting, but did not exhibit lymphedema. Examination showed that the lashes originated from the meibomian gland orifices of all 4 lids. Family history revealed that the proband's mother had distichiasis with onset of lymphedema at age 12 as well as ptosis and varicose veins. His maternal grandmother was also reported to have had lymphedema, distichiasis, and varicose veins. In addition, family pedigree showed an affected brother with distichiasis.

Mapping

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.

Molecular Genetics

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

In affected members of the family with lymphedema-distichiasis syndrome originally reported by Falls and Kertesz (1964), Erickson et al. (2001) identified a heterozygous insertion/deletion mutation in the FOXC2 gene (602402.0011), resulting in premature termination. Erickson et al. (2001) described truncating mutations in the FOXC2 gene in 8 additional families with the disorder.

Finegold et al. (2001) identified mutations in the FOXC2 gene in 11 of 86 families with lymphedema-distichiasis syndrome (see, e.g., 602402.0007 and 602402.0008).

In 6 affected members spanning 3 generations of a German-Irish family with lymphedema-distichiasis syndrome, Yildirim-Toruner et al. (2004) identified a 1-bp insertion in the FOXC2 gene (602402.0010). Affected individuals in this family also had renal disease and diabetes mellitus.

Van Steensel et al. (2009) screened a cohort of 288 patients with primary noncongenital lymphedema for mutations in the FLT4 (136352), SOX18 (601618), and FOXC2 genes, and identified 4 mutations in FLT4 (see LMPHM1, 153100) and 11 in FOXC2. None of the FOXC2 variants were found in 100 unrelated Dutch controls or in the dbSNP (build 130) database, and all involved highly conserved residues. Five of the FOXC2 changes were predicted to truncate the protein, and 6 were missense mutations. Two of the missense mutations were located within the forkhead DNA-binding domain, including the previously reported S125L mutation (602402.0012) and an R121C substitution (602402.0014), whereas the remaining 4 occurred outside the forkhead domain (see, e.g., 602402.0015 and 602402.0016). Functional analysis in HeLa Ohio and COS-7 cells showed that all 4 FOXC2 missense mutation outside the forkhead domain increased transcriptional and transactivation activity, whereas the missense mutations within the forkhead domain showed reduced activity. No genotype/phenotype correlations were observed. The authors concluded that gain-of-function mutations in FOXC2 can also cause lymphedema.

Michelini et al. (2012) screened the FLT4 and FOXC2 genes in a cohort of 46 Italian probands with primary lymphedema and identified FLT4 mutations in 6 (13%) and FOXC2 mutations in 6 (13%; see, e.g., 602402.0017). Tavian et al. (2016) restudied the 6 Italian probands with FOXC2-associated lymphedema, 4 of whom had distichiasis upon slit-lamp examination. Consistent with previous reports, the 3 patients with activating mutations showed lymphatic hypoplasia on scintigraphy, whereas the 3 patients with inactivating mutations showed hyperplasia, suggesting a genotype/phenotype correlation. The authors stated that the association between FOXC2 function and distichiasis was less clear: all 3 patients with activating mutations had distichiasis, whereas it was present in only 1 of the 3 patients with inactivating mutations; they suggested that further studies were required to elucidate these correlations. Tavian et al. (2016) concluded that either complete loss or significant gain of FOXC2 function can cause a perturbation of lymphatic vessel formation resulting in lymphedema.

In the proband from a 3-generation family with lymphedema-distichiasis, De Niear et al. (2018) identified heterozygosity for a 2-bp insertion in the FOXC2 gene that was not found in his unaffected brother. Mutation analysis of 4 other affected family members was not done.

Animal Model

Kriederman et al. (2003) performed dynamic lymphatic imaging and immunohistochemical examination of lymphatic tissues in mice heterozygous for a targeted disruption of Foxc2. Adult heterozygous mice characteristically exhibited a generalized lymphatic vessel and lymph node hyperplasia and rarely exhibited hindlimb swelling. Retrograde lymph flow through apparently incompetent interlymphangion valves into the mesenteric nodes, intestinal wall, and liver was also observed. In addition, Foxc2 heterozygous mice uniformly displayed distichiasis. Kriederman et al. (2003) noted that the craniofacial, cardiovascular, and skeletal abnormalities sometimes associated with lymphedema-distichiasis syndrome had previously been shown to be fully penetrant in homozygous Foxc2-null mice (Iida et al., 1997; Winnier et al., 1997). They concluded that Foxc2 haploinsufficient mice mimic closely the distinctive lymphatic and ocular phenotype of patients with lymphedema-distichiasis syndrome.