Clinical Description
Lymphedema-distichiasis syndrome (LDS) is characterized by lymphedema with onset in late childhood or puberty and is confined to the lower limbs and/or genitalia. Varicose veins are a frequent association and may develop before the onset of the lymphedema. Distichiasis, which may be present at birth, can be associated with ocular problems such as corneal irritation, recurrent conjunctivitis, and photophobia. Congenital ptosis involving one or both eyes may be present. Other less common findings include congenital heart disease, cleft palate, webbed neck, and renal anomalies. Severity varies within and between families, with some affected neonates presenting with hydrops fetalis.
Lymphedema is present in most individuals with LDS. While it typically appears in late childhood or puberty (age range: 7-40 years) [Erickson et al 2001, Brice et al 2002], congenital onset has been reported [Finegold et al 2001]. In females, pregnancy or use of oral contraceptives may precipitate the onset of swelling.
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].
Whereas primary lymphedema is usually associated with hypoplasia or aplasia of the lymphatic vessels, LDS is associated with an increased number of lymphatic vessels and inguinal lymph nodes [Dale 1987, Brice 2003]. The valves in the lymphatic vessels and veins are small and dysplastic, resulting in reflux and edema [Petrova et al 2004].
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 LDS [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 had 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 (in whom lymphedema could still develop) and her father [Brooks et al 2003].
Varicose veins. The incidence of varicose veins is much higher (and onset earlier) in individuals with LDS than in the general population. About 50% of individuals with LDS 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]. FOXC2 is essential for lymphatic and venous valve formation in the embryo [Lyons et al 2017].
Ptosis. Approximately 30% of individuals with LDS have unilateral or bilateral congenital ptosis of variable severity.
Congenital heart disease occurs in 7%-10% of individuals with LDS. Structural abnormalities include ventricular septal defect, atrial septal defect, patent ductus arteriosis, bicuspid aortic valve, 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 [Papoff et al 2016].
Other findings
Nonimmune hydrops fetalis or antenatal hydrothoraces have been reported as a rare complication of LDS. Hydrops fetalis can be caused by lymphatic abnormalities [
Bellini et al 2015]. If the fetus or neonate survives, the hydrops may resolve completely. It has been suggested that the hydrops and respiratory failure may be due to severe pulmonary lymphangiectasia [
de Bruyn et al 2012,
Sargent et al 2014].
Spinal extradural arachnoid cyst (SEDAC) is a cyst in the spinal canal that protrudes into the epidural space from a defect in the dura mater. Thus, SEDAC caused by a heterozygous
FOXC2 loss-of-function variant should be considered a feature of LDS. It may manifest as the sole finding, but more frequently the family history is positive for SEDAC, distichiasis, and/or lymphedema [
Kanaan et al 2006,
Ogura et al 2013].
Renal anomalies include hydronephrosis, ectopic kidney, and renal agenesis, which may be detected by antenatal ultrasound examination [
Jones et al 2017].
Other abnormalities include scoliosis, neck webbing, uterine 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.