Lymphedema-distichiasis syndrome (ORPHA:33001)
A rare autosomal dominant syndromic lymphedema characterized by lower-limb lymphedema and varying degrees of abnormal growth of eyelashes from the orifices of the Meibomian glands (distichiasis), with occasional associated manifestations.
Epidemiology
Prevalence is unknown.
Clinical description
Lymphedema-distichiasis syndrome is characterized by primary lower limb lymphedema (with or without genital edema in males) usually starting in childhood or puberty (but in some cases later or, occasionally, at birth) and associated with distichiasis (extra eyelashes growing from the Meibomian gland orifices in the inner eyelid). Ptosis of the eyelid(s) is frequent. Other associated manifestations can include: heart abnormalities, cleft palate (with or without Pierre Robin sequence), renal malformations, varicose veins and extradural cysts. Distichiasis may lead to infection (styes), congenital ectropion, photophobia corneal abrasion or ulceration.
Etiology
The causative gene is FOXC2 (previously referred to as MFH1, located at 16q24.3), coding for transcription factor FOXC2.
Diagnostic methods
Diagnosis is suspected on clinical presentation with the presence of 'extra' eyelashes arising from the inner eyelid, ptosis and lower limb lymphedema; although the latter may not present until later in childhood or adolescence. The condition can usually be confirmed by genetic testing.
Differential diagnosis
The differential diagnosis includes other conditions presenting with late onset (i.e. not congenital) lymphedema of the lower limbs. This includes Meige disease, Noonan syndrome, Emberger syndrome (part of the GATA2 deficiency spectrum) and CELSR-related lymphedema.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member. The nuchal translucency, visible by sonograph, is often slightly increased (3mm to 4.5mm). The fetus may develop fetal hydrops in the second trimester. There may be congenital heart disease and or congenital renal malformations.
Genetic counseling
The disorder is autosomal dominant. Although the condition is usually inherited from an affected parent, some cases occur sporadically. Genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
The standard treatment for the lower limb (and genital) lymphedema are made-to-measure compression garments with the option of intensive bandaging for moderate to severe swelling. Skin care is necessary to prevent infections. Every newly diagnosed patient should have a renal ultrasound and echocardiogram to exclude congenital malformations. They should also be examined for a cleft of the hard or soft palate. The distichiasis is often problematic, and they may require to be plucked or even electrolysis. If severe, they may require lamellar eyelid division and cryotherapy to the posterior lamella.
Prognosis
The severity may vary even within families. A normal life span is expected but there is a high mortality with the rare complication of fetal hydrops. Approximately 7% will have congenital heart disease but it is not usually severe. There is a high morbidity associated with recurrent cellulitis of the edematous limbs.

                            Last update: 
                            June 2024


                            - Expert reviewer(s): 
                            Dr Kristiana GORDON | VASCERN* - Pr Sahar MANSOUR | VASCERN*


                                * European Reference Network