Lymphedema-distichiasis is inherited in an autosomal dominant fashion. It is estimated that only ¼ of diagnosed individuals did not inherit the condition but rather acquired the syndrome via a de novo mutation. Symptoms emerge between the life stages of puberty to early adulthood. This is the result of a mutation in the FOXC2 gene. FOXC2 is a transcription factor associated with developmental processes. To date, at least 70 mutations of FOXC2 have been investigated in connection with lymphedema-distichiasis patients. These mutations are thought to be both loss of function and gain of function mutations. For some time, FOXC2 mutations were thought to be associated with lymphedema-distichiasis as a combined condition. However, there are now cases that indicate that FOXC2 mutations can cause distichiasis in humans without lymphedema.
Mutations
The A3G mutation is a pathogenic mutation that lowers FOXC2’s ability to turn on target genes. p.Y41F, a missense mutation, is also located in FOXC2 AD-1. p.Y41F is one of eleven mutations found in the FOXC2 gene. It was determined that of these 11 mutations, one was nonsense, six were missense, and four were frameshift mutations. It is hypothesized that gain of function mutations lead to hypoplasia and loss of function mutations lead to hyperplasia specifically in individuals with lymphedema.
Symptoms
The main symptoms of lymphedema-distichiasis are limb swelling and a double row of eyelashes. Symptoms that have been noted in some but not all cases include cysts, light sensitivity, cardiac defects, cleft palate, and eye problems such as astigmatism and cornea scarring.
Syndrome Diagnosis and Management
Currently, the most accurate test to determine if an individual is affected by lymphedema-distichiasis syndrome is done via Sanger sequencing, which includes whole genome analysis and single gene and multigene testing. Sequenced DNA that exhibits mutations in the FOXC2 gene are considered confirmed clinical diagnoses. In addition to Sanger sequencing, Multiplex Ligation Probe Amplification can be used to determine if duplications and deletions in FOXC2 are present in an individual, making it a practical testing mechanism. Lastly, diagnosis is sometimes determined without genome testing. If an individual exhibits multiple symptoms of lymphedema-distichiasis and has a medical history consistent with known lymphedema-distichiasis symptoms, then their diagnosis is confirmed via clinical evaluation. Lymphedema-distichiasis is a rare genetic disease, it is unknown how many individuals are affected and what the frequency of the condition is. As a result, there are few syndrome management techniques: Symptoms of distichiasis can be minimized via eyelash plucking, electrolysis and other various treatments. Limb swelling can be reduced using compression clothing and bandages. Lastly, rapid treatment of broken skin and cellulitis lessens severity of symptoms.
