Introduction
Autosomal Dominant Lymphedema-Distichiasis Syndrome (LDS) is a rare genetic syndrome that typically presents in pediatric patients and has risk for significant morbidity and mortality. Its’ prevalence is unknown.

 

Case Presentation
A previously healthy 15-year-old female initially presented to physiatry lymphedema clinic for lower extremity swelling. Initial workup indicated a diagnosis of primary lymphedema. However, history revealed symptoms of lower extremity paresthesias and weakness. Physical exam showed bilateral ankle clonus and upgoing great toes, raising concern for upper motor neuron pathology. Magnetic Resonance Imaging (MRI) of the entire spine was ordered.

 

Diagnostic Workup
MRI revealed a large spinal epidural arachnoid cyst, extending from T4-T9 with cord compression at T4-5, and a syrinx from T5-T8. She was referred to Neurosurgery, who agreed the cyst was unusual. 

 

Treatment and Management
Given her myelopathy, she underwent thoracic laminectomy with CT myelogram for excision of arachnoid cyst. The CT myelogram showed diffuse dural ectasia and operatively she was noted to have 3 separate epidural arachnoid cysts, with multiple loculations.  Surgical pathology indicated extradural arachnoid cyst.

 

Outcome and Follow-Up
She did well postoperatively and given the dural ectasia was referred to Clinical Genomics for evaluation of possible connective tissue disorder. Clinical Genomics noted that combination of spinal extradural cyst and lymphedema predominantly in lower extremities with onset at around puberty suggested the possibility of FOXC2-related disorder and proceeded with lymphedema panel.  This revealed a pathogenic variant in the FOXC2 gene consistent with a diagnosis of Autosomal Dominant Lymphedema-Distichiasis Syndrome (LDS). Further history based on this diagnosis revealed ptosis, possible extra row of eyelashes, and congenital renal anomalies.

 

Discussion
LDS is associated with lymphedema (in the lower limbs, with or without external genitalia involvement, beginning in late childhood/puberty) and distichiasis (extra, abnormal eyelashes, which can cause eye irritation). Other disease complications include cellulitis (secondary to edema), varicose veins, ptosis, congenital heart malformation, cleft palate, kidney abnormalities, spinal extradural arachnoid cysts, hydrops fetalis, and neck webbing. Management includes thorough evaluation of the above complications, as well as a referral to Clinical Genomics.

Identification of a heterozygous FOXC2 pathogenic variant confirms diagnosis. For patients with phenotypic findings concerning for LDS, clinicians can consider single-gene testing (sequence analysis of FOXC2, followed by gene-targeted deletion/duplication analysis if negative) or utilization of a primary lymphedema multigene panel.

FOXC2 gene mutations are inherited in an autosomal dominant manner. About 75% of the time, people with this condition inherit a pathogenic FOXC2 variant from a parent. The remaining 25% of the time, the pathogenic variant is de novo. Because of this, parental testing and genetic counseling is recommended to determine risk to siblings. If the FOXC2 variant is identified in any family member, prenatal testing and fetal echocardiography are recommended due to aforementioned complications.

 

Conclusion
Clinicians should be aware of LDS when encountering a pediatric patient with lymphedema.  A thorough physical exam should be completed for any evidence of distichiasis, cardiac involvement, renal involvement, spinal cord involvement, or neck webbing.  If any are positive, they should consider further evaluation and referral for genetic workup.