Random Dermatology MCQ - Lymphedema distichiasis Syndrome

A 17-year-old male presents with the new onset of bilateral, pitting edema of the lower legs and feet. His past medical history is notable for corrective surgery in early childhood for an extra row of eyelashes (distichiasis) that were causing corneal irritation. His father required similar eyelid surgery and developed leg swelling in his late teens. What is the most likely genetic mutation and associated systemic finding in this syndrome?

A. Mutation in the FOXC2 gene; associated with congenital heart defects.
B. Mutation in the FLT4 (VEGFR3) gene; associated with intestinal lymphangiectasia.
C. Mutation in the GJC2 (Connexin 47) gene; associated with peripheral neuropathy.
D. Mutation in the SOX18 gene; associated with hypotrichosis.
E. Mutation in the CCBE1 gene; associated with facial dysmorphism.

Correct Answer: A. Mutation in the FOXC2 gene; associated with congenital heart defects.

Answer and Explanation

The correct answer is A. This question describes the classic presentation of Lymphedema-Distichiasis Syndrome (LDS). The key features are the onset of lymphedema (typically around puberty) and the presence of distichiasis (an extra row of eyelashes arising from the Meibomian glands). The positive family history with an autosomal dominant pattern is typical. LDS is caused by mutations in the FOXC2 gene. A well-known associated systemic finding is an increased incidence of congenital heart defects, such as atrial septal defect, ventricular septal defect, and tetralogy of Fallot.

Why the Other Options are Incorrect:

• B. Mutation in the FLT4 (VEGFR3) gene...: Mutations in FLT4 cause Milroy disease, a form of congenital hereditary lymphedema that presents at birth or in early infancy, not at puberty. Distichiasis is not a feature of Milroy disease, though intestinal lymphangiectasia can be.

• C. Mutation in the GJC2 gene...: Mutations in GJC2 (Connexin 47) cause Hereditary Lymphedema type IC, which can have a later onset, but it is not associated with distichiasis. It can be associated with peripheral neuropathy.

• D. Mutation in the SOX18 gene...: Mutations in SOX18 cause Hereditary Lymphedema type II (lymphedema with hypotrichosis and telangiectasia), characterized by sparse hair and visible blood vessels, not extra eyelashes.

• E. Mutation in the CCBE1 gene...: Mutations in CCBE1 are associated with Hennekam syndrome, a rare syndrome of congenital lymphedema, intestinal lymphangiectasia, facial dysmorphism, and intellectual disability. Distichiasis is not a feature.

Additional High-Yield Information for Exams:

• Clinical Features:

  • Distichiasis: The pathognomonic feature. The accessory lashes often irritate the cornea, leading to blepharitis, conjunctivitis, and photophobia, usually requiring epilation or surgery.

  • Lymphedema: Onset is typically around puberty but can vary from birth to adulthood. It is usually bilateral and affects the lower limbs, but can involve other areas.

  • Other Associated Findings: Varicose veins, ptosis, cleft palate, spinal arachnoid cysts, and the aforementioned congenital heart defects.

• Genetics: Autosomal dominant with high penetrance but variable expressivity. Caused by mutations in the FOXC2 gene on chromosome 16q24, a transcription factor involved in lymphatic and vascular development.

• Differential Diagnosis: The main differential is other primary lymphedema syndromes. The presence of distichiasis is the key distinguishing feature of LDS from:

  • Milroy Disease (FLT4): Congenital, early-onset lymphedema.

  • Meige Disease (later-onset primary lymphedema): Presents around puberty but lacks distichiasis.

• Prognosis: The lymphedema is progressive and chronic but not life-threatening. The main morbidity comes from complications of chronic lymphedema (cellulitis, fibrosis, psychological impact) and from the ocular complications of distichiasis. Cardiac defects, if present, require their own management.

• Management & Rationale:

  • Rationale: The goal is to manage symptoms, prevent complications, and screen for associated conditions.

  • Ocular Management: Regular ophthalmologic care for distichiasis (epilation, electrolysis, or surgical correction).

  • Lymphedema Management: Complex decongestive therapy is the mainstay, including manual lymphatic drainage, compression bandaging/garments, skin care, and exercise.

  • Screening: A cardiac evaluation (echocardiogram) is recommended at diagnosis due to the association with congenital heart defects.

  • Genetic Counseling: Offered to the patient and family members.