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Original article
Clinical heterogeneity in lymphoedema-distichiasis withFOXC2 truncating mutations
  1. Robert P Ericksona,
  2. Susan L Dagenaisb,
  3. Mark S Caulderb,
  4. Catherine A Downsc,
  5. Gail Hermand,
  6. Marilyn C Jonese,
  7. Wilhelmina S Kerstjens-Frederiksef,
  8. Andrew C Lidralg,
  9. Marie McDonaldh,
  10. Christine C Nelsonc,
  11. Marlys Wittei,
  12. Thomas W Gloverb
  1. aAngel Charity for Children-Wings for Genetic Research, Steele Memorial Children's Research Center, University of Arizona Health Sciences Center, Tucson, AZ, USA, bDepartments of Human Genetics and Pediatrics, University of Michigan School of Medicine, Ann Arbor, MI, USA, cDepartment of Ophthalmology, University of Michigan, Ann Arbor, MI, USA, dDepartment of Pediatrics, College of Medicine and Public Health, Ohio State University, Columbus, OH, USA, eChildren's Hospital and Health Center and Department of Pediatrics, University of California, San Diego, CA, USA, fUniversity Hospital of Groningen, Groningen, The Netherlands, gSection of Orthodontics, College of Dentistry, Ohio State University, Columbus, OH, USA, hDepartment of Pediatrics, Duke University, Durham, NC, USA, iDepartment of Surgery, University of Arizona Health Sciences Center, Tucson, AZ, USA
  1. Dr Erickson, Department of Pediatrics/4341A, PO Box 245073, University of Arizona, Tucson, AZ 85724-5073, USA, erickson{at}peds.arizona.edu

Abstract

BACKGROUND Hereditary lymphoedema-distichiasis (LD) is an autosomal dominant disorder that classically presents as lymphoedema of the limbs, with variable age of onset, and extra aberrant growth of eyelashes from the Meibomian gland (distichiasis). Other major reported complications include cardiac defects, cleft palate, and extradural cysts. Photophobia, exotropia, ptosis, congenital ectropion, and congenital cataracts are additional eye findings. Recently, we reported that truncating mutations in the forkhead transcription family member FOXC2resulted in LD in two families.

METHODS The clinical findings in seven additional families with LD, including the original family described by Falls and Kertesz, were determined and mutational analyses were performed.

RESULTS Distichiasis was the most common clinical feature followed by age dependent lymphoedema. There is a wide variation of associated secondary features including tetralogy of Fallot and cleft palate. The mutational analyses identified truncating mutations in all of the families studied (two nonsense, one deletion, three insertion, and one insertion-deletion), which most likely result in haploinsufficiency ofFOXC2.

CONCLUSIONS FOXC2mutations are highly penetrant with variable expressivity which is not explicable by the pattern of mutations.

  • lymphoedema
  • distichiasis
  • forkhead gene
  • clinical heterogeneity

https://doi.org/10.1136/jmg.38.11.761

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