Pachyonychia Congenita Project

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FZD6 (Frizzled-6)

Commonly presents as “isolated nail dysplasia”

Facts

  • What does the FZD6 (Frizzled-6) gene do? Encodes a protein that serves as one of the receptors for Wnt signaling pathways and plays an important role in growth and guidance of nail plates.1
  • What happens when FZD6 becomes mutated? Formation of ectodermal appendages such as nails could be affected.2
  • Clinical significance of mutation? Isolated nail dysplasia including discoloration and thickening of the toenails and fingernails.1,3

About Nail Dysplasia Associated with FZD6 Mutation

Skin disease caused by FZD6 mutations has fairly recently been discovered in families presenting with isolated nail dysplasia. Specifically, the dysplasia was passed from parents to offspring in an autosomal recessive manner.1,3 This means that the affected children inherited one copy of mutated FZD6 from each parent, therefore having an autosomal recessive genotype. Two carrier parents without nail dysplasia may pass the nail dysplasia to their child if the child inherits one mutated copy of FZD6 from each parent. There have also been cases where one child was affected while their sibling was tested and found to be a heterozygous carrier. The importance of genetic testing is emphasized and some suggest that FZD6 should be added to the screening panel for pachyonychia congenita.3

Symptoms of FZD6

Signs of FZD6-related nail dysplasia typically appear at birth with discoloration and thickness.1,3 In some cases, the nails grow very slowly and rarely require trimming. In some affected individuals, the nails start to become claw-like around ten years of age.1 There have been reports of nails falling off the cuticle and mild inflammation as the new nail grows out.3 Hair and teeth abnormality is not reported in individuals with FZD6-related nail dysplasia.2

IPCRR Data for FZD6

Eight individuals fully enrolled in the International Pachyonychia Congenita Research Registry (IPCRR) were found not to have PC but instead carry a mutation in the FZD6 gene. Three are in the United States and two are in Turkey. Others are in Australia, Canada, and Iran. Seven are female and one is male. Below is select data from the registry.

Plantar Keratoderma12%
Plantar Keratoderma – OnsetN = 1
Birth or less than 1 year0%
1 to 4 years old100%
5 to 14 years old0%
15 years and over0%
Plantar Pain0%
Palmar Keratoderma38%
Always (never goes away)0%
Sometimes (clears up at times)25%
Seldom (hands usually clear)12%
OLYMPUS DIGITAL CAMERA
Toenail Dystrophy100%
all 10 toenails thickened100%
7-9 toenails thickened0%
4-6 toenails thickened0%
1-3 toenails thickened0%
Toenails – Onset
Birth or less than 1 year75%
1 to 4 years old25%
5 to 14 years old0%
15 years and over0%
Fingernail Dystrophy100%
all 10 toenails thickened100%
7-9 toenails thickened0%
4-6 toenails thickened0%
1-3 toenails thickened0%
Fingernails – Onset
Birth or less than 1 year88%
1 to 4 years old12%
5 to 14 years old0%
15 years and over0%
Oral Leukokeratosis12%
Cysts0%
Follicular Hyperkeratosis0%
Natal or Prenatal Teeth0%

Data from 2022 Sample Size N=8

References

  1. Naz G., Pasternack S.M., Perrin C., Mattheisen M., Refke M., Khan S., et. al.: FZD6 encoding the Wnt receptor frizzled 6 is mutated in autosomal-recessive nail dysplasia. Br J Dermatol 2012; 165: pp. 1088-1094.
  2. Fröjmark AS, Schuster J, Sobol M, et al. Mutations in Frizzled 6 cause isolated autosomal-recessive nail dysplasia. Am J Hum Genet. 2011;88(6):852-860. doi:10.1016/j.ajhg.2011.05.013
  3. Wilson NJ, Hansen CD, Azkur D, et al. Recessive mutations in the gene encoding frizzled 6 cause twenty nail dystrophy–expanding the differential diagnosis for pachyonychia congenita. J Dermatol Sci. 2013;70(1):58-60. doi:10.1016/j.jdermsci.2012.12.005

Above photos are from individuals in the IPCRR with confirmed FZD6 mutations.

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