Focal facial dermal dysplasia, type IV, is caused by mutations in CYP26C1

Abstract

Focal facial dermal dysplasia (FFDD) Type IV is a rare syndrome characterized by facial lesions resembling aplasia cutis in a preauricular distribution along the line of fusion of the maxillary and mandibular prominences. To identify the causative gene(s), exome sequencing was performed in a family with two affected siblings. Assuming autosomal recessive inheritance, two novel sequence variants were identified in both siblings in CYP26C1-a duplication of seven base pairs, which was maternally inherited, c.844_851dupCCATGCA, predicting p.Glu284fsX128 and a missense mutation, c.1433G>A, predicting p.Arg478His, that was paternally inherited. The duplication predicted a frameshift mutation that led to a premature stop codon and premature chain termination, whereas the missense mutation was not functional based on its in vitro expression in mammalian cells. The FFDD skin lesions arise along the sites of fusion of the maxillary and mandibular prominences early in facial development, and Cyp26c1 was expressed exactly along the fusion line for these facial prominences in the first branchial arch in mice. Sequencing of four additional, unrelated Type IV FFDD patients and eight Type II or III TWIST2-negative FFDD patients revealed that three of the Type IV patients were homozygous for the duplication, whereas none of the Type II or III patients had CYP26C1 mutations. The seven base pairs duplication was present in 0.3% of healthy controls and 0.3% of patients with other birth defects. These findings suggest that the phenotypic manifestations of FFDD Type IV can be non-penetrant or underascertained. Thus, FFDD Type IV results from the loss of function mutations in CYP26C1.

Figure 1.

Focal facial dermal dysplasia in the proposita. (A and B). White, shiny, atrophic papules measuring 3–10 mm were present on the right cheek (A) and left cheek (B). (C). Intraoral polyps in the proposita that were seen as small, polypoid lesions measuring 2–3 mm protruding 5–8 mm from the left buccal mucosa. (D). Teeth of the proposita, showing minor dental ridges. (E and F). Focal facial dermal dysplasia in the brother of the proposita. White, shiny, atrophic papules similar to those in the proposita are present on the right cheek (E) and the left cheek (F). (G and H). Facial features of the fifth patient with FFDD Type IV. Atrophic skin lesion on the right (G and left H) cheeks.