| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q32 | ?Ocular pterygium-digital keloid dysplasia syndrome | 621091 | Autosomal dominant | 3 | PDGFRB | 173410 |
A number sign (#) is used with this entry because of evidence that ocular pterygium-digital keloid dysplasia syndrome (OPDKD) is caused by heterozygous mutation in the PDGFRB gene (173410) on chromosome 5q32. One such family has been reported.
Ocular pterygium-digital keloid dysplasia syndrome (OPDKD) is an autosomal dominant disorder characterized by aggressive circumferential ingrowth of conjunctiva beginning in early childhood that is resistant to treatment, ultimately covering the cornea and resulting in loss of vision. Patients also develop digital keloid formation after minor trauma, which can become extensive and cause flexion contractures (Haugen and Bertelsen, 1998). Multiple fibromas and hardened auricles have also been observed (Bredrup et al., 2021).
Haugen and Bertelsen (1998) described a 60-year-old woman of Norwegian ancestry, originally studied as a child (case 1) by Stansbury (1950), and her 2 sons, who had conjunctivocorneal dystrophy and digital keloid formation. The mother and her older son developed bilateral conjunctival ingrowths within the first 2 years of life, which recurred despite attempts at excision and corneal transplantation, resulting in reduction of vision to counting fingers. The mother underwent evisceration of the left eye at age 22 years due to painful glaucoma. The younger son had a somewhat milder course, developing unilateral conjunctival ingrowth at age 6 years. By age 15 years, the right cornea was totally opacified and vision reduced to counting fingers in that eye, whereas his left eye remained unaffected. Digital keloid formation after minimal trauma developed in the mother at age 20 years; skin biopsy of one of the keloid nodules showed epithelial hyperplasia and scar tissue. The progressive keloid scar formation resulted in flexion contractures of several fingers. Keloid lesions were first observed on the fingers of the older son at age 22 years and of the younger at age 15.
Abarca et al. (2014) provided an update on the Norwegian family described by Haugen and Bertelsen (1998) with OPDKD. The younger son developed a pterygium in his previously unaffected left eye at age 20 years. The keloids on the sons' fingers were progressive, and a decade later, keloids appeared on their toes as well. All 3 affected individuals developed multiple broad-based cutaneous fibromas of the face, trunk, and extremities. In addition, the proband developed granuloma annulare-like lesions on her upper arms, with a sarcoma in one of them that was successfully treated. At age 73, she developed endometrial adenocarcinoma, and died at age 75.
Bredrup et al. (2021) also restudied the Norwegian family described by Haugen and Bertelsen (1998) with OPDKD. Both sons had developed enlarged hardened auricles. In addition, the older son had a 7-year-old daughter with a pterygium of the right eye that first appeared as a corneal nodule at age 3 years.
The transmission pattern of OPDKD in the Norwegian family reported by Haugen and Bertelsen (1998) was consistent with autosomal dominant inheritance.
By exome sequencing and haplotype analysis in a Norwegian family with OPDKD, Bredrup et al. (2021) identified a heterozygous missense mutation in the PDGFRB gene (N666Y; 173410.0009) that arose de novo in the mother and segregated with disease. The authors noted that the overgrowth in this disorder affects body parts (cornea and digits) that typically have temperatures lower than 37 degrees Celsius, and functional analysis demonstrated that the N666Y variant is a temperature-sensitive activating substitution: phosphorylation levels of PDGFRB and downstream targets were higher in OPDKD fibroblasts and transduced HeLa cells than in control cells at 37 degrees Celsius, and phosphorylation levels with the N666Y mutant further greatly increased at 32 degrees Celsius (the average corneal temperature). This temperature effect did not occur with control PDGFRB or with the Penttinen syndrome (601812)-associated variant at the same PDGFRB residue, N666S (173410.0008). The authors suggested that temperature-dependent autoactivation accounts for the strikingly different clinical outcomes of substitutions at the N666 codon of PDGFRB.
Associations Pending Confirmation
For discussion of a possible association between OPDKD and variation in the PELI2 gene, see 614798.0001.
Abarca, H., Mellgren, A. E., Trubnykova, M., Haugen, O. H., Hovding, G., Tveit, K. S., Houge, G., Bredrup, C., Hennekam, R. C. Ocular pterygium--digital keloid dysplasia. Am. J. Med. Genet. 164A: 2901-2907, 2014. [PubMed: 25124224] [Full Text: https://doi.org/10.1002/ajmg.a.36713]
Bredrup, C., Cristea, I., Safieh, L. A., Di Maria, E., Gjertsen, B. T., Tveit, K. S., Thu, F., Bull, N., Edward, D. P., Hennekam, R. C. M., Hovding, G., Haugen, O. H., Houge, G., Rodahl, E., Bruland, O. Temperature-dependent autoactivation associated with clinical variability of PDGFRB Asn666 substitutions. Hum. Molec. Genet. 30: 72-77, 2021. [PubMed: 33450762] [Full Text: https://doi.org/10.1093/hmg/ddab014]
Haugen, O. H., Bertelsen, T. A new hereditary conjunctivo-corneal dystrophy associated with dermal keloid formation: report of a family. Acta Ophthal. Scand. 76: 461-465, 1998. [PubMed: 9716334] [Full Text: https://doi.org/10.1034/j.1600-0420.1998.760413.x]
Stansbury, F. C. Lamellar corneal transplantation: preliminary report. Arch. Ophthal. 43: 891-904, 1950. [PubMed: 15414089] [Full Text: https://doi.org/10.1001/archopht.1950.00910010906014]