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Cole disease
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Condition

Cole disease

Cole disease is a rare genetic skin disorder marked by light‑colored patches and thickened skin on the palms and soles, and it may be accompanied by abnormal calcium deposits in tendons, skin, or breast tissue.

Overview

Cole disease is a disorder that affects the skin. Affected individuals have areas of unusually light‑colored skin (hypopigmentation)—typically on the arms and legs—and spots of thickened skin on the palms of the hands and the soles of the feet (punctate palmoplantar keratoderma). These skin features are present at birth or develop within the first year of life.

The condition is rare; its exact prevalence is unknown, and only a few affected families have been described in the medical literature.

Symptoms

  • Hypopigmented patches on the arms and legs
  • Punctate palmoplantar keratoderma (thickened skin on palms and soles)
  • Abnormal calcium accumulations (calcifications) in tendons, which can cause pain during movement
  • Calcifications may also occur in the skin or breast tissue

Causes & Risk Factors

Cole disease is caused by mutations in the ENPP1 gene. This gene provides instructions for making a protein that helps prevent minerals, including calcium, from being deposited in body tissues where they do not belong. The protein also participates in insulin signaling through interaction between its SMB2 domain and the insulin receptor.

Insulin signaling is important for regulating blood‑sugar levels, maintaining the epidermis, transporting melanin to keratinocytes, and supporting keratinocyte development. Mutations that alter the SMB2 domain disrupt its interaction with the insulin receptor, impairing melanin transport and keratinocyte development, which leads to the characteristic hypopigmentation and keratoderma. The same mutations may reduce ENPP1’s control of calcification, accounting for the ectopic calcium deposits seen in some patients. Despite these signaling changes, blood‑glucose control is not affected.

Gene associated with Cole disease

  • ENPP1

Inheritance

The disorder follows an autosomal dominant inheritance pattern, meaning a single altered copy of the gene in each cell is sufficient to cause the disease.

In most cases, the mutation is inherited from an affected parent. Some cases arise from de novo mutations in individuals with no family history of the disorder.

Other Names

  • Guttate hypopigmentation and punctate palmoplantar keratoderma with or without ectopic calcification

Additional Information & Resources

Genetic Testing Information

  • Genetic Testing Registry: Hypopigmentation‑punctate palmoplantar keratoderma syndrome

Genetic and Rare Diseases Information Center

  • Hypopigmentation‑punctate palmoplantar keratoderma syndrome

Patient Support and Advocacy Resources

  • National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

  • COLE DISEASE; COLED

Scientific Articles on PubMed

  • PubMed

References

  • Eytan O, Morice‑Picard F, Sarig O, et al. Cole Disease Results from Mutations in ENPP1. Am J Hum Genet. 2013 Oct 3;93(4):752‑757. doi:10.1016/j.ajhg.2013.08.007.
  • Moore MM, Orlow SJ, Kamino H, Wang N, Schaffer JV. Cole disease: guttate hypopigmentation and punctate palmoplantar keratoderma. Arch Dermatol. 2009 Apr;145(4):495‑497. doi:10.1001/archdermatol.2009.54.
  • Vignale R, Yusin A, Panuncio A, et al. Cole disease: hypopigmentation with punctate keratosis of the palms and soles. Pediatr Dermatol. 2002 Jul‑Aug;19(4):302‑306. doi:10.1046/j.1525-1470.2002.00084.x.

Frequently Asked Questions

Yes. Testing the affected individual for ENPP1 pathogenic variants establishes a molecular diagnosis. If a mutation is identified, carrier testing for parents and at‑risk siblings is recommended. For future pregnancies, prenatal testing (chorionic villus sampling or amniocentesis) or pre‑implantation genetic diagnosis can be offered to determine whether the fetus carries the same mutation.
Yes. ENPP1 loss‑of‑function can predispose to generalized arterial calcification of infancy and early‑onset osteoporosis. Periodic cardiovascular imaging (echocardiogram or CT angiography) and bone density scans are advisable, especially if the child shows signs of vascular stiffness or fractures. Monitoring serum calcium, phosphate, and alkaline phosphatase helps detect metabolic disturbances early.
Cole disease presents with light‑colored, non‑scaly patches mainly on the arms and legs, combined with punctate, sand‑grain‑like thickening on the palms and soles that appears in the first year. The coexistence of these two patterns plus possible calcified nodules in tendons is distinctive; other conditions (e.g., vitiligo, ichthyosis) lack the palm‑sole keratoderma and ectopic calcifications. A dermatologist can confirm the diagnosis with a skin biopsy and, if needed, radiographs to detect calcium deposits.
There is no cure, but management focuses on symptom relief. Low‑dose oral bisphosphonates (e.g., alendronate) have been used off‑label to slow calcium deposition, though evidence is limited. Topical keratolytics (urea 10‑20% cream) and regular mechanical debridement can soften palm‑sole keratoderma. Physical therapy and analgesics (NSAIDs or low‑dose opioids) help with tendon‑related pain. Surgical removal of large calcific nodules may be considered if they impair function.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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