Cole Disease

A number sign (#) is used with this entry because of evidence that Cole disease (COLED) is caused by heterozygous mutation in the ENPP1 gene (173335) on chromosome 6q23.

Description

Cole disease is a rare autosomal dominant disorder characterized by congenital or early-onset punctate keratoderma associated with irregularly shaped hypopigmented macules, which are typically found over the arms and legs but not the trunk or acral regions. Skin biopsies of palmoplantar lesions show nonspecific changes including hyperorthokeratosis, hypergranulosis, and acanthosis. Hypopigmented areas of skin, however, reveal a reduction in melanin content in keratinocytes but not in melanocytes, as well as hyperkeratosis and a normal number of melanocytes. Ultrastructurally, melanocytes show a disproportionately large number of melanosomes in the cytoplasm and dendrites, whereas keratinocytes show a paucity of these organelles, suggestive of impaired melanosome transfer (summary by Eytan et al., 2013). Some patients also exhibit calcinosis cutis or early-onset calcific tendinopathy (Eytan et al., 2013).

Clinical Features

Cole (1976) reported a family in which 6 members over 3 generations had a diffuse variegated pattern of hypopigmentation affecting almost the entire body; all affected members also had punctate keratosis of the palms and soles. The proband was an 18-year-old man who developed a diffuse irregular macular speckled pattern of hypopigmentation at 6 months of age, which remained unchanged and asymptomatic thereafter. Keratotic papules on his palms and soles were first noted at 3 years of age and also remained asymptomatic. Examination revealed moderately dark pigmented normal skin with sharply demarcated irregular macules showing varying degrees of hypopigmentation scattered diffusely over most of the body, with relative sparing of the acral portions of the body, including the head, neck, nipples, elbows, knees, genitalia, hands, and feet; there was no correspondence to a vascular or dermatomal pattern. The hypopigmented areas ranged in size from 1 to 15 mm in diameter, and many of the macules had small 1- to 2-mm islands of darker pigmentation within them. In addition, numerous flat-topped hypopigmented keratotic papules were present on the palms, soles, and dorsolateral aspects of the fingers and toes, varying from 2 to 6 mm in diameter; the papules did not seem to be concentrated over areas of trauma. Mucous membranes, irides, hair, teeth, and nails were all normal. The proband reported that his mother, maternal grandfather, and 3 brothers were similarly affected, although none of the family members were available for examination. Skin biopsy of hypopigmented skin showed focal areas of mild elongation of the rete ridges, with abundant melanin granules in the basal cell layer and other layers of the epidermis, and occasional small collections of melanophages in the upper dermis. The proband's normal skin showed a slight increase in melanin pigment in the basal cell layer, but was otherwise histologically similar to the hypopigmented skin. Biopsy of a palmar papule showed hyperkeratosis overlying a cup-shaped depression in the epidermis. Mild hypergranulosis and acanthosis was present, with an occasional melanocyte in the basal cell layer.

Moore et al. (2009) described a 2-year-old boy with congenital guttate hypopigmentation on the extremities as well as asymptomatic papules on the soles that first appeared at 3 months of age. There was no family history of similar skin lesions. Examination revealed irregularly shaped 2- to 10-mm hypopigmented macules on the extremities and scattered 2- to 8-mm pinkish-yellow keratotic papules on the soles. Hair, teeth, and nails were normal. Biopsy of hypopigmented skin showed patchy hypomelanosis and normal melanocyte density with rare melanophages in the papillary dermis. Biopsy of the largest plantar papule showed orthokeratosis and acanthosis, with small deposits of calcium in the papillary dermis.

Eytan et al. (2013) reviewed the clinical data for affected members of 2 multiplex French families who had hypopigmented macules primarily over the extremities and hyperkeratotic papules of the palms and soles. In addition to skin manifestations, 2 affected individuals from the first family exhibited early-onset calcific tendinopathy of the shoulders, wrists, hips, and heels, and 1 of the patients also had microcalcifications on mammography and a large splenic calcification. In the second family, 1 of the patients demonstrated calcinosis cutis. Serum phosphate and fasting glucose levels were normal in the patients tested.

Inheritance

The inheritance pattern of Cole disease in 2 French families studied by Eytan et al. (2013) was autosomal dominant.

Molecular Genetics

In 2 French families with hypopigmented macules primarily over the extremities and hyperkeratotic papules of the palms and soles, as well as the similarly affected family previously described by Moore et al. (2009), Eytan et al. (2013) performed whole-exome capture and next-generation sequencing and identified 3 different heterozygous missense mutations in the ENPP1 gene (173335.0020-173335.0022) that segregated with disease in each family, respectively. All 3 mutations involved highly conserved cysteine residues in the somatomedin-B-like-2 (SMB2) domain of ENPP1.