Two additional syndromes are associated with decreased pigmentation of the skin and eyes. The autosomal recessive Chediak-Higashi syndrome is characterized by eosinophilic, peroxidase-positive inclusion bodies in early leukocyte precursors, hemophagocytosis, increased susceptibility to infection, and increased incidence of an accelerated phase lymphohistiocytosis. Mutations in the LYST gene underlie this syndrome, which is often fatal in the first decade of life.[90,91,92]
Griscelli syndrome, also inherited in an autosomal recessive manner, was originally described as decreased cutaneous pigmentation with hypomelanosis and neurologic deficits, but its clinical presentation is quite variable. This combination of symptoms is now designated Griscelli syndrome type 1 or Elejalde disease. It has been attributed to mutations in the MYO5A gene, which affects melanosome transport. Individuals with Griscelli syndrome type 2 have decreased cutaneous pigmentation and immunodeficiency but lack neurological deficits. They also may have hemophagocytosis or lymphohistiocytosis that is often fatal, like that seen in Chediak-Higashi syndrome. Griscelli syndrome type 2 is caused by mutations in RAB27A, which is part of the same melanosome transport pathway as MYO5A. Griscelli syndrome type 3 presents with hypomelanosis and does not include neurologic or immunologic disorders. Mutations in the melanophilin (MLPH) gene and MYO5A have been associated with this variant.
Dystrophic epidermolysis bullosa
Approximately 95% of individuals with the heritable disorder dystrophic epidermolysis bullosa (DEB) have a detectable germline mutation in the gene COL7A1. This gene, which is located at 3p21.3, is expressed in the basal keratinocytes of the epidermis and encodes for type VII collagen. This collagen forms a part of the fibrils that anchor the basement membrane to the dermis, thereby providing structural stability and resistance to mild skin trauma. The lack of type VII collagen results in generalized blistering, often starting from birth, and is associated with skin atrophy and scarring. A registry of DEB mutations, The International DEB Patient Registry, is accessible on the Internet.
There are two recessively inherited subtypes of DEB: severe-generalized (HDEB-sev gen; previously named Hallopeau-Siemens type) and generalized-other (HDEB-O; previously named non–Hallopeau-Siemens type); and a dominantly inherited form, dominant dystrophic epidermolysis bullosa (DDEB). The clinical manifestations demonstrate a continuum of severity that complicates definitive diagnosis, especially early in life. The severe generalized subtype, associated with formation of pseudosyndactyly (a mitten-like deformity secondary to fusion of interdigital webbing) in early childhood, carries a SCC risk of up to 85% by the age of 45 years.[98,99] These cancers arise in nonhealing wounds and usually metastasize to cause death within 5 years of the diagnosis of SCC. In one case series, SCC was the leading cause of death for the 15 patients with the severe generalized subtype. Early mortality also has been observed in this disorder, with a mortality rate of up to 40% by the age of 30 years. Extracutaneous manifestations of HDEB-severe generalized include short stature, anemia, strictures of the gastrointestinal and genitourinary tracts, and corneal scarring that may result in blindness.