Amyloidosis cutis dyschromica (ACD) is a distinct form of primary cutaneous amyloidosis characterized by generalized hyperpigmentation mottled with small hypopigmented macules on the trunks and limbs. Affected families and sporadic case subjects have been reported predominantly in East and Southeast Asian ethnicities; however, the genetic cause has not been elucidated. We report here that the compound heterozygosity or homozygosity of GPNMB truncating alleles is the cause of autosomal-recessive ACD. Six nonsense or frameshift mutations were identified in nine individuals diagnosed with ACD. Immunofluorescence analysis of skin biopsies showed that GPNMB is expressed in all epidermal cells, with the highest staining observed in melanocytes. GPNMB staining is significantly reduced in the lesional skin of affected individuals. Hyperpigmented lesions exhibited significantly increased amounts of DNA/keratin-positive amyloid deposits in the papillary dermis and infiltrating macrophages compared with hypo- or depigmented macules. Depigmentation of the lesions was attributable to loss of melanocytes. Intracytoplasmic fibrillary aggregates were observed in keratinocytes scattered in the lesional epidermis. Thus, our analysis indicates that loss of GPNMB, which has been implicated in melanosome formation, autophagy, phagocytosis, tissue repair, and negative regulation of inflammation, underlies autosomal-recessive ACD and provides insights into the etiology of amyloidosis and pigment dyschromia.

Amyloidosis cutis dyschromica is a rare form of primary cutaneous amyloidosis without systemic involvement and characterized by asymptomatic, progressive hyper- and hypopigmentation. We present the first case of a patient with amyloidosis cutis dyschromica diagnosed previously elsewhere as having Addison disease with generalized hyperpigmentation of the skin. This case suggests that in patients presenting with asymptomatic cutaneous dyschromia a skin biopsy for histopathological examination should be considered.

Amyloidosis cutis dyschromica (ACD) is a rare form of primary cutaneous amyloidosis (PCA). There is a paucity of information in the dermatology literature to guide its diagnosis, investigation and treatment. We present two siblings with ACD and summarise the epidemiology, clinical features, natural history and treatments in 48 cases of ACD from the literature. Familial cases were more common (37) than sporadic cases. ACD is predominantly reported in those of East and South-East Asian ethnicity (63%). The mean age of onset was 6 years in familial cases, and 23 years in sporadic cases. The clinical features of familial and sporadic ACD do not differ substantially. Pruritus was the only symptom, and was reported in 19% of all cases. There were no reported ACD cases with systemic amyloidosis. Acitretin was reported to result in improvement in seven of 10 patients treated. Routine investigation for systemic involvement is not necessary. Acitretin may be helpful.