Lipoid proteinosis (LiP) (OMIM 247100) is a rare autosomal recessive disease caused by loss of function mutations in the extracellular matrix protein 1 gene, ECM1, on chromosome 1q21. LiP is characterized clinically by hoarseness in early infancy, followed by waxy papules and plaques on the face and body along with pox-like and acneiform scars. We studied a 20-year-old Japanese woman with LiP. She was born of consanguineous parents. Biopsy specimens obtained from a nodule on the elbow were used for histopathology, immunohistology and electron microscopy. Exons 6 and 7 of ECM1 were amplified by polymerase chain reaction (PCR) from genomic DNA from the proband, her parents, her brother and an unrelated person. PCR products were sequenced to detect the mutation. Histopathological examination revealed an irregular mass of calcium beneath deposits of a hyaline material in the dermis. Immunofluorescence double staining showed that the CD31-positive microvascular density was increased but that staining for the lymphatic-specific hyaluronan receptor LYVE-1 was drastically diminished in lesional compared with nonlesional skin of the patient and with normal skin. Electron microscopy revealed marked concentric reduplication of basal laminae not only around blood vessels but also around solitary dermal cells positive for Weibel-Palade bodies scattered in the hyaline material. Sequencing of the PCR products revealed a homozygous frameshift mutation, 507delT, in exon 6. This led to a premature stop codon 23 bp downstream. The results of immunopathological and ultrastructural characterization suggest that a failure of mucocutaneous lymphangiogenesis may underlie the clinical features of LiP. Identification of mutation 507delT in a Japanese patient with LiP further supports the thesis that this mutation represents a recurrent mutation in ECM1 in patients with LiP. To our knowledge, this case represents the first report of calcinosis cutis occurring in LiP.