PMC8671158_01
Clinical manifestations, imaging changes, and pathological changes in amyloidosis cutis dyschromica (ACD). (A1,A2) Hyperpigmented and hypopigmented macules on the abdomen of a patient with ACD. (B1,B2) Feature of ACD under dermoscopy. (B1) Hypopigmented areas: white patch (green arrow) with blurred margins, white and brown blotches (black arrow) surrounded. (B2) Hyperpigmented areas: large fulvous pigmentation spots (black arrow), interspersed with white grid-like stripes and patches (green arrow). (C1) RCM performance in some normal skin areas: no obvious amorphous deposits. (C2) Feature of ACD under RCM. The highly refractive substance inside the papillary dermis (like clumpy, dotted, and linear structures, green arrow) and highly refractive round cell scattered in the superficial dermis (yellow arrow). (D1) Mildly hyperkeratotic epidermis along with amorphous eosinophilic materials in the papillary dermis (HE, x100). (D2) Eosinophilic materials stained positive (Congo red, x400).
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F1
He did not have a history of systemic diseases or other skin diseases (Figure 1A1,A2). The hyperpigmented areas were patches composed of brownish spots, intermixed with striped or patchy white areas of hypopigmentation (Figure 1B1,B2). Parts of the hypopigmented areas showed highly refractive round cells scattered in the superficial dermis (Figure 1C2). Histopathology revealed sparse melanophages and focal pigment incontinence beneath the epidermis, mild hyperkeratosis in parts of lesions, and homogenous eosinophilic deposits in the papillary dermis that stained positive with CR and was consistent with amyloidosis (Figure 1D1,D2).
Pedigree map and gene mutation sites. (A) Pedigree of the proband. (B,C) Glycoprotein non-metastatic melanoma protein B (GPNMB) mutations detected in the proband.
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F2
The ANNOVAR annotation software indicated that the frequency of c.393T>G in all populations was 0.00001648, suggesting that this missense mutation was a pathogenic mutation (Figures 2B,C).
Structure and mutations of GPNMB. Schematic of 8 domains on human GPNMB and gene mutations responsible for ACD. Numbers correspond to amino acid residues; The RGD and di-leucine motifs are shown. A splice isoform of GPNMB (GPNMB-1) with an in-frame 12-amino-acid insertion (underlined) is also shown. Locations of GPNMB mutations (on the protein) identified in this study and those from an earlier study are indicated. (SIG, signal sequence; NTD, N-terminal domain; PKD, polycystic kidney disease-like domain; KRG, kringle-like domain; TM, transmembrane domain; CTD, C-terminal cytoplasmic domain).
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F3
So far, 14 ACD-related gene loci have been found on GPNMB, namely, 5 (35.7%) frameshift mutations, 4 (28.6%) non-sense mutations, 4 (28.6%) missense mutations, and 1 (7.1%) splice site mutation (Figure 3).