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case_images: Clinical and dermoscopic observation. (A-C) Diffuse hyperpigmentation intermingled with numerous hypopigmented macules on the limbs and back in 3 ACD patients, without the involvement of the dorsa of hands and feet. (D) Dermoscopy displayed ill-defined, irregular, white macules surrounded by brownish pigmentation, and indistinct linear vessels (original magnification x60).
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case_images: Cutaneous examination showed numerous reticulate hyper-/hypopigmented macules involving almost the entire body, with mild involvement of the face and neck and sparing of the dorsal of hands and feet (Fig. 1A). Two siblings had similar lesions (Fig. 1B-C), but other members including non-consanguineous parents were not affected. Dermoscopy displayed ill-defined, irregular, white macules surrounded by brownish pigmentation, and indistinct linear vessels (Fig. 1D).
case_images: Histopathological and immunohistochemical observation. (A) Hematoxylin-eosin stain showed hyperkeratotic epidermis with mild hyperpigmentation and focal basal liquefaction degeneration, amorphous eosinophilic deposits and sparse melanophagesin the papillary dermis (left side); and hyperkeratotic and partially atrophic epidermis with basal layer hypopigmentation (right side) (original magnification x200). (B) Cytokeratin 34betaE12 immunostaining revealed amyloid deposits in the upper dermis (original magnificationx200). (C-F) GPNMB immunoreactivity was weak in hyperpigmented lesion (C) and absent in hypopigmented lesion (D) of II5 patient, and moderate in forearm skin of II4 carrier with c.565C>T (E) and normal control (F) (original magnification x200).
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case_images: Light microscopy from an arm lesion revealed: a hyperkeratotic and partially atrophic epidermis with basal layer hypopigmentation in hypopigmented area; and hyperkeratotic epidermis with mild hyperpigmentation and focal basal liquefaction degeneration, amorphous eosinophilic deposits and sparse melanophages in the papillary dermis in hyperpigmented area (Fig. 2A). The deposits stained positive with Congo red stain and high-molecular-weight cytokeratin CK34betaE12 immunostaining (Fig. 2B). II4 carrier with c.565C > T. Immunohistochemically, cytoplasmic GPNMB expression in the basal and suprabasal layers was weak in hyperpigmented lesions or absent in hypopigmented lesion of ACD patients, and moderate in forearm skin of II4 carrier with c.565C > T and normal control (Fig. 2C-F).
case_images: Transmission electron microscopy. (A) Cytoplasmic Amyloid-like Filaments (AF) in 2 degenerated basal Keratinocytes (KC), Tonofilaments (Tf) in adjacent normal keratinocytes, partial disruption (arrowheads) of basal lamina and cytomembrane between the uppermost amyloid deposit and the degenerated basal cell, and fibrillar bodies (asterisks) in the papillary dermis (original magnification x8,000). (B) A Histiocyte (H) lay between 2 partly degenerated basal keratinocytes containing AF and Tf, partial disruption (arrowhead) of basal lamina and cytomembrane, and fibrillar bodies (asterisks) in the papillary dermis (original magnification x15,000).
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case_images: Homogeneous fibrillar bodies were surrounded by collagen bundles and fibroblastic and histiocytic processes in the papillary dermis (Fig. 3).
case_images: Pedigree and GPNMB sequencing and protein structure. (A) Pedigree of the family. Asterisks represent the participants with genetic testing. (B) Sanger sequencing of the proband showed compound heterozygous mutations of c.565C>T in exon 5 and c.1092delT in exon 7 of GPNMB. (C) Structure and 16 mutations of human GPNMB protein originating from 17 GPNMB mutants (p.V240Dfs*24 deriving from mutants c.717_718delTG and c.719_720delTG). A novel c.1092delT mutation in this pedigree is marked in red. Mutants GPNMB-1 (a splice isoform of GPNMB) with an in-frame 12-amino acid insertion (underlined), and RGD and Di-Leucine motifs are also shown. SIG, Signal Sequence Domain; 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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case_images: T (p.R189*) in exon 5 and c.1092delT (p.P365Lfs*21) in exon 7 of GPNMB in 3 affected siblings (Fig. 4A-B), which were respectively derived from her mother and father. Three affected siblings were diagnosed as ACD, and skin lesions of the proband remained stable at a 4.5-year follow-up. Hence, 17 ACD-associated GPNMB mutations of 29 ACD pedigrees (including our case) have been identified, namely, 7 (41.2%) frameshift, 5 (29.4%) nonsense, 4 (23.5%) missense, and 1 (5.9%) splice site mutations (Fig. 4C).