PMC8222900_01
(A) Schematic representation of intragenic mutations of USB1. Nonsense variants are in orange, frameshift in red, splicing in violet, and missense variants in blue. Protein domains are in gray and refer to HVSL, uncharacterized conserved protein. All variants were extrapolated from ClinVar (RefSeq NM_024598.3). They are distributed according to their ExAc frequency (gnomad.broadinstitute.org). The mutation identified in our proband is framed. (B) Family tree, with electropherogram results of affected patient and carriers.
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F1
He was born to young and healthy nonconsanguineous parents after an uneventful pregnancy (Figure 1B). This variant is already reported as pathogenic (ClinVar ID 156347), and segregation analysis confirmed that both parents were heterozygous for this variant, suggesting geographical consanguinity (Figure 1B).
(A) Diffuse reticulated squamous hyperpigmentation surrounding slightly hypopigmented areas of the lower limbs. (B) Brownish infiltrated plaque on the left arm. (C) On polarized light dermoscopy, a homogeneous light brown structureless area is observed. (D) Mottled hypo- and hyperpigmentation on the arms, lesions typically localized on photoexposed areas. (E) Pachyonychia of the toenails. (F) Plantar spiny keratoderma.
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F2
Dermatological examination showed diffuse reticulate scaly hyperpigmentation surrounding multiple slightly hypopigmented areas (Figures 2A,D). On the trunk and on the left arm, two brownish infiltrated papules were observed (Figure 2B). Polarized light dermoscopic examination revealed homogeneous light brown structureless areas (Figure 2C). Pachyonychia of the toenails and plantar spiny keratoderma were also present (Figures 2E,F).
(A) Histology of poikiloderma showing slightly atrophic and flattened epidermis, focal images of hydropic degeneration of the basal layer, light perivascular lymphohistiocytic infiltrate, and pigmentary incontinence. (B) Several Civatte bodies highlighted by high molecular weight cytokeratin (HMW-CK) immunostaining. (C) In mastocytoma, histological examination showed a dense cellular infiltrate occupying the superficial dermis. The cells were characterized by moderately abundant, amphophilic, and finely granular cytoplasm and oval-shaped nuclei with clumped chromatin. (D) Immunohistochemical investigation showing positivity for CD117 (c-Kit).
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F3
Histopathology on the first specimen confirmed the diagnosis of poikiloderma, showing slightly atrophic and flattened epidermis, focal images of hydropic degeneration of the basal layer, light perivascular lymphohistiocytic infiltrate, and pigmentary incontinence (Figure 3A). Several Civatte bodies were present, as highlighted by high molecular weight cytokeratin (HMW-CK) immunostaining (Figure 3B). The second specimen showed histological features compatible with the diagnosis of cutaneous mastocytosis, including a dense cellular infiltrate occupying the superficial dermis; the cells were characterized by moderately abundant, amphophilic, and finely granular cytoplasm and oval-shaped nuclei with clumped chromatin; immunohistochemical investigation demonstrated positivity for CD117 (c-Kit) (Figures 3C,D).