Amyloidosis, Primary Localized Cutaneous, 3

A number sign (#) is used with this entry because of evidence that primary localized cutaneous amyloidosis-3 (PLCA3) is caused by homozygous or compound heterozygous mutation in the GPNMB gene (604368) on chromosome 7p15.

Description

Amyloidosis cutis dyschromica (ACD), a rare form of primary localized cutaneous amyloidosis, is a pigmentary disorder in which keratinocyte-derived amyloid is deposited in the skin. Onset occurs before puberty and involves macular or reticulate hyperpigmentation admixed with symmetrically distributed guttate hypopigmented and hyperpigmented lesions. ACD can be distinguished from other conditions with similar clinical findings by a skin biopsy in which amyloid deposition in the papillary dermis is seen. Specific features that set ACD apart from the more common macular and lichenoid variants of primary cutaneous amyloidosis include dotted, reticular, or diffuse hyperpigmentation admixed with lentil-sized hypopigmented macules; mild or no associated pruritus; and, on histologic examination of skin from both hyper- and hypopigmented lesions, amyloid deposition confined to the papillary dermis, in close proximity to the epidermis (Huang et al. (2009); Mahon et al., 2016).

For a discussion of genetic heterogeneity of primary localized cutaneous amyloidosis, see 105250.

Clinical Features

Huang et al. (2009) described 4 patients from 2 unrelated families with amyloidosis cutis dyschromica. The 25-year-old proband from the first family (family 1) had progressive and asymptomatic mottled hyperpigmentation from age 8 years, with lesions initially on the trunk that later became generalized. There were areas of spotty hypopigmentation among the hyperpigmented macules. His 26-year-old sister was similarly affected, as were 2 brothers from a second family (family 2). Examination of the 2 sibs from family 1 and the 20-year-old brother from family 2 revealed generalized mottled hyper- and hypopigmented macules of variable size, ranging from 2 mm to 13 mm, in a symmetrical pattern with relative sparing of the neck, face, hands, and feet. Similar lesions in the 14-year-old brother from family 2 were limited to the lower legs bilaterally. Only a few itchy 2- to 3-mm papules with excoriation were noted on the extremities of the 3 older patients. Hair, nails, teeth, mucosa, palms, and soles appeared normal. Histopathologic analysis of skin biopsy specimens from all 4 patients were similar and showed amorphous eosinophilic material in the papillary dermis, with an increase of melanin in the basal layer and pigment incontinence in the papillary dermis by hematoxylin-eosin (HE) staining; the reticular dermis was unchanged. Based on the clinical and pathologic findings, a diagnosis of familial amyloidosis cutis dyschromica was made.

Mahon et al. (2016) reported a Filipino sister and brother who developed asymptomatic patchy hyperpigmentation over the extensor surfaces of the arms and legs at age 10 years. Examination at age 14 years and 13 years, respectively, showed patchy hyperpigmentation and numerous guttate hypopigmented macules on the lower legs and thighs as well as the extensor aspects of the upper arms. Skin biopsies from both hyper- and hypopigmented areas showed amorphous pink material within the papillary dermis on HE staining, and Congo red staining revealed amorphous eosinophilic masses in the papillary dermis that showed apple-green birefringence on polarization, consistent with the presence of amyloid.

Yang et al. (2018) studied 8 Han Chinese patients with ACD from 4 families showing autosomal recessive inheritance, including the 2 families originally reported by Huang et al. (2009), as well as 1 sporadic patient. Mean age of onset was 6 years (range, 2 to 13 years). Skin dyschromia and the area affected gradually increased with age and then stabilized. All affected individuals exhibited similar cutaneous manifestations, including generalized hyperpigmentation mottled with small hypopigmented macules or patches, distributed over the trunk and limbs in a symmetric pattern. Skin lesions on the neck and face were much milder, with some scattered hyper- and hypopigmented or only hypopigmented spots on the neck and forehead and around the hairline of the face. Small blisters were occasionally found on the arms in 4 affected sibs from 1 family (family A). Histopathologic, immunofluorescent, and electron microscopic analysis of affected skin from patients in family A revealed increased accumulation of DNA/keratin-positive amyloid deposits in the papillary dermis, intracellular fibrillary aggregates in epidermal cells, and infiltrated macrophages in hyperpigmented lesions compared to hypopigmented and depigmented macules. Hypopigmented lesions showed reduced melanin levels as well as slightly reduced numbers and uneven distribution of melanocytes compared to hyperpigmented lesions, whereas depigmented lesions had very few melanocytes.

Reviews

Mahon et al. (2016) reviewed 48 reported cases of ACD, of which 37 had a positive family history. In familial cases, the mean age at onset was 6 years, and males and females were equally affected. Most of the patients (63%) were of East Asian or Southeast Asian ancestry, with only 3 cases reported in Caucasian individuals. Mild pruritus was the only symptom reported, and was present in 7 cases. The distribution of dyschromia was symmetric and widespread in all cases, with a history of initial onset on the trunk then progressive involvement of the limbs, with sparing of the face, hands, and feet in most patients. The sporadic cases showed a later age of onset (mean, 23 years) and there were more women than men in that group, with all but 1 patient of East Asian ancestry. The incidence of pruritis and distribution of lesions was similar to the familial cases. There were no cases of systemic amyloidosis in either group.

Molecular Genetics

In 9 affected individuals from 5 Han Chinese families with amyloidosis cutis dyschromica, including the 2 families originally described by Huang et al. (2009), Yang et al. (2018) performed whole-exome sequencing and identified homozygosity and compound heterozygosity for truncating mutations in the GPNMB gene (604368.0001-604368.0006).