Late-onset amyloidosis cutis dyschromica: A rare case of progressive dyschromia caused by compound heterozygous GPNMB mutation

INTRODUCTION

Amyloidosis cutis dyschromica (ACD) is a rare form of primary cutaneous amyloidosis, distinguished by diverse patterns of widespread skin dyschromia, mild pruritus, onset before puberty, and the deposition of amyloid in the subepidermal layer.^[1] Altogether 48 cases of ACD fulfilling each of the clinical and histological criteria described by Morishima^[2] were identified. In 37 cases, there was a positive family history; the remaining cases were sporadic. The mean age at diagnosis was 30 years, with a mean age of onset of 6 years (3–22 years). Males and females were affected with equal frequency. As seen in Table 1, most of the patients were of East Asian (Chinese/Hong Kong Chinese,^[3-12] Taiwanese^[13,14] and Japanese^[15]) or South East Asian ethnicity (Thai,^[16,17] Filipino,^[13,18,19] Indonesian^[20] and Sri Lankans^[21]). There are also reported cases in South Asia (Indian^[21-29] and Pakistani^[30-32]), in Middle East/West Asia (Iranians,^[33,34] Kuwaitis^[13]), and in North Africa (Libyans^[35]). Only five case reports of ACD have been published in Caucasian/European descent patients (Americans^[36,37] and Turkish^[38-40]). To date, there are 3 published cases of ACD in Filipino patients.^[13,18,19] Genetic factors and impaired DNA repair from UV light are suspected contributors to the etiology of ACD.^[38] Here, we describe a rare presentation of ACD demonstrating classic histopathologic features, but notably with late onset, localized presentation, and no familial history. Only 2 cases to date were published with late-onset ACD.^[36,38]

CASE REPORT

A 34-year-old female presented with a 10-year history of a few, asymptomatic, mottled hypopigmented and hyperpigmented macules on her upper extremities. Over time, these lesions increased in size and number, progressing into diffuse, hyperpigmented patches and mottled hypopigmented macules on both upper and lower extremities [Figure 1]. No systemic symptoms were present. Family members, including non-consanguineous parents, were not affected. Baseline laboratory examinations, including full blood count and biochemical tests, were unremarkable.

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Figure 1:

Patient showing multiple, well-defined, mottled, hypopigmented macules surrounded by diffuse hyperpigmented patches on bilateral lower extremities.

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A skin punch biopsy in H&E stain revealed epidermal papillomatosis and widened dermal papillae containing eosinophilic amorphous deposits, confirming amyloid presence. Congo red stain and cytokeratin 5/6 immunostaining highlighted increased amyloid deposits, which confirmed the diagnosis of primary cutaneous amyloidosis [Figure 2]. Furthermore, peripheral blood specimens of both the patient and the mother were sent for genetic testing.

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Figure 2:

(a) Hematoxylin and eosin (H&E), 400×; (b) Congo red, 400×; (c) Cytokeratin (CK) 5/6, 400×. All images demonstrate eosinophilic, amorphous deposits consistent with amyloid deposition (black arrows).

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Whole exome sequencing identified two heterozygous variants in GPNMB. The first is a nonsense variant (c.565C>T, Arg189Ter) while the second is a missense variant (c.1238G>C, Cys413Ser). Sanger sequencing confirmed that the patient is a compound heterozygote for both mutations. Segregation analysis confirms the missense variant (c.1238G>C, Cys413Ser) was carried by the patient’s mother [Figure 3].

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Figure 3:

Sanger sequencing showing the presence of both glycoprotein nonmetastatic gene B variants. Segregation analysis confirms the missense variant (c.1238G>C, Cys413Ser) was carried by the patient’s mother.

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DISCUSSION

Primary cutaneous amyloidosis refers to the extracellular deposition of amyloid material in previously normal skin without systemic involvement. The major variants of primary cutaneous amyloidosis are macular and lichen.^[1] ACD, first described in 1970, is a rarely documented variant of cutaneous amyloidosis.^[2] Morishima described its features as the following: (i) dotted, reticular hyperpigmentation with hypopigmented macules distributed over nearly all of the body, (ii) no or little itch, (iii) onset before puberty, and (iv) focal amyloid deposition under the epidermis.^[2] The exact pathogenic mechanism of ACD is unknown; however, it is hypothesized that affected keratinocytes have an underlying genetic susceptibility to photodamage, causing defective DNA repair. Amyloid is then produced by these faulty keratinocytes that have undergone phagocytosis. The deposition of amyloid within the papillary dermis may cause stretching of the basement membrane and, therefore, a decrease in melanocyte density. As the disease is suspected to be familial, there are several genetic loci that are being studied for their relevance.^[18,40]

Mutations in the GPNMB are composed of 560 amino acids (GenBank: NP_0025011). It is a highly glycosylated type I transmembrane protein, and it was first isolated from weakly metastatic melanoma cells in 1995 as a regulator of tumor growth.^[41] It is highly expressed in melanocytes, is partially localized in melanosomes, lysosomes, and early endosomes.^[42] GPNMB was found to have critical roles in melanosome formation, autophagy/phagocytosis, clearance of apoptotic cell debris, and negative regulation of inflammation, which are associated with ACD.^[12] To date, 12 GPNMB mutations have been identified in ACD. Most mutations are nonsense or frameshift mutations with only two documented missense mutations, p.Cys413Arg and p.Cys413Ser, located within the Kringle-like domain of GPNMB, 5 suggesting that this region may be critical for protein structure and function.^[16] Identifying a GPNMB mutation can help confirm the diagnosis of ACD, especially in atypical cases, and may guide genetic counseling for affected individuals and their families. Understanding the role of GPNMB in ACD pathogenesis might open avenues for potential targeted therapies, though current treatment remains supportive and symptomatic.

Different treatment modalities, including sunscreen, topical corticosteroids, keratolytics, dimethyl sulfoxide, capsaicin, CO₂ laser, and acitretin, have been used with varying degrees of effectiveness.^[38] Vitamin A derivatives, like acitretin, are used to treat ACD as they may repair the defective keratinization that allows keratinocytes to degenerate into amyloid.^[40]

CONCLUSION

ACD is an extremely rare condition, with most cases reported in East Asian populations, though sporadic reports exist worldwide. Understanding the clinical and histological features of ACD is critical for distinguishing it from other pigmentary disorders and for establishing an accurate diagnosis. Currently, there is no definitive treatment for ACD, and management focuses on symptomatic relief and aesthetic improvement. Further research into the genetic and molecular mechanisms underlying ACD is needed to better understand its etiology and develop targeted therapies.