Familial Primary Cutaneous Amyloidosis Across Generations

Dear Editor,

Macular and lichen amyloidosis are variants of primary localized cutaneous amyloidosis (PLCA), a chronic pruritic condition characterized by amyloid deposition in the superficial dermis. While most cases are sporadic, 10% are familial and linked to mutations in the oncostatin M receptor beta (OSMRB) and IL31RA genes, or no pathogenic mutations.[1,2] Despite this, literature on familial amyloidosis remains scarce. This report presents three PLCA cases within a single family.

A young male in his 20s, the index case, presented to our outpatient department with pruritic, progressive skin pigmentation spanning six years, initially appearing spontaneously on the upper arm and later spreading to involve the trunk and limbs. The patient did not have any personal or family history of malignancies. A cutaneous examination revealed rippled hyperpigmentation primarily on the extensor aspects of the upper and lower limbs, the interscapular area, and the lower back [Figure 1a and b]. Similarly distributed rippled hyperpigmentation began during adolescence and was present in his twin brother [Figure 2a] and mother [Figure 2b; pedigree chart - Figure 2c]. The patient and family members did not have a history of atopy and denied the use of abrasives. The patient denied a family history of thyroid or adrenal tumors, and his thyroid examination was normal. He reported no history of headaches or palpitations, and his blood pressure was within normal limits. No other relevant cutaneous or systemic findings were noted in any of these patients. Histopathological analysis of the rippled pigmentary macules on the arm of the index case revealed pale, amorphous, eosinophilic acellular deposits beneath the basement membrane, staining red with Congo red and showing cytokeratin positivity [Figure 3a-c]. Based on clinical and histopathological findings, a diagnosis of PLCA was made. Whole-exome sequencing of the index case showed a heterozygous 3′ splice site variant in intron 6 of the KRT5 gene (chr12: g.52516858C>T; Depth: 106×) that affects the invariant AG acceptor splice site upstream of exon 7 (c.1219-1G>A; ENST00000252242.9), classified as a variant of uncertain significance (VUS). Treatment involved topical propylene glycol and antihistamines to control itching.

Figure 1.

(a and b) A 20-year-old male with rippled, hyperpigmented macules distributed on the extensor aspect of the upper limbs and back

Figure 2.

Similar distribution in twin brother (a), mother (b), and (c) pedigree chart depicting the inheritance

Figure 3.

(a) Pale, amorphous, eosinophilic acellular deposits beneath the basement membrane suggestive of amyloid (Hematoxylin and Eosin stain, 400x), (b) Congo red staining confirming amyloid deposition (Congo red stain, 400x), (c) Cytokeratin positivity (IHC stain, 400x)

Familial cases of PLCA typically arise between the ages of 5 and 18. It is an autosomal dominantly inherited condition that has been documented in various populations, including Japan, China, Taiwan, and Brazil.[1,3] Familial cases of macular and lichen amyloidosis may occur in association with multiple endocrine neoplasia type 2A, with mutations involving the RET proto-oncogene. Individuals suspected of having MEN2A should be thoroughly assessed for a family history of malignancies. A detailed examination of the thyroid, including serum calcitonin, ultrasound, and fine-needle aspiration cytology, is recommended if a solitary thyroid nodule is present to exclude medullary thyroid carcinoma. Additionally, patients should be asked about symptoms such as palpitations, headaches, and blood pressure changes. Biochemical testing, including the measurement of metanephrines, along with appropriate radiological imaging, should be conducted to rule out pheochromocytoma. Mutations in genes such as OSMR and IL31RA have been implicated in familial form, with OSMR mutations reducing receptor signaling, increasing keratinocyte apoptosis, and leading to subsequent amyloid deposition and pruritus.[2] Pathogenic mutations involving OSMR as a cause of PLCA was reported in 2008. Nine missense mutations have been reported in the literature involving the OSMR gene to date.[4] Although genetic mutations have been identified in most cases of familial PLCA, Sakuma et al.[1] reported that one affected individuals in the family did not harbor any pathogenic mutations. Epidermal proteins, such as keratins (KRT), are thought to form amyloid deposits and have been shown to bear GS (glycine-serine-rich) domains.[5] It is believed that GS-like domains of keratin proteins are involved in the generation of amyloid deposits.[5] Amyloid bodies have been identified in patients with Naegeli-Franceschetti-Jadassohn syndrome and epidermolysis bullosa simplex (mutations in keratin 14 and 5).[5] Our patient also was found to have a mutation involving keratin 5 (currently classified as a VUS; however, it is a plausible variant responsible for the disease) that could have led to amyloid deposition. The report by Sakuma et al.[1] and our report suggests that, in cases where patients lacked identifiable pathogenic mutations, high genetic heterogeneity may exist, and other pathogenic mutations associated with familial PLCA may not yet have been identified. Further genetic studies, such as genome-wide linkage analysis in the Indian subcontinent, are warranted to elucidate its genetic components and explore treatment strategies.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.