June 2009

Familial Primary Localized Cutaneous Amyloidosis in Brazil

Author Affiliations

Author Affiliations: Department of Dermatology (Drs Sakuma and Hans-Filho) and Pathology (Drs M. Odashiro and D. N. Odashiro), Federal University of Mato Grosso do Sul, Campo Grande, Brazil; Department of Dermatology, Federal University of the State of Rio de Janeiro, Rio de Janeiro, Brazil (Dr Sakuma); Genetic Skin Disease Group, St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, The Guy’s, King's College, and St Thomas' School of Medicine, London, England (Drs Arita and McGrath); Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan (Dr Arita); and University for the Development of the State and Pantanal Region, Campo Grande, Brazil (Ms Hans and Mr Hans-Neto).


Copyright 2009 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2009

Arch Dermatol. 2009;145(6):695-699. doi:10.1001/archdermatol.2009.107

Background  Macular and lichen amyloidosis are clinical variants of primary localized cutaneous amyloidosis (PLCA). Most cases are sporadic, but approximately 10% of cases may be familial. To our knowledge, the clinicopathologic and molecular features of such pedigrees, however, have not been studied in detail.

Observations  We assessed 2 Brazilian families with either lichen-type (family 1 had 14 affected subjects) or macular-type (family 2 had 7 affected subjects) PLCA. Typically, in both pedigrees, the onset of symptoms was around puberty, and pruritus usually began on the lower legs. Findings from lesional skin biopsy samples from both families showed thioflavin T–positive material in the papillary dermis, which was more prominent in the lichen phenotype in family 1. Spontaneous improvement occurred in 3 subjects (from both families) after age 25 years. All affected individuals in family 1 had a heterozygous missense mutation in the OSMR gene (p.I691T), but no pathogenic mutation in OSMR was found in family 2.

Conclusions  Familial PLCA shows autosomal dominant inheritance, but there is clinical and genetic heterogeneity and variable clinical penetrance. Demonstration of mutations in the OSMR gene provides new insight into mechanisms of itch and apoptosis in human skin.

Macular-type and lichen-type amyloidosis are clinical variants of primary localized cutaneous amyloidosis (PLCA [OMIM 105250]). They are characterized histologically by focal deposition of immunoglobulins and serum amyloid P component on collections of basal keratinocytes in the superficial dermis that are undergoing filamentous degeneration or apoptosis.13 Macular and lichen amyloidosis are not associated with other systemic forms of amyloidosis.1,4 Primary localized cutaneous amyloidosis (PLCA) is rare among Europeans and North Americans but is much more common in South Americans, Middle Easterners, and Asians.5 Although most cases are sporadic, approximately 10% of cases of PLCA may be familial. We report the clinicopathologic abnormalities seen in 2 Brazilian families with either lichen-type (family 1) or macular-type (family 2) variants of PLCA (Table). Family 1 represents, to our knowledge, the largest Brazilian family with PLCA to be reported and the third largest in the world.514

Image not available
Clinical Data of Families 1 and 2

Following ethics approval and informed consent, clinical evaluation, photography of the patients, and skin biopsies were performed. Of the 14 affected individuals in family 1, PLCA has been confirmed clinically in 12 (with additional skin biopsy confirmation in 8) and the other 2 have been reported by relatives to have the disease. Of the 7 affected members in family 2, all have been examined clinically and 5 have histopathologically confirmed PLCA.


The families' pedigrees are illustrated in Figure 1A and Figure 2A. Family 1 presented with the lichen-type variant. The age at onset of the disease ranged from 5 to 18 years. Symptoms typically started on the lower legs with severe pruritus, followed by local lichenification and appearance of papules (Figure 1B). Later, in some family members the papules spread to other areas, involving the abdomen, chest, back, arms, forearms, thighs, dorsa of the feet, and buttocks. Patient 3 also presented with a brownish macular lesion on the scapular region, suggesting coexistence of both lichen and macular variants. The same patient also had small papules grouped on the auricular concha of both ears, an uncommon feature of familial PLCA15 (Figure 1C). Family 2 presented with the macular amyloid variant. The age at onset was older (15-39 years), but the symptoms also started mainly on the lower legs with pruritus, followed by lichenification and darkening of local skin. The lesions were characterized by poorly delineated grayish or brownish pigmented macules, distributed mainly on the limbs and upper back. Patient 16 in family 2 also presented with brownish papules on the upper back, suggesting the coexistence of both macular and lichen variants. The symptoms and lesions in family 2 were less dramatic than in family 1, apart from patient 21, whose skin lesions also involved the arms, forearms, lower legs, neck, and upper and lower back (Figure 2B). For both families, the main symptom was pruritus, and there were concerns as well about the cosmetic appearances of the PLCA. Spontaneous improvement, however, especially in the severity of the pruritus, was observed in some subjects (patients 1, 2, and 15) and usually began after the age of 25 years.

Figure 1.
Image not available

Clinical and histological aspects of family 1. Circles indicate females; squares, males. The black symbols also show the patient number, with ages given below the symbols. A, Family 1's pedigree of lichen-type amyloidosis; B, multiple monomorphic skin-colored papules on the lower legs of patient 3; C, small papules grouped on the auricular concha of patient 3; D, amorphous eosinophilic material within papillary dermis (hematoxylin-eosin, original magnification × 40); E, polarized light showing bright fluorescence of the amyloid deposits (thioflavin T, original magnification × 80).

Figure 2.
Image not available

Clinical and histologic aspects of family 2. Circles indicate females; squares, males. The black symbols also show the patient number, with ages given below the symbols. A, Family 2's pedigree of macular-type amyloidosis; B, grayish macules with rippled appearance on the arm of patient 21.

To date, none of the family members has had symptoms, signs, or other evidence of systemic amyloidosis or of multiple endocrine neoplasia type 2A. Patients 4, 5, 6, 7, 10, 11, 16, and 17 all had an atopic background, which may have served as an exacerbating factor because scratching was reported as an important worsening factor in several individuals in both families. Most members of family 2 also described sun exposure as a further exacerbating factor. More clinical details are listed in the Table.

All affected individuals in family 1 had a heterozygous missense mutation in the OSMR gene (p.I691T),16 but no pathogenic mutation in OSMR was found in family 2. We then performed linkage analysis for the OSMR locus in family 2 using the microsatellite marker D5S418, as described previously.16 This analysis showed different alleles in the affected mother being transmitted to the 6 affected offspring. Specifically, the marker sizes for D5S418 in the mother were 156/165. We found that 4 of 6 affected offspring had inherited the 165 allele, whereas the other 2 had inherited the 156 allele (the marker sizes in their father were 150/150). These data indicate that this locus on chromosome 5 does not harbor the mutant gene in this particular family.


Family 1 presented with the typical clinical features of lichen amyloidosis, characterized by multiple, discrete, closely set, hyperkeratotic, brownish or skin-colored papules, distributed principally on the shins, although the heels, dorsa of the feet, thighs, extensor area of the arms, forearms, abdomen, chest, back, auricular concha, and buttocks were also affected in some members. Family 2 presented with very discrete, poorly delineated, brownish or grayish pigmented patches; only patient 21 had the characteristic linear rippled appearance of macular-type amyloidosis.

Patients 3 and 16 showed that both papules and macules can coexist in the same individual and that the histopathologic findings of macular and lichen forms of PLCA also overlap. Indeed, it has been shown previously that there are no important differences between lichen- and macular-type amyloidosis regarding the ultrastructure of the amyloid deposit.2 The precise clinical presentation of PLCA, therefore, seems to depend on the quantity of amyloid deposition and/or by secondary epidermal changes. Lichen amyloidosis corresponds to larger amyloid deposits and more pronounced epidermal changes compared with the macular variety.1,2,4 Various stains are useful for demonstrating amyloid deposits in tissue sections. Amyloid demonstrates periodic acid–Schiff positivity, crystal violet metachromasia, and thioflavin T fluorescence (Figure 1D and Figure 1E). Congo red stains amyloid red and produces an apple-green birefringence under polarized light, directly related to its B-pleated configuration.17,18

Recent genome-wide scans for familial PLCA in Taiwan suggested genetic linkage to 5p13.1-q11.2.19 With respect to the families in our study, Arita et al16 mapped family 1 to the same locus and went on to identify missense mutations in the OSMR gene, which encodes the oncostatin M receptor β (OSMRβ) in all affected individuals of family 1. Mutations in this gene were also identified in other pedigrees outside Brazil. To our knowledge, these data represent the first human germline mutations in this cytokine receptor complex and provide new insight into mechanisms of itching and apoptosis. Nevertheless, no pathogenic mutations were identified in family 2, and our additional linkage findings indicate that the chromosome 5 locus is not the correct one for this family. Not all families with PLCA therefore seem to have mutations in the OSMR gene, and genetic heterogeneity is present. Our linkage findings in family 2 also exclude the other interleukin 6 (IL-6) family gene receptors close to OSMR (IL6ST, LIFR, and IL31RA) as alternative candidate genes for PLCA in family 2.

OSMRβ is a component of the oncostatin M (OSM) type II receptor and the IL-31 receptor, and cultured familial primary localized cutaneous amyloidosis keratinocytes showed reduced activation of Jak/STAT, MAPK, and PI3K/Akt pathways after OSM or IL-31 cytokine stimulation.16 These pathways have been reported to have anti-apoptotic effects in several tumor cell lines.2023 Also, Ibuki and Goto24 suggested that the PI3-kinase/Akt pathway might be implicated, at least partially, in anti-apoptotic signaling after UV-B irradiation in cells detached from the extracellular matrix.

An interesting clinical observation was that most individuals experienced pruritus—the main symptom—before the skin lesions appeared, and many individuals of both families reported the habit of scratching as a worsening factor.

Weyers et al25 identified scratching as the most important trigger in the development of lichen amyloidosis, considering it a variant of lichen simplex chronicus. However, they could not explain the accumulation of amyloid in lichen amyloidosis, absent in most cases of LSC, and attributed it to an additional unknown factor.25

With regard to family 1, however, the new molecular data start to provide some new insight to account for the clinicopathologic abnormalities found in PLCA. It is plausible that chronic frictional epidermal damage in an individual whose genetic basis underpins a greater susceptibility to keratinocyte apoptosis determines greater cell death and leads to accumulation of degenerate keratinous material in the superficial dermis.

It is also possible that the triggering stimulus originates outside the skin, perhaps in the dorsal root ganglion, where OSMRβ is expressed.26 Therefore, PLCA may indeed be a “neurodermatitis,” although the mechanism of how OSMR gene mutations might affect the function of nociceptive neurons has not yet been fully elucidated.16,26

In summary, we have described 2 Brazilian families with either lichen-type or macular-type amyloidosis. Both pedigrees show similar histologic abnormalities and share pruritus as the main symptom. Family 1 (patient 3) had features of both lichen and macular PLCA, but all affected individuals had the same pathogenic mutation in OSMR. However, no pathogenic mutation in OSMR was found in family 2, and linkage excluded OSMR as the candidate gene, data that establish PLCA as a genetically heterogeneous disorder.

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Article Information

Correspondence: Thais H. Sakuma, MD, Rua Antonio Parreiras 148/102, Ipanema, Rio de Janeiro, 22411-020 Brazil (thais.sakuma@gmail.com).

Submitted for Publication: July 8, 2008; final revision received September 12, 2008; accepted September 16, 2008.

Author Contributions: Drs Sakuma, Hans-Filho, and McGrath had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Sakuma, Hans-Filho, and McGrath. Acquisition of data: Sakuma, Hans-Filho, Arita, M. Odashiro, D. N. Odashiro, Hans, Hans-Neto, and McGrath. Analysis and interpretation of data: Sakuma, Hans-Filho, and McGrath. Drafting of the manuscript: Sakuma, Hans-Filho, Arita, M. Odashiro, D. N. Odashiro, Hans, Hans-Neto, and McGrath. Critical revision of the manuscript for important intellectual content: McGrath. Obtained funding: McGrath. Administrative, technical, and material support: Sakuma, Hans-Filho, Arita, M. Odashiro, D. N. Odashiro, Hans, and Hans-Neto. Study supervision: Hans-Filho and McGrath.

Financial Disclosure: None reported.

Funding/Support: This study was supported in part by Action Medical Research

Role of the Sponsors: The sponsor had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; or in the preparation, review, or approval of the manuscript.

Additional Contributions: Patients of both families volunteered their time to participate in the research that led to this case report.

Breathnach  SM Amyloid and amyloidosis. J Am Acad Dermatol 1988;18 (1, pt 1) 1- 16
Kumakiri  MHashimoto  K Histogenesis of primary localized cutaneous amyloidosis: sequential change of epidermal keratinocytes to amyloid via filamentous degeneration. J Invest Dermatol 1979;73 (2) 150- 162
Kobayashi  HHashimoto  K Amyloidogenesis in organ-limited cutaneous amyloidosis: an antigenic identity between epidermal keratin and skin amyloid. J Invest Dermatol 1983;80 (1) 66- 72
Brownstein  MHHelwig  EB The cutaneous amyloidosis, I: localized forms. Arch Dermatol 1970;102 (1) 8- 19
Rajagopalan  KTay  CH Familial lichen amyloidosis: report of 19 cases in 4 generations of a Chinese family in Malaysia. Br J Dermatol 1972;87 (2) 123- 129
Vasily  DBBhatia  SGUhlin  SR Familial primary cutaneous amyloidosis: clinical, genetic, and immunofluorescent studies. Arch Dermatol 1978;114 (8) 1173- 1176
Porto  JAPosse Filho  A Amiloidose cutânea genuína familial. An Brasil de dermat e sif 1960;35 (4) 102- 103
De Souza  AR Familial bullous cutaneous amyloidosis: observation of 4 cases [in Portuguese]. Rev Hosp Clin Fac Med Sao Paulo 1963;18 (5) 413- 417
Ozaki  M Familial lichen amyloidosis. Int J Dermatol 1984;23 (3) 190- 193
Sagher  FShanon  J Amyloidosis cutis: familial occurrence in three generations. Arch Dermatol 1963;87 (2) 171- 175
Bergamo  FAnnessi  GRibuffo  MPetresca  MPiazza  P Familial lichen amyloidosus. Chron Derm 1997;7 (6) 959- 961
De Pietro  WP Primary familial cutaneous amyloidosis: a study of HLA antigens in a Puerto Rican family. Arch Dermatol 1981;117 (10) 639- 643
Newton  JAJagjivan  ABhogal  BMcKee  PHMcGibbon  DH Familial primary cutaneous amyloidosis. Br J Dermatol 1985;112 (2) 201- 208
Hartshorne  ST Familial primary cutaneous amyloidosis in a South African family. Clin Exp Dermatol 1999;24 (6) 438- 442
Mahalingam  MPalko  MSteinberg-Benjes  LGoldberg  LJ Amyloidosis of the auricular concha: an uncommon variant of localized cutaneous amyloidosis. Am J Dermatopathol 2002;24 (5) 447- 448
Arita  KSouth  APHans-Filho  G  et al.  Oncostatin M receptor-β mutations underlie familial primary localized cutaneous amyloidosis. Am J Hum Genet 2008;82 (1) 73- 80
Wang  WJChang  YTHuang  CYLee  DD Clinical and histopathological characteristics of primary cutaneous amyloidosis in 794 Chinese patients. Zhonghua Yi Xue Za Zhi (Taipei) 2001;64 (2) 101- 107
Steciuk  ADompmartin  ATroussard  X  et al.  Cutaneous amyloidosis and possible association with systemic amyloidosis. Int J Dermatol 2002;41 (3) 127- 134
Lee  DDLin  MWChen  IC  et al.  Genome-wide scan identifies a susceptibility locus for familial primary cutaneous amyloidosis on chromosome 5p13.1-q11.2. Br J Dermatol 2006;155 (6) 1201- 1208
Jee  SHChiu  HCTsai  TF  et al.  The phosphotidyl inositol 3-kinase/Akt signal pathway is involved in interleukin-6-mediated Mcl-1 upregulation and anti-apoptosis activity in basal cell carcinoma cells. J Invest Dermatol 2002;119 (5) 1121- 1127
Mirmohammadsadegh  AMota  RGustrau  A  et al.  ERK1/2 is highly phosphorylated in melanoma metastases and protects melanoma cells from cisplatin-mediated apoptosis. J Invest Dermatol 2007;127 (9) 2207- 2215
Chen  RHChang  MCSu  YHTsai  YTKuo  ML Interleukin-6 inhibits transforming growth factor-beta-induced apoptosis through the phosphatidylinositol 3-kinase/Akt and signal transducers and activators of transcription 3 pathways. J Biol Chem 1999;274 (33) 23013- 23019
Spano  JPMilano  GRixe  CFagard  R JAK/STAT signalling pathway in colorectal cancer: a new biological target with therapeutic implications. Eur J Cancer 2006;42 (16) 2668- 2670
Ibuki  YGoto  R Suppression of apoptosis by UVB irradiation: survival signaling via PI3-kinase/Akt pathway. Biochem Biophys Res Commun 2000;279 (3) 872- 878
Weyers  WWeyers  IBonczkowitz  MDiaz-Cascajo  CSchill  WB Lichen amyloidosus: a consequence of scratching. J Am Acad Dermatol 1997;37 (6) 923- 928
Tamura  SMorikawa  YMiyajima  ASenba  E Expression of oncostatin M receptor b in a specific subset of nociceptive sensory neurons. Eur J Neurosci 2003;17 (11) 2287- 2298