Extensive pyoderma gangrenosum-like lesions revealing a case of hyperzincemia and hypercalprotectinemia: when to suspect it?,

AnBrasDermatol.2019;94(6):713---716

Anais

Brasileiros

de

Dermatologia

CASE

REPORT

Extensive

pyoderma

gangrenosum-like

lesions

revealing

a

case

of

hyperzincemia

and

hypercalprotectinemia:

when

to

suspect

it?

夽,夽夽

Ludimila

Oliveira

Resende

_,

_Marilia

_Formentini

_Scotton

_Jorge

_,

Juliano

Vilaverde

Schmitt

a_{FaculdadedeMedicinadeBotucatu,UniversidadeEstadualPaulista,Botucatu,SP,Brazil}

b_{DepartmentofDermatology,FaculdadedeMedicinadeBotucatu,UniversidadeEstadualPaulista,Botucatu,SP,Brazil}

Received9July2018;accepted29December2018

Availableonline26October2019

KEYWORDS

Arthritis; Inflammation; Skinmanifestations; Zinc

Abstract Hyperzincemiaandhypercalprotectinemiaisarareinflammatorydiseasecausedby

amutationinthePSTPIP1gene,withadysregulationofcalprotectinmetabolism.Calprotectinis

azinc-bindingproteinwithantimicrobialpropertiesandpro-inflammatoryaction.Theauthors

reportthecaseofa20year-oldgirlwithcutaneousulcerscomparablewithpyoderma

gan-grenosum,growthfailureandchronicanemia,whowasgiventhediagnosisofhyperzincemia

andhypercalprotectinemia.Measurementofserumzincandcalprotectinconcentrations are

indicatedinthesecases.

©2019SociedadeBrasileira deDermatologia.PublishedbyElsevierEspa˜na,S.L.U.Thisisan

openaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).

Introduction

Hyperzincemia and hypercalprotectinemia (Hz/Hc) is an autoinflammatory disorder characterized by chronic sys-temicinflammation,cutaneouslesions,arthralgia/arthritis,

夽 _{Howto citethisarticle: ResendeLO, Jorge MFS,SchmittJV.}

Extensivepyodermagangrenosum-likelesionsrevealingacaseof hyperzincemiaandhypercalprotectinemia:whentosuspectit?An BrasDermatol.2019;94:713---6.

夽夽_{Studyconducted atthe HospitaldasClínicas, Faculdadede}

MedicinadeBotucatu,UniversidadeEstadualPaulista,Botucatu,SP, Brazil.

∗_{Correspondingauthor.}

E-mail:[email protected](L.O.Resende).

hepatosplenomegaly, pancytopenia, and growth failure, first described in 1985.1 _{The cause of this disease is}

related to a mutation in the proline-serine-threonine phosphatase-interactingprotein1(PSTPIP1) gene,leading to dysregulation of the metabolism of calprotectin. This protein has zinc-binding capacity, as well as antimicro-bial andproinflammatory activity.The literaturepresents few cases, and even fewer describe the dermatological aspects;furthermore,noneofthemarefromLatinAmerica (Tables1and2).2---4

Case

Report

A 20 year-old woman reported persistent ulcerated skin lesions with variable severity for five years, recurrent https://doi.org/10.1016/j.abd.2018.12.001

0365-0596/©2019SociedadeBrasileiradeDermatologia.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCC BYlicense(http://creativecommons.org/licenses/by/4.0/).

714 ResendeLOetal.

Table1 ReportsofHz/Hccasesdescribedintheliteraturewithdermatologicalevaluation.1,3,4

Previousreports Current

report

Ageatdiagnosis 18 18 9 14 35 21 10 5 20

Sex M M F M F M F M F

Growth Reduced Reduced Reduced Reduced Normal Normal Reduced Reduced Reduced

Hepatosplenomegaly--- Yes Yes Yes Yes Yes Yes Yes Yes

Skinlesions PG Vasc No No Vasc,

eczema Vasc, ulcers PG Eyelid lesions PG Rheumatologic changes

--- Arthritis Arthritis Arthritis Arthritis,

uveitis

Arthritis Arthritis Arthritis Arthritis

CRP(<10mg/L) --- 41---143 100---200 22 17 45---146 60 108 35 Hemoglobin(g/L) --- 8 9 10.9 12.5 8 5.5 7.6 7.3 Zinc(10---18␮m/L) 120---197 180---200 82---96 160---200 175 77 183 152 138 Calprotectin (<0.001g/L) --- 6.5 1.4---2.55 9 6.1 1.5 12.5 2.3 0.6

PG,pyodermagangrenosum;Vasc,vasculitis;CRP,C-reactiveprotein.

Table2 Summaryofclinicalcharacteristicsofthecasesof

Hz/Hcwithreportedcutaneouslesions.

Feature Value

Ageatdiagnosis(years)a _18.1(8.7)

Sex Female 3/7(43%) Male 4/7(57%) Hepatosplenomegaly 6/6(100%) Growthdeficit 5/7(71%) Arthritis 6/6(100%) Anemia 5/6(83%) Hemoglobin(g/L)a _8.2(2.1) Serumzinc(m/L)a _153.4(35.4) Calprotectin(g/L)b _{4.9(1.5---6.1)}

a_{Mean(standarddeviation).} b _{Median(1stquartile−3rdquartile).}

abdominalpainwithepisodesofdiarrheaandjointpainin bothkneesaccompaniedbyedemaandlocalerythemasince childhood.Shereportedchronicanemiathatwas unrespon-sive to several treatments. On the physical examination, thepatient had shortstature (percentile<3%), cutaneous ulcerations with violaceous edges, interspersed by scar tissueandpustuleswithfriable,bleedingandgranular cen-tralarea,togetherwiththepresenceofpurulent exudate and hematiccrusts, affecting both lowereyelids, breast, andlegs, inadditiontoapronouncedhepatosplenomegaly (Fig.1A---C).Thehistopathological examinationoftheskin lesions was nonspecific, but compatible with pyoderma gangrenosum (PG). Initial investigations revealed pancy-topenia,inversion of the albumin/globulin pattern (0.55; normal: 1.9---1.63), elevated C-reactive protein (CRP=35; normal<10mg/L) and hepatosplenomegaly on ultrasonog-raphy, which also evidenced preserved parenchyma with extramedullaryhematopoiesisintheliverbiopsy histopatho-logicanalysis.Thepatientalsohadportalhypertensionwith esophageal varices and pronounced osteoporosis, with a pathologicalT12.

Consideringthe diagnostic hypothesis of Hz/Hc,serum levels of zinc and calprotectin were measured: 869␮g/L (normal 70---120␮g/L) and 642␮g/L (normal<1.6␮g/L), respectively.

Cyclosporin A (3.5mg/kg/day) and prednisolone (1.5mg/kg/day)wereinitiated,leadingtowoundhealing, weight gain, and partial improvement of anemia, but the therapeutic response worsened after an attempt of waning, evolving with aggravation of preexisting lesions and development of an ulcerated lesion in the point of transcutaneous hepatic biopsy, compatible with pathergy (Fig. 1D---F). Immunosuppressive levels were restored, includingabiweeklyinfusionofadalimumab40mg,witha significantbutpartialimproveinthecutaneouslesions.

Inthegeneticassessmentofthepatient,thec.748G>A variant(Glu250Lys)wasfoundinheterozygosisintheexon 1ofthePSTPIP1gene.Thisvariantisconstitutedbya sub-stitutionofglutamicacidforlysineatthecodon250ofthe translatedprotein,whichhasbeendescribedaspathogenic in the Infervers and Clinvar databases (rs28939089) when associatedwithpyogenicarthritis,PG,andacne(PAPA) syn-drome(MIM604416).

Discussion

Hz/Hc is a rare autoinflammatory condition, clinically characterized by pustular and ulcerative inflammatory cutaneouslesions,recurrentarthritis,hepatosplenomegaly, pancytopenia,andgrowthfailure,withnopredilectionfor gender,andusuallydiagnosedduringyouth.Thediseaseis characterizedbylaboratoryfindings,suchasextremelyhigh serum levelsof zinc andmostly calprotectin (500---12,000 timesthenormallevels).3

CalprotectinisformedbyacomplexoftwoMRP8/14 pro-teinsthatareendogenousactivatorsofthetoll-likereceptor 4 (TLR-4) and belong to the familyof the alarmins. This proteinis found in theneutrophil cytosol and hasintense pro-inflammatory properties.5,6 _{Recently, a specific}

muta-tionresultinginasingleaminoacidsubstitutioninthegene of the PSTPIP1protein, a cytoskeleton-associated protein

Extensivepyodermagangrenosum-likelesions 715

Figure1 Skinlesionsbefore(right)andafter(left)sixmonthsoftreatment.

thatmodulatesT-cellactivationandIL-1brelease,hasbeen identifiedin thesepatients. Other mutationsin this same gene had already been associated with other autoinflam-matorydiseases, suchasPAPAsyndrome, thathasclinical similaritieswithHz/Hc,butnoneofthempresenthighlevels ofcalprotectinandzinc.2

To date, no treatment has been fully effective, with reports of the use of corticosteroids, cyclosporine, tacrolimus,TNF,andIL-1inhibitors.Hz/Hcisachronic mul-tisystem disease with nonspecific symptomatology and is present sincechildhoodinmostcases.2,4---7 _{Extremelyhigh}

levelsof serumzinc andcalprotectin arestrongly sugges-tiveofthediagnosis;therefore,insuspectedcases,serum levelassessmentsshouldbeconsidered.

The skin changes reported in Hz/Hc are vasculitis, eczemas, furuncle-like ulcers, and necrotic lesions.They tendtobeinflammatoryandulcerated,sometimespruritic, with clinical and histopathologic similarities to PG, usu-allyaffecting the lowerlimbs symmetrically,withreports of facial lesions, particularly on the eyelids. The obser-vation of chronic lesions in young children and adults withhepatosplenomegaly,arthralgia/arthritis,highCRP,and microcyticanemiaissuggestiveofHz/Hc.

Financial

support

Nonedeclared.

Author’s

contribution

Ludimila OliveiraResende: Elaborationand writing of the manuscript.

MariliaFormentiniScottonJorge:Elaborationandwriting ofthemanuscript;intellectualparticipationinpropaedeutic and/ortherapeuticconductofthecasesstudied.

Juliano Vilaverde Schmitt: Effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of the cases studied.

Conflicts

of

interest

Nonedeclared.

References

1.HambidgeKM,NorrisDA,GithensJH,AmbrusoD,Catalanotto FA.Hyperzincemiainapatientwithpyodermagangrenosum.J Pediatr.1985;106:450---1.

2.Holzinger D, Fassl SK, de Jager W, Lohse P, Röhrig UF, Gat-torno M, et al. Single amino acid switch defines clinically distinct proline-serine-threonine phosphatase-interacting pro-tein1(PSTPIP1)-associatedinflammatorydiseases.JAllergyClin Immunol.2015;136:1337---45.

716 ResendeLOetal.

3.SampsonB,FagerholMK,SunderkötterC,GoldenBE,Richmond P,KleinN,etal.Hyperzincaemiaandhypercalprotectinaemia:a newdisorderofzincmetabolism.Lancet.2002;360:1742---5. 4.IsidorB,PoignantS,CorradiniN,FouassierM,QuartierP,RothJ,

et al.Hyperzincemia and hypercalprotectinemia:unsuccessful treatmentwithtacrolimus.ActaPaediatr.2009;98:410---2. 5.EhrchenJM,SunderkötterC,FoellD,VoglT,RothJ.The

endoge-nousToll-likereceptor4agonistS100A8/S100A9(calprotectin)as

innateamplifierofinfection,autoimmunity,andcancer.JLeukoc Biol.2009;86:557---66.

6.StrízI,Trebichavsk´yI.Calprotectin---apleiotropicmoleculein acuteandchronicinflammation.PhysiolRes.2004;53:245---53. 7.SugiuraT, GotoK, Ito K,BanK, Okada S,Moriyama A, et al.

Effects ofcyclosporine A inhyperzincaemia and hypercalpro-tectinaemia.ActaPaediatr.2006;95:857---60.