Hermansky-Pudlak Syndrome with a Novel Genetic Variant in HPS1 And

4 3 2 1 olivermcelvaney@ A Revised 17May2018 Received 16 D I Royal Collegeof Centre for Genetic Lung D D C I B USA N Maryland, I Research N Hospital, S D reland, reland nstitutes ofHealth, D Hermansky-Pudlak Medical Genetics I urgeons in thoraxjnl-2018-211920 Year]. doi:10.1136/ [please include Mc Thorax Huizing M, Gahl W T eaumont Hospital, rish CentreforGeneticLung ccepted 21May2018 ublin 2, epartment ofMedicine, r orrespondence to isease, Royal Collegeof etwork, ational HumanGenome o cite: epartment ofRadiology, O liver J Mc B E D eaumont Hospital, I I pub aheadofprint: O nstitute, reland; USA ublin, yster I A reland, E E pril 2018 lvaney lvaney, D B S I reland rcsi. urgeons in ay, ay Month B N A ranch, D S B B ational O yndrome , et al. ethesda, N ublin, ie eaumont J, ew York, D I rish isease, phenocopy diseases D end ofalongroad.Although that required blood transfusions prompted my that required blood transfusionsprompted extraction bleeding episode followingatooth researching thearea. Several years later, a severe particularly since Ihadspentagreatdeal of time were dismissedwithoutadequate consideration, be linked by a rare disease. I felt that these concerns albinismwhether myandbleeding difficulties might At several of theseconsultations,Ienquiredasto have albinism with associated visual impairment. many tests,nobleedingissueswasidentified. I also of prolongedbleeding.Afterof thecompletion ogist in the late 1990s, following several episodes I firstunderwentspecialistreviewbyahaematol- the bestpossiblecare of mylungsgoingforward. opportunity toengage with the help needed totake was personallydevastating,itaffordedmethe The diseases. particularly withregardtocomplexdiagnosesandrare it re-emphasisestheimportanceofpatientvoice, diseases thatresultinsimilarphenotypes. Furthermore, common pulmonarydisordersbystudyinggenetic potential forelucidatingthepathogenesisofmore the conceptoflungphenocopyrelationshipsand advanced pulmonaryfibrosis. This casealsoillustrates relating totransplantation inthecaseofHP value ofsubtypeanalysisandthetechnicaldifficulties we discussthemanagementofHP progressive clinicalcourseofdiseaseinthiscase, to detailinganovelgeneticresultandoutliningthe heterozygote) splicesitevariants inHPS1. HP HPS1 gene. genetic testingconfirmingbiallelicmutationsinthe O minor surgicalanddentalproceduresinthecontextof prompted byseverebleedingcomplicationsfollowing presented followingaself-directedliterature review granulomatous colitis. We describeayoungmanwho onset accelerated pulmonaryfibrosis, neutropaeniaand bleeding diathesesand, inselectedindividuals, early- tyrosinase-positive oculocutaneousalbinism( of autosomal-recessivedisorderscharacterised by The Hermansky-Pudlaksyndrome(HP Abstr O accelerated pulmonaryfibrosis: significancefor genetic variant inHPS1andsubsequent Hermansky-Pudlak syndromewithanovel Case baseddis C eirdre Horan, liver JMc S A type1patientwithtwodifferent(compound

. HP patient: a S ct was clinicallysuspected, withsubsequent McElvaney OJ, et al.Thorax 2018; 0:1–4. doi:10.1136/thoraxjnl-2018-211920 O f interest, thisistheonlydescribed

E Arriving atmydiagnosismarkedthe lvaney, 1 PMarkLogan, c ussions 1 MarjanHuizing, S , the diagnosisitself theprognostic S ) isacollection 4 I n addition

S E -associated O mer PReeves, C A ), 2 William (IVS18 site variants in with twodifferentcompoundheterozygoussplice to represent the only described patient with Irish case on record.Furthermore, theycontinue finding intheCaucasianpopulationandfirst clinical diagnosis of HPS-1, a particularly rare gous splice site variants identified confirmed the HPS1 gene (figure testing whichrevealedbiallelicmutationsinthe to variantsequence. Neural Network, comparingwild-typesequence strength usingHumanSplice SitePrediction by published previously. We calculated splice site descent, noeffectofsplicesite oncDNAhadbeen previously beendescribedinsubjects ofCaucasian While variantc.1744-2A>C (IVS17-2A>C)has type) to0%,essentiallydeleting thesplicesite. changes splicesitepredictionfrom99%(wild A Gahl Institutes ofHealth,USAforfurtherstudies. He wasreferredtoourcolleagues at theNational enabling aworkingdiagnosisofHPStobemade. demonstrated anabsence of plateletdensebodies, Electron microscopy studies of platelet-rich plasma exclusively inindividualsofPuertoRican ancestry. his ethnicity, sincetheconditionoccursalmost (HPS) was suspected. Thiswas syndrome despite ination findings,however, the Hermansky-Pudlak Given lymphohistiocytosis. thehistoryand exam- and haemophagocytic syndrome Cross syndrome, X-linked OCA,Chediak-Higashisyndrome, Griscelli bilateral lowerlimbpetechiaewerenoted. and examination, periodicalternatingnystagmus and non-drinker.he wasalifelongnon-smoker On was negative.Familywas unremarkable and history and coagulopathyatanotherhospital dysfunction procedures. Astandardevaluationforplatelet complications followingminorsurgical and dental history of epistaxis and significant haemorrhagic (OCA) self-referred toourclinic in 2003 with a Caucasian Irish manwithoculocutaneous albinism bleeding issues. re-attempting tofinda team able to diagnosemy dental surgeon to suggest that it would be worth A Dr The differentialdiagnosisforOCAincludes Dr Oliver JMcElvaney 1 Gahl,

N Marjan

oel GMc

+2 T>C)isanovelvariant.Thisvariant (WAG): 2 Paul Huizing

The patientunderwentgenetic E HPS1. Variant c.1857+2T>C O

lvaney 1 ’ D ). The compound heterozy

(MH) onovan,

(OJMcE): 1 and

3 P

rofessor William C

hest clinic A 28-year-old

HPS-1

on September 28, 2021 by guest. Protected by copyright. by Protected guest. by 2021 28, September on Chest clinic Chest clinic 2 a usefulmeansofassessing diseasestatus and provides with HPS raphy in evaluating the extent of pulmonary disease in patients tion bronchiectasis. HRCT is more sensitive than chest radiog- worsening fibrotic lung disease over time with associated trac- reduction in diffusing capacity of the lung for carbon monoxide. mance overthecourseof ensuingdecade, with amarked exercisetolerance anddecliningcardiopulmonary testperfor experienced progressive exertional dyspnoea, decreased exercise therapy wascommenced.Despitethisintervention,thepatient fibrosis, pirfenidone pulmonary and signsof progressive toms teine had been prescribed. As the patientbegan to exhibit symp- sively worsening,fineend-inspiratorycrackles. pulmonary fibrosiswereapparent,latermatchedbyprogres early clubbing, and 2 scan the following year. By 2008, aged 33, thepatient displayed chiectasis was notedonthoracichigh-resolutionCT(HRCT) tive ofpulmonaryinvolvementwerepresentinitially, mild bron- experimental; FVC, forcedvitalcapacity; HPS1, Hermansky-Pudlaksyndromegene; HRCT, high-resolutionCT; ND, notdone. of pirfenidone(asterisk), steadydeclineintheseindicesovertimecanbeobserved. DLCO, diffusingcapacityofthelungforcarbonmonoxide; EXP, spirometry withDLCO(panelC), FVC(panelE)andcardiopulmonaryexercisetestingD). Despitebriefimprovementfollowingcommencement prediction 50%–80%)andred(lowsplicesite<50%). The patientunderwentmonitoringwithserialHRCTthoraximaging(panelB), to variant sequence). PredictedSpliceSiteScoresarevisualisedasfollows: green(highsplicesiteprediction>80%), yellow(mediumsplicesite Yes, i.e., splice splice sitevariants intheHPS1gene, includingapreviouslyundescribednovelvariant (panel A; †Exp. SpliceEffect: asreportedinliterature: ND; Figure 1 C Dr P Mark Logan Prior tothedevelopmentof significant fibrosis, dre Horan Dr hest clinic

Deir

Progressive HPS-associatedfibroticlungdisease

site effectw

(DH):

years later (PML): as demonstratedexperimentally.‡UsingHumanSpliceSitePredictionbyNeuralNetwork, comparingwild-typesequence

While no signs or symptoms sugges- While nosignsorsymptoms

Serial HRCT changesconsistentwith HRCT imaging confirmed N-acetylcys- . Geneticsequencingrevealedthefirstcaseoftwodifferentcompoundheterozygous - - pulmonary fibrosis(IPF).F progression toend-stagefibrotic lungdisease. the transplantlist,inlightof hisoverwhelminglikelihood of same. This process was commenced prior toqualification for anextendedworkup for transplantation, havingundergone nance. Radiologically HPS can differ somewhat fromidiopathic frequently bilateral changes thataremost with abasal predomi- and peribronchovascular thickening, in the context of fibrotic opacities (likely microfibrosis beyondtheresolutionofCT) thickening. HRCTmayrevealseptalthickening,‘ground-glass’ reticulonodular interstitialpatterns,perihilarfibrosisandpleural testing. ChestradiographicfindingsseeninHPSinclude bilateral thatcan be correlated withpulmonary function and progression pattern maybemorecommoninHPSthanIPF. in IPFthanHPS,while cysts and mosaic to bemorecommon OJMcE: McElvaney OJ, et al.Thorax 2018; 0:1–4. doi:10.1136/thoraxjnl-2018-211920

The patienthassubsequentlybeenlistedforlung or example, honeycombing appears

Thorax: first published as 10.1136/thoraxjnl-2018-211920 on 25 June 2018. Downloaded from from Downloaded 2018. June 25 on 10.1136/thoraxjnl-2018-211920 as published first Thorax: http://thorax.bmj.com/ on September 28, 2021 by guest. Protected by copyright. by Protected guest. by 2021 28, September on expectancy remainsbelow50yearsofage. classically occur in the fourth orfifth decades of life. Mean life fibrosis Clinical manifestations ofHPS-associatedpulmonary subtypes. to theoccurrenceofaccelerated fibroticlungdiseaseinthese due prognosis, and HPS-4areassociatedwiththepoorest HPS-1 (HPS-1 toHPS-10). The HPSspectrumincludes10disorders not beendefinitive. offibrosis,HPS-specificclinical slow theprogression trialshave pirfenidone mayanecdotally or offer temporaryimprovement transplantrecipients.While malignancy inimmunosuppressed increasestheriskofskin ence ofcutaneoushypopigmentation tological workupandbleedingriskassessment.Finally, thepres- haema- preoperative a comprehensive and theneedfor subtypes their disease given theaccelerated natureoffibrosisinthese in particularshouldbereferredearlytheclinical course of referral for lung transplantation. Patients with HPS-1 and HPS-4 of diseaseoccurs.Athirdissueexistsregardingthetiming Second, uncertaintyexistsastowhetherallograftrecurrence and/or recombinantfactorVIIa. prophylactic desmopressin tate additionaluseofintraoperativeplatelet transfusions and subsequently increasedmucosalbleeding.Thismaynecessi- lets impairsthenormalsecondaryaggregationresponse,with to this option. First, the absence of dense bodies in HPS plate- McElvaney OJ, et al.Thorax 2018; 0:1–4. doi:10.1136/thoraxjnl-2018-211920 provide valuable information, whichmaybe used toidentify as bronchoalveolar lavage fluid, brushings andblood standsto already takenhold.Thecollection ofbiological samples such the proverbial die iscastandestablished pulmonarydiseasehas course indetail, rather thanbeginningtheresearchprocessafter This enables the research clinician to assess the prefibrotic fibrosis byvirtueofhisHPS subtype. early onset-pulmonary case as an example, our patientwasvirtuallycertain todevelop non-genetic diseases, or ‘phenocopies’. To use this particular the pathogenesisofmorecommon,phenotypically clinicians by genetic conditions when itcomestounderstanding further issues. The first is the opportunityaffordedtoresearch in subtypes1,2and4. for HPS-associated identified infamilies,antenataltestingisavailable. wherever possible. Where disease-causing mutations have been prognostic and therapeutic implications, and should be sought with confirmatory genetic testing. Subtype identification has nary fibrosis, haemorrhagic episodes and granulomatous colitis. of causesdirectlyrelatedtothecondition,inparticularpulmo- of OCAshouldpromptsuspicionthediagnosis. zontal nystagmus. Early-onset pulmonaryfibrosis in the context the level of legal blindness, is generally accompanied by hori- prolonged menstrual bleeding. Decreased visual acuity, often to surgical proceduresorchildbirth.Womenwith may alsopresent or prolongedbleedingfollowingdentalextractions,minor tation. Patientsepistaxis, soft-tissueecchymosis may report cant bleeding inthecontextofsomedegreehypopigmen early-onset pulmonaryfibrosisandgranulomatouscolitis. bleeding diatheses and,inselectedindividuals, neutropaenia, OCA, characterised bytyrosinase-positive disorders system OJMcE: Discussion of plateletdensebodiesonwholemount Professor OJMcE: MH: WAG: Presentation usually occurs followingclinically signifi-

The diagnosis is achieved by demonstratingthe

1–3 The Approximately 75% ofthe HPS populationwill die

Lung transplantationistheonlydefinitivetreatment

Noel HPS is a collection of autosomal-recessive multi- G McElvaney 4 pulmonary fibrosis and has been performed Steroidtherapyisnoteffective. 3 Severalchallenges exist withrespect

(NGMcE): 3

electron microscopy This case raises two 3

absence similar, 1–3 3 -

www. at can be found EM testingandgeneticpanels for OCAandHPS to stay. listening towhata patient hastosay, a trend thatIhopeishere have changed,however. Doctorsthesedaysare moreopento HPS onthe basis that I am not ofPuertoRican extraction. Times and overagaindismissalsofthepossibilitymehaving featured whatfeltlike the futile re-running ofthesametestsover this manuscript has been acknowledged by co-authorship. It is our this manuscript has beenacknowledgedbyco-authorship. Itisour The involvement of the patient in the preparation and writing of Patient andpublicinvolvement CF-like phenotype. such asbronchiectasisandchronicbronchitis,contributingtoa function maybediminishedbyinflammationinconditions and generateddiscussionthatCFTR normal functionofCFTR The adventofionchannelmodulatorshashelpedclarifythe are readilytransferable. treatments all CF not NCFB, although manifestations havebenefitted advances forCFpulmonary characterised inthelungbyseverebronchiectasis.Therapeutic 7qresultingin gene on a chromosome multisystem disorder chloride channelopathy resultingfrommutationsin the CFTR bronchiectasis (NCFB)andCF. CFisanautosomal-recessive population. future use in a chronic obstructive pulmonarydisease/smoker sema asassessedbyCTdensitometry. Thisapproachmaybe of fied AAT, given intravenously, decreases of emphy progression an effective treatment forAATD wherebyweekly plasma-puri- workup fortransplantation. would pre-emptivereferralandspecialised been undertaken,nor for onsetandprogressionofpulmonaryfibrosiswouldnothave consistent effortstofinda diagnosis, it is likely that monitoring to be rebuffed, in large part due to hisethnicity. Without his unifying diagnosislinkingOCAandableeding diathesis, only the possibilityofa to medical professionals andproposed his concerns condition. Hehad,onseveraloccasions,reported exceptionalin hisown persistence,diligence andinvolvement rare diseases.Theindividualdescribedinthisreportdisplayed when itpertainstothediagnosisandassessmentofgenetic inform theclinician astothediagnosis.Thishasaddedrelevance ical value oflisteningtothepatientvoice,whichmayfrequently of AAT byoxidants fromcigarettesmoke. a functionaldeficiencyinthelungduetooxidative inactivation since smokers without antigenic deficiency of AAT may still have is smoking-inducedemphysema, lung. Theobviousphenocopy to liverdiseaseandadecreasedanti-NEprotectivescreeninthe polymerises inhepatocytesleading the mutantZprotein zygotes tase (NE) to prevent NE-induced tissue damage. In PiZZ homo 342. TheprimaryfunctionofAAT istoinhibitneutrophilelas- resulting in the substitution of glutamic acid for lysine at residue is causedbya in SERPINA1 single-nucleotide polymorphism disorder. Thethemostcommonseveredeficient variant (PiZZ) and bronchiectasiscysticfibrosis(CF). include emphysema and alpha-1 antitrypsin deficiency (AATD), conditions, suchasIPF. in turnbeapplicablefibrotic Such discoveriesmaythen to other aspects underlying thefibrotic of process. the pathophysiology potential biomarkers that herald the onsetofdisease, and reveal Patient information regarding the diagnosis ofHPS,platelet NGMcE: EPR: The NGMcE: Dr Emer P Reeves HPSnetwork.

patient: A furtherphenocopyrelationshipisthatbetween non-CF

The AA

This second issue highlighted in this paper is the crit- TD isanautosomal-co-dominantgenetic org

(EPR): journey was an arduous one initially. It

Other examples of lung phenocopies Other examplesoflungphenocopies 5 Thereiscurrently C hest clinic

3 - -

on September 28, 2021 by guest. Protected by copyright. by Protected guest. by 2021 28, September on Chest clinic Chest clinic 4 Ethics approval Patient consent C Research N Funding senior authorship. contributed towritingandfact-checkingthemanuscript. W C as awholetopromotethepatientvoicematterofpolicy. and weacknowledgetheworkdonebyThoraxBMJgroup belief that patient involvement strengthens the message of research, C ompeting interests ontributors GMc A G: hest clinic performedgeneticanalyses. PML: evaluated serialimaging. P E receivedfundingfromtheMedicalResearchCharitiesGroup/Health

B E oard PR acknowledgesfundingfromthe

O I reland. JMc

B O eaumont Hospital btained. E : theleadauthorandcorrespondingauthor. MHand

N one declared. E thics Committee. US

A lpha E O PR and ne Foundation and N O GMc ’ D and E : share D H: expressly granted. © Provenance andpeerreview article) 2018. 3 2 1 Refe 5 4

o A studies. Blood1959;14:162–9. pigmented reticularcellsinthebonemarrow: reportoftwocaseswithhistochemical V Engl JMed1998;338:1258–65. of patientswithaformoculocutaneousalbinism(Hermansky-Pudlaksyndrome). N Gahl Hermansky F Biol Chem2000;275:27258–65. methionine 358inalpha1-antitrypsincauseslossofanti-neutrophilelastaseactivity. J T Pudlak syndromepulmonaryfibrosis.Metab 2011;103:128–34. MolGenet S aggart C, Cervantes-Laurean yndrome.ThoracSoc 2016;13:1839–46. AnnAm rticle author(s)(ortheiremployer(s)unlessotherwisestatedinthetextof icary GW,icary Vergne Y, ’ B rien K, Troendle J, Gochuico r McElvaney OJ, et al.Thorax 2018; 0:1–4. doi:10.1136/thoraxjnl-2018-211920 W e A nc , B A rantly M, Kaiser-Kupfer M e , PudlakP. ll rightsreserved. s S antiago-Cornier A lbinism associatedwithhemorrhagicdiathesisandunusual D , B

N KimG, etal. R, etal. PirfenidoneforthetreatmentofHermansky- N o commercialuseispermittedunlessotherwise ot commissioned; externallypeerreviewed. I , etal. Geneticdefectsandclinicalcharacteristics A , et al. PulmonaryFibrosisinHermansky-Pudlak

xidation ofeithermethionine351or