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An unprecedented COPA gene mutation intwo patients in the same family:comparative clinical analysis of newlyreported patients with other known COPAgene mutationsAnjali Patwardhan1* and Charles H. Spencer2

Abstract

Introduction: The COPA syndrome is a newly recognized monogenic, autosomal dominant autoimmune diseasepresenting mostly presenting in childhood. Clinical features include inflammation of the lungs, kidneys, and joints.Approximately twenty-six patients with COPA syndrome worldwide have been investigated all originating fromeight families. Patients with this syndrome exhibit heterozygous monogenic missense mutations in the WD40domain. This domain is a functionally-significant area of the alpha subunit of coatomer-associated protein (COPα)which encodes the coat protein complex I (COPI). The COPI dysfunction is also associated with autoantibodyexpansion. We report two patients with COPA syndrome.

Methods: All testing and molecular genetic analysis were performed after obtaining the informed consent of boththe patient and parents. A retrospective chart review was carried out on both the patients. Demographic, clinical andlaboratory findings were abstracted from outpatient and inpatient encounters. Pulmonary function tests (PFTs), chestcomputed tomography (CT) scans, and lung biopsy histopathology reports were also reviewed and summarized.

Results: The index case and the father of the child both demonstrated a unique inflammatory pulmonary, arthritis, andrenal disease triad starting in early childhood including pulmonary hemorrhage. The two patients had a novel COPAmutation previously undescribed.

Conclusions: To date, only four pathological, genetic mutations have been reported that are compatible with COPAsyndrome. We here report two patients with COPA syndrome within the same family with a novel COPA genemutation different than the heterozygous monogenic missense mutations in the WD40 domain and distinct from theclinical phenotypes reported in the literature so far.

Keywords: Autoimmunity, COPA syndrome, Interstitial lung disease, Arthritis, Pulmonary hemorrhage, Alveolitis

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

* Correspondence: [email protected] of Missouri School of Medicine, 400 Keene Street, Columbia, MO65201, USAFull list of author information is available at the end of the article

Patwardhan and Spencer Pediatric Rheumatology (2019) 17:59 https://doi.org/10.1186/s12969-019-0359-9

http://crossmark.crossref.org/dialog/?doi=10.1186/s12969-019-0359-9&domain=pdfhttp://orcid.org/0000-0002-1467-1011http://creativecommons.org/licenses/by/4.0/http://creativecommons.org/publicdomain/zero/1.0/mailto:[email protected]

IntroductionThe Coatomer Protein, Subunit Alpha (COPA) gene ismapped on the chromosome one location 1q23.2 [1].The COPA protein is a 160-kD molecule that isexpressed at normal levels in patients with gene muta-tions such that immune dysregulation is the functionalconsequence of the mutation [2].In the most extensive series to date of 30 individuals

with known mutations attributable to COPA syndrome,nine subjects were asymptomatic, suggesting variable/in-complete penetrance [3]. The COPA gene is expressedin immune as well as non-immunologic cells but ispredominantly present in the microsomal and cytosolicfractions, and is absent in nucleus. Patients with thissyndrome exhibit heterozygous, monogenic missense mu-tations in the WD40 domain (a functionally-significantarea) of the alpha subunit of coatomer-associated protein(COPα) which encodes the coat protein complex-I(COPI). The COPI is an integral part of the intracellularcarrier complex in protein transport mechanism from theGolgi complex to the endoplasmic reticulum (ER).To explain the genetics better, the COPA gene’s Cyto-

genetic Location is positioned within the long (q) arm ofchromosome-1 at 23.2(1q23.2), and the molecular loca-tion is at the base pairs 160,288,587 to 160,343,564 onchromosome-1. The protein transport between theendoplasmic reticulum and the Golgi bodies is mediatedby the coat proteins (COPs) which operate as subunitsin a complex structure called coatomer coat proteincomplex-1, in all eukaryotic cells. The seven subunits ofthe coatomer complex are named as (alpha, beta, beta-prime, gamma, delta, epsilon, and zeta)-COP. Inhumans, alpha-COP protein is encoded by coatomerprotein complex subunit alpha (COPA gene), which isvery similar to the alpha subunit of the coatomer com-plex in yeast cells known as RET1P, used in COPA generesearch. The defective COPI function due to gene mu-tation leads to impaired retrograde Golgi-to-ER proteintransport which in turn leads to compensatory, but inef-fective protein translation, followed by ER stress and cel-lular autophagy [4]. ER stress causes the release of thepro-inflammatory cytokines (IL-1β and IL-6) that inturn, lead to an increase in the number of T-helper type17 (TH17) cells [1–3, 5, 6]. The CD4 (+) T cells derivedfrom COPA syndrome patients show skewing toward apreferential TH17 response and the changes in T cell pop-ulations are believed to foster immune dysregulation andautoimmunity [5]. Besides, COPI dysfunction is also asso-ciated with autoantibody expansion [3]. Volpi and collabo-rators have shown the presence of an interferon activationsignature in the peripheral blood of a COPA patient [7].The COPA syndrome is thus a newly recognized Men-

delian monogenic, autosomal dominant autoimmune dis-ease presenting usually in childhood, and characteristically

associated with the constellation of defined and specificclinical features. It is also known as HEP-COP andAutoimmune Interstitial Lung, Joint, and Kidney disease(AILJK). The AILJK term may be misleading as theinterstitial lung disease is not necessarily present in allcases. Twenty-six patients with COPA syndrome havebeen investigated worldwide originating from eightfamilies [3, 5]. To date, only four pathological, geneticmutations have been reported that result in the COPAsyndrome (Table 1). We report two COPA syndromepatients from the two generations in the same family (sonand father) with a novel gene mutation in the COPA geneand a different clinical presentation, distinct from theclinical phenotypes reported in the literature. To ourknowledge, this gene mutation and clinical syndrome havenot been reported before.

Materials and methodsAll testing and molecular genetic analysis were per-formed after obtaining the informed consent of both thepatient and parents. The protocol and data extractionfrom the medical records was approved by the Institu-tional Review Boards of the University of Missouri(approval number: 239766. Project #: IRB #2012122MU). The index patient was diagnosed with COPAsyndrome, and subsequently, his father was tested forCOPA gene mutation because he had a history of recur-rent pulmonary hemorrhage as a child. The father alsotested positive for same gene mutation as the index case.The retrospective chart review was carried out on boththe patients. Demographic, clinical and laboratoryfindings were abstracted from outpatient and inpatientencounters, and pulmonary function tests (PFTs), chestcomputed tomography (CT) scans, and lung biopsy histo-pathology reports were also reviewed and summarized.

ResultsIndex case (Fig. 1 and Fig. 2)Our index case (IC), a Caucasian- Hispanic 2 yearseight-months-old male, presented to the emergencyroom with a chronic cough, fatigue, increasing pallorand recurrent episodes of shortness of breath. He wasdiagnosed with hypochromic microcytic severe chronicanemia (hemoglobin 2.7 g/dl) and received a bloodtransfusion. He was admitted to the pediatric intensivecare unit (PICU) and required mechanical ventilationafter developing acute respiratory distress and failure.His laboratory tests revealed elevated inflammatorymarkers (ESR, CRP, IgG, and platelets), elevated reticu-locyte count (5%). Bilirubin, haptoglobin, and G6PDtesting were normal. An extensive work-up seeking aninfectious etiology was negative. No source could beidentified explaining the extensive blood loss.

Patwardhan and Spencer Pediatric Rheumatology (2019) 17:59 Page 2 of 13

He had a history of chronic eczema, and three episodesof ‘afebrile pneumonia’ in the past. The first episode wasat age 6 months which were empirically treated with anti-biotics. Due to poor growth and development, he wasevaluated for cystic fibrosis, immunodeficiency, hemolyticdisorder, infections, and malignancy, but all such diagnos-tic efforts were negative. Serum ferritin levels were nor-mal, but low normal iron saturation and high solubletransfer receptor levels were found. He appeared to makean uneventful recovery at the time and was discharged.Two months after discharge, he presented again to

urgent care with shortness of breath and was found tohave the hemoglobin of 7.9 g/dL. His general physicalexamination was positive for grade-two clubbing in allthe extremities. He was positive for Harrison’s sulcus,pectus carinatum, pallor, cyanosis, poor oxygensaturation but normal blood pressure. He was admittedto PICU again. His CT chest showed bilateral diffuseground-glass opacities without focal consolidation,interstitial infiltrates. The possibility of pulmonaryhemorrhage was considered.At this point, he also tested positive for ANA (1:

1280 speckled), and ANCA (1:2560–1:5120). He hadvariable positives for Anti MPO (10.6 to 106 RLU.normal range < =20.0), Anti PR3 (< 2.3 RLU. normalrange < =20.0), Anti RNP, Anti SSA/RO, Anti SSB/LA,Anti Smith, Anti-double-stranded DNA, i.e. all Ex-tractable Nuclear Autoantibodies (ENA) antibodies.He had a moderate elevation of inflammatory markers(ESR, CRP, platelets and immunoglobulin G) at thetime. The ESR and CRP values and clinical flares,though, did not coincide with ANCA peaks.He was negative for rheumatoid factor, and anti-CCP

autoantibody and his urinalysis and kidney function testswere normal. He also tested negative for celiac diseasesand cystic fibrosis. His bronchoalveolar lavage (BAL)fluid was Cloudy -tinged with blood and cell count ofBAL fluid was 5262/mcL (WBC-2125/mcl, red cells of3137/mcL). The BAL fluid was negative for any infectiveetiology (bacterial, viral or fungal). Histoplasma antigenwas negative in urine and BAL. The left lung wedgebiopsy was consistent with resolving pulmonarycapillaritis. Histopathologic features included frequenthemosiderin-laden macrophages, extravasation of redblood cells, interstitial inflammation, capillaritis, andfeatures of lymphocytic bronchiolitis, i.e. diffuse pulmon-ary lymphoid hyperplasia. There was a mild widening ofalveolar ducts and minimal distension of air spaces atthe periphery, suggesting a component of small airwayobstruction.He was initially treated with intravenous pulse methyl-

prednisolone 250 mg for three consecutive days followedby oral steroids. The oral steroids were tapered overtime to 5 mg/day as maintenance therapy with

Methotrexate (up to 12mg /M2/week). He did not re-spond to methotrexate and then azathioprine. He con-tinued to have episodes of shortness of breath (SOB),decreasing hemoglobin and pulmonary hemorrhages atthe same frequency as before and had several pediatricintensive care unit (PICU) admissions. On one occasionwhen spirometry could be performed successfully, theresults showed a presence of partially reversible smallairways obstruction mixed with some restrictive pat-terns. His flow rates were: FVC -1, 1 L (96% of predicted,100% of predicted post-treatment), FEV1–0.94 (121% ofpredicted, 117% of predicted after treatment), FEV1/FVC %-85 of predicted, and post-treatment 79% of pre-dicted. Rituximab was not approved for use by his insur-ance company. He was then started on mycophenolatemofetil (MMF) 30 mg/kg/day in two divided doses alongwith the low dose oral steroids. He showed a positive re-sponse as he has had no pulmonary hemorrhages andPICU/hospital admissions since. Three months into theMMF therapy, he was tested for COPA gene mutationwhich returned positive. His brother and father werealso tested for COPA gene mutations. The gene test forthe father returned as positive for the same genemutation as the index case.

The father of the index case (Fig. 1 and Fig. 2)He was a 29 years old Caucasian male. He first presentedwith chronic respiratory insufficiency (poor oxygensaturation), exertional dyspnea, recurrent coughing,breathlessness and polycythemia (hemoglobin of 15.8 g/dl, hematocrit of 48.2% and red cell count of 5.79mil/cu.mm). He had clubbing in all the fingers and toes andworsening respiratory symptoms. He was seen by acardiologist, and a cardiac etiology was ruled out forclubbing. He had a normal EKG and Echocardiogram.Past history revealed that he had his first admission to

PICU at 7 years of age which was for breathing difficul-ties, cyanosis, and low oxygen saturation, and chronicprogressive cough. At that time, his CT chest showeddiffuse ground-glass opacities and significantly promin-ent interstitial lung markings, as well as mild hyperinfla-tion of peripheral air spaces with occasional cystformations. His open lung biopsy at the time showeddiffusely distended alveoli, hemosiderin-laden macro-phages, and extravasated red blood cells. He had para-bronchial lymphoid infiltrates with prominent germinalcenters in his lung histology. Direct immunofluorescencestudies on the biopsy material showed 1+ C3 comple-ment lining some cystic spaces which were consideredto be nonspecific. No antibodies to basement mem-branes or Ig-G, Ig-M, Ig-A, C1q, fibrinogen or properdinwas detected on immunofluorescence staining. He hadmoderately elevated inflammatory markers (ESR, CRP,IgG, platelets). He tested positive for ANA (1:1280


homogenous) and ANCA. He was negative for ENA,rheumatoid factor (RF) and anti-CCP. Extensive testingfor infections was negative.He required artificial ventilation and pulse methyl-

prednisolone on admission for immediate control of hissymptoms and responded well. In the course of his dis-ease, he received several cycles of pulse steroids followedby moderate to low dose steroids for maintenance at anongoing basis up until the age of 12 years. He did showcontinuing patterns of moderate elevations in inflamma-tory markers during his ongoing flares over time but histhey did not seem to coincide with ANCA peaks everytime. He was given a diagnosis of idiopathic pulmonaryhemosiderosis at the time.Hydroxychloroquine was added to his low dose steroid

maintenance therapy later which he continued to takeup until 18 years. He lost to follow up for 8 years. As perhis records from childhood, he had several episodes oftransient arthralgias with intermittent brief morningstiffness but was never diagnosed with arthritis. Henever had abnormalities in the blood pressure, urineanalysis or renal function tests. He never hadhemoptysis. At 18 years of age, his DEXA scan for bonedensity showed decreased lumbar spine and whole-bodybone density (Z-score at both the areas was − 2.6). ThePFT at age 7, at the time of his first major pulmonaryhemorrhage, showed vital capacity (VC) =88% of pre-dicted, FEV1 = 69% of predicted, FEV1/FVC = 70% ofpredicted and FEF 25–75 (53% of predicted).Initially, the bronchodilators failed to improve his lung

volumes, but after a few years, he did show some inter-mittent response to bronchodilators. His lung volumesin 2008 showed FEV-1 of 2.97 l (72% predicted), FVCwas 4.07 l (84% predicted), total lung capacity was 81%of predicted, and DLCO was 62%. His serial plethysmog-raphy results revealed air trapping with increased re-sidual volumes and residual volumes over total lungcapacity ratios. He required intermittent home oxygentherapy several times for poor exercise tolerance and fre-quent desaturations up until the age of 12 years.After 8 years of lost follow up, he presented at the age

of 26 years with severe erosive polyarthritis involvingsmall and large joints. He was initially treated with eta-nercept (50 mg/week) and methotrexate (20 mg/week)but failed treatment. Etanercept was replaced with 40mg of adalimumab subcutaneous every other weekwhich he is still taking. His last PFT in 2016 showed re-strictive patterns with FEV1–65% of predicted and FEV-70% of predicted No DLCO not available. His CT cheston July 2018 showed nodular thickening along the rightmajor fissure measuring up to 6 × 3mm with an ovoidshape and well-circumscribed margins, possibly aintrapulmonary lymph node. The lung bases showedmultifocal reticular fibrotic changes with areas of

bronchiectasis: mild centrilobular and subpleural emphy-sema. He did not have a positive family history of otherlung, kidney, or autoimmune inflammatory arthritisproblems. There was no family history of autoimmunediseases. He has two older siblings who are well andhealthy suggesting he may have a de-novo mutation.Next Generation sequencing was performed for

genetic testing in our cases. The two separate incidencesof the c.722A > C p, Glu241Ala mutation in 2 affected in-dividuals and its absence in normal sibling/family mem-bers and a large number of genomes/exomes in publicallyavailable genome Aggregation Database supports itspathogenetic role in the disease occurrence [7, 9, 10].This novel mutation in both the cases is likely to be

pathogenetic according to the databases but functionstudies have not been taken as yet. Based on the avail-able information, the most compatible inheritance modelin our cases appears to the authors to be autosomaldominant, since two males in subsequent generationswere affected with the same disease, and no femalecarriers were identified.

Discussion and literature reviewThe description of COPA syndrome in this article isbased on the up to date published literature andinformation available on this disease. The COPA Syn-drome is considered a TH17-associated autoimmune-autoinflammatory disease but the relationship seems tobe complex. The other TH17-associated diseases (psoria-sis and inflammatory bowels diseases) are not reportedas commonly as expected co-morbidities in COPA Syn-drome patients [5]. One of the other reported COPAsyndrome patients developed systemic lupus erythema-tosus and macrophage activation syndrome in the courseof the disease (Table 1). The ER-stress and upregulationof TH17 cell population are already known to have the

Fig. 1 Index case and his father


causal relationship with interstitial lung disease andautoimmunity [11–15].Most cases of COPA syndrome are familial but de-

novo mutations are also reported. A female predomin-ance appears to exist, and the majority of patientsreported are caucasian, and a remaining minority ofpatients had been Asians. Organs that are known to beinvolved are lungs, joints, and kidney but lung inflamma-tion is believed to be the key prognostic factor. Mostly,the pulmonary or/and joint inflammation had been thepresenting symptoms, but pulmonary and joint diseaseswere not necessarily always seen to go hand in hand.The renal involvement is mostly reported late in the dis-ease course. Most patients presented during childhood.In the largest reported series, 76% of patients presentedbefore their fifth birthday [3]. The most common re-ported presenting symptoms are arthralgia/ arthritis,cough and tachypnea, hemoptysis, shortness of breathand more common than not, life-threatening pulmonaryhemorrhage requiring intensive care and artificial venti-lation [5].The less common presentation was insidious onset

with fatigue, cough, anemia due to unrecognizedpulmonary hemorrhage, and arthralgias. Each specificgene mutation does not appear to predict the exact sameclinical phenotype and disease course but may help indetermining the prognosis and outcomes broadly as welearn more. An example is the p. Glu241Lys gene muta-tion from the Watkin et al. series and the Jensson et al.[3, 4] series did not have a similar disease presentationand course and showed a significantly different pheno-type. In all reported series, the COPA syndrome patientsshowed only symptomatic and a partial response to im-munosuppression and lung disease progressed over timedespite chronic immunosuppressive treatment. With thecurrent level of disease understanding, it is difficult to

predict which patients may require a lung transplant inthe future.

Comparative analysis of different case series [Tables 1, 2,3 and 4]Autoantibody profileThe information on the full spectrum of autoantibodiesin COPA syndrome is still growing. In reported series,most patients were positive for antinuclear antibody(ANA) with titers measured as high as 1:1280 (indirectimmunofluorescence). The majority of patients had posi-tive anti-neutrophil cytoplasmic antibody (cANCA)/peri-nuclear antineutrophil cytoplasmic antibody (pANCA)and rheumatoid factor antibodies (RF). The other anti-bodies such as anti-myeloperoxidase antibodies (MPO),anti-proteinase-3 antibodies (PR3) were not performedin all the COPA syndrome patients but were positive ina small fraction of patients (Table 3). The presence andtiters of antibodies showed titer-variations with time anddisease activity but not enough evidence to use them asdisease- activity biomarkers for monitoring the therapy.However, with our limited understanding of thesyndrome, no single autoantibody has yet emerged as abiomarker of disease activity, disease severity or disease-damage. Patients also often had elevated serum inflam-matory markers including C-reactive proteins (CRP), im-munoglobulin-G titer and erythrocyte sedimentationrate (ESR) which seems to better correlate with the dis-ease activity [1]. The COPA patients mostly had normalwhite cell counts and differential white cell counts.

Pulmonary diseasePulmonary hemorrhage and interstitial lung disease arecommon in several autoimmune diseases and not justCOPA syndrome. The question remains if they all sharethe same or similar mechanisms for pulmonary inflam-mation. An immunologic finding triggering autoimmun-ity and inflammation consistently observed in COPApatients is the increased expression of cytokines IL-1β,IL-6, and IL-23 which in turn upregulates TH17 cellswith the reduction in TH1 cells in the affected tissues.The mechanism of pulmonary inflammation in COPApatients does not appear to be the same as in ANCA-as-sociated vasculitis syndrome patients, although bothgroups are positive for ANCA antibodies. Unlike COPAsyndrome patients, the capillary inflammation and dam-age in ANCA vasculitis syndrome patients is assumed tobe brought about by the autoantibodies. The mechanismof lung inflammation in COPA syndrome is also differ-ent from that in patients with SAVI and TMEM-173gene mutations, which appears to be due to Type-IInterferon dysregulation. The lung involvement inTMEM-173 gene mutation is mostly interstitial, andmost of these patients do not present with pulmonary

Fig. 2 Index case and his father. Both the patients had clubbing oftheir fingernails very early on in the diseases process


hemorrhage [5]. The COPA syndrome patients are alsodifferent from the patients with STING-associatedvasculopathy in which patient mostly presents at infancy(SAVI).Traditionally, the pulmonary disease and pulmonary

hemorrhages are always present in COPA patients andmostly occur early in the disease course as the present-ing symptom. Despite immunosuppressive therapy, thepulmonary aspect of the disease is believed to beprogressive, and a negative prognostic factor. The major-ity of the reported patients had pulmonary hemorrhagebefore their fifth birthday (Table 2). The pulmonaryhemorrhage ranges from being insidious to massive life-threatening hemoptysis requiring ventilatory support.

The pulmonary disease could be restrictive, obstructiveor mixed (obstructive + restrictive) in nature.The unique and specific CT chest finding in COPA

patients are diffuse ground-glass opacities, septal fibro-sis/thickening and, peripheral patchy hyperinflammationand presence of cysts in parenchymal spaces. The histo-pathology of the lung biopsy shows capillaritis, follicularbronchiolitis, perivascular neutrophilic cuffing of vessels,capillary wall necrosis (capillaritis), red cells and hemo-siderin-laden macrophages. Follicular bronchiolitis is de-fined as hyperplastic lymphoid follicles infiltrating thesmall airway walls and interstitium with hyperplasticgerminal centers which occur with or without peripheralsmall cyst formations/emphysema. The lung biopsies

Table 1 Genetic mutation, inheritance and disease patterns in different series

Group Gene mutation, inheritance and family history Diseases pattern

Watkin et al., 2015 [3]and Tsui et al., 2018 [2](n = 21)

Mutations:c.698G > A p.Arg233His,c.728A > G p.Asp243Gly,c.721G > A p.Glu241Lys,c.690G > T p.Lys230Asn.Four missense mutations in exons 8 and 9 of the COPAgene.Heritance: Autosomal dominant.(c.721G > A), (c.728A > G) and (c.698G > A) mutations:Mostly incomplete penetrance but showed completepenetrance over two generations in only one family.(c.690G > T) mutation: Inconclusive regardingpenetrance (carrier is just 1 year old and isasymptomatic at this point)

20/21 (95%) had Polyarthritis, 21/21 (100%) had aprogressive pulmonary disease.4 (19%) patients had an immune-mediated renaldisease.Two families with c.721G > A p. Glu241Lys mutation didnot have renal disease.One patient had a recurrent nonspecific rash.

Brynjar O. Jensson, et al. 2017 [4](n = 3)

Mutation: c.721G > A p. Glu241Lys.Heritance: Index case had de novo mutation as both ofhis parents were negative for gene mutation and werehealthy at the time of writing.2/3 (66%) had autosomal dominant with completepenetrance.

3/3 (100%) had polyarthritis.3/3 (100%) had a progressive pulmonary disease.No renal involvement.1/3 (33%) had nail clubbing.

Brennan MA. et al. 2017 [8](n = 1)

Mutation:c.727G > A/p. Asp243Asn. Substitution in exon-9.Heritance: De novo mutation.No family history but parental genetic status notavailable.

1/1 (100%) -had erosive destructive Poly JIA at age 30months of age as presentation.At age 6 years, presented with progressive restrictivelung diseasePositive for CF gene test [CFTR: genotype F508del/R117H(7 T). Sweat chlorides 52 and 38 mmol/L],GERD (needed fundoplication) Developed SystemicLupus Erythematosus later in the disease course.Developed MAS. No renal disease. Positive for fingerclubbing

Volpi S et.al. 2018 [7](n = 1)

Mutation: c.698GNA.Heritance: Autosomal dominant with variablepenetrance.Mother of the index case was identified to be anasymptomatic carrier of same gene mutation.

Presented with progressive severe destructivepolyarthritisYears later presented with progressive restrictivepulmonary diseases. No pulmonary hemorrhage orhemoptysis.No renal disease.

Patwardhan A et al. Mutation: c.722A > C p, Glu241Ala.Heritance: Autosomal dominant with completepenetrance. Son-the index case and his father.Sibling of the index case is negative for mutation.

2/2 (100%)-Presented with progressive mixedobstructive and restrictive lung disease, chronicrespiratory insufficiency, cough, oxygen requirement,artificial ventilation, pulmonary hemorrhages.1/2 (50%)- Father had arthralgias and later developeddestructive polyarthritis.0/2 (0%) -No renal disease

NB: (CF Cystic Fibrosis, MAS Macrophage activation syndrome. JIA Juvenile idiopathic arthritis. ENA Extractable nuclear antibodies. DLCO Diffusing capacity of thelungs for carbon monoxide. GERD Gastroesophageal reflux disease. Tsui JL.et al. group had common patients with Levi B Watkin et al. group but had moredetailed information on pulmonary symptoms


Table

2Dem

ograph

y,presen

tatio

n,andextrapu

lmon

arydiseasepattersin

different

series

Group

Total(n)

Age

ofpresen

tatio

nbe

low

fiveyearsandpatternof

presen

tatio

n.n(%)

Dem

ograph

yn(%)

Extrapulmon

arydiseasen(%)

Arthritis

Kidn

eydisease

WatkinLB.etal.,2015

[3]

(21).The

access

toclinical

inform

ationandDNAon

twen

ty-one

patientsfro

mthe

fivefamilies,the

rewas

atotal

oftw

enty-seven

affected

patient.

16/21(76%

)Presentation:

Hem

optysis,Tachypne

a,Cou

gh:14/21

(67%

),Arthralgia:5/21

(24%

).

Males:8/21(38%

).Females:

13/21(62%

).Age

rang

eat

presen

tatio

nwas

sixmon

thsto

22years.

Meanageat

presen

tatio

nwas

3.5years.

20/21(95%

)Destructivepo

lyarthritis20/21

(95%

)(Involvingbo

thsm

all

andlargejoints).

Mostcommon

lyaffected

jointswerekneesandthe

interphalang

ealjointsof

the

hand

s.2/21

(9.5%)had

osteon

ecrosisalon

gthe

femur,p

atella,and

tibiofib

ula.

1/21

(4.7%)hadfatne

crosis.

Nouveitis.

4/21

(19%

)Nospecificclinicalor

histop

atho

logicald

isease

patterns.

JenssonBO

.etal.2017[4]

(3)(twoge

neratio

nsin

the

samefamily)

1/3(33%

)Theinde

xcase

(IC):

diagno

sedat

32yearsof

age

buthadahistoryof

JIA.The

malechild

oftheinde

xcase

(MC2)

presen

tedat

11years

with

achroniccoug

hand

asthma-likesymptom

sand

polyarthritis,fem

alechild

(FC3)

at18

mon

thsof

ageas

JIAandat

tenyears

develope

dexercise

intolerance,recurren

trespiratory

infections,and

arecurringskin

rash

Allthethreepresen

tedas

JIAandyearslaterde

velope

dpu

lmon

arysymptom

s.The

pulm

onaryandjoints

symptom

sdidno

trunhand

sin

hand

.

1/3F(33%

)Ind

excase

diagno

sedat

32yearsbu

thadH/O

JIA.

(MC2)

1/3(33%

)presented

at11

yearsof

agewith

respiratory

symptom

sand

arthritis.

(FC3)

1/3(33%

)presented

at18

mon

thsof

agewith

arthritis.

Allthethreewerecaucasian-

Icelandic.

3/3(100%)

Polyarthritis(largeandsm

all

joints)w

hich

wen

tinto

remission

with

outjoint

destructionin

2/3(67%

)of

patients.NoUveitis.

0/3(0%)

Bren

nanMA.et.al.2017

[8]

(1)

1/1(100%)

Presen

tedwith

smalland

largejointarthritis

30mon

thsoldF,Caucasian.

1/1(100%)Po

lyarthritis(large

andsm

alljoints)NoUveitis.

Arthritiswen

tinto

remission

after13

mon

thswith

nojoint

destruction.Com

orbidities:

gastro-esoph

agealreflux,CF,

SLE,MAS.

0/1(100%)

VolpiS

et.al.2018

[7]

(1)

1/1(100%)

Presen

tedwith

arthritisof

wrists,cervicalspine

,metacarpo

phalange

aljoints,

andlefthip.

ThreeyearsoldCaucasian

female

Severe,p

rogressive

destructive,Po

lyarticular

(smalland

largejoints)

dege

nerativeosteoarthritic

change

s++.

Poor

respon

seto

immun

osup

pressantsand

0/1(100%)


Table

2Dem

ograph

y,presen

tatio

n,andextrapu

lmon

arydiseasepattersin

different

series(Con

tinued)

Group

Total(n)

Age

ofpresen

tatio

nbe

low

fiveyearsandpatternof

presen

tatio

n.n(%)

Dem

ograph

yn(%)

Extrapulmon

arydiseasen(%)

Arthritis

Kidn

eydisease

steroids.

Tsui

JL.et.al.2018

[2]

(14)

Age

atpresen

tatio

n:years<

1–1/14

(7%),2–9years-10/14

(71%

),10–12years–3/14

(21%

).Presen

tatio

n:Arthralgia-7/14

(50%

),he

mop

tysis-4/14

(28.5%

),Shortnessof

breath-9/14

(64%

),Renald

isease-0/14(0%)

Males:3/14(21%

),Females:11/14

(79%

),Caucasians:1

2/14

(86%

),Asian:2/14(14%

),

14/14(100%)-P

olyarthritis

(smalland

largejoints)

2/14

(14%

)had

cervicalspine

arthritis.

NoUveitis.

3/14

(21%

)Renal:2/3(67%

)ren

albiop

sies

hadIgG,IgA

,IgM

,C1q

positive.1/3(33%

)had

strong

lypo

sitiveIgA

immun

ofluorescence.Tw

owereANCApo

sitive(one

PR3

positive).N

onerequ

ired

hemod

ialysis.

Patw

ardh

A.et.al.

(2)(twoge

neratio

nsin

the

samefamily).Theinde

xcase

(IC)andthefather

ofthe

inde

xcase

(C2).

1/2(100%)

Both

presen

tedwith

achroniccoug

h,recurren

trespiratory

infections,asthm

a-likesymptom

s,de

terio

ratin

gexercise

tolerance,shortness

ofbreath,une

xplained

chronicanem

ia.

2/2(100%)m

ales.

IC:2

yearseigh

tmon

thsold

atpresen

tatio

n,mixed

race

(Caucasian-Hispanic).C

2:7

yearsold(m

aybe

youn

ger)at

presen

tatio

n,Caucasian

male.

0/2(0%)

C2hadarthralgiaup

until

26yearsof

agebu

tthen

develope

dsevere

destructive

polyarthritisinvolvingsm

all

aswellaslargejoints.Ind

excase

hadno

jointsymptom

s.

0/2(0%)

MASMacroph

ageactiv

ationsynd

rome.

ICInde

xcase

andC2

Father

oftheinde

xcase.M

C2Th

emalechild

ofinde

xcase.FC3

Afemalechild

oftheinde

xcase.FEV1Fo

rced

expiratory

volumein

1s,FVCFo

rced

vital

capa

city.A

TSAmerican

thoracicsociety.LFTLu

ngfunctio

ntest.TsuiJL.et

al.g

roup

hadcommon

patie

ntswith

Levi

BWatkinet

al.g

roup

butha

dmorede

tailedinform

ationon

pulm

onarysymptom

s


Table

3Autoantibod

iesprofile

invario

usseries

Group

ANCAn(%)

PR3n(%)

MPO

n(%)

RFn(%)

AntiC

CPn(%)

ANAn(%)

ENAn(%)

Treatm

entexpe

rience

WatkinLB.etal.,2015

[3]

(n=21)

15(71)

NA

NA

9(43)

NA

14(67).

0/0

(100%)

Symptom

aticpartialrespo

nseto

immun

osup

pression

21(100)

JenssonBO

.]etal.2017[4]

(n=3)

2(67)

NA

NA

3(100)

1(33%

)3(100)T

iters

upto

1:1280

NA

Partialrespo

nseto

immun

osup

pression

Respon

dedto

MMF,Hydroxychloroqu

ine,and

steroids.

Bren

nanMA.etal.2017[8]

(n=1)

NA

NA

NA

NA

NA

1/1(100%)

1/1(100%)

Pulseandoralsteroids,M

onthly-sixdo

sesof

Cycloph

osph

amide,MTX,Ritu

ximab.C

urrently

oncombinatio

ntherapy:MMF,

Hydroxychloroqu

ine,steroids.

Com

orbidities:GERD,C

ystic

Fibrosis,SLE.

Develop

edMAS.

VolpiS.et.al.2018

[7]

(n=1)

0/1(0%)

NA

NA

1/1(100%)

NA

Yes

(but

notat

the

presen

tatio

n)

NA

Partialrespo

nseto

immun

osup

pression

Tsui

JL.et.al.2018

[2]

(n=14)

9/12

(64%

)3/9(33%

)2/9(22%

)10/14(71%

)3/14

(21%

)12/14(86%

)titers1:40

to1:320

0/14

(100%)

Partialrespo

nseto

immun

osup

pression

Most

patientswith

diffu

sealveolar

hemorrhage(DAH)

respon

dedto

pulsemethylpredn

isolon

eand

mon

thly-sixdo

sesof

cyclop

hosphamide,bu

tfew

subseq

uentlyne

eded

rituxim

ab.Poo

rrespon

seto

Metho

trexate,AZA

,and

Etanercept.

Mostpatientsaredo

ingbe

tter

onlow

dose

pred

nisone

+MMF+

Hydroxychloroqu

ine.

2/14

(14%

)neede

dabilaterallun

gtransplant.

Patw

ardh

anA.et.al.

(n=2)

2/2(100%)

Inde

xcase:

Neg

ative

Father

ofthe

inde

xcase:N

A

Inde

xcase:

Neg

ative

Father

ofthe

inde

xcase:N

A

0/2(0%)

Inde

xcase:

Neg

ative

Father

ofthe

inde

xcase:N

A

2/2(100%)

Titersup

to1:1280

Inde

xcase:

Neg

ative

Father

ofthe

inde

xcase:

Neg

ative

IChadapartialrespo

nseto

immun

osup

pression

(norespon

seto

Metho

trexate,AZA

).Goo

drespon

seto

pulse

steroids

followed

byMMF+

low

dose

oralsteroids.

C2-was

treatedwith

repe

ated

pulsesteroids,

oralhigh

andlow

dose

steroids

andno

wwith

adalim

umab

andmetho

trexateforarthritis.

NB:

c-ANCA

Cytop

lasm

ican

tineu

trop

hilcytop

lasm

ican

tibod

ies.p-ANCA

Perin

uclear

antin

eutrop

hilcytop

lasm

ican

tibod

ies.PR

3an

tibod

yag

ainstproteina

se3of

neutroph

ilsan

dmon

ocytes.M

POAntibod

yag

ainst

myelope

roxida

seen

zymeexpressedin

neutroph

ils.R

FRh

eumatoidfactor.A

ntiC

CPAnti-C

yclic

Citrullin

ated

Peptide.

ANAAntinuclear

Antibod

ies.EN

AExtractableNuclear

Antigen

antib

odiespa

nel.NANot

available,

MMFMycop

heno

late

Mofetil.AZA

Azathioprine.

Tsui

JL.etal.g

roup

hascommon

patie

ntswith

Levi

BWatkinet.alg

roup

butha

dmorede

tailedinform

ationon

pulm

onarysymptom

s


Table

4Pu

lmon

arydiseaseandtreatm

entexpe

rience

Group

Pulm

onarydisease

n(%)

Histopatholog

yn(%)

Treatm

entexpe

rience

n(%)

Bilaterallun

gtransplant

n(%)

WatkinLB.etal.,2015

[3]

21/21(100%).Vario

uscombinatio

nsof

follicularbron

chiolitis,p

ulmon

ary

hemorrhage,andinterstitiallun

gdisease.

Interstitiallym

phocyteinfiltration

with

thege

rminalcenter

form

ation

inlung

interstitium

andpe

riphe

ral

airw

aywalls.C

D20+Bcells

with

inthege

rminalcentersin

thelung

biop

syspecim

enon

Immun

ohistochem

icalstaining

.Sign

ificantlyincreasedCD4+

Tcells

intheinterstitiallun

gtissue.

Symptom

aticpartialrespo

nseto

immun

osup

pression

21(100).

4/14

(29%

)patientshadalung

transplant.

3/4(75%

)werein

third

andfourth

decade

s1/4(25%

)was

insecond

decade

oflife.

Itisno

tpo

ssibleto

pred

ictwho

will

need

lung

transplant

with

the

curren

tlevelo

fun

derstand

ingof

the

disease.

Lung

diseaseislikelyto

prog

ress

over

timede

spite

chronic

immun

osup

pression

.

JenssonBO

.etal.2017[4]

3/3(100%).

3(100)p

resented

with

achronic

coug

h,breathlessne

ssand

worsening

exercise

tolerance.No

hemop

tysis.Diagn

osed

with

chronic

follicularbron

chiolitiswith

interstitial

lung

disease.

Twohadprog

ressiverestrictive,and

onehadob

structivelung

diseaseon

spiro

metry

test.1

(33)

hadrecurren

tpu

lmon

aryhe

morrhages

onhistolog

y.Allhadinitiallow

andworsening

diffu

sing

capacity

forcarbon

mon

oxide(DLC

O).2/3(66)

need

eda

bilaterallun

gtransplant.

open

lung

biop

sy2/3(67%

).Hyperplastic

lymph

oidfollicles

infiltratingthesm

allairw

aywallsand

interstitium

with

hype

rplastic

germ

inalcenters.Interstitial

lymph

oidinfiltrateandfib

rosisand

distalacinar

emph

ysem

aandcyst

form

ation.

1/3(33%

)had

adiffu

seintra-alveolar

hemorrhage.

Pulseandoralsteroids

and

immun

osup

pressants.1

/3(33%

)were

also

treatedwith

Bron

chod

ilators.

Lung

diseases

show

edapartial

respon

seto

immun

osup

pression

.(look

forsupp

lemen

talfilesfor

immun

osup

pressants)

2/3(67%

).Theinde

xcase

at44

years

andhe

rsonat

28years,received

bilaterallun

gtransplants.

Bren

nanMA.etal.2017[8]

Atage6yearsstartedwith

achronic

coug

h,shortnessof

breath.

Diagn

osed

with

prog

ressive

restrictivelung

disease,ILDand

finge

rclub

bing

.

Ope

nlung

biop

syrevealed

amixed

pictureof

inflammationand

aspiratio

n.

Pulseandoralsteroids,M

onthly-six

dosesof

Cycloph

osph

amide,MTX,

Rituximab.C

urrentlyon

combinatio

ntherapy:mycop

heno

late

+mofetil+

hydroxychloroq

uine

,predn

isolon

e.Com

orbidities:GERD,C

ystic

Fibrosis,

SLE.Develop

edMAS.

Partialrespo

nseto

immun

osup

pression

.

0/1(100%).

Thepatient

isin

herteen

sat

the

timeof

publication.

VolpiS.et.al.2018

[7]

Achroniccoug

h,breathlessne

ssand

worsening

exercise

tolerance.

Prog

ressiveinterstitiallun

gdisease.

Nopu

lmon

aryhe

morrhages.

Radiog

raph

icpattern:prom

inen

tinterstitial

involvem

entandthepresen

ceof

the

air-filledcysts.Restrictivelung

disease.

Nolung

biop

sybu

tBA

Lshow

edLymph

ocyticAlveo

litis.

Pulseandoralsteroids.Poo

ror

norespon

seto

Metho

trexateand

Abatacept.C

urrentlyon

Mycop

heno

late

Mofetil+

Hydroxychloroqu

ineandlow

dose

oralsteroids.

Partialrespo

nseto

immun

osup

pression

.

0/1(100%)


Table

4Pu

lmon

arydiseaseandtreatm

entexpe

rience(Con

tinued)

Group

Pulm

onarydisease

n(%)

Histopatholog

yn(%)

Treatm

entexpe

rience

n(%)

Bilaterallun

gtransplant

n(%)

Tsui

JL.etal.2018[2]

14/14(100%).

12/14subjectshadspiro

metry

that

met

ATS

criteria.2/12(17%

)had

amixed

obstructive/restrictive,8/12

(67%

)had

restrictive,1/12

(8%)had

norm

alspiro

metry,and

1/12

(8%)

hadan

obstructivelung

disease.

InitialDLC

Owas

notavailablefor4/

12patientsandwas

abno

rmalin

8/8

(100%).9/10

(90%

)patientsshow

edworsening

in%

pred

ictedFEV1

and

FVCover

time.Im

provem

entin

radiolog

yresults

didno

tcorrelate

with

spiro

metry

results

which

worsene

dwith

time.CTfinding

sinclud

edthin-w

alledscattered

parenchymalcysts,multip

lecentrilob

ular

nodu

les,grou

nd-glass

opacities,and

fibrosis.

10/14hadalung

biop

sy.2/10had

transbronchial,and

8/10

hadop

enlung

biop

sies.

Follicularbron

chiolitis,d

iffuse

alveolar

hemorrhage,capillaritis,

increasedinterstitialand

alveolar

neutroph

ils.Bronchiolocen

tric

airspace

enlargem

ent/cysticchange

,increasedhe

mosiderin-filledintra-

alveolar

macroph

ages.Lym

phoid

Hyperplasia.

Partialrespo

nseto

immun

osup

pression

.Mostpatients

with

diffu

sealveolar

hemorrhage

(DAH)respon

dedto

pulse

methylpredn

isolon

eandmon

thly-six

dosesof

cyclop

hosphamide,bu

tfew

subseq

uentlyne

eded

rituxim

ab.

Metho

trexate,AZA

,Etane

rcep

t.Most

patientsaredo

ingbe

tter

onlow

dose

pred

nisone

+MMF+

hydroxychloroq

uine

.2/14(14%

)ne

eded

abilaterallun

gtransplant.

4/14

(29%

).Nospecificfeatures

butthevaried

presen

tatio

nandclinicalfeatures

Patw

ardA.et.al.

2/2(100%)

Achroniccoug

h,breathlessne

ss,

worsening

exercise

tolerance,and

club

bing

,intermitten

tcyanosisand

desaturatio

ns.Recurrent

pulm

onary

hemorrhages

with

outhe

mop

tysis.

CTChe

st:g

roun

dglassappe

arance

andinterstitiald

isease.Spirometry:

Obstructivelung

diseasein

ICand

mixed

Obstructiveandrestrictive

lung

diseasein

C2.

Prog

ressivelyworsening

DLC

Oin

C2.

DLC

Ocouldno

tbe

done

onInde

xcase.

2/2(100%)hadan

open

lung

biop

sy.

Histopatholog

yshow

edpu

lmon

ary

capillaritis,hem

osiderosiswith

hemosiderin-lade

nmacroph

ages,

extravasationof

redbloo

dcells,

interstitialinflammation,pu

lmon

ary

diffu

selymph

oidhype

rplasia,

lymph

ocyticbron

chiolitis,w

iden

ing

ofalveolar

ductsanddisten

sion

ofairspaces

atthepe

riphe

ry,

perip

heralairw

ayscystform

ation.

Theim

mun

ofluorescencestaining

incase

C2was

negative.IC

didno

thave

immun

ofluorescencestaining

ofthebiop

sytissue.

Partialrespo

nseto

immun

osup

pression

.Ind

excase:d

idno

trespon

dto

Metho

trexate,AZA

.Goo

drespon

seto

pulsesteroids

followed

bylow

dose

oralsteroids+

MMF.Hehadan

inadeq

uate

respon

seto

bron

chod

ilators.

Nopu

lmon

aryhe

morrhages

and

PICUadmission

inpaston

eyear.

Father

oftheinde

xcase

was

treated

with

pulsesteroids

ororalhigh

and

low

dose

steroids

till18yearsof

age.

Hehadan

inadeq

uate

respon

seto

bron

chod

ilators.H

eison

adalim

umab

40mgand…

……

for

arthritis.

0/2(100)

NB:

ICInde

xcase

andC2

Father

oftheinde

xcase.TsuiJL.et

al.g

roup

hadcommon

patie

ntswith

Levi

BWatkinet

al.g

roup

butha

dmorede

tailedinform

ationon

pulm

onarysymptom

s


show deposits of hemosiderin suggesting chronichemorrhages. The majority of patients showed a trendof progressive reduction in total lung capacity, tidal vol-ume and carbon monoxide diffusion capacity. A percent-age of the reported patients (2/3 in Jensson et al. and 4/21 in Levi B Watkin et al. series) needed a bilateral lungtransplant, though the Jensson et al. and Levi B Watkinet al. series have several overlapping patients and mayrepresent the same patients.The significant interstitial lung disease is usually a

later manifestation and seen in their second decades oflife. The cystic lesions are reported to increase, andground glass picture on CT chest showed a reductionover time suggesting progressive restrictive lung disease.Immunohistochemical staining of lungs shows CD20+ Bcells and CD4+ T cells infiltration. Due to a limitednumber of patients with the diagnosis and availability ofpatchy retrospective data, no accurate predictions can bemade about the prognostic markers for lung disease orpredict which patients may need a lung transplant in thefuture. Although follicular bronchiolitis is not specific toCOPA syndrome and can be found in several otherautoimmune, immunodeficiency, and connective tissuediseases, it is the most common histopathology consist-ently reported in COPA syndrome patients. In our caseseries, both the index case and his father had recurrentpulmonary hemorrhages and progressive lung diseasebut did not have hemoptysis. They had typical CT (W/Ocontrast) and histologic features as described in otherreported cases. Their acute symptoms responded topulse methylprednisolone.

Musculoskeletal symptomsSevere arthralgia is a common finding, but polyarticularerosive arthritis is also reported in many patients withCOPA syndrome as a presenting symptom or early inthe disease course (Table 2). Arthritis involved largejoints as well as small joints. Temporomandibular (TMJ)involvement is not reported in these patients. In oneseries, 43% of patients had rheumatoid factor positivearthritis while in another series few patients had anti-cyclic citrullinated peptide antibody (anti-CCP) positive[5]. It is not clear if anti-CCP and RF antibodies havethe equal and same prognostic and diagnostic signifi-cance as they have for juvenile idiopathic arthritis (JIA)patients. The joint diseases and pulmonary symptomsare not always reported to go hand in hand, i.e., theflares or remissions of lung and joint disease do not al-ways coincide with each other. In our case series, boththe index case and his father did not have arthritis atpresentation. Although the father of the index case hadrecurrent, brief episodes of arthralgia and morning stiff-ness for initial 4 years of his disease course, he was seenseveral times by the rheumatologist (not a pediatric

rheumatologist) but never at any point diagnosed witharthritis. He later at the age of 26 years presented withdestructive polyarthritis.

Kidney diseaseCOPA patients are reported to run an increased risk for aheterogeneous nonspecific autoimmune renal disease. In apublished series of 21 patients, 44% had either abnormalrenal function and or had proteinuria (Table 2). The sixpatients who had been reported with renal biopsy datashowed abnormal but variable patterns of histopathology1. None of the patients with c.721G > A p.Glu241Lys mu-tation had renal disease suggesting that this mutation maybe protective for renal disease. Our index case presentedat 2 years 8 months of age and his father presented at 7years of age. Currently, the index case is 5.5 years old, andhis father is 29 years old. Both of our patients did not haverenal disease any time in their diseases course.

PrognosisLongitudinal data (5 to 20 years) on five patients fromLevi B Watkin et al. series [3] and three from Jensson etal. series [4] showed that despite treatment withimmunosuppressants and steroids therapy, their diseaseprogressed, and five (24%) from Levi B Watkin et al.series [3] and 2 (66.6%) from Jensson et al. series [4]needed bilateral lung transplants. They all received dif-ferent and practice-based immunosuppressant therapy,and their compliance is not included in the comparativeanalysis. The immunosuppressant therapy showed asymptomatic response in most of the COPA syndromepatients but did not necessarily affect the long-term out-come. The lung function tests, especially DLCO, contin-ued to show progressive worsening with time in mostcases. Most researchers believe that the lung diseasemay continue to progress despite immunosuppressivetreatment and immunosuppression may not affect thelong-term course of the disease. The researchers couldnot identify the markers which can inform as to whichpatients may need lung transplants in the future. Thepatients who received transplants had presented early intheir lives suggests that early onset of the disease may bean adverse prognostic factor. All these patients weretreated differently due to diagnostic uncertainties andignorance about COPA entity; therefore, comparison ofthe disease course and treatment responses for differentgene mutations is difficult.

ConclusionThe available information on COPA gene mutation andthe associated syndrome is not enough to predict thecourse of the disease but is enough to recognize thesymptoms and diagnose it early. COPA syndrome maybe new and a quite diverse disease but it may not be that


uncommon [8]. Sharing the new mutations and clinicalaspects is crucial to the development of better treatmentplans using pragmatic research to optimize the manage-ment options.

AbbreviationscANCA: Anti-neutrophil cytoplasmic antibody; COPA: Coatomer Protein,Subunit Alpha; DLCO: Diffusing capacity or transfer factor of the lung forcarbon monoxide.; MPO: Anti-myeloperoxidase antibodies;pANCA: Perinuclear antineutrophil cytoplasmic antibody; PICU: Pediatricintensive care unit; PR3: Anti-proteinase-3 antibodies; RF: Rheumatoid factor;SOB: Shortness of breath

AcknowledgmentsI acknowledge the help of Dr. L. Gozal MD, in reviewing the manuscript.The author would like to thank Charles H Spencer, MD for his editorialassistance in copywriting.

Informed consentPatient consent is taken for acceptance for publishing the case series andpublishing the unmasked pictures of both the patients. Institutional reviewboard approval is obtained for the case series reporting.

Authors’ contributionsEqual contribution in writing up the report and editing the manuscript. Bothauthors read and approved the final manuscript.

FundingNo funding obtained.

Availability of data and materialsIs available.

Ethics approval and consent to participateEthical Approval from IRB is obtained and patient/parent consent to publishtheir photographs and clinical information is obtained.

Consent for publicationConsent for publication is obtained from the patient/parents.

Competing interestsThe authors declare that they have no competing interests.

Author details1University of Missouri School of Medicine, 400 Keene Street, Columbia, MO65201, USA. 2University of Mississippi Medical Center, Batson Children’sHospital, Rm 289, 2500 North State St, Jackson, MS 39216, USA.

Received: 5 June 2019 Accepted: 7 August 2019

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2. Tsui JL, Estrada OA, Deng Z, Wang KM, Law CS, Elicker BM, et al. Analysis ofpulmonary features and treatment approaches in the COPA syndrome. ERJOpen Res. 2018;4(2):00017-2018. https://doi.org/10.1183/23120541.00017-2018.

3. Watkin LB, Jessen B, Wiszniewski W, Vece TJ, Jan M, Sha Y, et al. COPAmutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis. Nat Genet. 2015;47(6):654–60.

4. Jensson BO, Hansdottir S, Arnadottir GA, Sulem G, Kristjansson RP, OddssonA, et al. COPA syndrome in an Icelandic family caused by a recurrentmissense mutation in COPA. BMC Med Genet. 2017;18(1):129.

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https://doi.org/10.1183/23120541.00017-2018https://doi.org/10.1183/23120541.00017-2018

AbstractIntroductionMethodsResultsConclusions

IntroductionMaterials and methodsResultsIndex case (Fig. 1 and Fig. 2)The father of the index case (Fig. 1 and Fig. 2)

Discussion and literature reviewComparative analysis of different case series [Tables 1, 2, 3 and 4]Autoantibody profilePulmonary diseaseMusculoskeletal symptomsKidney diseasePrognosis

ConclusionAbbreviationsAcknowledgmentsInformed consentAuthors’ contributionsFundingAvailability of data and materialsEthics approval and consent to participateConsent for publicationCompeting interestsAuthor detailsReferencesPublisher’s Note

an unprecedented copa gene mutation in two patients in the ...the protocol and data extraction from...

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