IgG4-related disease: a systematic review of this unrecognized disease in pediatrics
Karim et al. Pediatric Rheumatology
IgG4-related disease: a systematic review of this unrecognized disease in pediatrics
Faiz Karim 0 3
Jan Loeffen 2
Wichor Bramer 1
Lauren Westenberg 0 3
Rob Verdijk 4
Martin van Hagen 0 3
Jan van Laar 0 3
0 Departments of Internal Medicine and Immunology Erasmus MC , 's-Gravendijkwal 230, 3015 CE Rotterdam , The Netherlands
1 Medical library, Erasmus MC , Rotterdam , The Netherlands
2 Department of Pediatrics Oncology, Erasmus MC-Sophia Children's hospital , Rotterdam , The Netherlands
3 Departments of Internal Medicine and Immunology Erasmus MC , 's-Gravendijkwal 230, 3015 CE Rotterdam , The Netherlands
4 Department of Pathology, Erasmus MC , Rotterdam , The Netherlands
Background: Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibro-inflammatory condition with an unclear pathophysiological mechanism affecting different parts of the body. If untreated, the disease can lead to fibrosis and irreversible organ damage. IgG4-RD mostly has been described in adults, hence it is generally unknown among pediatricians. This systematic search of the literature provides an overview of all reports published on IgG4RD in children in order to create awareness of IgG4-RD in pediatrics and to emphasize the broad clinical presentation of this disease. Methods: A systematic literature search of Embase, Medline, Web-of-Science, PubMed publisher, Cochrane and Google Scholar was performed for case reports on IgG4-RD in children. Results: Of total 740 articles identified by the search, 22 case reports including 25 cases of IgG4-RD in children were found. The median age of the children was 13 years, of which 64 % were girls. IgG4-related orbital disease (44 %) and autoimmune pancreatitis type 1/IgG4-related pancreatitis (12 %) predominantly occurred. Less frequently, other manifestations as pulmonary manifestation, cholangitis and lymphadenopathy were also found. Almost all cases were histologically proven. Prednisone was the first choice of treatment leading to favorable clinical response in 83 % of the cases. Maintenance therapy with steroid sparing agents was required in 43 % of the cases needing therapy. Rituximab was successful in all 4 cases, whereas, the disease modifying rheumatic drugs (DMARDs) mycophenolate mofetil, azathioprine and methotrexate were effective in almost 50 % of the cases. Conclusion: IgG4-RD in children is a generally unknown disease among pediatricians, but several pediatric cases have been described. Prednisone is the first choice of treatment leading to disease remission in the majority of the cases. DMARDs and rituximab are alternative effective steroid sparing agents with more positive evidence for the latter.
IgG4-RD is a systemic fibro-inflammatory disease affecting
different parts of the body [
]. The disease is characterized
by tumour-like infiltrations of IgG4 positive plasma cells in
the tissues, mostly with fibrotic abnormalities and often
elevated serum IgG4 levels [
]. The underlying
pathophysiological mechanism of IgG4-RD is still unclear, but when
untreated, the disease can lead to irreversible organ damage
because of the fibrosis. Early recognition and therapy is
therefore critical [
]. In recent time there has been a lot
of attention to IgG4-RD in adult care leading to evolving
knowledge about pathogenesis, diagnosis and treatment of
this disease. However, further studies are required to
provide more insight into this disease, in particular, the
underlying pathogenesis has yet to be clarified. The average age
at which IgG4-RD can occur, is estimated to be older than
50 years [
]. Although case reports are available on
IgG4-RD in children [
], no pediatric studies or reviews
about this disease have been published yet. Knowledge and
awareness of this disease is essential to prevent missing the
diagnosis and subsequent delay of treatment, especially in
We performed a systematic literature search in order
to make an overview of all the case reports that have
been published regarding IgG4-RD in children. The
main purpose of this study was to create awareness of
IgG4-RD in pediatrics and to emphasize the broad
clinical presentation of this disease. Furthermore, with the
current knowledge about the disease we wanted to
provide an overview on epidemiology, pathogenesis and
treatment of this disease for the pediatricians.
A systematic literature search was conducted to provide
an overview of all case reports and (if available) case
series regarding IgG4-RD in pediatrics. The study was
performed and reported in accordance with the PRISMA
statement for systematic reviews.
Data source, study selection and data extraction
Relevant articles on IgG4-RD in children were retrieved
from Embase.com, Medline (Ovid), Web-of-Science, and
the Cochrane Library from inception to last date of
inclusion July 16th 2015. Additional references were obtained
from PubMed (the subset as supplied by publisher,
containing references not yet indexed in Medline) and Google
Scholar (the most relevant citations). No filters for date or
language were used in the search strategy. See the
additional Appendix for the full search strategies for all
databases. Two authors reviewed and extracted the data
Of a total of 740 articles identified by the search, 34
articles on IgG4-RD in pediatrics were eligible (Fig. 1). After
screening, 22 case reports on IgG4-RD in children were
identified. Three articles described two pediatric patients
leading to a total of 25 cases of IgG4-RD [
main outcomes of this study are demonstrated in
With this systematic literature review we identified 22
case reports of IgG-RD in children. Identified studies
were published over a 5-year span (2010–2015). The
case reports included patients aged ranging from
22 months to 17 years of age. The median age of the
children in this study was 13 years and 64 % of the
children were girls.
The cases described in this study show a spectrum of
different organ manifestations (Fig. 2) of IgG4-RD.
Records identified through database searching (n = 740)
Additional records identified through others ources (n = 0)
Records after duplicates removed (n = 452)
Records excluded based on title and abstract (n = 418)
Eligible articles on IgG4-RD in pediatrics (n = 34)
Articlesincluded (n = 22 with 25 cases)*
Full text articlesexcluded
(n = 12)
Review on AIP (n = 3)
Duplicates (n = 1)
Non-IgG4-RD (n = 5)
IgG4-RD adult (n = 1)
Rosai-Dorfman disease(n = 1)
ALK1 positive inflammatory
myofibroblastic tumor (n = 1)
Fig. 1 Search strategy and selection of the articles. * Three articles demonstrated each two cases of IgG4-RD in children. Therefore, a total of 25
cases were available for this study
Y year, IgG4-ROD IgG4-related orbital disease, Mo months, H+ histology performed, Mikulicz disease IgG4-related orbital and submandibular disease, M male, AIP-1
autoimmune pancreatitis type 1, IgG-R IgG4-related disease, F female, Pred prednisone, Aza azathioprine, EL elevated, MMF mycophenolate mofetil, L U level unknown, N
normal, NM not measured, Methylpred Methylprednisolone, Lymphad Lymphadenopathy
aHistology without IgG4 staining
Column1 Organ manifestation of IgG4RD in children(%)
Column2 Column3 Column4 Column5
Organ manifestation of IgG4RD in
IgG4R pulmonary disease
However, most of the cases report IgG4-related orbital
disease (IgG4-ROD) (44 %) [
]. Other manifestations
were IgG4-related pancreatitis/autoimmune pancreatitis
type 1 (AIP 1) (12 %), IgG4-related cholangitis (8 %),
IgG4-related pulmonary disease (8 %), and the remaining
cases (28 %) were single cases of Riedel’s thyroiditis/
IgG4-related thyroid disease, IgG4-related sialadenitis,
IgG4-related mesenteritis, IgG4-related
lymphadenopathy, IgG4-related dacryoadenitis, IgG4-related sinonasal
disease and IgG4-related hepatic mass. Kidney
involvement was seen in three cases in combination with other
organ manifestations [
11, 13, 14
]. Systemic IgG4-RD
(two or more organ manifestations) occurred in 40 % of
the cases [
In this study, all cases of IgG4-RD were histologically
confirmed, except one case of Riedel’s thyroiditis [
whereby histology was performed without IgG4 staining.
Riedel’s thyroiditis is recently included in the spectrum of
], therefore we decided to include this case
report in this study. Furthermore, despite the presence of
IgG4 positive plasma cells in the tissue, two case reports
concerning Rosai-Dorfman disease and ALK-1 positive
inflammatory myofibroblastic tumor [
] were excluded,
because according to Boston consensus these diseases
should not be considered as IgG4-RD. Serum IgG4 was
measured in 23 of the 25 cases, and was found to be
elevated in 16 cases [
5, 6, 8, 10, 12, 14–19, 24–27
] (70 %).
Prednisone was the first choice of treatment in 23 of the
25 cases [
5–11, 14–20, 24–29
]. In one case no treatment
was initiated or mentioned , and in another case
surgery alone resulted in complete remission [
The doses of prednisone that was used were not
mentioned in all cases, but when specified was usually
between 0.5 and 2 mg/kg/day. Prednisone therapy
resulted in a rapid response in 19 of the 23 cases treated
5–11, 13, 14, 17–20, 24–29
]. Prednisone alone
induced remission and could be tapered and
discontinued without relapse in 10 of the cases (43 %), and thus
was the sole agent used [
6, 8, 18–20, 24, 26–29
Second line therapy was initiated in the 4 cases (17 %) that
did not respond completely to prednisone and in the 9
cases where prednisone alone did not induce
permanent remission. In 3 of 4 cases not responding to
prednisone, the prednisone doses were adequate, however,
in 1 case the dosage was not mentioned. DMARDs
were attempted as steroid-sparing agents in 11 cases.
Mycophenolate mofetil was successful as a steroid-sparing
agent in 3 of the 5 cases in which it was used [
7, 9, 10, 14,
]. Azathioprine was a successful as a steroid sparing
agent in 2 of 4 cases in which it was used [
5, 15, 17, 25
while methotrexate was successful in 1 of 2 cases [
Because of disease relapse despite azathioprine, one
patient achieved clinical remission with 5 mg
prednisone after high doses induction of prednisone [
Rituximab was initiated in 4 cases [
8, 11, 13, 16
therapy refractory diseases leading to positive clinical
outcomes in all these cases. Two of these cases
initiated rituximab single therapy [
], in one case
methylprednisolone was combined with rituximab [
in another case prednisone 10 mg daily was used as
maintenance therapy beside rituximab [
] and cyclophosphamide [
] were both successfully
used in therapy refractory cases.
In this systematic search of the literature we describe 25
published cases of IgG4-RD in children. The cases
demonstrate different organ manifestations of the disease
with different clinical outcomes emphasizing the broad
clinical spectrum of this disease.
IgG4-RD is a rare and recently recognized
fibroinflammatory condition of which the diagnosis is often
delayed or unrecognized because of unawareness.
Generally it occurs in middle aged patients, more often in men
than women [
]. However, in this study we identified
more female patients than male patients. In children
IgG4-RD is even more uncommon and will subsequently
lead to significant delayed or unrecognized disease. All
cases identified with this systematic review have been
only recently published demonstrating that awareness is
increasing in pediatricians. One can postulate that the
average age of patients is lower than suggested [
may be more frequent in the pediatric age group than
these 25 published cases might suggest.
Symptoms and organ manifestation
The symptoms of IgG4-RD are variable and depend on the
affected organs. It can be localized almost everywhere
(Table 2). In adults, IgG4-RD mostly affects the orbit, the
salivary tract, the pancreas and the lymph nodes, however,
manifestations in almost every part of the human have been
]. In this study we have demonstrated a similar
distribution of disease localizations in children. As in adults,
most pediatric patients had orbital or pancreatic
localizations. Therefore, IgG4-RD in children apparently is the
same entity as in adults. In cases of unexplained
inflammatory conditions, especially when tumor-like abnormalities
are observed by physical examination or imaging studies in
the preferential localization of the disease (pancreas,
salivary glands, orbit, lymph nodes), one should rule out
IgG4RD. Furthermore, conditions previously called Mikulicz’ s
disease, sclerosing sialadenitis, inflammatory orbital
pseudotumor or any pseudotumor, a subset of idiopathic
retroperitoneal fibrosis and Riedel’s thyroiditis are now
mostly reclassified as IgG4-RD and should raise suspicion
for IgG4-RD [
The diagnosis of IgG4-RD can only be confirmed
histologically, the gold standard, while clinical symptoms,
serological and radiological findings could be supportive
to establish the diagnosis. The typical histological
abnormalities (Fig. 3), according to the Boston consensus [
are dense lymphoplasmacytic infiltrate, storiform fibrosis
and obliterative phlebitis. The ratio of IgG4/IgG positive
plasma cells in tissues should be greater than 0.4 and
the numbers of IgG4 positive plasma cells per high
Ig4-related lymphadenopathy of several lymph nodes
Other abdominal manifestations
Small bowel obstruction caused by peritoneal IgG4-RD
IgG4-RD of stomach with chronic ulcer
Erythematous, subcutaneous papules or nodules of IgG4 origin
Orbital and ophthalmic manifestation
Inflammatory pseudotumors of orbit
Retinopathy due to IgG4-RD with
Trigeminal and orbital nerve compression
Nasolacrimal duct obstruction
IgG4-related coronary artery disease
Salivary and lacrimal gland
Küttner's tumor or IgG4-related submandibular gland disease
IgG4-related fibrosing mediastinitis
Increased risk of malignancy: lung, colon
and especially MALT lymphoma.
power field (HPF) should be greater than the numbers
agreed in the consensus [
]. IgG4 positive plasma cells
in tissues could also be observed in several other
conditions without meeting the histological diagnostic criteria
for IgG4-RD. Therefore, alternative diagnosis such as
xanthogranulomatous disease, granulomatosis with
polyangiitis and sarcoidosis should be excluded before
obtaining the diagnosis IgG4-RD [
]. In current study,
almost all cases were histologically proven, except a case
of Riedel’s thyroiditis, which is recently been recognized
as a spectrum of IgG4-RD [
Serum IgG4 is elevated in most of the cases of
IgG4RD, but about 30 to 50 % of histologically confirmed
cases have normal levels of serum IgG4, which can lead
to falsely rejecting the diagnosis [
]. A similar
percentage of pediatric patients had elevated serum IgG4 levels
(70 %) to those reported in the adult population. In
general the specificity and positive predictive value of serum
IgG4 are low, but if elevated can be useful in monitoring
response to treatment [
]. Inflammatory biomarkers
such as erythrocyte sedimentation rate and C-reactive
protein might be elevated, but normal levels of these
biomarkers are frequently observed in IgG4-RD making
them less specific as biomarkers [
recently, serological studies of IgG4 positive circulating
plasmablasts have been shown to be superior to serum
IgG4 levels in IgG4-RD [
]. So far this technique has
not been widely introduced for clinical applications.
The pathogenesis of IgG4-RD is unclear. Generally
abundant serological T-helper cells 2 and regulatory T-cells are
observed. These are most probably induced by an antigen
triggering the immune system [
interleukin (IL)-4,5,10,13 and transforming growth factor
(TGF)beta have been assumed to activate B-cells, hence
producing IgG4 expressing B-cells and fibrosis [
]. The role of
IgG4 antibodies in the pathogenesis is unclear, but
because of characteristics of these antibodies [
most probably act as anti-inflammatory antibodies as
response to an unknown trigger (Fig. 4).
When untreated, IgG4-RD can cause irreversible organ
damage hence early and aggressive treatment is
]. Glucocorticoids are the first choice of the
treatment for the adults, mostly effective at a prednisone
dosage of 0.5 -1 mg/kg/day, adjusted according to
aggressive disease [
]. In the presented study prednisone
appeared first choice therapy for pediatric IgG4-RD.
There is no consensus on prednisone dosage in
pediatrics, but in general prednisone 1 to 2 mg/kg/day
should be appropriate. Prednisone can thereafter be
tapered according to individual response. Treatment with
prednisone is often rapidly effective, but this treatment
should be maintained for 2 to 4 weeks after initiation. In
the presented study prednisone was generally effective
first line therapy in 83 % of the cases. However, only in
43 % of the cases prednisone single therapy sufficed. The
rest of the cases required maintenance
(immunosuppressive) therapy. According to previous studies, especially
on adults, about 25 % of patients show relapse of the
disease despite prednisone maintenance therapy making
steroid sparing agents necessary [
]. MMF, azathioprine
and methotrexate were effective in about 50 % of the
cases in this study. The role of DMARDs in the
treatment of IgG4-RD is not yet clear and management of
this disease with these agents has not been outlined
]. Recently, increasing evidence for the efficacy of
rituximab treatment of IgG4-RD has been demonstrated
]. In this review four patients were treated with
rituximab leading to significant clinical outcomes in all cases.
We recommend rituximab as a strong alternative when
a patient is refractory to therapy. Intravenous or
subcutaneous immunoglobulin treatment has been
successfully used in other inflammatory or immune mediated
Fig. 4 Proposed mechanism of the formation of IgG4 antibodies by ‘’Fab-Arm” exchange. IgG4 antibodies continuously exchange half molecules
with other antibodies making them bivalent reactive antibodies with two different antigen-binding fragments. These antibodies are also unable
to activate the classical complement system and can bind to antigens. However, as a result of bivalent reactivity unable to form immune complexes.
Because of these characteristics the IgG4 antibodies are most probably anti-inflammatory agents rather than pro-inflammatory. Fab = antigen
diseases, but this therapy has not yet been applied in
Serum IgG4, when elevated, can be used in disease
activity monitoring after initiating treatment, however, the
role of serum IgG4 as disease activity marker has not yet
fully been outlined [
]. Studies should define the role of
serum IgG4 as disease marker, same applies to
circulating plasmablasts. Imaging studies, especially PET scan is
useful in disease monitoring. Studies have shown the
usefulness of FDG-PET/CT scan for diagnosis, staging
and the degree of organ involvement and monitoring of
therapy response, and this imaging method seems to
detect more lesions than conventional methods like
ultrasonography and CT [
In conclusion, IgG4-RD is a relatively new disease and
generally unknown to pediatricians. The results of this
study suggest that the average age of patients is lower
than suggested in the literature. Early recognition and
therapy are important to prevent serious and irreversible
organ damage. Treatment with prednisone is the first choice
for this disease, but maintenance therapy with DMARDs is
often required. Rituximab may be a good alternative in
therapy refractory disease. Further (epidemiological) studies
should confirm these preliminary conclusions. Moreover,
serological and histological studies and studies on treatment
of children with IgG4-RD are needed in order to confirm
the same results in children compared with previous studies
performed in adults.
Search terms used in the medical databases for the
literature search in this systematic review on IgG4-RD in
(‘immunoglobulin G4 related disease’/exp OR ‘Mikulicz
disease’/exp OR ((G4 OR igg4 OR ‘igg 4′ OR Mikulicz
OR kuttner OR riedel*) NEAR/3 (rd OR related OR
associat* OR autoimmun* OR disease* OR inflammat*
OR tumor* OR thyroidit*)):ab,ti) AND (child/exp OR
newborn/exp OR adolescent/exp OR adolescence/exp
OR ‘child behavior’/de OR ‘child parent relation’/de OR
pediatrics/exp OR childhood/exp OR ‘child nutrition’/de
OR ‘infant nutrition’/exp OR ‘child welfare’/de OR ‘child
abuse’/de OR ‘child advocacy’/de OR ‘child
development’/de OR ‘child growth’/de OR ‘child health’/de OR
‘child health care’/exp OR ‘child care’/exp OR ‘childhood
disease’/exp OR ‘child death’/de OR ‘child psychiatry’/de
OR ‘child psychology’/de OR ‘pediatric ward’/de OR
‘pediatric hospital’/de OR ‘pediatric nursing’/exp OR
‘pediatric anesthesia’/exp OR ‘pediatric surgery’/exp OR
(adolescen* OR infan* OR newborn* OR (new NEXT/1
born*) OR baby OR babies OR neonat* OR child* OR
kid OR kids OR toddler* OR teen* OR boy* OR girl* OR
minors OR underag* OR (under NEXT/1 (age* OR
aging)) OR juvenil* OR youth* OR kindergar* OR puber*
OR pubescen* OR prepubescen* OR prepubert* OR
pediatric* OR paediatric* OR school* OR preschool* OR
highschool* OR picu OR nicu OR picus OR nicus):ab,ti)
(Mikulicz’ Disease/OR ((G4 OR igg4 OR igg 4 OR Mikulicz
OR kuttner OR riedel*) ADJ3 (rd OR related OR associat*
OR autoimmun* OR disease* OR inflammat* OR tumor*
OR thyroidit*)).ab,ti.) AND (exp child/OR exp infant/OR
adolescent/OR exp pediatrics/OR exp Child Health
Services/OR Hospitals, Pediatric/OR (adolescen* OR infan*
OR newborn* OR (new ADJ born*) OR baby OR babies
OR neonat* OR child* OR kid OR kids OR toddler* OR
teen* OR boy* OR girl* OR minors OR underag* OR
(under ADJ (age* OR aging)) OR juvenil* OR youth* OR
kindergar* OR puber* OR pubescen* OR prepubescen* OR
prepubert* OR pediatric* OR paediatric* OR school* OR
preschool* OR highschool*).ab,ti.)
(((G4 OR igg4 OR ‘igg 4’ OR Mikulicz OR kuttner OR
riedel*) NEAR/3 (rd OR related OR associat* OR
autoimmun* OR disease* OR inflammat* OR tumor*
OR thyroidit*)):ab,ti) AND ((adolescen* OR infan* OR
newborn* OR (new NEXT/1 born*) OR baby OR babies
OR neonat* OR child* OR kid OR kids OR toddler* OR
teen* OR boy* OR girl* OR minors OR underag* OR
(under NEXT/1 (age* OR aging)) OR juvenil* OR
youth* OR kindergar* OR puber* OR pubescen* OR
prepubescen* OR prepubert* OR pediatric* OR
paediatric* OR school* OR preschool* OR highschool* OR
picu OR nicu OR picus OR nicus):ab,ti)
TS = ((((G4 OR igg4 OR “igg 4” OR Mikulicz OR kuttner
OR riedel*) NEAR/2 (rd OR related OR associat* OR
autoimmun* OR disease* OR inflammat* OR tumor* OR
thyroidit*))) AND ((adolescen* OR infan* OR newborn*
OR (new NEAR/1 born*) OR baby OR babies OR
neonat* OR child* OR kid OR kids OR toddler* OR teen*
OR boy* OR girl* OR minors OR underag* OR (under
NEAR/1 (age* OR aging)) OR juvenil* OR youth* OR
kindergar* OR puber* OR pubescen* OR prepubescen*
OR prepubert* OR pediatric* OR paediatric* OR school*
OR preschool* OR highschool* OR picu OR nicu OR
picus OR nicus)))
PubMed publisher (33)
(Mikulicz’ Disease[mh] OR ((G4[tiab] OR igg4[tiab] OR
“igg 4”[tiab] OR Mikulicz[tiab] OR kuttner[tiab] OR
riedel*[tiab]) AND (related[tiab] OR associat*[tiab] OR
autoimmun*[tiab] OR disease*[tiab] OR inflammat*[tiab]
OR tumor*[tiab] OR thyroidit*[tiab]))) AND (child[mh]
OR infant[mh] OR adolescent[mh] OR pediatrics[mh]
OR Child Health Services[mh] OR Hospitals,
Pediatric[mh] OR (adolescen*[tiab] OR infan*[tiab] OR
newborn*[tiab] OR new born*[tiab] OR baby OR babies OR
neonat*[tiab] OR child*[tiab] OR kid OR kids OR
toddler*[tiab] OR teen*[tiab] OR boy*[tiab] OR girl*[tiab]
OR minors OR underag*[tiab] OR under age*[tiab] OR
under aging*[tiab] OR juvenil*[tiab] OR youth*[tiab] OR
kindergar*[tiab] OR puber*[tiab] OR pubescen*[tiab] OR
prepubescen*[tiab] OR prepubert*[tiab] OR
pediatric*[tiab] OR paediatric*[tiab] OR school*[tiab] OR
preschool*[tiab] OR highschool*[tiab])) AND (publisher[sb]
OR inprocess [sb])
Google scholar (100)
DMARDs: disease modifying antirheumatic drugs; Fab: antigen binding
fragment; HE: hematoxylin and Eosin; HPF: high-power field;
IgG4RD: immunoglobulin G4-related disease.
The authors declare that they have no competing interests.
FK conceptualized and designed the study, formulated search terms,
reviewed and extracted articles for the study, reviewed the articles, designed
the tables and the figures, drafted the initial manuscript and after final
approval of all authors, finalized the manuscript as submitted. WB formulated
the search terms, conducted the search using the search terms and drafted
the initial method section of the manuscript, and approved the final
manuscript as submitted. LW (independently) reviewed and extracted the
articles for the study, studied the articles and drafted the initial introduction
of the manuscript, and approved the final manuscript as submitted. JvL
conceptualized and designed the study, studied the included articles and
delivered suggestions, studied the drafted manuscript and delivered
suggestions, and approved the final manuscript as submitted. JL studied the
included articles and delivered suggestions and studied the drafted
manuscript. He delivered suggestions from de pediatric perspective, and
approved the final manuscript as submitted. RV studied the articles and
delivered his opinion on the histological diagnosis of IgG4-RD in the extracted
case reports. Further, he drafted the initial section about the histology in the
manuscript and arranged histology figures with description, and approved the
final manuscript as submitted. MvH conceptualized and designed the study,
studied the included articles and delivered his suggestions and studied the
drafted manuscript and added his comments and suggestions, and approved
the final manuscript as submitted.
This study was supported by grant 3.3.0 from the Combined Ocular Research
The authors have indicated that they have no financial relationships relevant
to this article to disclosure.
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