Reports
Other than these Saudi Arabian children, there is 1 report of
LRPAP1-related high myopia in a Chinese 5-year-old boy homo-
zygous for the LRPAP1 mutation c.199delC (p.Gln67Serfs*8).3
Axial lengths were 32.59 mm and 32.24 mm, and visual acuities
were not provided. That patient was reported to have myopia
of
8.00, but this is inconsistent with his axial lengths of >30
mm. It is also inconsistent with our experience, as we have
found recessive LRPAP1 mutations typically to be associated
with cycloplegic refraction greater than
20, ranging from
17
to
32 with a median of
24 in our series.
The clinical and biometric features we describe in this report
characterize LRPAP1-related high myopia and should raise suspi-
cion for mutations in the gene. Other than dominant monogenic
forms of nonsyndromic high myopia (mutations in ZNF644, SCO2,
SLC39A5, P4HA2, or CCDC111), the majority of which have not
been carefully phenotyped to date, the other major monogenic
cause of high myopia in children is vitreoretinopathy.4 There are
several recognized forms of vitreoretinopathy associated with
high myopia.4 Most of these are autosomal dominant and can be
differentiated from LRPAP1-related high myopia by the presence
of vitreopathy or extraocular features. The most common
vitreoretinopathy associated with high myopia is Stickler
syndrome, characterized by midfacial hypoplasia, hearing loss,
arthropathy, juvenile lens opacity, and a propensity to retinal
detachment independent of the degree of myopia.4 Worldwide,
autosomal dominant mutations in collagen type II alpha 1
(OMIM 120140, COL2A1) are the most common cause, but
mutations in other genes also can cause the phenotype.4 Some
patients with certain COL2A1 mutations can have an ocular
phenotype only.4 A less common but even more distinctive
vitreoretinopathy that is associated with high myopia is
Knobloch syndrome, characterized by occipital defect, high
myopia, and a distinctive vitreoretinopathy that includes smooth
irides, juvenile lens opacities, ectopia lentis, and a propensity to
retinal detachment independent of the degree of myopia.5
Recessive mutations in collagen type XVIII alpha 1 (OMIM
*120328, COL18A1) are the only known cause, and the
syndrome can be diagnosed by the presence of the
pathognomonic eye phenotype alone.5 As is the case for Stickler
syndrome, some patients with Knobloch syndrome have the
ocular phenotype only without extraocular features.5
ARIF O. KHAN, MD1,2
MOHAMMED A. ALDAHMESH, PHD2
FOWZAN S. ALKURAYA, MD2,3
1 keratitis, and the majority (74%) had a family history of atopy and
Division of Pediatric Ophthalmology, King Khaled Eye Specialist
Hospital, Riyadh, Saudi Arabia; 2Department of Genetics, King Faisal
Specialist Hospital and Research Center, Riyadh, Saudi Arabia;
3
Department of Anatomy and Cell Biology, College of Medicine,
Alfaisal University, Riyadh, Saudi Arabia
Financial Disclosure(s): The authors have no proprietary or commercial
interest in any materials discussed in this article.
Funded in part by a King Salman Center for Disability Research grant
(F.S.A.) and a King Abdulaziz City for Science and Technology Grant
13-BIO1113-20 (F.S.A.).
Author Contributions:
Conception and design: Khan, Aldahmesh, Alkuraya
Data collection: Khan, Aldahmesh, Alkuraya
Analysis and interpretation: Khan, Aldahmesh, Alkuraya
Overall responsibility: Khan, Aldahmesh, Alkuraya
Correspondence:
Arif O. Khan, MD, Division of Pediatric Ophthalmology, King
Khaled Eye Specialist Hospital, PO Box 7191, Riyadh 11462, Saudi
Arabia. E-mail: arif.khan@mssm.edu.
References
1. Holden B, Sankaridurg P, Smith E, et al. Myopia, an
underrated global challenge to vision: where the current
data takes us on myopia control. Eye (Lond) 2014;28:
1426.
2. Aldahmesh MA, Khan AO, Alkuraya H, et al. Mutations in
LRPAP1 are associated with severe myopia in humans. Am J
Hum Genet 2013;93:31320.
3. Jiang D, Li J, Xiao X, et al. Detection of mutations in LRPAP1,
CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 in 298 fam-
ilies with early-onset high myopia by exome sequencing. Invest
Ophthalmol Vis Sci 2014;56:33945.
4. Edwards AO. Clinical features of the congenital vitreo-
retinopathies. Eye (Lond) 2008;22:123342.
5. Khan AO, Aldahmesh MA, Mohamed JY, et al. The distinct
ophthalmic phenotype of Knobloch syndrome in children. Br J
Ophthalmol 2012;96:8905.
Atopic Keratoconjunctivitis in
Children: Clinical Features and
Diagnosis
Distinguishing between vernal keratoconjunctivitis (VKC) and
atopic keratoconjunctivitis (AKC) can be challenging. Historically,
AKC is rarely recognized as a diagnostic entity before puberty and
is thought to occur predominantly in adults. If a young patient were
to present with AKC-like symptoms and atopic dermatitis, they
might be diagnosed with VKC.1 The aim of this report was to
establish guidelines for distinguishing diagnosis between AKC
and VKC.
We conducted a case survey of 23 pediatric patients with severe
keratoconjunctivitis and atopic dermatitis who presented at 4 cen-
ters between 2011 and 2013. Mean ages at onset of symptoms and
at initial presentation to an ophthalmologist were 5.2 and 8.1 years,
respectively. All patients suffered from eczema and conjunctivitis/
were affected by asthma and allergic rhinitis. The clinical features
of patients with AKC are presented in Table 1 and Figure 1
(available at www.aaojournal.org). The most prevalent clinical
features within this study were conjunctival hyperemia and
eczema, both of which were reported in 96% of patients. Other
clinical features include follicles, keratitis, and thickened dry
skin, which were present in 83% of patients. Papillae,
DennieeMorgan folds of the lower lid and blepharitis were
present in 65% of patients. Other clinical features such as giant
papillae (>1 mm diameter), DennieeMorgan double folds of the
upper lid, pseudoptosis, inltration of the inferior conjunctiva,
HornereTrantas dots, and madarosis were present in 39% of
patients.
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 Ophthalmology Volume 123, Number 2, February 2016

Table 1. Clinical Features of Patients (n 23) with Atopic AKC-related clinical features and the absence of VKC-related
Keratoconjunctivitis clinical features, in combination with a history of eczema and
conjunctivitis/keratitis, may promote accurate diagnosis of AKC in
Clinical Features Present, n (%) children. Atopic keratoconjunctivitis and VKC differ in relation to
Conjunctival hyperemia 22 (96) specic treatment needs. The dermatologic manifestations of AKC
Follicles 19 (83) need to be treated with emollients and demulcents and, if neces-
Papillae upper/lower 19 (83) sary, corticosteroids. Furthermore, although immunomodulators
Giant papillae (> 1 mm diameter) 14 (61) such as cyclosporine and tacrolimus are effective treatments for
HornereTrantas dots (limbus) 9 (39)
Swelling of the limbus 9 (39)
both severe AKC and VKC, lower concentrations of these drugs
Chemosis (conjunctival) 6 (26) may be required in patients with AKC.5 These differences in the
Limbaldneovascularization/corneal opacication 11 (48) optimal treatment of AKC and VKC highlight the importance of
Keratitis (supercial punctate keratitis, shield ulcer, 20 (87) early and accurate diagnosis, in informing effective treatment
ulcerations and corneal erosions) strategies and improving patient outcomes.
Inltration of inferior conjunctiva 12 (52)
DennieeMorgan
Double fold lower lid 18 (78) DOMINIQUE BRMOND-GIGNAC, MD, PHD1,2
Double fold upper lid 13 (57) KEN K. NISCHAL, MD, PHD3,4
Pseudoptosis 12 (52)
Facial cutaneous ssures (ears and canthus) 15 (65)
BRUNO MORTEMOUSQUE, MD, PHD5
Anterior blepharitis 15 (65) EVA GAJDOSOVA, MD, PHD3
Posterior blepharitis 15 (65) DAVID B. GRANET, MD, PHD6
Eczema, thickened and dry eyelid 22 (96) FRDRIC CHIAMBARETTA, MD, PHD7
Thickened and dry skin 1
Facial 20 (87) Pediatric Ophthalmology Department, University Hospital Necker-
Body 19 (83) Enfants Malades, Paris, France; 2CNRS Unit FR3636, Paris V
Madarosis 10 (44) University, Paris, France; 3Clinical and Academic Department of
Ophthalmology, Great Ormond Street Hospital for Children, London,
UK; 4Pediatric Ophthalmology, Strabismus and Adult Motility UPMC
Eye Center, Childrens Hospital of Pittsburgh, Pittsburgh,
Pennsylvania; 5Ophthalmology Department, University Hospital of
In this report, AKC in children is dened as the presence of Pontchaillou, Rennes, France; 6Ratner Childrens Eye Center and
severe allergic conjunctivitis with atopic dermatitis that is diag- Shiley Eye Center, University of California, San Diego, California;
nosed before 16 years of age. This may be accompanied by the 7
Ophthalmology Department, University Hospital Gabriel Montpied,
presence or absence of the following clinical features: conjunctival Clermont-Ferrand, France
hyperemia with eczema, madarosis, and blepharitis, with the
absence of HornereTrantas dots and giant papillae. The clinical Financial Disclosure(s): The authors have made the following disclo-
features described here may be used to dene a grading system for sures: Allergan, Inc. (Irvine, CA) funded medical writing support but
the identication of AKC in children. No single clinical feature had no role in the design or conduct of this research.
viewed in isolation can accurately differentiate between AKC and
VKC. Author Contributions:
Vernal keratoconjunctivitis is a rare, yet severe, form of allergic Conception and design: Brmond-Gignac, Nischal, Mortemousque,
Gajdosova, Granet, Chiambaretta
conjunctivitis, estimated to affect 3.2 out of every 10 000 in-
Analysis and interpretation: Brmond-Gignac, Nischal, Mortemousque,
habitants in western Europe.2 Vernal keratoconjunctivitis generally Gajdosova, Granet, Chiambaretta
ends at puberty; however, in some cases, it is thought that VKC Data collection: Brmond-Gignac, Nischal, Mortemousque, Gajdosova,
may evolve into AKC in adulthood.2 In the absence of typical Granet, Chiambaretta
clinical signs of VKC, a child with atopic dermatitis may be Overall responsibility: Brmond-Gignac, Nischal, Mortemousque,
diagnosed with AKC and not VKC.1 Vernal keratoconjunctivitis Gajdosova, Granet, Chiambaretta
presents with highly specic symptoms, such as photophobia,
tearing, pseudoptosis, thick mucus discharge, and shield ulcers.2 Correspondence:
Children with VKC may present with atopic dermatitis; however, Dominique Brmond-Gignac, Pediatric Ophthalmology Department,
it is not a prerequisite for diagnosis.1 In contrast, evidence of AP-HP, University Hospital Necker-Enfants Malades, 149 Rue de
Svres, 75015 Paris, France. E-mail: dominique.bremond@nck.aphp.fr.
atopic dermatitis must be present for a diagnosis of AKC to be
made.1
In accordance with the ndings reported herein, AKC in chil- References
dren may be more prevalent than initially believed; in an epide-
miologic study of 134 patients with allergic conjunctivitis, 55% of
patients with AKC reported an onset of symptoms before 10 years 1. Calonge M, Herreras JM. Clinical grading of atopic kera-
tonconjunctivitis. Curr Opin Allergy Clin Immunol 2007;7:4425.
of age.3 In Japanese populations, VKC cases with any history of
2. Bremond-Gignac D, Donadieu J, Leonardi A, et al. Prevalence
atopic dermatitis is diagnosed as AKC, regardless of patient of vernal keratoconjunctivitis: a rare disease? Br J Ophthalmol
age.4 In Europe, these cases would only be diagnosed as AKC if 2008;92:1097102.
the symptoms continued past puberty and occurred concurrently 3. Belfort R, Marbeck P, Hsu C, et al. Epidemiological study of
with keratoconjunctivitis.1 The multifactorial assessment of key 134 subjects with allergic conjunctivitis. Acta Ophthalmol
clinical signs presented, taking into consideration the presence of Scand 2000;78:3840.

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 Reports

4. Ebihara N, Ohashi Y, Uchio E, et al. A large prospective
observational study of novel cyclosporine 0.1%
aqueous ophthalmic solution in the treatment of severe allergic
conjunctivitis. J Ocul Pharmacol Ther 2009;25:36572.
5. Erdinest N, Solomon A. Topical immunomodulators in the
management of allergic eye diseases. Curr Opin Allergy Clin
Immunol 2014;14:45763.
In Vivo Characterization of
Retinal Microvascular Network in
Multiple Sclerosis
Multiple sclerosis (MS) is an inammatory demyelinating disorder
of the central nervous system characterized by progressive neuro-
degeneration. Current management aims to reduce the inamma-
tion through immunomodulation. However, the effectiveness of
these treatments for preventing degeneration is unclear. Vascular
alterations, which may be caused by inammatory cerebral endo-
theliopathy,1 could play a role in neurodegeneration. Indeed,
increased incidence of ischemic stroke and diffuse hypoperfusion
in normal-appearing white and gray matter have been reported in
MS patients.1 Thus, studying cerebral microvascular changes may
reveal the underlying pathophysiology that connects inammation
and neurodegeneration. Because the retina is an extension of the
brain, the cerebral and retinal vasculature shares similar anatomic
and physiologic features. Furthermore, thinning of the retinal
nerve ber layer (RNFL) and of the ganglion layer are ocular
biomarkers of neurodegeneration in MS.2 Therefore,
characterizing retinal microvascular changes in MS may help to
determine the role of vascular dysfunction in neurodegeneration.
Direct measurement of the retinal vascular function can occur
through the transparent ocular media. We have developed a
method to quantitatively analyze noninvasive capillary perfusion
maps (nCPMs) obtained by the Retinal Function Imager (Optical
Imaging Ltd, Rehovot, Israel).3 This study was performed to
determine the macular microvascular network changes in patients
with relapsing and remitting MS.
We recruited 17 relapsing and remitting MS patients and
17 age- and gender-matched controls (Table 1; available at
www.aaojournal.org). Subjects with high refractive errors of
more than 6.0 or
6.0 diopters (owing to the limit of the
imaging device), with any history of eye disease, or have been
on systemic corticosteroids within 3 months before the study
were excluded. Patients with a history of cerebral cardiovascular
disease, hypertension, diabetes, or kidney disease were also
excluded. The institutional review board approved this study and
every subject signed informed consent. Each MS patient had an
ophthalmic examination, including optical coherence tomography
imaging (Cirrus, Carl Zeiss Meditec, Dublin, CA) of the
peripapillary RNFL (200200 scan protocol). The nCPMs at

Figure 2. Retinal microvessel network analysis in patients with multiple sclerosis (MS) and controls. The microvessel fractal dimension (Dbox) in the fovea-
centered, circular zone (diameter 3.6 mm) was signicantly lower in MS patients in comparison with controls (A). Among the quadrantal zones, the Dbox
in the superior zone (B) was signicantly lower in the MS group (P 0.02). Among the annular zones (C), the Dbox of MS groups was signicantly lower in
the 1.1- to 1.6-mm and 2.1- to 3.6-mm annular zones in comparison to the control group in the same zones (P < 0.05). The area under the curve of the
receiver operator curve (D) was 0.73 (P 0.03) with a cutoff value of 1.5 for Dbox in the 2.1- to 3.6-mm annular zone. This provides a sensitivity of 77% and
a specicity of 70% for predicting MS microvasculature impairment. SD standard deviation; SE standard error.

437