Congenital Aniridia: Clinical Guidelines

List of Abbreviations

AK — aniridic keratopathy

AFS — aniridic fibrosis syndrome

CA — congenital aniridia

IOP – intraocular pressure

AQH – aqueous humor

CC — congenital cataract

DD — disc diameter

DNA – deoxyribonucleic acid

ONH – optic nerve head

DL-TSCC — diode-laser transscleral contact cyclophotocoagulation

VEP – visual evoked potentials

IOL — posterior chamber intraocular lens, pseudophakic***

ICD-10 – International Classification of Diseases 10th Revision

LSCD – limbal stem cell deficiency

NRR – neuroretinal rim

OCT – optical coherence tomography (optical examination of the retina using a computer analyzer, optical examination of the anterior segment of the eye using a computer analyzer, optical examination of the posterior segment of the eye using a computer analyzer)

SP – static perimetry

STE – trabeculectomy (sinustrabeculectomy)

ACA – anterior chamber angle

CCDS – ciliochoroidal detachment

TENS – transcutaneous electrical stimulation

ERG – electroretinography

EP – electrophysiological studies

C/D – optic disc cup-to-disc ratio

Terms and Definitions

Congenital aniridia (CA) – a congenital genetic complex disease manifested by complete or partial hypoplasia of the iris of the eye and characterized by pathological changes in all ocular structures.

Foveal and optic nerve head (ONH) hypoplasia – absence of a properly formed retina in the fovea and ONH area (underdevelopment of these structures), characterized by the absence of foveal depression of the macular contour and a reduction in ONH dimensions.

Goniodysgenesis – congenital anomalies of the anterior chamber angle (ACA) and the drainage system of the eye resulting from a delay in the development and differentiation of these structures.

Aniridic keratopathy – impairment of corneal transparency with the loss of epithelial cells, which may be accompanied by inflammation with immune cell infiltration, vascularization, and chronic progressive opacification, occurring against the background of primary limbal stem cell deficiency (LSCD) and gradually progressing from the periphery to the center.

Aniridic fibrotic syndrome (AFS) – a complication that impairs visual functions, described exclusively in association with CA. It represents a non-inflammatory fibrous scarring process associated with the development of hypotony and phthisis bulbi [40], occurring following surgical interventions.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Congenital aniridia (OMIM #106210) is a rare genetic developmental defect of the eye, externally manifested by complete or partial hypoplasia of the iris and characterized by pathological changes in all structures of the eye. The disease is inherited in an autosomal dominant manner with complete penetrance and variable expressivity [1, 2, 3].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The etiology of CA, as an independent nosological entity, is based on PAX6 gene mutations in 90% of cases (OMIM *607108), including chromosomal rearrangements of the 11p13 region involving the PAX6 locus or, in 5% of cases, a distant cis-regulatory region controlling PAX6 gene expression [1]. In 5% of cases, the development of CA is associated with mutations in the PITX2 (OMIM *601542), FOXC1 (OMIM *601090), FOXE3 (OMIM *601094), CYP1B1 (OMIM *601771), PITX3 (OMIM *602669), FOXE3 (OMIM *601094), FOXC1 (OMIM *601090), and PXDN (OMIM *605158) genes [2, 4]. The pathogenesis of CA, clinical manifestations, and the severity of damage to various ocular structures are determined by genetic heterogeneity, including both locus heterogeneity (mutations in different genes) and allelic heterogeneity (types of mutations). A major role in shaping the clinical picture is played by the genetic background, i.e., the set and combination of genetic variants that lead to reduced adaptation [5].

Currently, there is no single unified classification of CA. In 1996, A. Churchill proposed classifying CA from the perspective of etiopathogenesis and clinical profile. According to this classification, CA belongs to the group of mesenchymal dysgeneses of the eye (OMIM phenotypic series #107250) [6]. Subsequently, following the discovery of genes involved in the etiopathogenesis of anterior segment dysgeneses, 8 clinical and genetic types associated with mutations in various genes (PITX3 [OMIM *602669], FOXE3 [OMIM *601094], FOXC1 [OMIM *601090], PITX2 [OMIM *601542], CYP1B1 [OMIM *601771], PXDN [OMIM *605158]) were identified within this classification [7, 8]. In addition, other conditions caused by mutations in the same genes can be attributed to this group: Axenfeld–Rieger syndrome group anomalies (OMIM #602482), type I and II iridogoniodysgeneses (OMIM #601631 and OMIM #137600), and Peter's anomaly (OMIM #604229) [9].

Based on etiopathogenesis, the clinical picture of CA, the establishment of the primary molecular nature, and literature data, it is currently advisable to systemize the anomaly under consideration as follows.

1. Isolated congenital aniridia (or non-syndromic congenital aniridia). In 75% of CA cases, it develops as an isolated ocular anomaly involving only the visual analyzer without changes in other organ systems [10]. According to the OMIM database, three forms are distinguished: AN1 (OMIM #106210), AN2 (OMIM #617141), and AN3 (OMIM #617142). They are associated respectively with the PAX6, ELP4 (OMIM *606985) [11], and TRIM44 (OMIM *612298) genes. However, a decrease or alteration in PAX6 gene function remains the sole known cause of CA. In addition to CA, this group includes anomalies belonging to ophthalmological syndromes: Axenfeld–Rieger (OMIM #602482), iridogoniodysgenesis type I and II (OMIM #601631 and OMIM #137600), Peter's anomaly (OMIM #604229), and certain others [9].

2. Aniridia as part of a hereditary syndrome symptom complex. In 25% of cases, CA is a symptom of a hereditary syndromic pathology affecting, in accordance with embryogenesis, the neurological, endocrine, musculoskeletal, and other systems, either in combination with each other or separately. Hereditary syndromes with multi-organ involvement and congenital iris anomalies occur in approximately 12% of cases. This group of diseases is associated with mutations and chromosomal rearrangements involving both the PAX6 gene locus [12, 13] and other genes (up to 5%) [2, 4, 14, 15]. The primary syndrome of this group, accounting for more than half of all cases of syndromic CA and 2.5–13% of all cases of isolated iris anomaly, is the WAGR spectrum (syndrome) (OMIM #194072), which is characterized by four clinical features: Wilms tumor (W), congenital aniridia (A), genitourinary anomalies (G), and intellectual disability / psychomotor retardation (R). The etiology of the WAGR spectrum is associated with deletions of varying length in the telomeric part of the 11p13 chromosomal region (hg19: chr11:31,000,001–36,400,000), simultaneously encompassing the PAX6 and WT1 genes, identified in the literature as the WAGR region [1, 12, 16].

In addition to the WAGR spectrum, congenital iris anomaly has been described as part of Gillespie syndrome (OMIM #206700), which is characterized by partial iris hypoplasia, intellectual disability, cerebellar ataxia, and cerebellar hypoplasia. An association with the 11p13 locus has been identified in only three cases [17, 18]. In 2016, the genetic cause of autosomal dominant Gillespie syndrome was discovered to be the ITPR1 gene (OMIM *147265) [19, 20].

CA in combination with currently known syndromes and as part of certain multiple congenital malformations has been described in isolated cases with mutations in the FAM111A (OMIM *615292), PORCN (OMIM *300651), and BBS1 (OMIM *209901) genes [21], as well as in chromosomal syndromes 22q11 [22] and ring chromosome 6 [23, 24, 25].

In conclusion of this section, it should be noted that advances in molecular biology have significantly altered our initial perception of etiopathogenesis, the clinical picture, and the possibilities for therapeutic and rehabilitative measures. This process is only gaining momentum and suggests the possibility of further deciphering the action of genes and their influence on pathogenetic mechanisms.

1.3 Epidemiology of the Disease or Condition

According to the database of rare and orphan diseases, the prevalence of isolated congenital aniridia (ORPHA:250923) is 1–9 per 100,000 [26].

According to literature data, the incidence of CA varies from 1:50,000 to 1:100,000 newborns [27–29]. The ratio of familial to isolated (sporadic) cases differs according to various authors: from 2:1 [2, 14, 30] to 1:2 [4, 31].

1.4 Features of Coding the Disease or Condition

Congenital malformations of the anterior segment of the eye (Q13)

Q13.1 – Aniridia.

1.5 Classification of the disease or condition

clinical presentation of CA;

clinical correlations with PAX6 mutation types;

clinical presentation of glaucoma in CA;

clinical presentation of cataract in CA;

clinical presentation of foveal and ONH hypoplasia in CA

1.6 Clinical presentation of the disease or condition

Patients and parents rarely present with complaints. Symptoms are mostly detected by pediatricians during physical examinations. When the iris is minimally involved in the pathological process, the disease is diagnosed during routine screening by an ophthalmologist. The extent of the iris defect varies from complete absence to minor hypoplasia. With a mild degree of expression, pupil size may be normal; however, alterations in iris structure may be observed during gonioscopy (see section 2.3). Other iris changes are characterized by partial defects in the form of an atypical coloboma, eccentric pupil, polycoria, or iris ectropion.

The panocular nature of damage, in addition to the iris defect, is characterized by keratopathy, glaucoma, cataracts, foveal and ONH hypoplasia, microphthalmos, and microcornea [5].

Corneal changes in CA

Aniridic keratopathy (AK) is one of the most frequent complications of aniridia, leading to a significant decrease in visual functions and discomfort. In most studies, the incidence of visible corneal changes is 80-90%. In childhood, the initial stages of AK prevail in 85% of cases [32].

The cause of AK is associated with limbal stem cell deficiency [10] and alteration of the limbal microenvironment due to a mutation in the PAX6 gene [33]. The slow progression of AK is accompanied by centripetal growth of the conjunctival pannus, neovascularization, and the appearance of fibrous areas involving the corneal epithelium and its anterior stroma. It has been established that the AK process develops in stages, gradually progressing from the corneal periphery to the center.

Corneal changes in AK involve more than just its epithelial layers. Abnormal development of the epithelial basement membrane and Bowman's membrane, as well as an increase in corneal stromal thickness, have been noted [31, 34-36, 37, 38]. At the same time, morphological changes do not affect Descemet's membrane and endothelial cells [39].

Iris changes in aniridia:

• complete absence of the iris — gonioscopy always reveals rudimentary iris tissue;

• partial absence of the iris;

• atypical coloboma;

• ectropion of the vascular network.

Lens opacities develop in 50-85% of patients with aniridia.

Clinical features of cataract in aniridia:

In childhood, cataractous opacities are predominantly congenital, accounting for 44-67% of cases [29, 32].

• congenital cataract is most commonly manifested as anterior and posterior polar cataracts without signs of progression [32];

• lens subluxation, which is a manifestation of insufficient stability of the zonular apparatus.

Depending on the severity of aniridia and the state of the zonules of Zinn, lens subluxation may be diagnosed, with characteristic ectopia into the upper half.

Clinical features of glaucoma in aniridia:

The most frequent concomitant manifestation of aniridia is glaucoma, which in most cases manifests in childhood and adolescence [24, 32, 40]. Intraocular fluid retention during the glaucomatous process in aniridia is caused by the presence of various forms of goniodysgenesis, including closure of the iridocorneal angle due to iridocorneal synechiae, as well as tractional tension of rudimentary iris tissue remnants over the trabecular meshwork, and defects in the trabecular meshwork itself. The gonioscopic picture demonstrates the presence of thin strands, the contraction of which leads to closure of the iridocorneal angle.

Clinical features of foveal and optic disc hypoplasia in aniridia:

Children with aniridia are characterized by varying degrees of foveal hypoplasia, which causes nystagmus due to sensory deprivation and congenital reduction of visual acuity (0.1 with correction). The frequency of foveal hypoplasia manifestations in patients with aniridia ranges from 50 to 84%. In 1/3 of cases, aniridia is accompanied by delayed visual maturation (DVM), which is a slowdown in the ability to develop gaze fixation during the first three months of life [5]. Compared to foveal hypoplasia, optic disc hypoplasia is much less common and is noted in 10.7-23% of patients [32, 41].

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of aniridia is established based on anamnestic data, the results of a clinical ophthalmologic examination—which includes a set of standard and highly informative additional diagnostic methods—and the results of molecular genetic testing (Table 1) in accordance with the developed algorithm (Appendix B) [42]. A complete ophthalmologic examination includes visometry, tonometry, gonioscopy, ocular biomicroscopy, ophthalmoscopy, measurement of central corneal thickness, optical coherence tomography (OCT) of the macular area and optic disc, and/or visual examination using a slit lamp with a detailed, comprehensive description. Photographic documentation of ocular manifestations is performed. In some patients, however, fundus examination is impossible (due to opacity of the optical media caused by central corneal opacity and lens changes) or limited by pronounced nystagmus. Additional complications involving the nervous system, kidneys, endocrine and other organ systems are noted. A questionnaire to be completed by the geneticist and ophthalmologist is provided in Appendix A3.

Table 1. Examination methods

In children with aniridia presenting with early-onset glaucoma and the clinical picture of classic hydrophthalmos, diagnosing glaucoma is not particularly difficult. With later onset, it can be challenging due to the absence or mild expression of characteristic symptoms, as well as a protracted pathological process over time.

Early diagnosis aims to detect signs of eye enlargement caused by elevated intraocular pressure (IOP), initial manifestations of atrophy in the optic disc, and the retinal nerve fiber layer. Establishing an early diagnosis of glaucoma must be based on a comprehensive data analysis, taking into account the asymmetric nature of clinical and morphofunctional characteristics of fellow eyes.

Detection of lens opacities (cataracts) is uncomplicated and is usually diagnosed during ocular biomicroscopy.

2.1 Complaints and Anamnesis

Comments: All children must be examined by a pediatrician, neurologist, pediatric cardiologist, geneticist, and, if necessary, other specialists for somatic pathology. Gathering information about the early postnatal period: frequency and severity of infectious diseases, chronic pathology, allergic reactions. Identifying possible causes and predisposing factors of the disease ( intrauterine infections, nutritional factors, etc.) by reviewing the mother's health status and obstetric-gynecological history. If a child with aniridia has glaucoma, a targeted analysis of the onset time of glaucoma signs is an important aspect of interviewing the parents.

2.2 Physical Examination

Physical examination is uninformative.

2.3 Laboratory Diagnostics

Comments: DNA extraction from peripheral blood leukocytes of patients collected in an EDTA tube ((S01XA05)) is carried out according to one of the standard DNA purification protocols. Urine and buccal epithelial samples are used to analyze parental mosaicism for the mutation detected in the proband. For karyotyping and in situ hybridization (FISH) from blood collected in a sodium heparin tube**, a nuclear suspension is prepared.

Comments: If large deletions are detected, genotyping of affected families using several microsatellite markers of chromosome 11 is performed for validation.

If large deletions involving the WT1 gene are detected, fluorescence in situ hybridization (FISH) with a WT1 gene-specific probe is performed to validate the hemizygous state of the locus in the proband. Such patients are given a presumptive diagnosis of WAGR spectrum and recommendations for lifelong follow-up by a pediatric oncologist up to 8 years of age.

In probands with detected large chromosomal deletions, karyotyping is mandatory to establish the cause of the chromosomal imbalance: a simple interstitial deletion 11p13, or a chromosomal inversion or translocation. If a translocation has occurred, parental karyotype analysis is also required.

Comments: Next, the proband's mutation is identified in affected family members, if a family history is present. If there is no clear history, it is necessary to confirm the de novo mutation status by proving the absence of the proband's mutation in the parents, as well as confirming biological parentage. At this same stage, analysis for possible somatic mosaicism in the parents is performed, which is important for assessing the prognostic risk for subsequent offspring.

Pathogenicity confirmation of newly discovered intragenic mutations in the PAX6 gene is performed using predictive analysis software, evidence of the absence of this variant in a cohort of healthy individuals and/or healthy family members, and, if necessary, functional analysis.

All intragenic mutations are designated in accordance with the PAX6 transcript variant 1 (NM_000280.4). Deletion boundaries are named according to the position of the MLPA probes with a reduced signal.

2.4 Instrumental Diagnostics

Comments: Children with congenital aniridia exhibit refractive errors in all cases, with the majority having various types of astigmatism. As is known, in children with congenital aniridia and glaucoma, myopic refraction develops as the eye stretches, with high myopia occurring in a third of cases. With further glaucoma progression and significant, often uneven, stretching of the ocular tunics, the degree of astigmatism increases, substantially reducing visual acuity—which is already quite low in such children.

Accordingly, the assessment of clinical refraction in children with glaucoma or suspected glaucoma serves two purposes: diagnosing the glaucomatous process and evaluating its progression rate on the one hand, and providing timely optical correction of ametropia on the other.

Currently, skiascopy remains the gold standard method of refractometry in young children. At the same time, it is successfully supplemented by instrumental methods, including those performed using portable refractometers. The undeniable advantages of the latter include the ability to perform examinations under any conditions, including under anesthesia, as well as the ability to accurately determine the astigmatism meridian.

Comments: examination of peripheral vision is extremely important for diagnosing and assessing the stage and dynamics of the glaucomatous process. Naturally, static computer perimetry is feasible only in older children with a sufficient level of intellectual development. In this regard, examining the visual field using both moving (kinetic perimetry) and stationary stimuli (static perimetry) is relevant.

Kinetic perimetry is important for diagnosing the stage of glaucoma (however, only in primary adult glaucoma, as modern classifications of congenital glaucoma lack quantitative perimetric criteria) and assessing the dynamics of the glaucomatous process (in both adults and children). The presence of impaired photosensitivity at the peripheral boundaries of the visual field, Bjerrum's area, and the borders of the blind spot are subject to evaluation.

The kinetic perimetry method has already proven its efficacy in monitoring patients with moderate and advanced stages of glaucoma. However, for the purpose of early glaucoma detection, this method is inferior to static perimetry.

The quantitative static perimetry method consists of determining light sensitivity in various areas of the visual field using stationary objects of variable brightness. Modern computerized devices ensure the examination is performed in a semi-automated mode (computerized or static perimetry (SP)).

The method allows for the detection of even minimal defects in both the central and peripheral visual fields, which makes it possible to detect the disease at early stages and significantly increases the effectiveness of glaucoma monitoring in school-age children and adolescents.

Repeat examinations are advisable twice a year; in newly diagnosed glaucoma (or when adjusting therapy, or following surgical treatment), examinations are recommended every 2–3 months during the first two years of follow-up.

Comments:

Cornea

Aniridia-related keratopathy (AK) of varying severity is diagnosed. AK presents as corneal opacity in the form of a peripheral pannus in the early stages of the pathological process, and involves the central zones of the cornea in late stages. The superficial layers are predominantly affected, after which the stroma is involved, leading to an increase in corneal thickness. The initial manifestations are avascular, followed by vessel ingrowth into the opacity zone. Corneal neovascularization begins at the 6 and 12 o'clock meridians and progresses further circumferentially. There are several classifications of AK, one of which was developed by Swedish researchers in 2010 [30], and another by Lopez-Garcia in 2006 (Table 2) [3].

Table 2. Classification of congenital aniridia-related keratopathy (by Eden) [30]

Diagnosis of AK manifestations should be carried out from the earliest age because, despite the absence of clinical symptoms, initial signs of corneal transparency loss may be observed as early as birth, predisposing to a high risk of subsequent AK progression.

In most cases, limbal stem cell deficiency (LSCD) progression in AK is manifested by the destruction of the limbal barrier, the spread of conjunctival epithelium into the central areas of the cornea, the appearance of goblet and inflammatory cells on its surface, and the degradation or complete absence of Vogt's palisades [15, 27, 41, 50, 51].

When glaucoma develops, the clinical picture of corneal involvement may be different. In the initial stage, with minimal corneal stretching, a mild edema in the form of opalescence is observed.

With further progression of glaucoma, the corneal diameter increases, causing the formation of single and subsequently multiple striate opacities, breaks, and cracks on the endothelium and Descemet's membrane. Due to the disruption of the barrier function, intraocular fluid (IOF) penetrates into the corneal stroma, metabolic processes are disturbed, causing edema and subsequent corneal opacity. There is also an enlargement (stretching) of the limbus, predominantly the upper limbus, and subsequently, in the far-advanced stage, in all parts (up to 5–6 mm).

When glaucoma develops in children with existing signs of AK, an increase in intraocular pressure (IOP) may cause deterioration of the corneal condition: the addition of edema phenomena or an increase in the intensity of opacity.

Anterior chamber

Normally, the depth of the anterior chamber in the pupillary area is 2.75–3.5 mm. In the presence of partial aniridia, visualization of the anterior chamber depth is not difficult. In the absence of the iris, the anterior surface of the lens serves as a landmark. Often, due to developmental anomalies, the anterior chamber may be shallower than average.

With lens opacification and/or swelling, the anterior chamber may become shallower. When glaucoma develops in children with an early stage, the anterior chamber is of normal depth or slightly deeper than normal. As the eyeball stretches in such children, the anterior chamber continues to deepen and can reach 5–6 mm. It is also necessary to perform a comparative assessment of chamber depth in both eyes. Asymmetry of this parameter is an important diagnostic sign of the condition in question.

Iris

In congenital aniridia (CA), there may be complete aniridia (although gonioscopy always reveals rudimentary iris tissue formations) or partial aniridia with preservation of a varying volume of hypoplastic iris.

Lens

Along with transparency, size, and shape, pigment dispersion, phacodonesis, subluxation, or other lens dislocations are noted. Anterior and posterior polar congenital cataracts without signs of progression are most common. Depending on the state of the zonules, lens subluxation may be diagnosed, with its ectopia into the upper half being more typical.

Comments: it is a method that allows visualization of rudimentary iris tissue when its detection is impossible with standard eye biomicroscopy.

The gonioscopic picture demonstrates the presence of a high attachment of the iris stump, the absence of a differentiated trabecular zone, the presence of bridges of various sizes, the contraction of which leads to the closure of the ICA. The presence of a pronounced degree of goniodysgenesis in children with CA can be a predictor of the development of a glaucomatous process in the future.

With the advent of wide-field digital pediatric retinal cameras, it has become possible to examine ICA structures in children without anesthesia. This method allows for the digital documentation of research results and a comparative analysis of changes over time. Iridocorneal goniography using a retinal camera is an objective method for the early diagnosis of pathological processes in the ICA of the eye [53].

Comments: to control IOP, it is recommended to use the TGD-01 intraocular pressure tonometer (according to Maklakov) (the standard of tonometry in the Russian Federation) or various types of non-contact tonometers. Automatic portable tonometers with a contact (rebound) measurement method appear to be the most convenient for children, allowing IOP measurement without local anesthesia and with minimal contact with the cornea, which is especially important for aniridic corneas with a high risk of keratopathy, including in young children.

When analyzing ophthalmotonometry data, absolute IOP values, daily fluctuations, and the difference in ophthalmotonus between the eyes are taken into account. Daily fluctuations in IOP levels, as well as its asymmetry between fellow eyes in healthy individuals, as a rule, are within 2–3 mm Hg and only in rare cases reach 4–6 mm Hg.

Due to the fact that the evaluation of ophthalmotonometry data is significantly influenced by the thickness and diameter of the cornea, which undergo substantial changes in children against the background of glaucoma development, it is advisable to take these parameters into account as well.

Examination of corneal thickness allows for the correct interpretation of ophthalmotonometry results. Ophthalmotonometry data in eyes with a central corneal thickness of more than 580 µm require downward correction (the actual IOP is lower than the obtained data).

Comments: in CA, the acoustic picture of the anterior segment of the eye is typically characterized by the presence of a rudimentary iris along the entire circumference or in separate areas with varying degrees of hypoplasia. Pathological changes can also be found regarding the structure, size, and position of the ciliary body, its processes, and other structures of the eyeball. Moreover, the features of these changes in the presence of glaucoma to a certain extent make it possible to develop optimal surgical treatment tactics for such patients, especially in case of impaired transparency of the optical media of the eye. In complete aniridia, standard eye biomicroscopy rarely allows for the identification of existing rudimentary remnants of iris tissue (iris stumps).

Comments: The optimal method for detecting changes in the structure of the optic disc (OD) and retina is ophthalmoscopy (indirect ophthalmoscopy with a slit lamp using non-contact diagnostic ophthalmic lenses, direct ophthalmoscopy with a slit lamp through the central part of a gonioscope for fundus examination, such as the Van Beuningen type). In newborns and infants, it is advisable to use a pediatric ophthalmic retinal camera or a digital medical camera for visualization and photographic recording of fundus structures.

One of the causes of vision reduction in children with CA is hypoplasia of the foveal region and the optic disc. The color of the optic disc can vary from pale pink to pale, its size from normal to reduced (hypoplastic), and the optic disc may have an oval and elongated shape. The macular zone and fovea may have varying degrees of light reflex anomalies indicating their hypoplasia: blurring, irregular shape, absence of the light reflex. Hypopigmentation-type pigmentation anomalies are often found in the peripheral part of the retina.

When glaucoma manifests, glaucomatous optic neuropathy develops, which affects the further reduction of visual functions and naturally requires a detailed characterization of optic disc changes. The difficulty lies in the impossibility of visualizing fundus structures in children due to corneal opacities.

Glaucoma is characterized by atrophic changes in the optic disc, manifested by decoloration (pallor) of disc areas, enlargement and deformation of its excavation, a decrease in the area and thinning of the neuroretinal rim (NRR).

When examining the optic disc in suspected glaucoma and in established glaucoma, it is necessary to perform a quantitative (optic disc size, cup-to-disc ratio (C/D), NRR-to-optic disc ratio) and qualitative assessment of the following parameters (shape, height, and color of the NRR, its absence (marginal excavation) or tendency to thinning, decoloration of optic disc areas, shift of the vascular bundle).

C/D ratio. Physiological excavation of the optic disc usually has a horizontally oval shape: the horizontal diameter is longer than the vertical one by about 8%. An enlarged physiological excavation with a large disc size is more often circular. Normally, the excavation is symmetrical in both eyes. At the same time, in 96% of cases, the C/D ratio is within 0.2 disc diameters (DD). In the initial stage of glaucoma, there are no clear differences between physiological and glaucomatous excavation. A shift and kinking of the vascular bundle can be visualized. With the progression of congenital glaucoma with high IOP values, a rather voluminous excavation is formed already at the moderately advanced stage.

The expansion of excavation in glaucoma usually occurs in all directions, but most often vertically due to the thinning of the NRR in the upper and lower sectors of the optic disc, which is associated with the structural features of the lamina cribrosa.

Neuroretinal rim. As the glaucomatous process develops, a gradual decrease in the width of the NRR occurs, which can be uniform along the entire circumference, local marginal, or combined. Glaucoma is characterized by atrophic changes in the optic disc. Clinically, they manifest as decolorization (pallor) of the NRR areas, most frequently in the temporal zone (it is necessary to differentiate this from optic atrophy of non-glaucomatous origin).

Peripapillary atrophy is the thinning/destruction of the chorioretinogenic tissue around the optic disc. In glaucoma, the prevalence of peripapillary atrophy is higher, especially on the nasal side of the peripapillary space.

It should be remembered that any of the listed symptoms taken individually is not sufficient for making a correct diagnosis. A correct decision can only be made through a comprehensive assessment of the state of the optic disc and the peripapillary retina. Color photography is convenient to use for documenting the condition of the optic disc.

Comments: Anterior segment OCT can be useful in determining the depth of stromal opacities, corneal thickness, and visualizing the structures of the anterior chamber of the eye in the presence of media opacities.

Comments: the devices are equipped with computer programs that facilitate image acquisition, as well as the creation and maintenance of a database providing quantitative image analysis.

The research method under consideration allows for a quantitative assessment of the state of retinal and optic nerve parameters in children with aniridia.

Specific features of structural changes in the optic disc in glaucoma in children with aniridia have been identified.

In the majority of children with congenital aniridia, smoothing of the macular contour is determined due to a decrease in foveal depression, which is characteristic of macular hypoplasia. Specific features of the retinal structure in congenital aniridia have been noted: in most children, there is a decrease in the total macular volume parameter and an increase in retinal thickness in the center of the fovea (macular central minimum zone), which confirms the absence of proper formation of the macular region or its hypoplasia.

During the development of the glaucomatous process, the characteristic features obtained using OCT are:

• a decrease in the thickness of the retinal nerve fiber layer in the peripapillary zone with predominant changes in the temporal zone, increasing as glaucoma progresses;

• a change in the arterio-venous index predominantly towards its increase, digital confirmation of hemodynamic disturbances in the vascular branches of the central retinal artery and central retinal vein in the form of a decrease in their caliber;

• a decrease in the thickness of the ganglion cell layer and the ganglion cell complex.

OCT (Heidelberg retinal tomography method) is particularly useful in characterizing the state of the optic disc in glaucoma. In particular, with the progression of glaucoma, there is a significant increase in the main parameters of optic disc excavation: cup volume, maximum cup depth, as well as cup area, and a decrease in NRR values: rim volume and rim area. The most significant factor of structural atrophy in congenital glaucoma is the parameter characterizing the mean RNFL thickness (mean RNFL thickness), the value of which significantly decreases in glaucoma.

At the same time, it should be emphasized that the data obtained using the considered instrumental methods are not "gold standards" in the diagnosis of the glaucomatous process, but only complement the results of a comprehensive examination of the child, which should be evaluated in their entirety.

However, the confirmed deterioration of the optic disc state is an important prognostic sign of glaucoma progression.

Comments: the electroretinogram and its components serve as an objective indicator of the functional state of the retina in children with congenital aniridia and associated pathologies (glaucoma, optic disc and macular hypoplasia, etc.). Modern computer systems are used to record VEPs, allowing small potentials to be extracted from noise by employing averaging and filters that neutralize various artifacts. The study is carried out both while the child is awake and during medicinal sleep or anesthesia. Primary attention is paid to latency indicators. When analyzing the obtained data, it is taken into account that the formation of the P1 peak of the VEP is mainly influenced by the integrity of the retinocortical pathway, the maturity of the foveal region of the retina, and the integrity of the striate cortex. In addition, it should be borne in mind that this method does not make it possible to assess the preservation of associative and cognitive functions of the brain that provide "visual recognition".

EPT data appear particularly important when it is impossible to assess visual acuity due to the child's age and in cases of corneal opacities when the structures of the posterior pole cannot be visualized.

In the presence of optic disc hypoplasia and macular structures, EPT parameters change: during VEP recording, amplitude parameters decrease and latency is prolonged; ERG demonstrates a decrease in amplitude characteristics.

When the glaucomatous process develops, EPT results have certain specific features.

In glaucoma, a series of sequential EPTs before and after the normalization of IOP allows for the assessment of the state of the retina and optic nerve, the dynamics of changes, and the prediction of final functional outcomes.

The recording of a supernormal ERG simultaneously with high IOP figures indicates a short period of hypertension and a favorable functional outcome. High IOP figures with a low ERG amplitude are characteristic of more pronounced pathological changes in the retinal structure and a poorer functional prognosis. Following IOP normalization, the ERG amplitude decreases within 3–6 months to values corresponding to the stage of the disease and the preservation of the retinal neuroepithelium. With sustained normalization of IOP, the ERG tends to show a moderate increase in amplitude.

In glaucoma, VEPs alter their amplitude-time characteristics across the entire range of spatial frequencies, reflecting the state of retinal ganglion cell axons, even at the initial stage of the disease.

As the disease progresses, VEPs show a direct correlation between changes in amplitude-frequency characteristics and the stage of glaucoma. Latency increases as the disease progresses and transitions to a later stage, while amplitude decreases, and by the absolute stage of glaucoma, VEPs are no longer recordable. With sustained IOP compensation, stabilization and then partial restoration of the VEP amplitude-time characteristics occur.

2.5 Other Procedures

Not informative

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

3.1.1. Prevention and treatment of aniridic keratopathy

Comments:

Main provisions:

• treatment should be initiated from an early age;

  the maximum number of topical preparations used should not exceed three to avoid further corneal damage;

• continuously use only preservative-free ophthalmological preparations;

  drugs with the same pharmacological action must not be used in combination.

Efficacy indicators:

• absence of aniridic keratopathy progression;

• absence of effect reduction over a long period;

• minimal systemic impact;

• minimum of side effects;

• good tolerability.

3.1.2 Anti-glaucoma drugs and miotics (antihypertensive agents) (prostaglandin analogues (S01EE), beta-blockers (S01ED), carbonic anhydrase inhibitors (S01EC), sympathomimetics for glaucoma treatment (S01EA), parasympathomimetics (S01EB)) in the presence of glaucoma

Congenital glaucoma requires surgical treatment. However, during the preoperative preparation period, and in some cases postoperatively as well—when the hypotensive effect of the intervention is insufficient—medical ocular hypotensive therapy remains necessary.

Comments: The main registered drugs and their age restrictions are presented in Table 3.

Table 3. Age restrictions for the prescription of the most common hypotensive drugs in the Russian Federation

If treatment with approved drugs is ineffective, with the informed consent of the patient's parents and the permission of the medical commission, drugs that are not officially approved for use in children may also be prescribed [82-85, 91].

Algorithm for prescribing anti-glaucoma drugs and miotics (antihypertensive agents) for aniridic glaucoma:

• carbonic anhydrase inhibitors and beta-blockers remain the first-line drugs of choice for congenital glaucoma;

• in case of high IOP, treatment should be started immediately with combination drugs, and if efficacy is insufficient, a drug from another pharmacological group should be added (prostaglandin analogues (S01EE), sympathomimetics for glaucoma treatment (S01EA), parasympathomimetics (S01EB) ) [82, 91];

• the use of two or more anti-glaucoma drugs and miotics (antihypertensive agents) is one of the criteria for an expedited transition to surgical treatment;

An ophthalmologist encounters the following problems in the conservative treatment of aniridic glaucoma:

• severe ocular surface damage due to aniridia-related keratopathy;

• poor tolerance of local hypotensive therapy (consequently leading to low compliance with this therapy in children and adults);

• the need to use several anti-glaucoma drugs and miotics (antihypertensive agents) aggravates corneal problems, including the appearance of punctate keratopathy and recurrent erosions, which enhance neovascularization processes;

• systemic side effects of local hypotensive therapy: this problem primarily affects children, significantly limiting the range of drugs that can be used;

• side effects of systemic hypotensive therapy: sometimes temporary use of carbonic anhydrase inhibitors is necessary to reduce IOP, which can lead to alterations in blood electrolyte balance (low potassium levels), nausea, vomiting, and decreased physical activity [64, 65].

3.1.3 Neurotrophic treatment

Comments: The complex of neurotrophic treatment includes drugs that affect peripheral blood circulation and improve microcirculation: other psychostimulants and nootropics (N06BX), angioprotectors (C05), vitamins, multivitamins in combination with other agents (A11A), and other drugs used in ophthalmology S01X. Therapy should be carried out regularly 2 times a year under the supervision of a neurologist (Neurologist appointment (examination, consultation)).

3.2 Surgical treatment (indications for emergency, including repeat, surgical treatment; surgical methods)

3.2.1 Methods of surgical treatment of glaucoma in congenital aniridia

Comments: Indications for emergency surgical treatment (including repeat surgery):

• high IOP level that cannot be normalized by any other treatment method except surgery;

• impossibility of implementing other treatment methods (including non-compliance with medical recommendations, pronounced side effects) or inaccessibility of appropriate drug therapy;

• repeat surgeries must be performed even when residual visual functions are present.

Surgical treatment of glaucoma in children with congenital aniridia is central to the therapeutic measures implemented for such patients.

There are two target directions of surgical interventions for congenital glaucoma.

The first involves the restoration (more precisely, formation) of aqueous humor outflow, either by eliminating the obstruction in its natural pathway or by creating a new outflow pathway (fistula) bypassing the natural drainage pathways.

The second direction of surgical treatment for children with this pathology is represented by interventions aimed at reducing aqueous humor production by the ciliary body.

The main approach in the surgical treatment of glaucoma is the use of minimally invasive methods with minimal trauma to the cornea and limbal zone.

• operations aimed at eliminating organic obstacles in the path of aqueous humor to the trabecular meshwork (goniotomy, including goniopuncture A16.26.067; trabeculotomy ab interno A16.26.069; laser goniotrabeculopuncture A22.26.006);

• fistulizing interventions involving the formation of a new channel from the anterior chamber of the eye outward into the intrascleral space (trabeculotomy ab externo A16.26.069; sinustrabeculectomy (STE) and its modifications A16.26.070.

Leveled Clinical Recommendations CLevel of Evidence 4Level of recommendation confidence C (level of evidence – 4)

Comments: a number of foreign clinics propose trabeculotomy ab interno and ab externo as the operation of first choice. However, as practice shows, this surgical intervention presents difficulties in locating the scleral sinus during surgery, and the frequent presence of neovascularization in the iridocorneal angle makes this type of surgical treatment difficult to implement and associated with an increased risk of intraoperative hemorrhagic complications.

The most stable hypotensive effect is achieved by trabeculectomy (STE). This modification of the surgical intervention aims to form a fistula from the anterior chamber of the eye into the intrascleral space (the volume of which is expanded by deep sclerectomy). A specific feature of this surgical procedure in children with aniridia is the excision of the trabecular meshwork without performing a full basal iridectomy and a broader excision of the trabecular zone, which is associated with a tendency toward postoperative fibrosis in this patient group. It is also recommended to place scleral sutures and suture the conjunctiva more meticulously to rule out postoperative hypotony.

Comments: In recent years, with the advent of modern drainage designs that are well-tolerated by the pediatric eye, the preferred approach in glaucoma surgery for congenital aniridia has been the use of drainage devices as the primary surgical choice. The use of various modifications of drainage devices (resorbable antiglaucoma drainage, antiglaucoma filtration device (glaucoma treatment shunt***)) is relatively straightforward and makes it possible to prolong the hypotensive effect of the surgery and establish a controlled IOP level. However, when choosing this treatment strategy in children with aniridia, one must take into account the high risk of an active fibrous process in the postoperative period.

Comments: These surgical interventions are based on thermal effects applied directly to the ciliary processes or to the posterior long ciliary arteries supplying them.

Laser transscleral cyclophotocoagulation is most often performed in several stages, involving no more than 2 quadrants per stage. The objective of the intervention is to achieve normalization of IOP to normal values or to levels that allow IOP normalization with the help of hypotensive eye drops. It is advisable to maintain an interval of at least three months between stages of surgical treatment to stabilize IOP parameters and resolve the inflammatory process in the surgical area.

Micropulse diode laser transscleral cyclophotocoagulation is a modern, safer, and minimally invasive method that, unlike continuous-wave cyclophotocoagulation, has two cycles: "on" and "off". During the "off" cycle, the areas of the ciliary body that have been exposed to thermal energy cool down, protecting them from excessive thermal damage. The hypotensive effect is achieved through gentle thermal damage to the ciliary body, reduction of aqueous humor secretion, and enhancement of uveoscleral outflow. The method avoids excessive irreversible damage to the ciliary body and, in addition to indications for standard diode laser cyclophotocoagulation, can be used not only as an organ-saving method in terminal stages of glaucoma and contraindications to filtering procedures (like standard diode laser cyclophotocoagulation), but also as a less traumatic primary intervention in eyes with aniridic keratopathy. Traumatization of the limbal zone during trabeculectomy in the presence of limbal stem cell deficiency leads to the progression of aniridic keratopathy, making the use of gentle non-invasive methods of lowering IOP more preferable in such eyes [94, 95].

Following the aforementioned surgeries, the child is prescribed oral carbonic anhydrase inhibitors for 2–3 days at an age-appropriate dosage, thereby combining surgical and medicinal suppressive effects on the ciliary body [92].

3.2.2 Surgical treatment of cataracts in congenital aniridia

Comments: the primary factor in determining the timing of surgery for both bilateral and unilateral cataracts in aniridic eyes is the severity of lens opacities, determined by the type of cataract, which affects the development of the child's visual functions during the sensitive period.

Surgical treatment of congenital cataracts in children with congenital aniridia is indicated in the presence of optically significant lens opacities located along the visual axis of the eye and causing a decrease in visual function. As a rule, non-progressive polar lens opacities in the absence of the iris do not exert a depriving effect and do not require early surgical intervention. Surgery may be delayed until an older age depending on the progression dynamics of cataract opacities and the decrease in visual acuity.

Cataract surgery in patients with aniridia is associated with certain challenges:

• preoperative IOL power calculation may be difficult due to an unstable ocular surface, nystagmus, and polar cataracts;

• incision size, length, and location must be carefully planned to avoid the onset or exacerbation of aniridic keratopathy in these patients;

• examination of the lens capsule revealed a 50% reduction in capsule thickness in children compared to normal controls;

• due to a hypoplastic iris leading to the absence of the ciliary sulcus in aniridia, in-the-bag implantation is the only option for intraocular correction of aphakia.

Modern cataract surgery technology includes:

• tunnel corneal or corneoscleral micro-incisions followed by suture fixation of the main incision, and creation of paracenteses at the 3 and 9 o'clock positions;

• use of modern ophthalmic viscosurgical devices to protect the corneal endothelium;

• application of differentiated anterior continuous curvilinear capsulorhexis techniques with a minimal diameter (less than 5 mm) for more stable IOL fixation in the capsular bag;

• automated or manual aspiration-irrigation of lens masses;

• endocapsular implantation of flexible acrylic IOLs.

The techniques for cataract phacoaspiration correspond to the congenital cataract removal techniques described in more detail in the clinical guidelines for congenital cataracts.

Comments: it is important to know that surgical intervention (for glaucoma and cataracts) can provoke the progression of aniridic keratopathy, and glaucoma surgery can stimulate lens dislocation and opacification. According to literature data, the most common complication of cataract surgery was the development of glaucoma, subsequently requiring additional antiglaucoma interventions to normalize IOP.

It is important to know that the absence of the iris, the polymorphism of identified ocular changes, including the presence of limbal stem cell deficiency, determine the specific features of the intra- and postoperative course of aniridic keratopathy and affect the outcomes of surgical treatment and the prognosis of the disease.

A complication of surgery described exclusively in congenital aniridia is aniridic fibrosis syndrome (AFS), which is a fibrous scarring process associated with the development of hypotony, reducing visual functions, and in some cases leading to ocular subatrophy.

Unfavorable factors complicating the postoperative course of primary glaucoma include excessive scarring and active regeneration caused by the proliferation of Tenon's capsule and episcleral fibroblasts in the surgical area. In children with aniridia, proliferation processes in the surgical zone in the early postoperative period are more active than in typical children and adults, which explains the lower efficacy of antiglaucoma surgeries in treating glaucoma.

Scarring in the surgical area is promoted by: insufficient volume of the excised trabecular portion, closure of the surgical zone by goniosynechiae resulting from postoperative iritis and hyphema, and increased adhesive processes.

Modern methods to prevent excessive proliferation include: minimizing surgical trauma, wide excision of the conjunctiva and episclera, and the use of corticosteroids (S01BA), enzymes in the form of subconjunctival injections [84, 86-89].

In addition to excessive scarring, the efficacy of antiglaucoma surgeries depends on a number of other complications: shallow chamber syndrome, ciliochoroidal detachment, hyphema, and macular edema.

Shallow anterior chamber syndrome in the postoperative period may be associated with increased aqueous humor filtration through the surgical fistula, external filtration due to poor adaptation of the conjunctival incision, as well as ciliochoroidal detachment.

Ciliochoroidal detachment has been noted as the most frequent postoperative complication in children with aniridia. The IOP fluctuation occurring during surgery serves as a trigger for the clinical manifestation of vascular pathology, while the absence of the iris reduces the effectiveness of medical IOP stabilization.

Medical therapy for congenital aniridia-associated glaucoma includes topical corticosteroids (S01BA), systemic corticosteroids (H02A), and mydriatic and cycloplegic agents (S01F). In the absence of effect, surgical treatment is indicated in the form of sclerectomy, trepanation of the sclera (A16.26.073).

In the early postoperative period, recurrence of hypertension may develop either due to blockade of the trabeculectomy zone by iris root remnants (in cases of partial aniridia) and lens block (ciliolenticular block), or due to adhesion formation between the scleral or conjunctival flaps. Conservative treatment is recommended in these cases; if ineffective within 5–7 days, revision (needling) of the filtering bleb (A16.26.120) may be performed to separate structures obstructing aqueous humor outflow.

If planar synechiae form between the iris root (in partial aniridia) and the internal fistula zone, Nd:YAG (neodymium-doped yttrium aluminum garnet) laser intervention can be performed (laser synechiolysis A22.26.020) (no later than 1 month after adhesion development).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: Prescription of spectacle correction is recommended: both pairs of glasses must have a UV filter (UVA and UVB block) for light with a wavelength greater than 400 nm; one pair should have a light tint of 20% (for indoors and cloudy days outdoors), and the other with maximum tint (up to 80%) (for outdoor use). However, if the child has no photophobia, spectacle correction with initially clear lenses that feature blue light blocking (L400) and photochromic properties can be prescribed. If visual acuity is 0.1 or less (with maximum correction), the use of a video magnifier, monocular, and other visual rehabilitation aids is recommended.

5. Prevention and Dispensary Observation

Comments: Children with congenital aniridia are placed on the outpatient dispensary register with follow-up examinations scheduled every 3–6 months. Regular monitoring of intraocular pressure (IOP), eye dimensions, and visual acuity is extremely critical. As part of the dispensary observation, all children undergo a comprehensive examination, including assessment of the anterior and posterior segments of the eye, IOP measurement, determination of refraction and visual functions: visometry (A02.26.004), refractometry (A03.26.008), ophthalmotonometry (A02.26.015), biomicroscopy of the eye (A03.26.001), ophthalmoscopy (A02.26.003) / fundus biomicroscopy (A03.26.018), ultrasound biometry of the eye (A04.26.004), ultrasound examination of the eyeball (A04.26.002), computer perimetry (static A02.26.005, automated A03.26.020), optical examination of the retina using a computer analyzer if necessary (A03.26.019), optical examination of the optic nerve head and nerve fiber layer using a computer analyzer (A03.26.019.003), optical coherence tomography, recording of visual evoked cortical potentials (A05.26.002) and electroretinography (A05.26.001), and recording of the pattern electroretinogram complex (advanced study) (A05.26.001.003). It should be noted that contact examination methods may not be feasible for all children due to their age. If comorbid systemic pathology is present, children with congenital aniridia must be under the dispensary observation of a pediatrician.

6. Organization of Medical Care

• If a child is suspected of having an anterior segment developmental anomaly and an aniridia or has a confirmed diagnosis of congenital aniridia, primary care pediatricians and general practitioners (family doctors) shall refer the children for a consultation with an ophthalmologist. The ophthalmologist evaluates the state of the eye and conducts an examination, including instrumental research methods to clarify the diagnosis. If diagnostic procedures under anesthesia are required, children are referred to the pediatric ophthalmology department.

• If there are indications for surgical treatment in a child with congenital aniridia and a diagnosed glaucoma and/or cataract, this treatment is carried out in an inpatient setting within the pediatric ophthalmology department. After receiving medical care, the child is referred to the pediatric ophthalmology office. Subsequently, they remain under the dispensary observation of the ophthalmologist at the pediatric ophthalmology office.

7. Additional Information

Genotype-phenotype correlations.

Analysis of genotype-phenotype correlations between the type of defect in the PAX6 gene locus and damage to various ocular structures revealed a milder phenotype in patients with chromosomal deletions of the 3′-cis-regulatory region of the PAX6 gene that do not affect the coding sequence. Patients with this type of 11p13 chromosomal deletion are significantly less likely to have keratopathy, foveal hypoplasia, and nystagmus. It was also revealed that in patients with deletions of the WAGR region, the position of the deletion on the chromosome affects the risk of developing nephroblastoma. The tumor develops significantly more often when the LMO2 gene locus (11p13 OMIM*180385), which encodes the tumor suppressor "LIM domain-only protein 2", is involved in the deletion area. Thus, if DNA diagnostics reveals a chromosomal deletion of the 3′-cis-regulatory region of the PAX6 gene in a patient, the prognosis of the disease course is more favorable; however, this does not cancel the care and monitoring required to maintain vision in such patients. In particular, the risk of developing glaucoma in patients with a deletion of the 3′-cis-regulatory region remains as high as in other patients with congenital aniridia [81].

When a chromosomal deletion of the WAGR region is identified in a patient with aniridia, their risk of developing nephroblastoma dramatically increases to 50–70%; if the identified deletion captures the LMO2 gene locus, this risk rises to 90%.

This information can and should be used by medical geneticists during genetic counseling for patients with congenital aniridia and the WAGR spectrum. Aniridia fibrosis syndrome (AFS) is a complication that reduces visual functions, described only in congenital aniridia. It represents a non-inflammatory fibrous scarring process associated with the development of hypotony and phthisis bulbi [82], occurring after surgical interventions. To avoid the development of AFS or late complications such as chronic uveitis, it is advisable to perform minimal surgical incisions, use elastic unpainted intraocular lenses, and exclude the implantation of artificial diaphragms mimicking iris tissue [82].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Katargina, Lyudmila Anatolyevna – Head of the Group, Chief freelance pediatric ophthalmologist of the Russian Ministry of Health, Deputy Director for Research at the National Medical Research Center for Eye Diseases named after Helmholtz of the Ministry of Health of the Russian Federation, Professor, Doctor of Medical Sciences, Moscow; Presidium member of the All-Russian Public Organization "Association of Ophthalmologists", Presidium member of the Russian Ophthalmological Society, Chief freelance pediatric ophthalmologist of the Ministry of Health of the Russian Federation, Chairperson of the Profile Commission on Pediatric Ophthalmology of the Ministry of Health of the Russian Federation, Deputy Chairperson of the Profile Commission on Ophthalmology of the Ministry of Health of the Russian Federation, Honored Doctor of the Russian Federation, Honored Scientist, Moscow;

2. Zinchenko, Rena Abulfazovna – Deputy Director for Research and Clinical Work at the Research Centre for Medical Genetics, Head of the Laboratory of Genetic Epidemiology, Professor, Doctor of Medical Sciences, Moscow;

3. Baranov, Alexander Alexandrovich – Advisor to the Head of the Research Institute of Pediatrics and Children's Health of the Central Clinical Hospital of the Russian Academy of Sciences, Honorary President of the Union of Pediatricians of Russia, Professor at the Department of Pediatrics and Pediatric Rheumatology at the Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Chief freelance pediatrician of the Ministry of Health of Russia, Academician of the RAS, Professor, Doctor of Medical Sciences, Moscow;

4. Namazova-Baranova, Leyla Seymurovna – Head of the Research Institute of Pediatrics and Children's Health of the Central Clinical Hospital of the Russian Academy of Sciences of the Ministry of Science and Higher Education of the Russian Federation, Head of the Department of Faculty Pediatrics at the Pediatric Faculty of the Pirogov Russian National Research Medical University of the Ministry of Health of Russia, Chief freelance pediatric specialist in preventive medicine of the Ministry of Health of Russia, Chief freelance pediatric specialist in preventive medicine of the Ministry of Health of Russia, Chairperson of NITAG of the Russian Federation, President of the Union of Pediatricians of Russia, Past-President of the European Pediatric Association (EPA/UNEPSA), Academician of the RAS, Professor, Doctor of Medical Sciences, Moscow;

5. Sukhanova, Natella Vakhtangovna – Ophthalmologist at the Sechenov Center for Mother and Child Health, Federal State Autonomous Educational Institution of Higher Education Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Candidate of Medical Sciences, Moscow;

6. Marakhonov, Andrey Vladimirovich – Senior Researcher at the Laboratory of Genetic Epidemiology, Research Centre for Medical Genetics, Candidate of Biological Sciences, Moscow;

7. Vasilyeva, Tatyana Alekseevna – Researcher at the Laboratory of Genetic Epidemiology, Research Centre for Medical Genetics, Candidate of Biological Sciences, Moscow;

8. Pozdeyeva, Nadezhda Alexandrovna – Director of the Cheboksary Branch of the S.N. Fyodorov Eye Microsurgery Federal State Institution of the Ministry of Health of the Russian Federation, Member of the Russian Ophthalmological Society, Doctor of Medical Sciences, Cheboksary;

9. Voskresenskaya, Anna Alexandrovna – Ophthalmologist of the first qualification category at the Cheboksary Branch of the S.N. Fyodorov Eye Microsurgery Federal State Institution of the Ministry of Health of the Russian Federation, Member of the Russian Ophthalmological Society, Candidate of Medical Sciences, Cheboksary.

Conflict of interest: none declared

Appendix A2. Methodology for Developing Clinical Guidelines

Methods used for evidence collection/selection: electronic database searches; analysis of current scientific developments on glaucoma in Russia and abroad; synthesis of practical experience of Russian and foreign colleagues.

The preliminary version of these guidelines was reviewed by independent experts who commented on the accessibility and interpretability of the evidence underlying the guidelines for practitioners and patients.

The comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and appropriate changes were made to the guidelines.

In these clinical guidelines, all data are ranked by level of reliability (evidence) depending on the quantity and quality of studies on the issue.

Target audience for these clinical guidelines:

1. Ophthalmologists

2. Pediatricians

3. General practitioners (family physicians)

4. Neonatologists

5. Geneticists

6. Medical students, residents, and postgraduate students.

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following documents:

1. "Procedure for Providing Medical Care to Children with Diseases of the Eye, Its Adnexa, and Orbit", approved by Order of the Ministry of Health of the Russian Federation No. 442n dated October 25, 2012.

2. International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) (World Health Organization) 1994.

3. Order of the Ministry of Health of Russia No. 804n dated October 13, 2017 (as amended on September 24, 2020, with rev. dated October 26, 2022) "On Approval of the Nomenclature of Medical Services".

4. Federal Law No. 323-FZ of November 21, 2011, "On the Fundamentals of Health Protection of Citizens in the Russian Federation."

Appendix A3.1 Description of the potential symptom complex, treatments and low-vision devices used, and previous surgeries

Appendix B. Physician Action Algorithms

Confirmatory molecular genetic diagnostics of congenital aniridia

Algorithm of actions for an ophthalmologist in congenital aniridia

Appendix C. Patient Information

Important for all age groups:

1. If surgery is planned:

• You must be sure that you understand all the nuances explained to you by your ophthalmologist;

• do not hesitate to ask questions;

• do not hesitate to consult another specialist to get a second opinion;

• consult your local aniridia patient support organization.

Additional things that help living with aniridia:

0–2 years

• stay in contact with your national aniridia patient support organization,

• share experience and knowledge with other parents and learn from parents with older children,

• learn about the procedures for submitting disability documents and apply for disability status.

2–8 years

• begin connecting with families of younger children with aniridia to help them adapt and share advice you received when your child was younger;

8–18 years

• young people with aniridia can start participating in aniridia conferences and various meetings to meet peers with the same diagnosis and start communicating;

• try participating in sports activities with other visually impaired individuals.

adults

• become active members of your national aniridia patient support organization,

• share your experience with other aniridia patients regarding treatment, visual aids, etc.,

• study and follow the latest scientific advances.

Scheduled examinations and complication detection are the main goal of medical management in congenital aniridia.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Absent