KÄSMANN-KELLNER, A. VIESTENZ, B. SEITZ

Department of Ophthalmology, University Medical Center of Saarland UKS, Kirrberger Str. 100, building 22, Homburg (Saar), Germany, D 66424

Barbara Käsmann-Kellner — MD PhD, professor, Head of the Section Paediatric Ophthalmology, Orthoptics, Low Vision & Neuroophthalmology, Medical Advisor to Aniridia WAGR Support Group Germany e.V., ministerial appointed ophthalmologist for citizens with low vision or blindness in the county of Saarland, tel. +49-6841-1622312, e-mail: kaesmann@gmail.com

Arne Viestenz — MD PhD PD, Retinal and Anterior Segment Consultant, Consultant of ophthalmopaediatric surgery, Vice Chairman of the Department of Ophthalmology

Berthold Seitz — MD PhD ML, professor, Chairman of the Department of Ophthalmology, Corneal surgeon, Head of the Corneal Section of the German Association of Ophthalmologists (DOG)

Congenital aniridia manifests in different forms: it can be transmitted in an autosomal dominant way, as sporadic aniridia, and as part of several syndromes including WAGR- and WAGRO-syndrome and syndromes with intellectual impairment. Furthermore recent research shows that aniridia associated with alterations in the PAX6 gene often shows further systemic implications (endocrine, metabolic and neurological pathologies). Therefore, PAX6-related aniridia is more and more thought of and described as «Aniridia Syndrome» or «PAX6-Syndrome».

We present a group of 130 patients of our patient group with congenital aniridia to enhance awareness of the ocular complexity and the systemic implications of the inborn ocular malformation.

Different to other congenital visual impairments aniridia is characterized by many ocular complications arising during life which may lead to total blindness (cataract, aniridic keratopathy, secondary glaucoma). Furthermore, there is a specific surgical risk entity: Aniridia fibrosis syndrome or Anterior Segment Fibrosis Syndrome (ASFS) which leads to a non-infectious fibrous scarring and membrane formation of the anterior segment, often followed by hypotonia and phthisis. Aniridic glaucoma presents yet another severe complication which often is diagnosed late due to diagnostic problems and which may lead to irreversible optic nerve damage.

Our main aim is to point out that complications in aniridia involve several ophthalmosurgical subspecialties (cornea, cataract, glaucoma, anterior and posterior segment surgery) and that aniridia patients may encounter problems concerning a comprehensive treatment of all possible complications plus concerning low vision support, academic and professional aid and compensation strategies if they are treated by one subspecialty surgeon.

Key words: сongenital aniridia, Aniridia-Syndrome, PAX6-Syndrome, aniridia associated keratopathy, aniridic glaucoma, aniridia fibrosis syndrome, Low Vision, aniridia guide.

 

List of abbreviations

Abbreviation	Stands for:	Describes:
AFS / ASFS	Aniridia Fibrosis Syndrome resp. Anterior Segment Fibrosis Syndrome	Profibrotic intraocular progressive fibrotic scar formation hitherto only described in aniridia following intraocular surgery. Scar formation leads to a firm fibrotic plate [1]
AN	Aniridia	Formerly AN2 was used in OMIM to describe PAX6-relatd aniridia, this has been changed to PAX6 related aniridia
AAK	Aniridia-associated keratopathy	Typical LSCI (see below) caused progressive keratopathy in aniridia
CYP1B1	Cytochrome P450 Family 1 Subfamily B Polypeptide 1 — Gen	Aniridia without relation to PAX6, further manifestations in CYP1B1-deficit: Buphthalmia, ASD Anterior Segment Dysgenesis, Peters Anomaly [2]
FOXC1	Forkhead box C1 Gen	Aniridia without PAX6 association in ididogonodysgenesis
LSCI	Limbal stem cell insufficiency	Limbal stem cell insufficiency is the main cause for all three major complications in aniridia: namely keratopathy, but glaucoma and cataract formation seem to be related to LSCI as well
PAX	PAired-BoX-Gene	Developmental old genes which code for transcription factors which are crucial for embryonal tissue differentiation and for embryonal organ formation. In addition, postnatally they are important for physiological function of specific cell types [3, 4]
PAX6	PAired-Box-6-Gene	Master-Gene of embryonal ocular differentiation. PAX6 is in addition important in the embryonal differentiation of the central nervous system, the olfactory bulbs, the pancreas. Up to now, over 350 mutations associated with aniridia have been described. Further ocular manifestations of PAX6 insufficiency can be coloboma of iris, choroid, and retina, morning glory anomaly (coloboma) of the optic nerve head and Peters Anomaly [3, 4]
PITX2	Paired-like Homeodomain Transcription — factor 2	Aniridia without relation to PAX6 in Axenfeld-Rieger-Syndrome Type1 RIEG1, Iridogoniodysgenesis Type II IRID2, Peters Anomaly
WAGR(O)	Wilms-Tumor, aniridia, genito-urethral anomalies, retardation (plus obesity)	Nephroblastoma in over 50% of affected children, occuring mostly between 1st and 4th year of life. Higher risk of renal insufficiency in adult age. Genito-urethral anomalies may lead to ambiguous morphology of the sexual organs. Mental retardation, in cases of microdeletion 11p14-p12 obesity is frequent [3, 5, 6]

 

Aniridia Guide: a proposal to improve the care for aniridia patients

We suggest a model of «aniridia pilotage» or «aniridia guide» where one ophthalmologist, preferably a paediatric and low vision specialist with a thorough knowledge of aniridia and a functional network to ophthalmosurgical subspecialists, follows the patient over years, thus caring for his low vision needs, supporting inclusion and observing possible complications – and if those arise, send the patient to a subspecialty surgeon to treat the complications. This guiding ophthalmologist will care for the patient following any surgical procedure, he will adapt low vision support according to changes in visual acuity and will ensure that no aniridia patient gets lost between the different subspecialty surgeons.

In addition, the guiding ophthalmologist should inform the aniridic patients about possible systemic manifestation of PAX6-Syndrome concerning metabolic and neurologic implications and should initiate appropriate investigations if applicable.

Other possible aspects to improve the care of aniridia patients

The following approaches might help to improve the lifelong care of aniridia patient and might benefit the aim to lessen the impact of complications in aniridia:

• topical routine prophylaxis of aniridic corneal epitheliopathy from very early age onwards
• early support of young aniridia children:
  • early correction of refractive errors
  • introduction to low vision support services and Early Intervention measurements
  • alternating patching to promote visual development in each eye (depending on the presence or absence of strabismus)
  • glare reducing filter glasses without change of colour perception
• regular measurement of intraocular pressure starting in young children
• yearly VEP measurements, routine visual field testing as soon as possible
• comprehensive optimization of surgical care independent of department location (only the very best surgeons within their subspecialty should treat the different complications) while one experienced paediatric and low vision ophthalmologist should follow the patient continuously («aniridia guide» for the patient), thus monitoring the disease and stages of complications and advising the patient where to go for surgical treatment.
• this low vision ophthalmologist continuously follows the patient´s course including adaptation of low vision aids according to the course of the disease, helping the patient concerning integration at school and at the place of work and advises about social and legal compensation possibilities.

 

Introduction

«Aniridia» is actually a misnomer, because the “absence” of the iris is the most obvious sign in childhood. However, there always is a small iris stump visible on gonioscopy. In addition, the lack of iris itself is not the reason for the progressive visual loss during life. Congenital Aniridia is a severe pan-ocular congenital eye malformation including changes in the anterior and posterior segments of the eye and systemic findings. Most cases are associated with dominantly inherited mutations or deletions of the PAX6 gene.

Children with aniridia characteristically have a variable degree of iris hypoplasia and foveal hypoplasia, which leads to sensory defect nystagmus (SDN) and congenitally impaired visual acuity (usually 0,1 best corrected). Other congenital features may include corneal opacification, glaucoma, cataract, lens subluxation, strabismus, optic nerve coloboma and hypoplasia.

Later during life, progressive sight-threatening complications include cataracts, glaucoma, corneal opacification due to limbal stem cell insufficiency and a high risk of aniridia fibrosis syndrome following intraocular surgery.

Furthermore there are often systemic, mostly metabolic abnormalities in PAX6 gene associated aniridia. It would therefore be more precise to call PAX6-related aniridia «Aniridia Syndrome» or «PAX6-Syndrome».

With this chapter, we want to propose a change in the standard life-long ophthalmological care of patients with aniridia, who often need several ophthalmosurgical subspecialists to address their different complications such as glaucoma, cataract and corneal scarring. Changing subspecialists or remaining with just one subspecialist may promote a belated diagnosis of other complications. This might, as in belated diagnosis of glaucoma, lead to irreversible visual loss.

In our opinion, one surveying low vision and paediatric ophthalmologist should “guide” aniridia patient, searching the best subspecialists for any complication arising, and caring for the patient postoperatively. This is why we propose the AGOs — Aniridia Guides in Ophthalmology, hoping that this new approach can perhaps improve the care of many patients.

PAX6-Related Aniridia (PAX6-Syndrome) and other forms of aniridia

One can distinguish PAX6-gene-related aniridia and other forms of aniridia without changes in PAX6. PAX6-related aniridia, however, occurs much more frequently, and these present the typical clinical complications more often than in aniridia without PAX6 association.

PAX6 related aniridia (Aniridia Syndrome, PAX6-Syndrome)

PAX6-gene related aniridia can be categorized into the autosomal dominant and the sporadic types. In addition, rare syndromes can be found, which are also PAX6 linked and inherited in an autosomal recessive way: Gillespie syndrome (Aniridia, cerebellar ataxia, mental retardation). See Table 1 for references according to ICD, OMIM and others.

In former years PAX6-linked aniridia was divided into so-called «isolated» aniridia and «syndromatic» aniridia. During the last years, however, it became more and more evident that many types of PAX6-linked aniridia often show systemic manifestations and comorbidities. Therefore, PAX6-linked aniridia should rather be called Aniridia Syndrome or PAX6-Syndrome [3, 7, 8, 9]. Table 2 gives an overview of PAX6 gene linked types of aniridia with possible syndromes and accompanying disorders.

Caveat: PAX6-associated aniridia is a pan-ocular profound developmental disorder of the eyes, the consequences of which can lead to blindness in the course of life. Also, there are often systemic manifestations in PAX6-Syndrome with metabolic and neurological alterations. Aniridia patients may as well have other sensory deficits including reduced olfaction (hyposmia) and hearing problems.

Homozygous PAX6 mutations are not compatible with life. Missense mutations of PAX6 often are accompanied by atypical phenotypes (small iris anomalies up to Peters anomaly) and microphthalmia. There are some PAX6 mutations where patients achieved visual acuities far above the aniridia average and showed a lower rate of complications [10, 11].

WAGR-Syndrome, WAGRO-Syndrome

Larger deletions of PAX6 gene, affecting the adjacent WT1 (Wilms tumor) gene are the underlying cause of the WAGR/O syndrome (Wilms tumor, Aniridia, Genitourinary anomalies, and mental Retardation/Obesity) [5, 6, 12, 13]. Patients with sporadic aniridia have a risk of about 30% of developing Wilms tumor and if there is contiguous gene deletion of PAX6 and WT1 patients show a risk of 50% of developing this tumor. Contiguous gene syndrome means that the affected DNA segment encompasses several neighbouring genes, and it comes to a phenotype with involvement of several body and cellular subsystems. Wilms tumor occurs at 80% between the first and fifth year of life (Fig. 1).

Aniridia unrelated to alterations in PAX6 gene

There are a lot of other loci and genes whose alterations can be associated with an incomplete or complete aniridia. Table 3 shows a survey on aniridia manifestations without linkage to PAX6. It has to be remembered that any case of microphthalmia can be associated with incomplete or complete aniridia [2, 14, 15, 16]. Aniridia unlinked to PAX6 show significantly less the typical complications of corneal pannus formation and vascularisations due to limbal stem insufficiency (LSCI) [3, 17] — this again promotes the nomenclature PAX6-Syndrome. Fig. 2 shows the distribution of clinical types of aniridia in 130 of our aniridia patients in Homburg/Saar. Within the higher proportion of (supposedly) sporadic aniridia, patients where no PAX6 mutation was detected are summarized as well (in particular patients with above-average good visual acuity or associated microphthalmia). In addition, this group includes patients in whom up to now no molecular genetics has been carried out (patients from abroad European or Asian (n=17) or patients with a migration background (n=18). Similarly, one has to bear in mind that germline mutations can lead to apparently sporadic aniridia, but will then be inherited and transmitted in a dominant pattern. The greater percentage of presumably sporadic aniridia is also frequently mentioned in the literature [12, 14, 15]. In our patients there is a higher frequency of female patients in the group of dominant familiar aniridia as compared to (apparently) sporadic aniridia which was not described in literature before [ADD1-3].

Ocular and systemic findings in aniridia, treatment specifics

Ocular findings at birth and during childhood

Children with manifest «aniridia» are usually diagnosed early by the paediatrician, while children with only moderate iris pathology may go undiagnosed for many years.

Variations in iris pathology range from almost total absence to only mild hypoplasia of the iris. In the less severe cases the pupil size may be normal, but there may be loss of the iris surface architecture or transillumination defects. Other iris changes include partial iris defects as atypical coloboma (not directed to the 6 o´clock position), eccentric pupils, polycoria or iris ectropion. Iris pathology can show different manifestations in severity between the two eyes of one individual (Fig. 3B).

Central small lens opacifications of the anterior or posterior capsule are often present at birth and often remain unchanged. (Fig. 4). Premature and progressive cataract formation, however, is a frequent sign in aniridia especially in children aged 5 to 15 years.

Characteristically babies have a variable degree of iris hypoplasia and foveal hypoplasia, which leads to sensory defect nystagmus (SDN) and congenitally impaired visual acuity (usually 0,1 best corrected). Aniridia is in one third of all patients accompanied by delayed visual maturation DVM — a delayed development of fixation capabilities during the first months of life which is characteristic for many inborn visual impairments. Other congenital features may include corneal opacification, glaucoma, cataract, lens subluxation, strabismus, optic nerve coloboma and hypoplasia.

There is a high intra-individual variability of ocular findings even in familiar aniridia. However, there usually are only few differences between the two eyes of an individual patient.

The following list gives a survey on possible ocular findings in Aniridia Syndrome.

Overview of the possible ocular findings in Aniridia syndrome

• Globe
  • Microphthalmia
• Cornea
  • Microcornea
  • LSCI with pannus formation: circular limbal grayish opacification extending to the corneal center, first changes are avascular, then vessels follow the
  • Corneal epithelium can contain ectopic conjuctival goblet cells
  • Corneal neovascularizations often start at the 12 and 6 position, later progress circumferentially
• Iris ( 3)
  • «Complete aniridia» — gonioscopic examination always reveals a rudimentary iris stump
  • incomplete aniridia
  • atypical coloboma
  • Ectropium uveae
• Crystalline lens
  • Congenital: frequent central polaris cataract anterior or posterior without any signs of progression ( 4)
  • Premature cataract formation → Cataract surgery often needed in childhood or youth
  • Subluxation or lentis ectopia caused by insufficient zonular fibres stability
• Intraocular pressure
  • Aniridia related secondary glaucoma often starts in childhood
  • Mechanism/pathophysiology: there is a contractile membrane over the anterior chamber angle which causes an increasing displacement of the iris stump towards the corneal endothelium, thus causing progressive blockage of the anterior chamber angle.
  • Caveat: Undiagnosed secondary glaucoma is the highest risk factor for persistant vision loss and blindness in aniridia.
• Macula and fovea
  • Hypoplasia of the macular structures
  • Foveal and foveolar hypoplasia
• Optic nerve head
  • Optic nerve head often very small
  • Hypoplasia of optic nerve
  • Dysplasia of optic nerve
• Peripheral retina
  • Hypopigmentation of the peripheral retina (i.e. the pigment epithelium) is frequent
• Changes of the sensory system
  • Congenitally underdeveloped visual acuity — inborn low vision
  • Atypical visual development
  • Delayed visual maturation (DVM)
  • Nystagmus (up to 90% of all patients)
  • Strabismus is frequent (over ¾ of patients)

 

Ocular findings and aniridia related complications in young and adult patients

Aniridia related complications: general aspects

Aniridia is characterized by numerous ocular complications possibly developing during life. This makes aniridia very different from other congenital ocular abnormalities like albinism, as patients with aniridia cannot count on their visual acuity to remain stable during school and professional life. Therefore, a patient with aniridia may be much more exposed to difficulties during academic and professional life, including long sick leaves and changing needs of adaptive technology.

The main reasons for complications with visual loss are ocular surface disease OSD due to LSCI and associated AAK (fig. 6, 7) [1, 18, 19, 20]. Premature cataract development and insufficiently managed intraocular pressure in aniridic glaucoma are further reasons for complications associated with vision loss — especially aniridia glaucoma can ultimately lead to blindness by late-diagnosed glaucomatous optic atrophy [1, 21, 22].

Anterior Segment Fibrosis Syndrome ASFS = Aniridia Fibrosis Syndrome

One further visually devastating complication has up to now only been described in aniridia: aniridia-fibrosis syndrome (AFS) (Fig. 8). This represents a non-inflammatory intraocular fibrotic scar formation, often associated with hypotension and phthisis [23] following intraocular surgery. This challenging postoperative course was first described by Tsai and colleagues in 2005 as «anterior segment fibrosis syndrome ASFS» [1].

Complications related to the crystalline lens

At birth, there often is a cataract polaris anterior or posterior (Fig. 4) usually showing no progression. Depending on the severity of aniridia and of the anomaly of the zonular fibers an early a subluxation of the lens can result, usually upwards (Fig. 5, 7). Cyclodestructive procedures may worsen the tendency of dislocation and premature cataract formation and should therefore be avoided.

Premature cataract formation often renders cataract surgery necessary in young patients. In order to avoid AAFS/AFS or late complications like chronic uveitis, we suggest to perform the smallest possible incision, foldable untinted lenses and the strict exclusion of iris replacements, iris lenses or artificial diaphragmas, ring segments and large incisions.

Secondary glaucoma (aniridic glaucoma)

Secondary glaucoma is the most threatening complication for permanent visual loss in aniridia [21, 22]. Progressive angle closure is caused by iridocorneal adhesions: a tractive membranous process pulling the rudimentary iris tissue over the trabecular meshwork. In aniridia gonioscopic examination shows fine strands which contract and close the anterior chamber angle, while Axenfeld-Rieger syndrome shows broad tissue strands.

Fig. 9 shows the optic nerve heads of an aniridic boy with distinct glaucomatous changes in the optic nerve OD. He has had a successful trabeculotomy 1,5 years ago which lead to a slight reduction in glaucomatous excavation.

Potential hazards to vision are numerous and lie within the diagnosis, follow-ups, conservative treatment and the complications of glaucoma surgery and are summarized as follows:

• Problems in diagnosing aniridic glaucoma and in the follow-up of glaucoma
  • Development of glaucoma may occur already in childhood and might be overlooked due to:
    • Reduced compliance during
    • Visual field measurements, laser scanning of the optic nerve rim, photographic documentation and other glaucoma examinations are either not possible or difficult and unreliable in young children and in patients with high amplitude nystagmus
  • Evaluation of the optic nerve head is more challenging due to :
    • Cataract
    • Progressive corneal opacification (F 6)
    • Nystagmus
    • Inborn form anomalies of the optic nerve head which render he evaluation of glaucomatous cup-disc-relation difficult: optic nerve hypoplasia and optic nerve dysplasia
    • In pre-perimetric children:
      • Use VEP (preferably pattern VEP) as a baseline for glaucoma follow up
      • Evaluate monocular colour vision and colour comparison OD/OS
    • Estimation of the validity of intraocular pressure measurement is difficult due to:
      • Corneal thickness usually is higher in aniridia.
      • Changes during the course of disease may however change this:
        • Progressive fibrotic scarring may lead to thinner cornea.
        • Secondary endothelial decompensation with edema would render an addition to the measured IOP necessary
      • Regular corneal parameter measurements are therefore necessary in aniridia patients.
    • Problems in conservative, non-surgical treatment of aniridic glaucoma
      • Severity of ocular surface disease due to LSCI in aniridia
        • Topical medications are not tolerated as well as in non-aniridic patients
        • Compliance may therefore be lower in children and in adults
        • Local pain, foreign body sensations may lead to reduced treatment adherence
        • The more local medications are needed, the more corneal problems can arise including punctate keratopathy and recurring erosions, leading to increased neovascularizations
      • Systemic side effects of topical antiglaucomatous drugs
        • This affects mainly children, but may limit the spectrum of drug subgroups decidedly
        • Beta blockers often lead to tiredness and loss of physical strength in children
      • Systemic side effects of systemic antiglaucomatous medication
        • Sometimes a temporary use of dorzolamide is necessary to regulate IOP. This may lead to
          • Lab electrolyte changes (low potassium)
          • Sickness, vomiting
          • Reduced physical fitness
        • Problems in surgical treatment of aniridic glaucoma leading to further reduction of vision
          • Spectrum of indications of antiglaucomatous surgeries differs from non-aniridic glaucoma patients
            • Gonioscopic laser surgery to reduce IOP is neither possible nor indicated in aniridia
            • Cyclophotocoagulation
              • Cyclophotocoagulation is more difficult due to:
                • Anatomic anomalies in the position of the ciliary body and the angle
              • Cyclopotocoagulation shows more postoperative complications:
                • Severe intraocular inflammation
                • Destruction of zonula fibers with consequent subluxation of the lens
                • Worsening of presenile cataract formation
              • Cyclophotocoagulation should be avoided
            • Trabeculotomy should be preferred to trabeculectomy
              • Reduced risk of Aniridia Fibrosis Syndrome
              • Repeatable if necessary
              • May be difficult due to
                • Anatomical malposition of Schlemm´s Canal
                • Limbal stem cell insufficiency and reduced visualisation
              • Glaucoma surgery involving valves (Ahmed, Baervaldt)
                • May be needed earlier than in non-aniridic patients
              • Prognosis of surgery is lower and intra-/postoperative risks of glaucoma surgeries are higher:
                • Intraoperative risks:
                  • Higher bleeding tendency
                  • Higher prevalence of inflammatory response
                  • Less predictability of surgery
                • Postoperative risks:
                  • Less predictability of stability of IOP lowering
                  • Higher scarring risk
                  • Higher risk of recurrence of elevated IOP
                  • Risk of permanent low pressure, choroideal detachment without normalization of IOP and consequent atrophy and phthisis formation
                  • Risk of developing Aniridia Fibrosis Syndrome is directly related to the extent of trauma during intraocular surgery
                • Repeat surgery is needed more frequently than in non-aniridia glaucoma surgery
                  • This should be explained to the patient
                  • Better do a careful surgery with less risk of AFS and secondary scar formation even if that means doing a repeat surgery than doing a glaucoma surgery too forcefully
                • Anatomy of Schlemm´s Canal and trabecular meshwork is different
                • High rate of scarring and of consequently insufficient lowering of IOP
                • CAVE: risk of Aniridia Fibrosis Syndrome
                • Valve surgery is needed more often than in non-aniridic glauccoma
              • Summary: Points to remember when treating aniridia patients and treating aniridic glaucoma
                • Diagnosis of glaucoma
                  • Glaucoma may occur early in childhood
                  • Each visit of any aniridia patient has to include IOP measurement, irrespective of age
                  • Lack of cooperation or visibility must not lead to undiagnosed glaucoma!
                  • If in doubt: perform exam under general anaesthesia
                  • Take corneal thickness into account
                • Follow-up in aniridic glaucoma
                  • Check corneal parameters at least yearly
                  • Try perimetry as soon as possible
                  • Do a baseline VEP (pattern)
                  • Low IOP is the best neuroprotective treatment – IOP should not exceed 16 mm Hg
                  • If in doubt à treat!
                • Conservative treatment of glaucoma
                  • Take corneal surface disease and LSCI into account
                  • Monitor OSD and LSCI
                  • Limit of topical drugs should be 3 to avoid further strain to the cornea
                  • Always use preservative free eye drops (!)
                  • Add corneal epithelial support (dexpanthenone, hyaluronic acid) if a patient constantly needs antiglaucomatous treatment
                • Surgical treatment of glaucoma
                  • Repeat surgery is needed more frequently than in non-aniridia glaucoma surgery
                    • This should be explained to the patient
                    • Better do a careful surgery with less risk of AFS and secondary scar formation even if that means doing a repeat surgery than doing a glaucoma surgery too forcefully
                  • Anatomy of Schlemm´s Canal and trabecular meshwork is different
                  • High rate of scarring
                  • CAVE: risk of Aniridia Fibrosis Syndrome
                  • Valve surgery is needed more often than in non-aniridic glauccoma

 

Corneal complications — LSCI: pannus formation, vascularized corneal scars, AAK, secondary nodular degeneration of Salzmann.

While secondary glaucoma massively endangers aniridia patients visually, patients with AAK commonly suffer from recurring and sometimes severe OSD related pain and changes in visual acuity, both of which significantly affect everyday life.

PAX6-related aniridia shows a congenital anomaly of the stem cell niche and consequently leads to severe LSCI limbal stem cell insufficiency, thus impairing epithelial cell integrity, epithelial regeneration and healing.

The first sign of LSCI is a grayish avascular pannus formation in the corneal periphery, starting at the 6 and 12 o`clock position (Fig. 6), then involving the whole limbal circumference.

With progressing conjuctivalization of the cornea and immigration of goblet cells, neovascularizations start to invade the cornea and progress centripetally [3, 18, 19]. This development is accompanied by increasing loss of epithelial integrity and epithelial wound healing problems, recurrent erosiones and the risk to develop corneal ulcerations. In some patients, in addition to the vascularized corneal opacities a Salzmann´s secondary nodular degeneration develops. This, however, can be treated more easily than the vascularized corneal scars: Eximer laser assisted phototherapeutic keratectomy (PTK) and pannectomy can notably improve the corneal surface and provide the patient with a slightly better visual acuity at least for some months or years.

Extensive cyclophotocoagulation in aniridia glaucoma can massively speed up the process of corneal decompensation and vascularized scar formation (Fig. 10) and should therefore be avoided.

Prevention respectively delay of corneal complications?

Up to now, there is no evidence-based prevention of AAK. In our opinion the most efficient preventive treatment of LSCI-related AAK is the prophylaxis of chronic nutritional disorders of the cornea, as these usually result in epithelial disintegration and ocular surface disease. A continuous local therapy started in early childhood with preservative-free gels, artificial tear drops or ointments, e.g. medications containing hyaluronic acid, may according to our still limited experience slow down at least a quick progression of AAK.

Systemic findings in patients with PAX6 related aniridia

In recent years, more systemic abnormalities were also revealed in patients with PAX6-related aniridia, emanating from the other anatomical areas where PAX6 acts as important control gene of embryonic development [3, 4, 11]. The systemic features are summarized in table 2 [3, 4, 11, 24].

The knowledge about these PAX6 gene related developmental influences is especially important when caring for aniridic children who show developmental delays — not everything might be due to inborn low vision, but could be directly related to PAX6-Syndrome. We therefore suggest to examine any aniridia child exhibiting a suspended development according to the findings listed in table 2.

Routine examinations and complication management — proposal to implement supra-regional «Aniridia Guides» (AGOs)

Proposal of implementation of regional «Aniridia Guides» — AGO: Aniridia Guide Ophthalmology

Congenital aniridia is a disease which involves nearly all ophthalmological subspecialties: during the first years a paediatric ophthalmologist with experience in congenital low vision and nystagmus is needed, plus examinations and treatment for strabismus and amblyopia are necessary (too often amblyopia is missed in visually handicapped children!). Later, other subdisciplines are needed as aniridia related complications arise: anterior segment surgery (cataract), glaucoma specialist, corneal specialist, in case of Aniridia Fibrosis Syndrome or retinal detachment (higher prevalence in aniridia) a vitreoretinal surgeon is needed.

Livelong the patient will need a dedicated low vision ophthalmologist who, apart from trying and prescribing low vision devices, can as well support the patient with many socio-legal aspects (application for handicap-related state benefits, requesting a specialized handicapped identity badge, claiming the benefit of time extension for written exams and many more) where professional expertise and written expert opinions are mandatory.

Our experience

Many patients of our aniridia center had been seen for many years by one single ophthalmologist. Usually, that was in a hospital setting, not in one-physician health insurance covered practices which usually deal with approx. 80% of all ophthalmological patients in Germany. Often, the regional university or municipal hospital and the treating ophthalmologist had been chosen when a first complication had manifested — therefore, the patients were either with an anterior segment surgeon, a glaucoma specialist or with a corneal consultant and surgeon.

Usually the patients remained there for further examinations.

From our patients we learned that very often the subspecialist would mainly concentrate on his specialty. This could lead to progression of other complications and in the worst case could even result in blindness due to permanent optical nerve damage. In addition, the treating ophthalmologist (mostly being a surgeon) had no or little connection to and knowledge about low vision support services. We often see patients who had up to now not been informed in detail about academic, occupational and social low vision and legal support possibilities. In no way do we want to be the weisenheimer of fault-finder — on the contrary. We just want to point out that nowadays, with techniques progressing in all fields and subspecialty knowledge expanding, it is not possible any more to comprehensively treat a disease as complex as aniridia by just one ophthalmologist / one hospital.

Conclusion: supraregional AGOs (Aniridia Guides Ophthalmology) for continuous care of all aniridia related aspects and — if needed — only the best subspecialists in case of complications AGOs (Aniridia Guides for Ophthalmology) should possess the following standards in order to successfully support the aniridia patient:

• Main consultancy as low vision and / or paediatric ophthalmologist
• Interest in the demanding task of following up aniridia patients
• Technical requirements for a comprehensive follow-up should be in-house:
  • Glaucoma services (computer assisted perimetry, laser scanning of the optic nerve, OCT)
  • Corneal services including topography, anterior segment OCT
  • Ocular surface disease clinics

 

• Broad experience in re/habilitative care and socio-legal aspects of low vision patients of all ages, including
  • A low vision department in his/her clinics
  • Functional contact members:
    • Early visual support teams
    • Schools for visually handicapped
    • Inclusion / integration support offices
    • Social benefit / welfare offices
    • Manufacturers of adaptive, optical and electronical low vision devices

 

• Profound ophthalmological and ophthalmopathological knowledge, especially in:
  • Glaucoma
  • Limbal stem cell insufficiency and sequelae
  • Ocular surface disease
  • Postoperative care for corneal transplants and glaucoma surgery patients

 

• Having or creating a functionally effective network to experienced surgeons of all subspecialties (!)
  • Arranging cooperation and quick referral options for the patient

 

From this short list, two facts seem evident:

• The AGO usually works in a hospital setting, mostly at a University Hospital
• Usually, not all subspecialists work at the same place à the AGO uses his subspecialists network to send the patient for optimal surgical treatment and sees the patient postoperatively.

In our opinion, a country of the size of Germany (~ 370.000 km²) and a population of nearly 81 million people should at least have 4, better 6 AGOs evenly distributed in Germany depending on population densities.

As the Fig. 11 shows, population density is very variable in Germany (as in most European countries) and contrasts with the density of ophthalmologists. There are areas of high population density and high ophthalmologist density — especially counties like Nordrhein-Westfalen have many Universities, many confluent cities and thus a high rate of ophthalmologists per 100.000 citizens.

There are regions in Germany, however where the ophthalmologist density seems to be sufficient (Sachsen-Anhalt, Thüringen, Mecklenburg) but where the population density is so low that individual patients have to travel long ways to reach an ophthalmologist.

All these aspects have to be taken into account if one wants to implement supraregional AGOs for Germany who will have equal shares and demands to work up with the aniridic patients.

Mismanagement or delayed treatment in each of the subspecialties can potentially lead to blindness, which might be irreversible (fibrosis syndrome, glaucoma). In addition, as the patients reach school age and later needs to find and follow an occupational career, low vision support has to be flexible to changing visual acuities due to complications and their treatment. In aniridia, vision can never be expected to be stable and reliable as in other congenital visual impairments — e.g. albinism.

The following conclusive enumeration summarizes the «to dos» of routine check-ups and complication management in aniridia patients.

Non-surgical care

Early improvement of retinal image and promoting visual development

The young aniridic child should be treated and supported as early as possible to promote the development of visual acuity and to prevent or delay the occurrence of complications.

Early visual support helps the brain to learn to use (reduced) visual inputs as well as possible — in spite of the morphological changes of the eyes.

The following schedules should be followed for children with aniridia as soon as the diagnosis is confirmed:

• Protection from glare and optimization of the visual input and the retinal image
  1. Cycloplegic refraction
     1. In aniridia there is often a myopia or hyperopia and astigmatism – these are optical aberrations of the eye which can and should be corrected to improve the visual quality the child perceives
  2. Prescription of two pairs of spectacles
     1. Both pairs of spectacles need to block UVA and UVB light, they need a blocking filter at 400nm
     2. One pair should have a light dampening of 20% (for inside and cloudy days outside)

• The other pair of glasses should have a tint of 80% (outside, sunny days)

Early Intervention for low vision children

The paediatrician and the ophthalmologist should not underestimate the benefits of early low vision intervention for the very young aniridics: of course, one cannot actually «treat» foveal hypoplasia and optic nerve dysplasia. But in spite of them being present, one can promote and improve visual perception and therefore enhance visual development during the first 6 years. Neither anterior segment changes nor foveal and optic nerve hypoplasia imply a “given” or “static” low visual acuity.

Vision is a learned function!

One can train visual development, and the difference between 0,05 and 0,2 may be very important for later life! Muscles, for example, can be trained life-long. But with visual development and the plasticity of the brain, one is confined to the first 6-8 years. Chances not used then are lost forever.

Therefore any aniridic child should be correctly refracted, should be given spectacles and should be connected to Early Low Vision Intervention services as soon as possible. In addition, parents should be encouraged to support visual development in a playful manner at home.

• Support of early visual development
  1. Getting into contact with early low vision intervention services
     1. The services can often be located at the regional schools for visually handicapped children.
  2. Tell parents to start early support at home by playfully inspiring the child to look at high contrast objects, promoting the eye-hand-contact and the child´s interest to visually explore the surroundings — this as well helps the general development concerning motor and social and cognitive development.

Early prevention of possible complications

Details for prevention and possible delay of aniridia related complications see above. The following list summarizes the most important aspects.

Prevention respectively delay of later complications

1. Early start of protective cornea and tear film treatment à supports corneal epithelium
   1. Artificial tear drops over the day
   2. Gel or nourishing ointment to be applied every night

• No preservation additives!

1. Regular measurements of IOP à early detection of glaucoma
2. Wearing the UV-blocking glasses à may delay cataract formation, beneficial for OSD

Low Vision Aids Prescription

Low vision control strategies

• Establish the cause of visual loss
• Surgical interventions if appropriate
• Assessment of the child’s various visual functions (distance vision, near vision, contrast sensitivity, and visual field)
• Contrast sensitivity testing
• Glare testing
• Color vision testing
• Refraction and provision of spectacles
• Examine and improve contrast sensitivity and contrast vision (important!)
• Low vision devices (magnifiers)
• Non-optical low vision devices (reading stands)
• Training in the use of devices with follow-up
• Monitor stability or progression of disease and changes in visual abilities as rehabilitation progresses
• Assess eccentric viewing postures and skills
• Assess scanning ability (for patients with restricted fields)
• Assess patient motivation
• Teach basic concepts and skills (i.e., to eccentrically view) relevant to the rehabilitation process.

The goal of a low vision exam is to help maximize the use of remaining vision. Contrast sensitivity has emerged as a valuable measure of visual glare sensitivity, amount of light needed. Reduced contrast sensitivity can affect reading ability, ability to navigate through the environment, and risk for falls.

Surgical Care

Just the best subspecialists for the aniridia patient!

As said above, in our opinion only the best surgical subspecialists should treat aniridia patients. This will ensure that «the best» subspecialists will have more exposure to aniridia patients which helps for future treatments.

This may include sending the patient away from the hospital where the AGO works — but good networking should ascertain that the patient returns for postoperative and future checks.

In our opinion this might be the only way to reduce vision threatening complications like aniridia fibrosis syndrome.

Other ophthalmosurgery in aniridia

Often aniridia patients need additional ophthalmic surgery, as for example:

• Ptosis
• Nystagmus
• Strabismus

 

Social, academic and legal support given by the «Aniridia Guides» and Low Vision Consultants

Support group

All families afflicted by aniridia should be brought into contact with the regional and national Aniridia Support group. Aniridia Russia is already a very active support group trying to achieve the best possible care for all Russian patients.

Help for integration and inclusion

Inclusion refers to the integration of students with special needs learning alongside students without special needs in regular schools and classes with appropriate supportive services. Inclusion helps blind /low vision children go to schools within their own localities and interact with children within their own communities and adopt norms and values of their own communities.

Medical and educational assessment provides the opportunity for parents of blind and low vision children to work with them. It helps equip them with skills on how to motivate them to explore the wider world and engage in daily living and survival skills.

Low Vision and assessment centres are ideal for early clinical identification, diagnosis, appropriate intervention and placement for blind and low vision children. There is however, the need to make kindergarten and schools more inclusive with the availability of accessible schools, support services teaching and learning materials.

Vision is not defined by the eyes only!

A person with low vision has severely reduced visual acuity and/or has significantly obstructed field of vision that cannot be corrected by glasses, medicine or surgery. Persons with visual impairments face a variety of challenges on a day-to-day basis. These difficulties often lead persons with visual impairments to suffer from loneliness, social and peer isolation, and depression with behavioural challenges.

Congenital low vision may cause a lifelong reduction in a child’s visual performance. Reading is one of the main avenues for education and educational achievement. If visual impairment affects the child’s ability to read, it could be a great impediment of his/her educational success.

Reading is a first step in education and is a predictor of good academic success. Children with low vision usually need some form of magnification to resolve letters that are lower than their threshold. With a detailed low vision examination and an accurate visual correction, children might achieve a better reading performance. There are other examinations than visual acuity that should be included in the low vision examination. Acuity reserve and contrast reserve are good predictors of reading performance and are important in children. The optimum magnification, acuity reserve and contrast reserve tend to lead to the optimum possible reading fluency. 

Conclusions

Table 4 and fig 12 summarizes the conclusions, and lists the points the supervising ophthalmologist needs to think about when caring for an aniridia patient, depending on age and course of disease. The aim should be to prevent a rapid progression and reduce complications as much as possible.

Table 4 is a modification of a table developed for the Aniridia Broschure recently presented by the European Aniridia support group Aniridia Europe. The author was one of the authors of the broschure and developed the «What to think of» table. Therefore there is no copyright problem present — and physicians should know as well as our patients what the important points in treating aniridia are!

 

REFERENCES

1. Shimo N., Yasuda T., Kitamura T., Matsushita K. et al. Aniridia with a heterozygous PAX6 mutation in which the pituitary function was partially impaired. Intern Med, 2014; 53(1): 39-42.
2. Käsmann-Kellner B., Seitz B. Das Aniridie-Syndrom. Klinische Befunde, problematische Verläufe und Vorschlag zur Betreuungsoptimierung („Aniridie-Lotse“). Ophthalmologe, 2014; DOI 10.1007/s00347-014-3058-4.
3. Hingorani M., Hanson I., van Heyningen V. Aniridia. Eur J Hum Genet, 2012; 20(10): 1011-1017.
4. Peter N., Leyland M., Mudhar H., Lowndes J. et al. PAX6 mutation in association with ptosis, cataract, iris hypoplasia, corneal opacification and diabetes: a new variant of familial aniridia? Clin Experiment Ophthalmol, 2013; 41(9): 835-841.
5. Simioni M., Vieira T., Sgardioli I., Freitas E. et al. Insertional translocation of 15q25-q26 into 11p13 and duplication at 8p23.1 characterized by high resolution arrays in a boy with congenital malformations and aniridia. Am J Med Genet A, 2012; 158A: 2905-2910.

6. Tsai H., Freeman J., Chan C. et al. A progressive anterior fibrosis syndrome in patients with postsurgical congenital aniridia. Am J Ophthalmol, 2005; 140: 1075-1079.

1. Bamiou D., Campbell N., Musiek F., Taylor R. et al. Auditory and verbal working memory deficits in a child with congenital aniridia due to a PAX6 mutation. Int J Audiol, 2007; 46(4): 196-202.
2. Bamiou D., Free S., Sisodiya S., Chong W. et al. Auditory interhemispheric transfer deficits, hearing difficulties, and brain magnetic resonance imaging abnormalities in children with congenital aniridia due to PAX6 mutations. Arch Pediatr Adolesc Med, 2007; 161(5): 463-469.
3. Malandrini A., Mari F., Palmeri S., Gambelli S. et al. PAX6 mutation in a family with aniridia, congenital ptosis, and mental retardation. Clin Genet, 2001; 60(2): 151-154.
4. Beby F., Dieterich K., Calvas P. A [c.566-2A>G] heterozygous mutation in the PAX6 gene causes aniridia with mild visual impairment. Eye (Lond), 2011; 25(5): 657-658.
5. LimT., Seo E., Kim G., Ahn H. et al. Comparison between aniridia with and without PAX6 mutations: clinical and molecular analysis in 14 Korean patients with aniridia. Ophthalmology, 2012; 119(6): 1258-1264.
6. Grønskov K., Olsen J., Sand A., Pedersen W. et al. Population-based risk estimates of Wilms tumor in sporadic aniridia. A comprehensive mutation screening procedure of PAX6 identifies 80% of mutations in aniridia. Hum Genet, 2011; 109(1): 11-18.
7. Law S., Sami M., Piri N., Coleman A. Asymmetric phenotype of Axenfeld-Rieger anomaly and aniridia associated with a novel PITX2 mutation. Mol Vis, 2011; 17: 1231-1238.
8. Brémond-Gignac D., Bitoun P., Reis L., Copin H. et al. Identification of dominant FOXE3 and PAX6 mutations in patients with congenital cataract and aniridia. Mol Vis, 2010; 16: 1705-1711.
9. Henderson R., Williamson K, Cumming S., Clarke M. et al. Inherited PAX6, NF1 and OTX2 mutations in a child with microphthalmia and aniridia. Eur J Hum Genet, 2007; 15(8): 898-901.
10. Khan A., Aldahmesh M., Mohamed J., Hijazi H. Complete Aniridia with Central Keratopathy and Congenital Glaucoma is a CYP1B1-related Phenotype. Ophthalmic Genet, 2014; 35(3): 187-189.
11. Le Q., Deng S., Xu J. In vivo confocal microscopy of congenital aniridia-associated keratopathy. Eye (Lond), 2013; 27(6): 763-766.
12. Gregory-Evans K., Cheong-Leen R., George S., Xie J. et al. Non-invasive anterior segment and posterior segment optical coherence tomography and phenotypic characterization of aniridia. Can J Ophthalmol, 2011; 46(4): 337-344.
13. Kothari M., Rao K., Moolani S. Recurrent progressive anterior segment fibrosis syndrome following a descemet-stripping endothelial keratoplasty in an infant with congenital aniridia. Indian J Ophthalmol, 2014; 62(2): 246-248.
14. Netland P., Scott M., Boyle J., Lauderdale J. Ocular and systemic findings in a survey of aniridia subjects. J AAPOS, 2011; 15(6): 562-566.
15. Almousa R., Lake D. Intraocular pressure control with Ahmed glaucoma drainage device in patients with cicatricial ocular surface disease-associated or aniridia-related glaucoma. Int Ophthalmol, 2014; 34(4): 753-760.
16. Gramer E., Reiter C., Gramer G. Glaucoma and frequency of ocular and general diseases in 30 patients with aniridia: a clinical study. Eur J Ophthalmol, 2012; 22(1): 104-110.
17. Käsmann-Kellner B., Seitz B. Kongenitale Aniridie oder PAX6-Syndrom? Ophthalmologe, 2014; DOI 10.1007/s00347-014-3058-4.
18. Rixen J., Cohen A., Kitzmann A., Wagoner M. Treatment of aniridia with Boston type I keratoprosthesis. Cornea, 2013; 32(7): 947-950.

 

Table 1.

References to PAX6 aniridia

References	Meaning	Aniridia PAX6-associated (11p13)
ICD-9	International Classification of Disease, Version 9	743.45
ICD-10	International Classification of Disease, Version. 10	Q13.1
OMIM	Online Mendelian Inheritance in Man	–      106210 – AN–      194072 – WAGR–      612469 – WAGRO–      206700 – Gillespie-Syndrom –      136520 – Foveal Hypoplasia Type I FVH1 with or without anterior segment anomalies
DiseaseDB	Disease Database	723
MeSH	Medical Subject Headings	D015783

 

Table 2.

Subtypes of PAX6 related aniridia

OMIM	Details
106210	AN – «Isolated» Aniridia (haploinsufficiency in intragenic mutation): Possible metabolic findings:ê  Diabetesê  Obesity ê  Disturbances of melatonin metabolism (Epiphyseal gland) Possible anatomical and neuroanatomical findings: ê  Hyposmia, anosmia (hypoplasia of the bulbi olfactorii) ê  Hypoplasia or aplasia of the epiphyseal gland ê  Unilateral disturbances of gyration ê  Hypoplasia of corpus callosum ê  Hypoplasia of the anterior commissura Possible nephrologic findings: ê  WAGR or WAGRO-Syndrome ê  Not depending on WAGR(O): renal insufficiency may present in middle adult age
106210	Syndromatic aniridia — Subtypes:ê  Aniridia + mental retardationê  Aniridia + ptosis + mental retardationê  Aniridia + ptosis + mental retardation + obesity – sporadic ê  Aniridia + ptosis + mental retardation + obesity — dominant ê  Aniridia + missing patella ê  Aniridia + uni- or bilateral renal agenesis + mental retardation ê  Aniridia + progressive renal insufficiency
194072	WAGR – Syndrome (Miller-Syndrome, 11p-Syndrome)
612469	WAGRO – Syndrome
206700	Gillespie-Syndrome: Aniridia + cerebellar ataxia + mental retardation
136520	Foveal hypoplasia Type I FVHI with or without anterior segment anomalies

 

Table 3.

Clinical manifestations of complete or incomplete aniridia without association to PAX6 gene defects (selection)

Chromosome	Gene	Clinical Manifestationen (described with and without aniridia)	Heredity
6p25.3	Forkhead box C1 Gen (FOXC1)	Iridogoniodysgenesis Type I IRID1	AD
4q25	Paired-like Homeodomain Transcriptions faсtor 2 (PITX2)	Rieger-Syndrome Type 1 RIEG1Iridogoniodysgenesis Typ II IRID2Peters Anomaly	ADADAR >> AD
2p22.2	Cytochrome P450 Family 1 Subfamily B Polypeptide 1 — Gen(CYP1B)	Congenital Glaucoma Type 3AJuvenile GlaucomaPeters Anomaly [2]	ARARAR >> AD
Microphthalmia	SOX2, OTX2, PAX2, CHD7, POMT1		AR

 

Table 4.

Suggestions for optimization of the care for aniridia patients

 

Figure 1.

There are syndromatic faces of two unrelated WAGR patients. WAGR children often show slight syndromatic signs: hypotonia, anteverted nares, slightly low-set ears

 

Figure 2. Distribution of clinical types of aniridia in 130 patients in Homburg/Saar

 

Figure 3. A — photo eye with complete aniridia; B — patient’s photo with different manifestations in severity between the two eyes

 

 

Figure 4. Aniridia polar anterior cataract

 

Figure 5. Subluxation or lentis ectopia caused by insufficient zonular fibres stability, lens subluxation leads to refractive problems

 

Figure 6. Photo demonstrates in three youngsters with PAX6-related aniridia how different the clinical course in LSCI and AAK may be in individuals

 

Figure 7. Girl, 14 years, IOP 40+, severe finding of keratopathy, mature and luxated cataract. Visual acuity at first presentation is no light perception

 

Figure 8. Aniridic eye having suffered from AFS. Anterior chamber filled with fibrotic scars, corneal decompensation (female patient, aged 64)

 

Figure 9. Aniridic boy, 4 years, cataract left eye ˃ right eye, OD successfully treated by trabeculotomy 1.5 years ago

Figurе 10. Boy, aged 6, aniridia glaucoma from 1^st year of life, had multiple cyclophototreatments elsewhere; now continuous pain (reason of first presentation), ulcus formation, IOP not regulated

 

Figure 11. Density of ophthalmologist compared to density of inhabitation / citizens per km²

Source: Destatis, Database GENESIS, Health 2014, Data: IGES and Bertelsmann Foundation; own choice of parameters and compilation (2014)

Figure 12. Graphical representation of all requirements and medical and non-medical needs an aniridia patient faces during life and demonstrating the need of an Aniridia Guide Ophthalmology (AGO)