Lupine Publishers | Aspects of Correction of Ametropiya in Children Congenital Cataracts

 Lupine Publishers | Trends in Ophthalmology Open Access Journal 

Introduction

Congenital cataract (CC)is the most common cause of treatable childhood blindness. It is responsible for 5-20% of the cases of blindness worldwide. However, the incidence of visual impairment may be higher in developing countries [1]. The prevalence of childhood cataract varies from 1.2 to 6.0 cases per 10,000 infants. Pediatric cataracts are responsible for more than one million cases of childhood blind- ness in Asia. In developing countries, such as India, 7.4-15.3% of childhood blindness is due to cataracts [2,3]. Therefore timely removal of a cataract with the subsequent fast visual rehabilitation has paramount value for children. The Congenital Cataracts take an important place in structure of blindness and low vision and are one of the main reasons for disability on sight since the childhood. Now the cataract of children is one of current problems of children’s ophthalmology considering its rather high prevalence and a significant role in structure of blindness and low vision.

As a consequence of lenticular opacity, the development of the visual analyzer is disturbed and amblyopia is formed, the treatment of which requires significant and long-term efforts on the part of ophthalmologists and parents. Among the causes of blindness in children for the share of congenial cataracts falls from 7,5 (in economicallt developed countries) upto 27,4% (in socially deprived regions). The prevalence of cataracts in developed countries, as well as in Russia makes 1,6-2,4 per 100 000 children [4].

Due to the early violation of the correct development of an organ of vision, a delay of normal psychological formation of the personality and high level of an invalidization restoration of sight at children with a cataract is an important problem of ophthalmology. An important point after extraction of CC is the early, full and constant korretion of an afakiya promoting normal maturing of the central mechanisms of the touch analysis on the basis of which process of visual perception is implemented [5]. There are several reasons for which the correction of aphakia differs between children and adults. First, a child’s eye is still growing during the first few years of life and during early childhood, the refractive elements of the eye undergo radical changes. Second, the immature visual system in young children puts them at risk of developing amblyopia if visual input is defocused or unequal between the two eyes. Third, the incidence of many complications, in which certain risks are acceptable in adults, is unacceptable in children [6].

Currently, the only type of treatment of a cataract is surgical intervention. Modern tactics of maintaining children with CC is based on early surgical treatment. In surgical treatment of CC for many years technology of the operation was improved [7]. One of the most important is the issue of the timing of surgical measures at CC. At present most of the authors adhere to the opinion, that total, lamellar and cantral cataracts with the area of opacification more than 2.5mm should be operated within first three monhts after the birth of a child [8-11], and at the paracentral and central cataracts less than 2.5mm in the diameter-perhaps dynamic observation. Such differentiated approach is caused, first of all, by high risk of carrying out surgical intervention, especially at small children and, undoubtedly, complexity of selection of adequate correction of an afakiya that can aggravate already available violations of binocular interaction [4,12].

Currently, the question of expediency of excision of the posterior capsule during extraction of CC remains debatable. According to the data of the number of authors single-step posterior capsulorhexis does not prevent the development of secondary cataracts, which is preconditioned by the high regeneratory ability of the child’s eye, that is why it is recommended to to primarily preserve the transparent posterior capsule in order to prevent inflammatory reactions, stabilization of the crystalline humor and intraocular lenses (if it’s implanted) and other complications. And in the future, the second stage, if the posterior capsule has gone dull witin the time, to perform YAG-laser (laser on yttrium-aluminium garnet, activated by the neodymium) or surgical posterior capsulotomy. Other authors inform about the primary posterior capsulotomy at planned aphakia or pseudophakia in order to prevent the development of secondary cataracts, as well in small children, who are not capable of dealing with YAG-laser capsulotomy without anesthesia [13].

The first implantation of intraocular lenses (IOL) at children in the early fifties carried out E. Epstein and P. Choyce [14]. Also, a controversial issue in surgery of CC is the method of correction of aphakia -there is no any concurrent view yet, assuming a systematic approach to the issue of correction of aphakia. Removal of cataract is necessary to perform simultaneously with full, constant, more physiological correction of aphakia, which ensures ingress of a clearly focused image into the retine, receipt of full-fledged signals in the optic nerve and promoting normal maturation of the central mechanisms of sensory analysis. However, there are two alternative methods of correction of aphakia: using IOL and soft contact lenses (SCL). Each of them has its advantages and shortcomings.

Intraocular correction a more physiological, provides continuous early correction, many studies have shown the effectiveness (reduction of aniseikonia size 2.5 times, high frequency of recovery of binocular vision), good tolerance and safety of IOL. Therefore, most surgeons use use only intraocular correction as a primary optical correction [9].

Multiple studies have shown that it may be technically feasible to implant an IOL shortly after birth, but outcomes have not dramatically improved and the rate of adverse events has increased. Recently, the prospective Infantile Aphakia Treatment Study (IATS) has reported no significant benefit in this approach, with the conclusion by Plager et al. [12] that surgeons should exercise caution when considering IOL implantation in children younger than 7 months.

However, some authors do not implant IOL to children before 18 months of life, and at the age between 18 -24 months under special sircumstances (for example, lack the chance to use SCL) and only at ACC and without comorbidity in the form of microphthalmia [4]. Other authors incline to application of contact correction of an aphakia, including it in the first corrective way which undoubted advantage is the possibility of modeling of refraction effect in the growing eye of the child [3,15]. However, apart from the wellknown negative aspects of exposured correction (microtrauma, development of infectious complications, individual intolerance) in children of an early age, there is a problem of compliance with the continuity of correction, the frequency of incidence of which increaes with age, also the replacement of dioptricity at exial eye growth and change of refringance. But the uncorrected aphakia is equal to the non-operated CC [16].

These literatures on postoperative complications at intraocular and contact correction (secondary glaucoma, ocular hypertension, manifest deviation, inflammatory reaction, secondary cataracts, dihescence, pupillary block, IOL dislocation, detached retina, erosion, corneal ulcer, keratopathy) after extraction of CC are various which also change depending on the period of observation [14]. However, there is still no single approach in choosing the method of correction of aphakia [9]. The most optimal correction of aphakia at the present time is the implantation of the posterior chamber intraocular lens (IOL) [10] now. At the same time, despite existence of a set of formulas of calculation of optical power of IOL, refraction mistakes are one of problems of intraocular correction of a congenital cataract in children and make according to various authors from - 10.0 up to 6.5 D [10].

In the development of visual functions after removal of the CC the adequate correction of aphakia plays an important role, which should be constant and complete, providing an hit of a clearly focused image into the retina, the receipt of full signals to the optic nerve, contributing to the normal maturation of the central mechanisms of sensory analysis [5]. Alternative advanced methods of correction of aphakia are intraocular and exposired, each of which has its advantages and disadvantages [10]. Implantation of IOL in children, though not without disputed issues, has obvious positive result [7].

Many questions are raised by discussions to this day. At description of cataract surgery in children, especially junior group, main particularity is that, that the eye is not fully formed and continues to grow. It causes difficulties in calculation of IOL and sometimes in the surgical equipment. There are nomograms for calculation of IOL in children, but, according to a number of authors, they can be used only in some standard cases. In practice it is necessary to consider the age of the child, bilateralism of a cataract, the status of an ambliopiya, possible difficulties connected with glasses wearing or contact lenses, the hereditary anamnesis, the accompanying general and eye diseases, adequacy and the social status of parents. When doubting of correctness of postoperative vision of a child (care and wearing of contact linses, timely replacement and selection of spectacle correction, competent and regular pleopto-orthoptic treatment), at implanting of intraocular lens it is better to focus on emmetropic refraction, as it is better to get myopia in the perspective with corrected visual acuity, than amblyopia [17,18].

In case of unilateral cataract the prognosis is worse, as the visual analyzer on this side does not develop unlike the healty eye. That is why unilateral cataract should be operated as early as possible: according to the data of some authors (Dr. Packer), within the first 3 weeks of life, as soon as the pediatricians say that the baby can tolerate anesthesia [19,20]. Other authors give the period of first 10 weeks of life [21]. Patients with ambilateral cataract can wait for longer from 6 months up to one years old, since both eyes do not see and none of them has the opportunity to dominate over the other one. Aphakia is possible in cases of ambilateral cataract with foloowing implanting of intraocular lens to 4-6-years of age [22]. But even with bilateral cataract waiting is not the best way to get perfect postoperation result. Data on functional results regarding the methods of correction of aphakia are also contradictory and ambiguous [18].

So, in some works at the comparison of aphakia correction methods statistical difference on vision acuity is not observed [4]. In the study of children with unilateral pseudophakia and aphakia, also no any difference is shown and the authors recommend to perform intraocular correction only in those cases where the use of SCL would be more onerous and will result in significant periods of correction absence [23]. However, the study of long-term results of visual acuity after extraction of two-sided CC with and without IOL implantation showed the best results in intraocular correction (with IOL implantation vision reduction made 29.0%, without IOL implantation-71.0%) [1]. Questions related to the calculation of the strength of the implantable intraocular lens remains open to date. When choosing intraocular correction of aphakia, the optical power of IOL is calculated individually for each patient according to the formulas SRK-II, SRK/T, Holliday 1, Vinkhorst, Hoffer Q, Haigis, Ivashina -Kolinko and automated techniques. In this case, the key point is the choice of the target refraction [24].

Difficulties of calculation of optical power of IOL and forecasting of desirable refraction effect of operation are connected with the forthcoming growth of the children’s eye which is followed by change of a refraction. L. N. Zubareva, A. L. Moskvichev (1992) identified the age groups by the growth of the anterior - posterior axis of the pseudofakic eye: from 5 to 9 years 2/3 of the growth of the anterior-posterior axis of the eye and 1/3-from 9-10 to 14 years. This necessitates the correction of ametropia of the artificial eye in the long term after surgery. Calculation of the optic power of IOL is performed mainly by the formula SRKII and SRKТ, considering sagittal size of the eyeball (APA), refracting power of the cornea and individual constants of the chosen model of IOL, also HofferQ and HolladayI, depending on the age of a child. At the calculation of the optical power of the implanted IOL in children of the first year of life, define the quantity of hypocorrection (from +4,0D to +14,0D) of the optical power of IOL, calculated by the formula, taking into account the optical power of the cornea and difference of the origina; APA and forecasted APAafter completion of a physiological growth of an eye [19].

There are different coints of view when choosing the power of implanted intraocular lens in children: implant IOL, calculated per emmetropia at the moment of surgery, with the following replacement, excimer correction or implant IOL less wit the account of hypocorrection, deductible from the calculated lens per emmetropia at the moment of surgery. None of this methods is perfect. Their drawbacks are the risks of development of ametropia of different level, refractive amblyopia, necessity in repeated surgical intervention at an older age [14].

The literature data presented in relation to the approach to the choice of the optical power of the implanted IOL remain poorly reasoned and contradictory (taking into account the age of children at the moment of surgery, only the size of the axial length of the eye at the time of surgery or bi-and unilateral nature of the CC). In the other work at the unilateral CC it is recommended to choose the optic power of IOL to emmetropia, and at the bilateral CC to implant the lens of such optical power, so the necessary correction does not exceed ± 3,0 dptr. N. F. Bobtova, А. К. Djekov at the choice of the optical power of the implanted IOL forcused on the age of children at the moment of surgery, performing the hypocorrection of IOL in the average to +7,1 ± 1,2 dprt during surgery at the age of up to 6 months, +4,0 ± 1,3 dptr, during surgery at the age of 7 -12 months and +2,0 ± 1,3 dptr, in children at the age from 1 to 2 years, «gradually» decreasing to years up to +1,7 ± 1,5 dptr [10]. Similar approach to the calculation of IOL, focusing on the age of children at the moment of surgery, described I. S. Zaydullin, R. А. Aznabayev: hypocorrection +10,0 -(+ 12,0) dptr in 1 -2 months, +8,0 -(+10,0) dptr in 3 –6 months, +7,0 -(+8,0) dptr in 7 -10 months, +5,0-(+6,0) dptr in 11-12 months [12] .

Foreign authors, relying on age of children at the time of surgery, 4 -6 week age make calculation of IOL for receiving a refraction 8.00 dptr at babies and 6.00 dpr at babies 6 weeks of life are more senior [25]. Other authors when calculating optical power of the implanted IOL suggested to consider initial sizes of eyes. So, at axial legth up to 22.0mm to make hypocorrection 6.0 dptr and at the size of axial length of an eye more than 22.0mm -4.0 dptr, or to implant an artificial crystalline lens 22.0 dptr with a axial length of 21.0mm, 24.0 dptr at the size of an eye of 20.0 mm, 26.0 dptr at 19.0 mm, 27.0 dptr at axial length of 18.0mm and 28.0 dptr axial length of 17.0mm [26-28].IOL implantation showed the best results in intraocular correction (with IOL implantation vision reduction made 29.0%, without IOL implantation-71.0%) [1]. Questions related to the calculation of the strength of the implantable intraocular lens remains open to date. When choosing intraocular correction of aphakia, the optical power of IOL is calculated individually for each patient according to the formulas SRK-II, SRK/T, Holliday 1, Vinkhorst, Hoffer Q, Haigis, Ivashina -Kolinko and automated techniques. In this case, the key point is the choice of the target refraction [24].

Difficulties of calculation of optical power of IOL and forecasting of desirable refraction effect of operation are connected with the forthcoming growth of the children’s eye which is followed by change of a refraction. L. N. Zubareva, A. L. Moskvichev (1992) identified the age groups by the growth of the anterior - posterior axis of the pseudofakic eye: from 5 to 9 years 2/3 of the growth of the anterior-posterior axis of the eye and 1/3-from 9-10 to 14 years. This necessitates the correction of ametropia of the artificial eye in the long term after surgery. Calculation of the optic power of IOL is performed mainly by the formula SRKII and SRKТ, considering sagittal size of the eyeball (APA), refracting power of the cornea and individual constants of the chosen model of IOL, also HofferQ and HolladayI, depending on the age of a child. At the calculation of the optical power of the implanted IOL in children of the first year of life, define the quantity of hypocorrection (from +4,0D to +14,0D) of the optical power of IOL, calculated by the formula, taking into account the optical power of the cornea and difference of the origina; APA and forecasted APAafter completion of a physiological growth of an eye [19].

There are different coints of view when choosing the power of implanted intraocular lens in children: implant IOL, calculated per emmetropia at the moment of surgery, with the following replacement, excimer correction or implant IOL less wit the account of hypocorrection, deductible from the calculated lens per emmetropia at the moment of surgery. None of this methods is perfect. Their drawbacks are the risks of development of ametropia of different level, refractive amblyopia, necessity in repeated surgical intervention at an older age [14].

The literature data presented in relation to the approach to the choice of the optical power of the implanted IOL remain poorly reasoned and contradictory (taking into account the age of children at the moment of surgery, only the size of the axial length of the eye at the time of surgery or bi-and unilateral nature of the CC).

In the other work at the unilateral CC it is recommended to choose the optic power of IOL to emmetropia, and at the bilateral CC to implant the lens of such optical power, so the necessary correction does not exceed ± 3,0 dptr. N. F. Bobtova, А. К. Djekov at the choice of the optical power of the implanted IOL forcused on the age of children at the moment of surgery, performing the hypocorrection of IOL in the average to +7,1 ± 1,2 dprt during surgery at the age of up to 6 months, +4,0 ± 1,3 dptr, during surgery at the age of 7 -12 months and +2,0 ± 1,3 dptr, in children at the age from 1 to 2 years, «gradually» decreasing to years up to +1,7 ± 1,5 dptr [10]. Similar approach to the calculation of IOL, focusing on the age of children at the moment of surgery, described I. S. Zaydullin, R. А. Aznabayev: hypocorrection +10,0 -(+ 12,0) dptr in 1 -2 months, +8,0 -(+10,0) dptr in 3 –6 months, +7,0 -(+8,0) dptr in 7 -10 months, +5,0-(+6,0) dptr in 11-12 months [12] .

Foreign authors, relying on age of children at the time of surgery, 4 -6 week age make calculation of IOL for receiving a refraction 8.00 dptr at babies and 6.00 dpr at babies 6 weeks of life are more senior [25]. Other authors when calculating optical power of the implanted IOL suggested to consider initial sizes of eyes. So, at axial legth up to 22.0mm to make hypocorrection 6.0 dptr and at the size of axial length of an eye more than 22.0mm -4.0 dptr, or to implant an artificial crystalline lens 22.0 dptr with a axial length of 21.0mm, 24.0 dptr at the size of an eye of 20.0 mm, 26.0 dptr at 19.0 mm, 27.0 dptr at axial length of 18.0mm and 28.0 dptr axial length of 17.0mm [26-28].

Conclusion

Finally, surgery represents a step in the management of cataract in children and the cooperation between parents and ophthalmologists is fundamental to achieve optimal visual rehabilitation. Thus, the issues of optimal correction of ametropia in children after cataract removal to date have not been fully disclosed and require further study

https://lupinepublishers.com/ophthalmology-journal/fulltext/aspects-of-correction-of-ametropiya-in-children-congenital-cataracts.ID.000134.php

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Lupine Publishers | Keratoconus and Cone-Rod Dystrophy among Brothers: Clinical Case Study and Genetic Analysis

 Lupine Publishers | Trends in Ophthalmology Open Access Journal

 

 

Abstract

Background: Advances in genomics continue to enable the discovery of gene variants which cause various inherited ophthalmic disorders. Several case reports have shown an association between keratoconus and retinal disease but whether there is a genetic basis for this is still not known.

Methods: Clinical case study with Pentacam imaging, fundus autofluorescence (FAF), macular optical coherence tomography (OCT), electrophysiology studies, and genetic analysis.

Results: We report three brothers, two of whom have keratoconus and one who was found to have bilateral cone-rod dystrophy. This was supported by color vision and electrophysiology testing, fundus autofluorescence, and macular OCT findings. Genomic data analysis revealed three rare gene variants (MAP3K19, ADGRV1, and PIK3CG) common to the brother with cone-rod dystrophy and one brother with keratoconus. There was also a very significant variant in the CHST6 gene in the latter. Whole exome sequencing data revealed a rare missense variant for IMPG2 gene in both brothers.

Conclusion: Among the four genes with shared mutations in two of the brothers, IMPG2 has been linked to retinal disease while MAP3K19 and PIK3CG carry high risk scores for keratoconus pathogenesis. A highly damaging CHST6 variant detected in the brother with keratoconus is known to cause macular corneal dystrophy and corneal thinning. This study offers the first familial genetic analysis for keratoconus and cone-rod dystrophy. More studies with genomic investigations are needed in order to further elucidate the possible relationship between these two diseases.

Keywords: keratoconus; Cone-rod dystrophy; Autofluorescence; Electrophysiology; Genetic testing

Introduction

Keratoconus is a multifactorial degenerative corneal disorder characterized by corneal thinning and ectasia, with most cases occurring sporadically. However, it also occurs in families and may be inherited in an autosomal dominant or recessive pattern. By taking its pathophysiology into consideration, a number of candidate genes for keratoconus has been suggested, most notable of which are VSX1, ZNF469, SOD1 and miR184 [1-3]. The gene most concretely associated with keratoconus, albeit in a very small number of cases, is miR184 [4]. However, the evidence so far has been inconclusive regarding the degree of contribution of these genes to the development of disease.

Rarely, keratoconus has been reported in conjunction with various retinal disorders, including retinitis pigmentosa, optic disc pit, optic disc coloboma, and congenital Leber amaurosis [5-8]. The co-existence of diffuse tapetoretinal degeneration with keratoconus has also been described [9]. Cone and cone-rod dystrophies, a group of inherited retinal disorders, constitute other rare co-morbidities of keratoconus. The earliest report of cone dystrophy associated with keratoconus was made in 1995 by Wilhelmus, and four more cases of cone dystrophy associated with keratoconus have been reported since [10-13]. However, genetic analysis was not done in these cases, and whether a basis exists for the association of keratoconus with cone dystrophy is still not known.

Case Report

We report three brothers, two of whom were diagnosed with keratoconus and one who was found to have bilateral bull’s-eye maculopathy secondary to cone-rod dystrophy. The eldest and the youngest consulted at ages 53 and 45, respectively, for progressive blurring of vision. The eldest brother, P.V., had undergone penetrating keratoplasties for keratoconus in both eyes. Visual acuities were 8/10 and 6/10 in the right and left eyes. The 4-year old graft in the right eye was clear while there was mild haze in the older 24-year old graft of the other eye. Fundoscopy and macular optical coherence tomography (OCT) findings were unremarkable. We performed deep anterior lamellar keratoplasty on the left eye, and the graft did well for six years. Descemet stripping automated endothelial keratoplasty and phacoemulsification with toric intraocular lens implantation were done recently due to failing endothelium and a beginning cataract.

The youngest brother, G.V., presented with clear corneas bilaterally. Visual acuities were 7/10 on the right and 6/10 on the left eyes. An epiretinal membrane without traction was seen on macular OCT on the right. The left eye was diagnosed with keratoconus and collagen crosslinking was done. His Pentacam maps ten years later (Figure 1) show only mild posterior elevation in the right eye, while the left eye was stable with K2 51.2D and thinnest pachymetry of 488um.

The second brother, Z.V., consulted us six years after his brothers at age 50 for blurring of central vision described as a positive scotoma after an accident two years earlier. He also developed an epileptic disorder which necessitated multidrug maintenance treatment including levetiracetam and lamotrigine. He claimed to have always had good vision until then. The patient did not have regular intake of chloroquine or hydroxychloroquine. Family ocular history was negative for keratoconus or any other disorder. There was no evidence of nystagmus, and only a minor inferior stromal scar was found on slitlamp examination. Visual acuity was 3/10on the right eye and 4/10 on the left. Pentacam imaging (Figure 2) showed asymmetric with-the-rule bowtie astigmatism on the right due to the corneal scar, while the left eye had symmetric oblique bowtie astigmatism. Although the corneas were relatively thin, the elevation maps appeared normal and Belin-Ambrosio Enhanced Ectasia showed no signs of keratoconus in both eyes.

‘Bull’s-eye’ annular macular lesions were seen in both eyes on fundoscopic exam (Figure 3A) and testing with Hardy-RandRittler’s pseudoisochromatic plates (4th edn.) revealed severe redgreen color deficiency. Fundus autofluorescence (FAF) (Figure 3B) showed a hyperautofluorescent ring surrounding an area of hypo autofluorescence in the fovea of both eyes.

Spectral domain OCT (Figure 4) shows disruption of the outer layers of the fovea above the retinal pigment epithelium complex, specifically the external limiting membrane, the inner segmentouter segment junction or ellipsoid zone, and the cone outer segment tips line or interdigitation zone in both eyes. Follow-up after three years showed a decrease in BCVA to 1/20 on the right eye and 1/10 on the left. Repeat FAF showed an increase in the size of the macular lesions as well as increased hypo autofluorescence.

Electrophysiology

Electrophysiology tests were performed on Z.V. according to the International Society for Clinical Electrophyisiology of Vision (ISCEV) protocols. Pattern and Flash visual evoked potentials (PVEPFVEP) were severely subnormal, while Pattern electroretinogram (PERG) was undetectable in both eyes.

 

Electroretinogram (ERG) (Figure 5) was performed with DTL electrodes using complementary extra flashes apart from the ISCEV standard protocols in dark-adapted (DA) and light-adapted (LA) conditions. Scotopic ERG was normal, apart from a slight delay in the β-wave at DA 10 flash. Photopic ERG was again normal except for borderline implicit times in LA 30 Hz flicker flash. These results show a diagnosis of macular dystrophy with borderline recordings in photopic and scotopic ERG, suggestive of a cone-rod dystrophy.

Genetic Analysis

Z.V. and P.V., diagnosed with cone-rod dystrophy and bilateral keratoconus, respectively, underwent genomic data analysis as a family case study by Avellino Laboratories, Inc. (CA, USA), which specializes in corneal diseases. The focus was on genetic variants which were common to both brothers.

Using the Avellino keratoconus detection panel, Z.V. was found to have a total of six gene variants, three of which are shared with his brother (MAP3K19, ADGRV1, and PIK3CG), highlighted blue in Table 1. P.V. was found to have five gene variants, almost all of which have high risk scores for keratoconus pathogenesis. As mentioned previously, three of these variants, found in three different genes, are shared with his brother. PXN gene variants were also found in both brothers, but on different exons, highlighted yellow in Table 1. Additionally, P.V. has a very significant variant in CHST6 gene.

Because of severe pathogenic phenotype in the two brothers and possible diagnosis of cone-rod dystrophy, each individual’s variant analysis resulting from whole exome sequencing data was examined for other significant variants outside the keratoconus panel. A missense variant for IMPG2 gene in both brothers was detected (Table 2). IMPG1 gene however was not part of the panel.

 

Discussion

A diagnosis of cone-rod dystrophy in Z.V. was supported by color vision and electrophysiology testing, fundus autofluorescence, and macular OCT findings. Deteriorating vision and larger lesions on repeat FAF showed that the disorder was progressive. A drug-induced effect was ruled out because his anti-epileptic drugs levetiracetam and lamotrigine are not associated with any maculopathy [14].

Genomic data analysis with the Avellino detection panels revealed three mutations which carry high risk scores for keratoconus in Z.V. and four in P.V. Among these, PIK3CG and MAP3K19 are shared while PXN gene variants were found on different exons (Table 1). The fourth high-risk variant in P.V. is CHST6, which is associated with macular corneal dystrophy and corneal thinning. In a study by Dudakova et al., patients with this variant exhibited diffuse corneal thinning with paracentral steepening of the anterior corneal surface on Pentacam. This was graded as keratoconus by the software, but posterior corneal surface ectasia and focal thinning were not seen [15]. Among all the detected variants, this has the highest risk score for keratoconus pathogenesis and is the most deleterious and damaging.

Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Gamma (PIK3CG)

PIK3CG activates signaling cascades involved in cell growth, survival, proliferation, motility and morphology, and is involved in various immune, inflammatory and allergic responses. Mutations in this gene could lead to multiple phenotypes and secondary diseases and are seen in less than 1% of the population. Variant in this gene is mostly missense, which corresponds to amino acid changes of arginine to histidine [16]. PIK3CG gene variant has been reported in two other keratoconus cases in the Avellino archive, but not in any sample from control individuals. A search of the NCBI CLINGEN database shows that two cysteine deletion variants in the PIK3CG gene have been reported by the Institute of Human Genetics of the Polish Academy of Sciences to be linked to keratoconus, although the significance is still considered uncertain [17].

Mitogen-Activated Protein Kinase Kinase Kinase 19 (MAP3K19)

Downstream signaling pathways of MAP3 kinases induce proliferation, differentiation, inflammation and eventually apoptosis. MAP3K19 variant found in both brothers is also a missense mutation, where serine is replaced by leucine [18-19]. This is also a rare mutation in the population (< 1%), and has been reported in seven other keratoconus cases in the Avellino archive but not in any of control samples. Based on predictive computational algorithms, this variant found in both brothers is significant and carries a high-risk score.

Adhesion G Protein-Coupled Receptor V1 (ADGRV1)

ADGRV1 is a cell-surface protein, a G-protein coupled receptor, which has an essential role in the development of hearing and vision [20-23]. The variant found in both brothers is a missense variant located at a Calx-beta domain. This is also a rare mutation seen in less than 1% of the population and has been reported in three other keratoconus cases in the Avellino archive. However, it has also been seen in one sample from control individuals; this possibly damaging variant therefore does not carry a risk score.

Interphotoreceptor Matrix Proteoglycan 2 (IMPG2)

MPG1/2 genes are very well studied in ocular pathogenesis, and there are several studies on IMPG1- and IMPG2-associated retinitis pigmentosa, vitelliform macular dystrophy, and other ocular diseases. This missense variant is significant in that it affects DNA replication, nuclear organization and gene transcription [24]. The population allele frequency is very small, suggesting that this variant is a very rare mutation in total population as well. In summary, among the shared gene variants, IMPG2 is linked to retinal disease while both MAP3K19 and PIK3CG carry high risk scores for keratoconus pathogenesis. This study offers the first familial genetic analysis for keratoconus and cone-rod dystrophy. However, more studies with genomic investigations are needed in order to further elucidate the possible relationship between these two diseases.

https://lupinepublishers.com/ophthalmology-journal/fulltext/keratoconus-and-cone-rod-dystrophy-among-brothers-clinical-case-study-and-genetic-analysis.ID.000133.php

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