Axenfeld-Reiger syndrome: A search for the missing links

Abstract

BACKGROUND

Axenfeld-Rieger syndrome (ARS) is a rare cause of congenital glaucoma and may result in loss of vision. ARS is mostly autosomal dominant in nature characterized by developmental abnormalities in the angle of anterior chamber and iris of the eye, also associated with structural abnormalities in the body.

AIM

To study and observe the demographics and clinical findings in a very rare ocular disease known as ARS.

METHODS

Case records of symptomatic patients attending Ophthalmology outpatient department and diagnosed to have ocular hypertension or glaucoma in 3 years from March 2017 to March 2020 were evaluated to search for cases diagnosed with ARS. Records of all patients diagnosed with ARS were then analysed for demographic and clinical characterization as well as management and success of therapy.

RESULTS

Eight out of ten patients with positive clinical signs were symptomatic and had glaucoma. One of these patients had limbal stem cell deficiency and another had vernal keratoconjunctivitis.

CONCLUSION

Clinical characterization of ARS is important for making a definitive diagnosis and determining prognosis.

Key Words: Axenfeld-Reiger Syndrome; Glaucoma; Limbal stem cell deficiency; Vernal keratoconjuctivitis

Core Tip: Clinical characteristic of Axenfeld-Rieger syndrome (ARS) is well defined and approximately 50% develop glaucoma later in life. Despite significant progress in unraveling the genetic basis of ARS, many questions still remain unanswered. One of the key challenges in studying this syndrome is the wide variability in clinical presentation, even among individuals with the same underlying genetic mutation. This suggests the involvement of additional genetic and environmental factors that modulate the phenotypic expression of the syndrome. Researchers are actively exploring epigenetic modifications, gene-gene interactions, and gene-environment interactions to uncover these missing links.

INTRODUCTION

Axenfeld-Rieger syndrome (ARS) is a rare clinical entity proposed to have an autosomal dominant inheritance with a prevalence of 1:100000 to 1:200000 population[1]. This disease is typically characterized by developmental abnormalities in the angle of the anterior chamber and iris of the eye, often associated with structural anomalies in the body[2]. It occurs as a result of the spectrum of disorders associated with failure of neural crest cell migration[1,3]. ARS is genetically heterogeneous, with 40%–60% of cases associated with heterozygous pathogenic variants in the transcription factor-encoding genes; PITX2 (4q25, OMIM*601542) or FOXC1 (6p25, OMIM*601090). However, mutations in other genes, such as PAX6, PITX3, and CYP1B1, have also been identified in a small subset of ARS patients, indicating the complex genetic landscape of this syndrome[4-6].

ARS can present with different combinations of ocular features. Commonly found features are posterior embryotoxon, sclerocornea, iris hypoplasia, corectopia/eccentric pupil, high myopia, ectopia lentis, polycoria and secondary glaucoma[6]. The condition can be defined under three subcategories[7,8]: Axenfeld anomaly characterized by a prominent Schwalbe’s line with prominent iris strands extending from the peripheral iris to this line; Rieger’s anomaly diagnosed in the presence of central iris changes like stromal hypoplasia, polycoria, and corectopia along with the previously mentioned features; Axenfeld Syndrome and Rieger’s Syndrome, respectively referring to an association of features of Axenfeld anomaly or Rieger’s anomaly with systemic manifestations. It is usually bilateral and asymmetric in presentation. Dental abnormalities like hypodontia (missing teeth), microdontia (small teeth), and enamel hypoplasia (underdeveloped tooth enamel) are commonly observed. Facial dysmorphism, such as a flat mid-face, a broad nasal bridge, and a thin upper lip, can also be present.

To the best of the authors’ knowledge, there have been very few reports depicting the clinical features of ARS published from the Indian sub-continent[9,10]. We present a study on ARS in Indian individuals wherein, through a case records-based search for patients with diagnosed glaucoma and features of ARS over a period of three years, 8 out of 10 patients with positive clinical signs were found to have glaucoma. Demographic and clinical characterization of these patients, as well as management and success of therapy are reported, emphasizing the importance of variability of presentation and active screening of family members of index cases.

MATERIALS AND METHODS

Study design

This was a retrospective study conducted at the Ophthalmology outpatient department of a tertiary eye care hospital of Rajasthan, India. Case records of patients diagnosed to have ocular hypertension or glaucoma in 3 years from March 2017 to March 2020 were evaluated.

Records of patients with diagnosis within the spectrum of ARS were evaluated in terms of (1) demographic characters including age, sex, ethnicity, place of residence and consanguinity; and (2) clinical characters including presenting complaints and their duration, treatment history, slit-lamp findings of anterior segment structures, intraocular pressure (IOP), clinical photographs if acquired, posterior segment findings including fundus evaluation, optical coherence tomography and ultrasound B-Scan whenever performed, treatment modality and response to treatment. Any associated ocular problem recorded was also considered. Case records of family members of the patients who were evaluated to look for features of ARS were also included in the study. All records of follow up of the index cases as well as asymptomatic cases diagnosed as a result of active search in relatives of index cases were evaluated to monitor the control of intra-ocular pressure and look for any new rise in IOP or other clinical features.

Ethical considerations

The study conforms to the tenets of the Declaration of Helsinki. Anonymity of subject identity was maintained at every stage of the study.

RESULTS

Of the 1826 records examined, 10 cases were found to be diagnosed with ARS based on slit-lamp biomicroscopy (0.58%). Demographic parameters (Table 1), clinical history (Table 2), visual acuity and IOP (Table 3), anterior segment findings (Table 4) and posterior segment findings (Table 5) of all these cases are presented. Of note, none of the patients were born out of consanguineous marriage. Three patients had only Axenfeld’s Anomaly and the others had a combination of ocular features (Figure 1). None of these cases had any systemic associations. All the patients were advised follow-up at intervals of 1 to 3 mo.

Figure 1 Slit lamp photographs. A: Polycoria with corectopia; B: Status post-trabeculectomy with iris atrophy; C: Membrane across corneal endothelium and iris; D: Posterior embryotoxon, polycoria and corectopia; E: Aniridia implant in case of Rieger’s anomaly

Table 1 Demographic characteristics of cases of Axenfeld-Rieger syndrome (N = 10).

Case No.		Age (yr)	Sex	Religion	Residence
Familial cases
Family 1	Case 1	11	Male	Hindu	Barmer, Rajasthan, India
	Case 2	9	Female	Hindu	Barmer, Rajasthan, India
Family 2	Case 3	20	Male	Hindu	Pali, Rajasthan, India
	Case 4	17	Male	Hindu	Pali, Rajasthan, India
	Case 5	11	Male	Hindu	Pali, Rajasthan, India
	Case 6	6	Male	Hindu	Pali, Rajasthan, India
Sporadic cases
Case 7		1	Male	Hindu	Jodhpur, Rajasthan, India
Case 8		28	Male	Hindu	Barmer, Rajasthan, India
Case 9		34	Male	Hindu	Jaisalmer, Rajasthan, India
Case 10		19	Male	Hindu	Jodhpur, Rajasthan, India

Table 2 Symptoms and treatment history of cases of Axenfeld-Rieger syndrome (N = 10).

Case No.	Symptoms	Duration	Previous treatment (in both eyes)	Symptomatic	Diagnosed on active search
Case 1	Decreased vision	2 yr	Eye Drop Travoprost 0.004% HS; Eye Drop Brimonidine 0.2% + Timolol 0.5% BD; Eye Drop Dorzolamide 2% TDS	Yes	No
	Photophobia	2 mo
	Pain	2 mo
	Watering	2 mo
Case 2	Decreased vision in left eye	Since childhood	None	Yes	Yes
	Right eye lost to trauma	3 yr
Case 3	Decreased vision in both eyes	Since childhood	None	Yes	No
Case 4	Burning sensation and itching in both eyes	1 yr	Eye drop Travoprost 0.004% HS; Eye drop Brimonidine 0.2% + Timolol 0.5% BD	Yes	Yes
Case 5	None	NA	None	No	Yes
Case 6	None	NA	None	No	Yes
Case 7	Blinking, crying and watering of both eyes on exposure to light	8 mo	None	Yes	No
Case 8	Decreased vision in both eyes	15 yr	Trabeculectomya	Yes	No
Case 9	None; Diagnosed glaucoma in both eyes	17 yr	Eye drop Brimonidine 0.2% BD	Yes	No
Case 10	Decreased vision in both eyes	5 yr	Eye drop Brimonidine 0.2% + 0.5% Timolol BD	Yes	Yes

^aNo documents pertaining to this surgery were available for review.

HS: At night; BD: Twice daily; TDS: Thrice daily; NA: Not applicable.

Table 3 Visual acuity and intraocular pressure of cases of Axenfeld-Rieger syndrome (N = 10).

Case No.	Vision BCVA (logMAR)		IOP (mmHg)
	RE	LE	RE	LE
Case 1	2.5	2.5	42	28
Case 2	a	1.3	a	36
Case 3	0.3	HMCF	22	42
Case 4	0.5	2.5	14	16
Case 5	0.0	0.0	16	14
Case 6	0.0	0.0	32	26
Case 7	NA	NA	26	26
Case 8	0.5	2.5	15	16
Case 9	1.8	1.8	18	19
Case 10	0.4	0.4	24	25

^aEye lost to trauma.

BCVA: Best corrected visual acuity; IOP: Intraocular pressure; RE: Right eye; LE: Left eye; HMCF: Hand movements close to face; NA: Visual acuity unrecordable on logMAR chart.

Table 4 Anterior segment findings in cases of Axenfeld-Rieger syndrome based on slit-lamp biomicroscopy (N = 10).

Sr. No.	Corneal abnormalities		Iris tissue abnormalities						Associated ocular features
	Posterior embryotoxon		Corectopia		Polycoria		Iris hypoplasia
	RE	LE	RE	LE	RE	LE	RE	LE
Case 1	+	+	+	+	+	+	+	-	LSCD BE, PAS on Gonioscopy BE
Case 2	NA	+	NA	-	NA	-	NA	+	Corneal oedema, Nystagmus, Aniridia LE
Case 3	+	+	-	+	-	+	-	-	Mature cataract LE, 360° NVI LE
Case 4	+	-	-	+	-	+	-	-	BE cobblestone papillae with RE Shield’s Ulcer s/o VKC, Cornea Plana, Corneal oedema BE
Case 5	+	+	-	-	-	-	-	-	-
Case 6	+	+	-	-	-	-	-	-	-
Case 7	+	+	-	-	-	-	-	-	BE Corneal Haze
Case 8	+	+	-	-	-	+	-	-	Nystagmus, LE Large Surgical PI, Well-formed functioning bleb BE
Case 9	+	+	+	+	+	+	+	+
Case 10	+	+	+	+	+	+	+	+

BCVA: Best Corrected Visual Acuity; IOP: Intraocular Pressure; RE: Right eye; LE: Left eye; BE: Both eyes; LSCD: Limbal Stem Cell Deficiency; PAS: Peripheral Anterior Synechiae; PI: Peripheral iridectomy; NVI: Neovascularization of iris; s/o: Suggestive of; VKC: Vernal keratoconjunctivitis; NRR: Neuroretinal rim.

Table 5 Posterior segment findings of cases of Axenfeld-Rieger syndrome (N = 10).

Sl. No.	Fundus findings		OCT-RNFL		B-Scanb
	RE	LE	RE	LE
Case 1	C:D 0.9	Glaucomatous Optic Atrophy	CNBA	CNBA	ND
Case 2	a	No view due to hazy media	a	CNBA	ND
Case 3	C:D 0.8	No view due to hazy media	CNBA	CNBA	ND
Case 4	C:D 0.4	No view due to hazy media	CNBA	CNBA	WNL BE
Case 5	C:D 0.3	C:D 0.3	WNL	WNL	WNL BE
Case 6	C:D 0.6	C:D 0.6	WNL	WNL	WNL BE
Case 7	C:D 0.9	C:D 0.9	CNBA	CNBA	WNL BE
Case 8	C:D 0.8, Tilted Disc, Peripapillary Atrophy	C:D 0.8, Tilted Disc, Peripapillary Atrophy	CNBA	CNBA	WNL BE
Case 9	C:D 0.8, Circumferential NRR thinning	C:D 0.8, Circumferential NRR thinning	CNBA	CNBA	WNL BE
Case 10	C:D 0.5	C:D 0.5	WNL	WNL	WNL BE

^aEye lost to trauma.

^bComments on vitreous, retinochoroid and sclera on B-scan USG.

Optic nerve head findings are as clinically correlated. C:D: Cup: Disc ratio; NRR: Neuroretinal rim; CNBA: Could not be acquired; ND: Not done; WNL: Within normal limits.

Out of 10, eight patients were found to have glaucoma at presentation or were under treatment for the same (Table 2). Out of these eight cases, two eyes were managed surgically; Trabeculectomy was done with biodegradable collagen matrix implant (Ologen^TM) as an adjunct in right eye of case 1, and with 0.02% Mitomycin-C in left eye of case 2, both resulting in good control of IOP over a year of follow-up. Other eyes were managed medically. The IOP in Case 3 could not be controlled despite maximal medical therapy, and the patient was advised surgical management, which he refused and was lost to follow-up.

DISCUSSION

Clinical presentation

ARS is characterized by a diverse range of clinical features that primarily affect the eye, dental structures, and facial development. Ocular manifestations include anterior segment dysgenesis, which refers to malformation or underdevelopment of the cornea, iris, and angle. This can lead to conditions like glaucoma and corneal opacity, causing visual impairment or even blindness. Our patients did not have systemic manifestations, however, the pattern of ocular involvement was peculiar.

A potentially blinding disorder, ARS may be asymptomatic in many of the affected. Here, the cases that presented to the outpatient department were usually symptomatic. Association with limbal stem cell deficiency was found in one case and vernal keratoconjunctivitis with dry eye in another case.

Importance of family screening

In the present study, 4 out of 10 cases of ARS were diagnosed as a result of active search in family members of the index cases. This emphasizes the importance of active screening in family members of the index case. In this analysis, six among ten cases had familial association while the other four were sporadic. These cases are often misdiagnosed to have irido-corneal endothelial syndrome or buphthalmos especially if they present in childhood when thorough slit-lamp evaluation may not be possible due to lack of patient co-operation in which case examination under anaesthesia with a hand-held slit lamp biomicroscope is warranted[8]. For instance, one of our patients was treated in childhood as a case of buphthalmos. For sporadic as well as familial cases, genetic counselling and counselling regarding negative eugenics is essential. The current study emphasizes the variability in presentation and importance of active screening of family members of index cases.

What is already known?

Clinical characteristics of ARS are well-defined and approximately 50% are known to develop glaucoma later in life as described in the classical literature[8]. Appropriate and timely follow-up to ensure early detection of the development and progression of glaucoma in these patients is essential and forms the most crucial part of the management of these patients.

Understanding the missing links

ARS is a genetically heterogeneous disorder caused by mutations in different genes. Mutations in the PAX6, PITX2, and FOXC1 genes have been associated with aniridia and ARS[11]. Mutations in the genes FOXC1 and PITX2 account for about 40% of the cases, but in majority of the rest, the genetic basis of ARS is unexplained[8]. Recently, Reis et al[12] have demonstrated that the incidence of glaucoma in FOXC1- and PITX2-related genetic variants of ARS is higher than previously described (up to 77%)[13]. This is in concordance with the present study where 8 out of 10 cases (80%) were found to have glaucoma at presentation. Thus despite significant progress in unraveling the genetic interactions behind the pathogenesis of glaucoma in ARS, many questions remain unanswered.

One of the key challenges in studying this syndrome is the wide variability in clinical presentation, even among individuals with the same genetic mutation. This suggests the involvement of additional genetic and environmental factors that modulate the phenotypic expression of the syndrome. Researchers are actively exploring epigenetic modifications, gene-gene interactions, and gene-environment interactions to uncover these missing links[12]: Recent studies have shown that epigenetic factors, such as deoxyribonucleic acid methylation and histone modifications, can affect the expression of genes implicated in ARS. Understanding these epigenetic mechanisms may provide insights into the variability of clinical features and help explain why individuals with the same genetic mutation can exhibit different phenotypes.

In addition, it is likely that multiple genes interact with each other, either synergistically or antagonistically, to regulate eye and facial development. Investigating these gene-gene interactions through experimental models and advanced computational approaches can shed light on the intricate network of genes involved in ARS and help identify potential therapeutic targets.

Studies have suggested that certain environmental factors, such as maternal smoking during pregnancy, can increase the risk of developing glaucoma in individuals with specific genetic mutations[14]. Moreover, the severity of ocular and dental manifestations may be influenced by environmental factors such as infection, nutrition, and exposure to toxins. Unraveling these gene-environment interactions is crucial for a comprehensive understanding of ARS and developing personalized treatment strategies.

Therapeutic options in ARS

While there is currently no cure for ARS, management of glaucoma is key for long-term outcome in these cases. In our study, out of eight cases of glaucoma, two eyes were operated upon while others were medically managed. Trabeculectomy with adjunctives (antimetabolites or Ologen^TM implant) have previously been reported to be successful in ARS as in our study[13,15]. However, the evidence regarding long-term IOP control and visual outcome is lacking.

Gene therapy, which involves delivering healthy copies of the mutated gene or modulating the expression of other related genes, holds promise for treating genetic disorders like ARS[16]. Preclinical studies using animal models have shown encouraging results, and ongoing research aims to translate these findings into clinical trials. Additionally, advancements in regenerative medicine and tissue engineering provide hope for the treatment of ocular abnormalities associated with ARS for restoring visual function in affected individuals[17].

Limitations of the present study

Limitations of this study include its retrospective design, inability to obtain B-scan ultrasonography for the first three cases and lack of genetic testing due to constraints of instrumentation. There were no cases of ARS with systemic manifestations in our study. Further follow-up of our patients could not be performed due to the subsequent COVID-19 pandemic.

CONCLUSION

ARS remains a challenging disorder due to its genetic heterogeneity and wide phenotypic variability. However, recent advancements in genetic and molecular research have shed light on the underlying mechanisms and brought us closer to understanding the missing links. Further exploration of epigenetic modifications, gene-gene interactions, and gene-environment interactions will likely unravel the complex nature of this syndrome. With ongoing therapeutic developments, there is hope for improved treatments that can alleviate the burden on individuals affected by ARS and improve their quality of life.

What this study adds to existing knowledge

In our study, a high proportion of cases (80%) was found to have glaucoma and we suggest having a high degree of suspicion while performing anterior segment evaluation. We recommend screening of family members for early detection and management of ARS in them. We found a rare association with limbal stem cell deficiency and vernal keratoconjunctivitis. We also recommend Trabeculectomy with adjuncts as the line of surgical management in patients refractory to maximal medical therapy, and long-term follow-up to prevent vision loss in eyes with ARS.

ARTICLE HIGHLIGHTS

Research background

A retrospective study at a tertiary eye care centre of National Importance. To study and observe the demographics and clinical findings in a very rare ocular disease known as Axenfeld-Rieger syndrome (ARS).

Research motivation

ARS has autosomal dominant inheritance and a prevalence of 1:100000 to 1:200000 population. This disease is typically characterized by developmental abnormalities in the angle of the anterior chamber and iris of the eye, often associated with structural anomalies in the body. To the best of the authors’ knowledge, there have been very few reports depicting the clinical features of ARS published from the Indian sub-continent.

Research objectives

Case records of symptomatic patients attending Ophthalmology outpatient department and diagnosed to have ocular hypertension or glaucoma in 3 years from March 2017 to March 2020 were evaluated to search for cases diagnosed with ARS. Records of all patients diagnosed with ARS were then analysed for demographic and clinical characterization as well as management and success of therapy.

Research methods

Patients’ presenting complaints and their duration, treatment history, slit-lamp findings of anterior segment structures, intraocular pressure, clinical photographs if acquired, posterior segment findings including fundus evaluation, optical coherence tomography and ultrasound B-Scan whenever performed, treatment modality and response to treatment were recorded. Case records of family members of the patients who were evaluated to look for features of ARS were also included in the study.

Research results

Of the 1826 records examined, 10 cases were found to be diagnosed with ARS based on slit-lamp biomicroscopy (0.58%). Three patients had only Axenfeld’s Anomaly and the others had a combination of ocular features. Out of 10, eight patients (80%) were found to have glaucoma at presentation or were under treatment for the same. Out of these eight cases, two eyes were managed surgically, while other eyes were managed medically. All the patients were advised follow-up at intervals of 1 to 3 mo.

Research conclusions

In our study, a high proportion of cases (80%) was found to have glaucoma and we suggest having a high degree of suspicion while performing anterior segment evaluation. We recommend screening of family members for early detection and management of ARS in them. We found a rare association with limbal stem cell deficiency and vernal keratoconjunctivitis. We also recommend Trabeculectomy with adjuncts as the line of surgical management in patients refractory to maximal medical therapy, and long-term follow-up to prevent vision loss in eyes with ARS.

Research perspectives

ARS remains a challenging disorder due to its genetic heterogeneity and wide phenotypic variability. Recent advancements in genetic and molecular research have shed light on the underlying mechanisms and brought us closer to understanding the missing links. Further exploration of epigenetic modifications, gene-gene interactions, and gene-environment interactions will likely unravel the complex nature of this syndrome. With ongoing therapeutic developments, there is hope for improved treatments that can alleviate the burden on individuals affected by ARS and improve their quality of life.