Axenfeld Reigers Syndrome – Implications from Dentist point of view

SUMMARY Up to 150 words summarising the case presentation and outcome (this will be freely available online)

A 4 year old male patient reported with the complaint of multiple decayed teeth. On oral examination, ankyloglossia and hypodontia affecting deciduous as well as permanent teeth dentition were evident along with multiple carious teeth. The child also presented with ocular abnormalities which included microphthalamus, microcornea, bilateral nystagmus, alternating esotropia, corectopia, keratoirides adhesions of the left eye, bilateral cataracts and partial vision loss with both the eyes. Systemic review revealed a ventricular septal defect. The diagnosis of Axenfeld Reigers syndrome (ARS) was made on the basis of these clinical findings. This condition if untreated leads to loss of vision resulting from glaucoma. The child was timely referred for management thus preventing complete vision loss. ARS has an extremely variable clinical expression and dental involvement is highly penetrant and easily visualized. The dentist plays a crucial role in early diagnosis of the condition and in preventing the resultant permanent disability.

BACKGROUND Why you think this case is important – why did you write it up?

Axenfeld Reigers syndrome is grouped under anterior segment dysgenesis which is a spectrum of ocular malformations characterized by abnormal development of anterior chamber and iris. The incidence of this disease is 1 in 200,000 live births with equal gender predisposition.¹ Cases are most often recognized in infancy or childhood because of abnormal appearance of the anterior segment. In some infants the concerns could be tearing photophobia, and corneal clouding which are the signs of infantile glaucoma. While some patients may present with visual loss. Orofacial abnormalities are among the other significant features which constitute this syndrome. ²

We here by present a case of ARS where dental findings played a crucial role in diagnosis and early referral thus preventing further complications. This patient had no positive family history, implying that ARS can also be seen sporadically.

CASE PRESENTATION Presenting features, medical/social/family history

A four year old male patient reported to the dental department with the chief complaint of multiple decayed teeth. The child was born full term from a non-consanguineous marriage. Developmental milestones were attained normally. On extra oral examination the child showed Dolicocephaly with microcephaly preauricular tags (Figure 1) and a beak shaped nose (Figure 2). Intraoral examination revealed that the deciduous lower lateral incisors and canines were clinically missing bilaterally. Root stumps was observed in the region of all the left and right maxillary and mandibular central incisor as well as maxillary left lateral incisor. Dental caries was noted with respect to 52, 54, 55, 64, 65, 74, 75, 84 and 85. The child also presented with ankyloglossia (Figure 3).

On general examination the child was afebrile, the height and weight were normal for his age. The child presented with bilateral corneal clouding which was noticed since birth. Since past 6 months the child also had the complaint of decreased vision. There was no contributing family history. On ophthalmic examination the child presented with microphthalamus, microcornea, bilateral nystagmus, alternating esotropia, corectopia, keratoirides adhesions with the left eye, bilateral cataracts and partial vision loss with respect to both the eyes (Figure 4).Other systemic findings included ventricular septal defect and a hypo pigmented patch on the right scapula. The diagnosis of Axenfeld Reigers syndrome was reached based of clinical findings.

INVESTIGATIONS If relevant

An Orthopantomograph was advised to confirm hypodontia. The Orthopantomograph (Figure 5) revealed that the lower deciduous lateral incisors and canines were missing. Also the permanent tooth buds of lower incisors, canines and first premolars (31, 32, 33, 34, 41, 42, 43, and 44) were absent. Whereas the maxillary arch showed no missing teeth.

DIFFERENTIAL DIAGNOSIS If relevant

TREATMENT If relevant

Oral prophylaxis, restorations of 52, 54, 55, 64, 65, 74, 75 and 84, extractions of 51, 61, 62, 71 and 81 and frenectomy were planned after obtaining medical clearance.

OUTCOME AND FOLLOW-UP

DISCUSSION Include a very brief review of similar published cases

Axenfeld Reigers syndrome is an autosomal dominant genetic condition in most cases, but can also be seen sporadically, as in this reported case as there was no positive family history. Systemic abnormalities and anterior segment dysgenesis are pathognomic to ARS. In 1920 Axenfeld described posterior embryotoxon and adherent iris strands, and congenital iris abnormalities with iris hypoplasia, poly cornea and corectopia with other systemic findings like dental, facial anomalies were described in 1935 by Reiger. The combination of the Axenfeld Anomaly and Reiger syndrome is collectively known as Axenfeld Reigers syndrome (OMIM: 180500).^{3, 4}

Dental defects in ARS vary from microdontia, hypodontia to complete anodontia. Missing lateral mandibular incisors are described to be the most common feature. Maxillary hypoplasia can also be seen in the ARS patients. ⁵ The presenting case showed hypodontia affecting deciduous as well as permanent teeth along with ankyloglossia, which is a rare and unique finding. Other systemic findings include ear abnormalities, hearing loss, pituitary and cardiac abnormalities, short status, hypospadius and limb defects.

The etiology of ARS is thought to be improper differentiation, migration and or arrested development of neural crest cells in the anterior chamber of the eye, teeth facial bones, cardiovascular system, and pre umbilical skin. The molecular basis of this syndrome resides with the PITX2 and the PITX3 gene which represent the family of homeobox containing transcription factor genes. PITX2 gene mutations (4q25q26) show variability both between and within families. ^{4, 6, 7.} The reported phenotypes include Reiger and Axenfeld anomaly or combined syndrome. Peter’s anomaly and partial aniridia form the differential diagnosis. The dental findings are highly penetrant; only about 9% of patients with PITX2 mutations display isolated ocular defects. Several genes have been identified which cause anterior segment dysgenesis. The rarity, low incidence, high morbidity and potential complications call for a through recording and maintaining a data base. This could provide an insight into the pathogenesis so that genetic counselling is necessitated and early and prompt treatment could be available for this debilitating condition.

Glaucoma in infancy presents as photophobia, tearing and corneal clouding with corneal enlargement which is the complication of ARS. If diagnosed, at this point surgical intervention can prevent vision loss. When glaucoma is diagnosed in early adulthood, the disease is already in the advanced stage. The best scenario at this point is to screen the sibling or the offspring of the patient with ARS, so that the disease is diagnosed at an early stage and loss of vision can be prevented.⁸

LEARNING POINTS/TAKE HOME MESSAGES 3 to 5 bullet points – this is a required field

• Diagnosis of ARS is based on clinical findings primarily the abnormal development of the anterior segment of the eye which can be detectable at birth.
• Visual impairment and visual loss resulting from glaucoma is the serious complication of ARS.
• Only 9% of ARS cases show exclusive ocular findings. Dental involvement in ARS is significant. Cases with mild ocular and systemic involvement which could go undiagnosed, a pediatric dentist with the knowledge of ARS would play a crucial role in diagnosing and referring the patient for ophthalmic management, thus saving the patient from visual compromise or even loss of vision.

REFERENCES Vancouver style (Was the patient involved in a clinical trial? Please reference related articles)

1. Waring GO 3rd, Rodrigues MM, Laibson PR: Anterior chamber cleavage syndrome. A stepladder classification. Surv Opthalmol 1975; 20:3.

2. Shields MB, Buckley E, Klintworth GK, Thresher R. Axenfeld- Rieger syndrome. A spectrum of developmental disorders. Surv Ophthalmol 1985; 29:387-409.

3. Axenfeld TH. Embryotoxon cornea posterius. Klin Monatsbl Augenheilkd. 1920; 65: 381-82.

4. Alward WL: Axenfeld- Reiger syndrome in the age of molecular genetics. Am J Opththalmol 2000; 130: 107-15.

5. Fitch N, Kaback M: The Axenfeld syndrome and the Reiger syndrome. J Med Genet 1978; 15:30.

6. Semina EV,Datson NA, Leysens NJ, Zabel BU, Carey JC, Bell GI, Bitoun P, Lindgren C, Stevenson T, Frants RR, van Ommen G, Murray JC. Exclusion of epidermal growth factor and high resolution physical mapping across the Reiger syndrome locus. Am J Hum Genet 1996; 59:1288-96.

7. Schinzel A, Brecevic L, Dutly F, Baumer A, Binkert F, Largo RH: Multiple congenital anamolies including the Reiger eye malformation in a boy with interstitial deletion of (4) (q25 → q27) secondary to a balanced insertion in his normal father: evidence for halotype insuffiency causing Reiger malformation. J Med Genet 1997; 34: 1012-14.

8. Stevenson RE, Hall JG. Human malformations and Related Anamolies. 2nd ed Newyork: Oxford University Press.inc; 2006. P.311-313.

FIGURE/VIDEO CAPTIONS figures should NOT be embedded in this document

Figure 1. The left ear showing preauricular tags.

Figure 2. Image showing Beak shaped nose.

Figure 3. Intraoral photograph showing Root stumps 71, 81, clinically missing 72, 73, 82, 83 and ankyloglossia.

Figure 4. Eyes showing bilateral corneal clouding, esotropia and corectopia.

Figure 5. Orthopantomograph showing congenital missing 72, 73, 82 and 83 and also absence of permanent tooth buds of 31, 32, 33, 34, 41, 42, 43, and 44.

PATIENT’S PERSPECTIVE Optional but encouraged

Copyright Statement

I, Shital Kiran, The Corresponding Author, has the right to assign on behalf of all authors and does assign on behalf of all authors, a full assignment of all intellectual property rights for all content within the submitted case report (other than as agreed with the BMJ Publishing Group Ltd) (“BMJ”)) in any media known now or created in the future, and permits this case report (if accepted) to be published on BMJ Case Reports and to be fully exploited within the remit of the assignment as set out in the assignment which has been read. http://casereports.bmj.com/site/misc/copyright.pdf.

Date:9/9/14

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