Accepted Manuscript Jalili syndrome presenting with situs inversus totalis and keratoconus: the first case in the Indian subcontinent Parth Purwar, B.D.S, M.D.S, Senior Resident, Dr., Sagar Sareen, B.D.S, Post graduate student, Dr., Kishlay Bhartiya, B.D.S, Post graduate student, Dr., Sayyed Rayyan Sayed Inayatullah, M.B.B.S, M.S, Junior Consultant, Dr., Dr Mayank Bansal, M.B.B.S, D.M.R.D, Senior Resident, Vikas Chahal, M.B.B.S, Post graduate student, Dr., Sanjay Gupta, M.B.B.S, M.S, Associate Professor, Dr., Jaya Dixit, B.D.S, M.D.S, Professor & Head, Dr., Vaibhav Sheel, B.D.S, Post graduate student, Dr., Priya Rai, B.D.S., Dr. PII:

S2212-4403(15)00617-3

DOI:

10.1016/j.oooo.2015.04.002

Reference:

OOOO 1178

To appear in:

Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology

Received Date: 26 December 2014 Revised Date:

2 April 2015

Accepted Date: 9 April 2015

Please cite this article as: Purwar P, Sareen S, Bhartiya K, Inayatullah SRS, Bansal M, Chahal V, Gupta S, Dixit J, Sheel V, Rai P, Jalili syndrome presenting with situs inversus totalis and keratoconus: the first case in the Indian subcontinent, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2015), doi: 10.1016/j.oooo.2015.04.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Jalili syndrome presenting with situs inversus totalis and keratoconus: the first case in the Indian subcontinent

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Authors:

Dr. Parth Purwar B.D.S, M.D.S, Senior Resident*, Dr. Sagar Sareen B.D.S, Post graduate student*, Dr. Kishlay Bhartiya B.D.S, Post graduate student*, Dr. Sayyed

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Rayyan Sayed Inayatullah, M.B.B.S, M.S, Junior Consultant‡, Dr Mayank Bansal M.B.B.S, D.M.R.D, Senior Resident#, Dr. Vikas Chahal M.B.B.S, Post graduate

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student†, Dr. Sanjay Gupta M.B.B.S, M.S, Associate Professor†, Dr. Jaya Dixit B.D.S, M.D.S, Professor & Head*, Dr. Vaibhav Sheel B.D.S, Post graduate student*, Dr. Priya Rai B.D.S.§

*Department of Periodontology, Faculty of Dental Sciences, King George’s





Udgir Lions Hospital, Udgir, Latur, Maharashtra, India. Department of Ophthalmology, King George’s Medical University, Lucknow,

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Uttar Pradesh, India. #

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Medical University, Lucknow, Uttar Pradesh, India.

Department of Radiodiagnosis, King George’s Medical University, Lucknow,

§

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Uttar Pradesh, India.

Private Practioner, Varanasi, Uttar Pradesh, India.

Correspondence Address: Dr. Parth Purwar, Senior Resident, Department of Periodontology, Faculty of dental Sciences, Fifth Floor, New Dental Block, King George Medical University, Lucknow, Uttar Pradesh, India. Tel no: +918765285612 (can be published)

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E-mail Id: [email protected] (can be published). Word count for abstract: 116

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Complete manuscript word count: 3070 Number of figure legends: 12 Number of references: 33

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no conflicts of interests in the study.

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No external funding was available for this study. The authors declare that there are

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Abstract: Jalili syndrome (JS) (MIM#217080) is a rare genetic disorder characterized by the co morbid appearance of cone–rod dystrophy (CORD) and amelogenesis imperfecta (AI). JS is an autosomal recessive inherited disorder

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caused by different mutations all with a linkage at achromatopsia locus 2q11 on the metal transporter gene, CNNM4. The case report presented describes JS with distinct phenotypic variations such as situs inversus totalis (SIT) along with additional ophthalmic findings like keratoconus and ectopia lentis. It is the first

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case of JS reported from Indian subcontinent, affecting a male patient of 'Muslim faith', belonging to an area having high fluoride levels in the ground water. A

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positive history of consanguineous marriage in his past generation was also evident.

Introduction: Jalili syndrome (JS) was first identified by IK Jalili and NJD Smith, in an Arab family which inherited as an autosomal recessive trait.1 To date, only 71

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patients belonging to 17 different families have been reported globally.2 JS is an inherited condition manifesting as a combination of a dental anomaly (amelogenesis imperfecta) and an ocular disorder (cone-rod dystrophy).

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Amelogenesis imperfecta (AI) are also an inherited

group of diseases where the common clinical entity is an abnormality of tooth

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enamel, which may be thin (hypoplastic), or poorly mineralized (hypo mineralized), or a combination of the two affecting primary as well as secondary dentition.3 Cone-rod dystrophies (CORD) are a constellation of retinal disorders characterized by the degeneration of cone and subsequently rod photoreceptors manifesting as an initial loss of central vision, color vision, photophobia and may be associated with night blindness and restricted visual fields.4 Situs inversus or “situs transversus” is a congenital condition characterized by presence of major visceral organs on the contra lateral side as compared to their normal physiologic

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positions.5 Situs inversus is an autosomal recessive condition, although it can be Xlinked and may be found among identical twins.6 Co-occurrence of AI and CORD, being two distinct

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pathologic entities affecting two different tissues could be either be a chance or may be due to a tight linkage between the individual genes concerned.2 Michaelides et al.7 ascertained a 2-generation family from Kosovo in which the

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ocular disorder was associated with the hypoplastic/hypo mineralized variant of AI. Downey et al 8 identified the concerned locus on chromosome 2q11at which AI

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and CORD co-segregate. Parry et al.9 minted the term “Jalili syndrome” and ultra structural analysis of the exfoliated teeth showed that the enamel was only 50% mineralized in the affected individuals. They also stated that the resulting radiographic appearance of the teeth corresponds to the hypo mineralized variant of AI. CNNM4 gene mutations in JS patients were found simultaneously by Parry

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et al 9 and Polok et al.10

The present case report illustrates a rare syndrome, the

Jalili syndrome along with the novel phenotypic findings (situs inversus totalis,

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keratoconus and ectopia lentis). This case report is an endeavor to extend our

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knowledge about JS.

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Case description Methodology: A 35 year old male patient reported to the Dental Faculty of King George’s Medical University, Lucknow, U.P with a chief complaint of malformed

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and discolored teeth since childhood and inability to see clearly during evening time. During further elaboration of his complaint the concerned patient revealed that he was able to see more clearly in the daytime and worked as a school teacher in his rural area. Further questioning revealed that the propositor family members

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had similar ocular and dental features although to a different degree. The concerned patient as well as the family members did not seek any treatment until

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now due to the lack of medical and dental facility in his area. It was only now, when he realized that he avoided hard food substances and suffered from progressive loss of vision, upon consultation in the district hospital he was referred to the Medical University. Referring to the patient complaints the propositor was sent in for dental, ophthalmological and radiological investigations for making the

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appropriate diagnosis of the case.

Family History: All the affected members in the family including the propositor had abnormal and discolored teeth and also suffered from vision loss, sensitivity to

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bright light and poor color vision. The history was given solely by the patient and was neither supported by any previous clinical records nor did any family member

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visit the Medical University for consultation and examination despite repeated attempts to convince the family members. Methods: Dental investigations included orthopantamograms (OPG) and tooth sectioning of extracted teeth to confirm the dental anomaly. Slit lamp biomicroscopy, advanced macular visualization on spectral domain optical coherence tomography (SDOCT) and general ophthalmic examination was done to characterize the positive ocular phenotype and findings. Postero-anterior view (PA

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view) of the chest and ultrasonography (USG) of abdomen was done for collaborating the radiological findings with the clinical findings. The detailed family tree was also charted to confirm the inheritance pattern.

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Clinical Examinations:

1. Dental Phenotype: On intraoral examination, teeth were found to be discolored, grossly malformed and associated with severe attrition (Fig 1).

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Teeth no-12, 13, 36 and 37 were missing while tooth no-26 had sole carious lesion. Teeth no- 16,17,46,47 and left upper canine had grade -3mobility.

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OPG showed absence of enamel in almost all the teeth (Fig 2). The surfaces of the teeth were rough and exhibited yellowish brown discoloration due to absence of enamel over teeth and dentinal layers being shown through. The emergence pattern and teeth eruption timings were within the normal reference range. The teeth were discolored and had abnormal shape at the

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time of eruption. Pronounced shift in midline and class-3 malocclusion with mandibular prognathism was also present. Five teeth were extracted for sound clinical reasons. Macroscopic examination of the extracted teeth

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showed either no enamel or only vestiges of the enamel in the cervical area. Microscopically, ground sections made with the help of corborundum disk

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showed complete absence of enamel (Fig 3).The features were reported as being compatible with the provisional diagnosis of amelogenesis imperfecta of the hypoplastic/ hypo mineralized type. The propositor had poor oral hygiene status and presence of generalized gingivitis with severe staining of teeth. The differential diagnosis of enamel and environmental hypoplasia, dentinogenesis imperfecta, dentin dysplasia and regional odontodysplasia was made. The definitive diagnosis of autosomal recessively inherited amelogenesis imperfecta (AI) of hypoplastic/hypominearalized type was

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made on the basis of patient’s age, history, clinical presentation, radiographic findings and hereditary nature. 2. Ocular Phenotype: On ophthalmic examination, visual acuity on the first

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presentation was observed as perception of hand movements in the right eye and finger counting close to one meter in the left eye. Direct and consensual pupillary reaction was present in both the eyes but was ill- sustained in the left eye. Mild ptosis was present in the left upper lid which was of little

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clinical significance (Fig 4). Slit lamp biomicroscopy revealed ectopia lentis in the right eye while in the left eye cornea was clear.

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a) Anterior segment examination with slit lamp biomicroscopy showed Vogt’s striae secondary to keratoconus in the left eye (Fig 5). The keratometric values K1 and K2 in the right eye were 51.50D and 32.00D and in the left eye were found to be 43.75D and 37.27D respectively. The ophthalmic findings were suggestive of ectopia lentis in the right eye (Fig 6). However

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the clear cut differentiation with retrolental opacity could not be confirmed due to financial and technical constraints Posterior segment was examined using direct and indirect ophthalmoscope

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along with slit lamp biomicroscopy. Fundus examination showed generalized depigmentation with retinal pallor and bony spicules scattered throughout the posterior pole which were suggestive of cone rod dystrophy

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b)

(CORD) bilaterally. Additionally, there was generalized arterial attenuation with waxy pallor which was more profound in the temporal half of the optic disc. Focal chorioretinal atrophy was seen inferior to the fovea in the macular region of about 2 disc diameters in size (Fig 7a and 7b). Fundus findings were suggestive of retinitis pigmentosa type conditions.

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Advanced macular visualization on spectral domain optical coherence tomography (SDOCT) (Fig 8a and 8b) showed thinned out inner neural retinal layer which were more hypo reflective than normal. The reflectivity of the outer retinal layer was mm3

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also less than normal. Central subfield thickness of 184 µm, cube volume of 5.8 and cube average thickness of 162 µm was also observed. The reference

range of central field thickness and cube average thickness is 180-220 µm and 180250 µm respectively and cube volume ranges from 8-11 mm3. Single layer map

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showed global uneven topography of retina in the macular region which indicated presence of retinal folds. However, vision in the right eye was too low for

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obtaining proper fixation for SDOCT (Fig 9).

Based on the ocular findings and investigations we concluded that patient had cone rod dystrophy (CORD) bilaterally, Vogt’s striae

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and keratoconus in left eye and ectopia lentis in right eye. Peripheral field testing, color vision could not be done as patient was unable to fixate due to profound loss of vision in both the eyes. Electrophysiology testing was not done owing to the

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financial constraints of the patient.

3. Radiological Examination: PA view of the chest radiograph of the patient

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showed the cardiac apex pointing towards the right side and the aortic arch as well as the stomach bubble on the right side (Fig 10). Ultrasonography (USG) of the abdomen showed the presence of major visceral organs on the opposite side of their normal presence i.e. liver and gall bladder on the left side of the abdomen while spleen in the right hypochondrium. The relationship of the aorta and inferior vena cava (IVC) is reversed. IVC was

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seen on the left side of aorta. The radiological findings were suggestive of situs inversus totalis (SIT) (Fig 11a-e). 4. Genetics: Family history of the patient revealed that his 3 brothers, 1 sister,

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grandmother, maternal grandfather and aunt’s male and female child had common dental and ocular features whereas parents were phenotypically normal. The pedigree analysis presents five generations of Indian Muslim affected family (Fig-12). There was one consanguineous marriage between

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cousins in generation III. Analysis of pedigree indicated an autosomal recessive mode of inheritance. Among the living siblings examined (n=27),

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M: F ratio 1.25:1), the percentage of the living affected examined (n=10) of the total number of the siblings were 37.03 % (M: F ratio 1.67:1). Both the families belonged to the same district although information on any previous intermarriages could not be accounted for due to limited family history presented. The information regarding presence of associated systemic

compliance.

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abnormalities could not be acquired from the family members due to non

Routine hematological investigations were carried out which were found to be

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within the reference range. The propositor did not suffer from hearing loss and any

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other systemic complications.

Based on the intraoral examinations, ophthalmological and

radiological investigations along with the clinical presentation and the pedigree analysis the case was diagnosed as Jalili syndrome (JS) with situs inversus totalis, keratoconus, ectopia lentis and ptosis as the phenotypic variation.

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Treatment and follow up: Initially, the patient was treated with thorough scaling and roots planing (SRP) with the help of hand curettes as well as with ultrasonic instruments. Comprehensive oral hygiene instructions were instituted to improve

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the oral hygiene. The patient was also prescribed tablets containing lutein, zeaxanthin and bilberry once daily for 3 months initially for treatment of associated ophthalmic findings.11On first recall visit, patient showed improvement in periodontal health and the teeth associated with poor prognosis were extracted at

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the same appointment. Patient is currently undergoing rehabilitation of the teeth in the Department of Conservative and Prosthetic Dentistry. On 3month recall visit

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the vision improved to finger counting in right eye counting to 1 meters while no improvement is seen in the left eye. The medications were prescribed further for 3

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months.

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Discussion: The report describes first case of Jalili syndrome (JS) from Indian subcontinent along with the additional phenotypic variations associated with it in a 35 year old male patient.

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Amelogenesis imperfecta (AI) describes the group of inherited conditions affecting tooth enamel formation. Amelogenesis, an exquisitely orchestrated process involved in enamel formation and is under strict

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genetic regulation. The most commonly accepted classification recognizes 4 major types of AI as proposed by Witkop3 based on the phenotype and their mechanism of development. Four genes have been found to be associated with AI - AMELX12

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ENAM13,14, KLK4 and MMP2015,16. The holistic approach for correlating the molecular basis with the associated phenotypes of AI have not been developed.17Concomitant occurrence of AI with ocular anomalies have often been reported in oculo; skeletal syndrome

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and coloboma of iris.19 The case under

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discussion presented with severely attrited and discolored teeth with absence of enamel noticed clinically and histologically. Based on the propositor intra oral examination the clinical entity was diagnosed as hypoplastic or hypomineralized AI. Since the genetic analysis is underway currently it is impossible to correlate the

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dental phenotype with the molecular etiology. The intra oral findings were in

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agreement to those reported previously for AI in JS patients.1 Cone-rod dystrophies (CORD) are a relatively rare group of

progressive cone disorders presenting during the first two decades of life, with symptoms of progressive loss of central visual acuity, color vision, photophobia, nystagmus and absence of night blindness.4,

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However some reports have also

shown presence of night blindness in association with CORD’s as seen in the current case.9,10 The refraction ranges in CORD patients ranges from low myopia to high hyperopia.1,9,20 Maculopathy has been observed in majority of patients of

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JS1 however in few cases normal morphology have also been reported.9 Various patterns of macular degeneration have also been observed in JS patients ranging from bull’s eye1,20, coloboma,20,21 atrophic macular degeneration with pigment

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mottling10 to retinal arteriolar attenuation4. The propositor demonstrated an ocular phenotype with reduced visual acuity, keratoconus and Vogt’s striae in the left eye, ectopia lentis in the right eye, retinal pallor; focal chorioretinal atrophy and retinal

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the previously reported findings in JS patients.

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folds are also seen. The ophthalmic findings of the propositor were an addition to

Situs inversus (SI) is a congenital genetic condition characterized by transposition of the major organs within the thorax and abdomen to the contra lateral side when compared to their physiologic positions through the sagittal plane. In patients of SI the heart is located on the right side of the thorax, the

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stomach and spleen on the right side of the abdomen and the liver and gall bladder on the left side and is also referred to as "situs inversus with dextrocardia" or "situs inversus totalis (SIT)" as seen in the case under discussion. If congenital heart

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defects (CHD) are present along with SIT the systemic health is compromised however in absence of CHD such individuals are phenotypically normal and can

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lead healthy lives, without any untoward complications. Ocular anomalies such as peters anomaly 24

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, retinitis pigmentosa23, cerebello oculo renal syndrome

,monocular elevation deficiency

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and nanopthalmos26 have been found to be

associated with SIT. The propositor was unaware of his unusual anatomy until radiological investigations were carried out which revealed presence of SIT.

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The existence of AI has been reported with syndromic conditions which includes Kohlschutter–Tonz syndrome and oculodentodigital dysplasia (oculodento-osseous dysplasia). 27 However ocular conditions associated

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with dental abnormalities other than AI have also been reported. These include micropthalmia, iris coloboma, myopia and other anamolies of ocular adnexa, retinitis

pigmentosa,

Kartgener’s

syndrome,

lacrimo-auriculo-dento-digital

(LADD) syndrome, oculodentodigital dysplasia syndrome and peters' anomaly.18,19

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presented an association of JS with type 1

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Zobor et al.

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However this case report is first of its kind showing co-existence of AI with SIT.

neurofibromatosis with mutations occurring in two different genes. JS is a condition in which single gene mutation in a single protein may affect two different tissue types and high levels of fluoride in ground water may have a determining role to play in establishing the original mutation. Evidence exists that

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long-term exposure to fluoride may have genotoxic effects.20 It is plausible that high fluoride levels in ground water along with other factors such as increased water intake in hot climates and low calcium intake due to malnutrition, high level of consanguinity and the high fertility rate in the population could have triggered

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the mutagenesis in the current case. The socio demographic information showed that the patient and his family are residents of area which falls under high fluoride

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levels in drinking water in India. This seems to be noteworthy pertaining to the recent case report by Doucette L et al29 in 2013 who reported first case of JS in Newfoundland (North America), an area known to have high fluoride levels in ground water. The high concentration of fluoride in drinking water (recommended is1.5ppm) is a major issue affecting a large segment of rural population in India. Therefore it becomes customary to address the high fluoride levels to decrease the incidence of JS. Genetic counseling and

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family planning may be beneficial in the patients of JS.

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Acknowledgements: The authors extend their regards to Prof. Ravi Kant, Honourable Vice Chancellor for his valuable insights into evidence based medicine which has helped me to report the current case. References:

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Jalili I K, Smith NJD. A progressive cone-rod dystrophy and amelogenesis imperfecta: a new syndrome. J Med Genet. 1988; 25(11):738-740. Nair P, Obeid T, Tadmouri GO, Al-Khaja N, Jalili IK. A study in pleiotropy: Jalili syndrome. Hamdan Med J. 2013; 6:233-240. Witkop CJ Jr. Amelogenesis imperfecta, dentinogenesis imperfecta and dentin dysplasia revisited: problems in classification. J Oral Pathol. 1988; 17: 547 – 553. Moore AT. Cone and cone-rod dystrophies. J Med Genet.1992; 29: 289 – 290. Ferkol TW, Leigh MW IC. Ciliopathies: the central role of cilia in a spectrum of pediatric disorders. J Pediatr. 2012; 160(3):366-367. Casey B. Two rights make a wrong: human left-right malformations. Hum Mol Genet. 1998; 7(10):1565-1571. Michaelides M, Bloch-Zupan A, Holder G E, Hunt DM, Moore AT. An autosomal recessive cone-rod dystrophy associated with amelogenesis imperfecta. (Letter) J. Med. Genet. 2004 ; 41: 468-473. Downey LM, Keen TJ, Jalili IK, McHale J, Aldred MJ, Robertson SP, Mighell A, Fayle S, Wissinger B, Inglehearn CF. Identification of a locus on chromosome 2q11 at which recessive amelogenesis imperfecta and cone-rod dystrophy cosegregate. Eur J Hum Genet. 2002; 10(12):865-869.

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Parry DA, Mighell AJ, El-Sayed W, Shore RC, Jalili IK, Dollfus H, BlochZupan A, Carlos R, Carr IM, Downey LM, Blain KM, Mansfield DC, Shahrabi M, Heidari, M, Aref P, Abbasi M, Michaelides M, Moore AT, Kirkham J, Inglehearn CF. Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta. Am. J. Hum. Genet.2009; 84: 266-273. Polok B, Escher P, Ambresin A, Chouery E, Bolay S, Meunier I, Nan F, Hamel C, Munier FL, Thilo B, Mégarbané A, Schorderet DF. Mutations in CNNM4 cause recessive cone-rod dystrophy with amelogenesis imperfecta. Am J Hum Genet. 2009; 84(2):259-265. Ma L, Lin XM. Effects of lutien and zeaxanthin on aspects of eye health. J Sci Food Agric. 2010; 15(90):2-12. Fincham AG, Simmer JP. Amelogenin proteins of developing dental enamel. Ciba Found Symp. 1997; 205:118-130. Rajpar MH, Harley K, Laing C, Davies DM, Dixon MJ. Mutation of the gene encoding the enamelspecific protein, enamelin, causes autosomaldominant amelogenesis imperfecta. Human Mol Genet. 2001; 10 :1673– 1677. Mardh KC, Backman B, Holgren G, Hu JC-C, Simmer JP, Forsman-Semb K. A nonsense mutation in the enamelin gene causes local hypoplastic autosomal dominant amelogenesis imperfecta (AIH2). Human Mol Genet. 2002;11: 1069–1074. Hart PS, Hart TC, Michalec MD, Ryu OH, Simmons DG, Hong SP, Wright JT. Mutation in kallikrein 4 causes autosomal recessive hypomaturation amelogenesis imperfecta. J Med Genet. 2004; 41:545–549. Kim JW, Seymen F, Lin BP, Kiziltan B, Gencay K, Simmer JP, Hu JC. ENAM mutations in autosomal dominant amelogenesis imperfecta. J Dent Res. 2005a; 84:278–282. Aldred MJ, Savarirayan R, Crawford PJM. Amelogenesis imperfecta: A classification and catalogue for the 21st century. Oral Disease. 2003; 9:19– 23. Mégarbané A, Ghanem I, Waked N, Dagher F. A newly recognized autosomal recessive syndrome with short stature and oculo-skeletal involvement. Am J Med Genet. 2006; 140(14):1491-1496. Atasu M, Eryilmaz A, Genc A, Ozcan M, Ozbayrak S. Congenital hypodontia of maxillary lateral incisors in association with coloboma of the

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iris and hypomaturation type of amelogenesis imperfecta in a large kindred. J Clin Pediatr Dent. 1997; 21(4):341-355. Jalili IK. Cone-rod dystrophy and amelogenesis imperfecta (Jalili syndrome): phenotypes and environs. Eye (Lond) 2010; 24:1659-89. Erratum in: Eye (Lond). 2010 ; 24(11):1734-1735. Jalili IK. Gaza C family with cone rod dystrophy and amelogenesis imperfecta (Jalili syndrome) type A. URL: http://www.jalili.co/covi/ft_gazac.pdf. Kresca LJ, Goldberg MF. Peters' anomaly: dominant inheritance in one pedigree and dextrocardia in another. J Pediatr Ophthalmol Strabismus. 1978 ; 15(3):141-146. Madhavan C, Bhende P, Gopal L, Vasanthi SB, Kumaramanickavel G. Retinitis pigmentosa patients with sickle cell disease and dextrocardia and situs inversus syndrome. Indian J Ophthalmol. 2001; 49(3):193-195. Aydinoz S, Ersen A, Karademir F, Suleymanoglu S, Ozkaya H, Gocmen I. A case of cerebello-oculo-renal syndrome with situs inversus totalis: a new phenotype. J Child Neurol. 2007; 22(2):204-207. Zafar SN, Zafar AN, Hussain I. Monocular elevation deficiency with associated dextrocardia and situs inversus. Saudi J Ophthalmol. 2013; 27(2):121-3. Sahin A, Oltulu R, Kivrak AS, Ozkagnici A. Nanophthalmos and situs inversus totalis. Indian J Ophthalmol. 2012; 60(4):319-321. McKusick VA. Mendelian inheritance in man. Baltimore1986: Johns Hopkins University Press, 7th ed. Zobor D, Kaufmann DH, Weckerle P, Sauer A, Wissinger B, Wilhem H, Kohl S. Cone–rod dystrophy associated with amelogenesis imperfecta in a child with neurofibromatosis type 1. Ophthalmic Genet. 2012; 33:34–38. Doucette L, Green J, Black C, Schwartzentruber J, Johnson GJ, Galutira D, Young TL. Molecular genetics of achromatopsia in Newfoundland reveal genetic heterogeneity, founder effects and the first cases of Jalili syndrome in North America. Ophthalmic Genet. 2013; 34(3):119-129. Handa BK. Geochemistry and genesis of fluoride: containing ground waters in India. Ground Water.1975; 13: 275-281. Edmunds WM. Rainwater harvesting as remediation for fluoride endemic areas. http://gwadi.org/sites/gwadi.org/files/CaseFluoride.pdf.

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Ghosh A. Fluoride contamination in ground water. http://www.slideshare.net/ghosh51/fluoride-contamination-in-ground-water. Luder HU, Gerth-Kahlert C, Ostertag-Benzinger S, Schorderet DF. Dental phenotype in Jalili syndrome due to a c.1312 dupC homozygous mutation in the CNNM4 gene. PLoS One. 2013 Oct 23; 8(10):e78529.

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Figure Captions:

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Figure-1: Intra oral clinical picture revealing severely discolored, attrited and malformed teeth with heavy staining suggestive of amelogenesis imperfecta. Figure-2: Orthopantamogram showing absence of enamel in multiple teeth and compromised periodontal status. Figure-3: Ground section (10x) done with the help of bur of an extracted molar confirming absence of enamel. Figure-4: Front face photograph demonstrating mild ptosis in the left eye. Figure-5: Slit lamp biomicroscopy showing anterior keratoconus and Vogt’s striae in the left eye. Figure-6: Slit lamp biomicroscopy showing ectopia lentis in the right eye superotemporally. Figure-7(a) & (b): (a) Color fundus photo showing generalized pigmentary changes in the right eye (b) Color fundus photo showing diffuse pigmentary changes and a hypopigmented patch present one disc diameter infranasal to the optic disc in the left eye. Figure-8: Spectral domain optical coherence tomography images of left eye showing diffuse atrophy of the retinal pigment epithelium. Figure-9: Single layer map showing presence of retinal folds. Figure-10: Chest radiograph of the patient showing shadow of heart on opposite side. Figure-11: Ultrasonography of abdomen showing transposition of major visceral organs. Figure-12: Pedigree analysis of the affected Indian family with Jalili syndrome.

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Figure-1: Intra oral clinical picture revealing severely discolored, attrited and malformed teeth with heavy staining suggestive of amelogenesis imperfecta. Figure-2: Orthopantamogram showing absence of enamel in multiple teeth and compromised periodontal status. Figure-3: Ground section (10x) done with the help of bur of an extracted molar confirming absence of enamel. Figure-4: Front face photograph demonstrating mild ptosis in the left eye. Figure-5: Slit lamp biomicroscopy showing anterior keratoconus and Vogt’s striae in the left eye. Figure-6: Slit lamp biomicroscopy showing ectopia lentis in the right eye superotemporally. Figure-7(a) & (b): (a) Color fundus photo showing generalized pigmentary changes in the right eye (b) Color fundus photo showing diffuse pigmentary changes and a hypopigmented patch present one disc diameter infranasal to the optic disc in the left eye. Figure-8: Spectral domain optical coherence tomography images of left eye showing diffuse atrophy of the retinal pigment epithelium. Figure-9: Single layer map showing presence of retinal folds. Figure-10: Chest radiograph of the patient showing shadow of heart on opposite side. Figure-11: Ultrasonography of abdomen showing transposition of major visceral organs. Figure-12: Pedigree analysis of the affected Indian family with Jalili syndrome.

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Jalili syndrome presenting with situs inversus totalis and keratoconus: the first case in the Indian subcontinent.

Jalili syndrome (JS) (MIM#217080) is a rare genetic disorder characterized by the comorbid appearance of cone-rod dystrophy (CORD) and amelogenesis im...
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