Dear Editor Jalili syndrome (JS) was first described by IK Jalili and NJD Smith as an autosomal recessive disorder in an Arab family. JS is an inherited disorder caused by a mutation in the CNNM4 gene.1 Major features include cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI).2 Ophthalmic features arise due to defective cone receptors, resulting in reduced central visual acuity, photophobia, loss of color vision, nystagmus, and occasional rod dysfunction.1,3 AI presents as a defect in enamel formation, contributing to defective structure and composition of both primary and secondary dentition.3,4 We report two cases (a girl of 11 years of age and her younger brother of 5 years of age) from the same family with distinct retinal and dental findings depicting intrafamilial phenotypic variability. Case Report Two siblings (one male and one female) were referred to the ophthalmology department. They were products of consanguineous marriage. Corrected visual acuity was finger counting at one meter ocuclus uterque (both eyes) (OU) in the female and 20/200 OU in the male child, respectively. The female had hypermetropia of 5–6 D, and the male had hypermetropia of 2–2.5 D with cycloplegic refraction. There was a history of both indoor and outdoor photophobia. The female child had exotropia and nystagmus that were increasing on the cover-uncover test. The male child was orthophoric. Fundus examination revealed bull’s eye maculopathy in the female and normal fundus in the other Fig. 1a and b.Figure 1: (a). Fundus picture of the female patient showing bull’s eye maculopathy. (b). Normal-appearing fundus in a male patientFull-field electroretinogram (ERG) conducted on both patients showed findings indicative of CRD, with dark-adapted (DA) (Scotopic) responses showing reduced or non-recordable (DA: 0.01 – rod response) with prolonged implicit times, and mixed rod-cone response (DA: 3.0 or 10.0) shows markedly reduced a- and b-wave amplitudes, cone response (Light adaptation (LA): 3.0), as well as 30 Hz flicker shows reduced amplitudes Figs. 2 and 3. Dental examination demonstrated defective enamel formation, i.e., AI. In JS, CNNM4 mutations cause both retinal degeneration and enamel malformation due to their role in magnesium transport, affecting both photoreceptors and ameloblasts. There was marked discoloration, sensitivity, and brittleness of teeth with premature tooth loss in the female child Fig. 4. The male child showed a mild variant of AI Fig. 5. Genetic testing (CNNM4 gene sequencing) could not be performed due to financial constraints. However, the dual ocular and dental phenotype is highly characteristic and supports the clinical diagnosis.Figure 2: Full-field ERG conducted on male patient showed findings indicative of cone-rod dystrophy, with dark-adapted (DA) (Scotopic) responses showing reduced or non-recordable (DA: 0.01rod response) with prolonged implicit times, and mixed rod-cone response (DA: 3.0 or 10.0) shows markedly reduced a- and b-wave amplitudes, cone response (LA: 3.0), as well as 30 Hz flicker shows reduced amplitudesFigure 3: Full-field ERG conducted on female patient showed findings indicative of cone-rod dystrophy, with dark-adapted (DA) (Scotopic) responses showing reduced or non-recordable (DA: 0.01rod response) with prolonged implicit times, and mixed rod-cone response (DA: 3.0 or 10.0) shows markedly reduced a- and b-wave amplitudes, cone response (LA: 3.0), as well as 30 Hz flicker shows reduced amplitudesFigure 4: Dental examination demonstrated defective enamel formation, i.e., amelogenesis imperfecta (AI), severe form in a female patientFigure 5: Mild variant amelogenesis imperfecta (AI) in the male patientDiscussion We have described two siblings from the same family with CRD with AI. AI describes certain inherited conditions affecting tooth enamel formation. Previous reports have noted the simultaneous presence of AI with ocular anomalies in various oculo-skeletal syndromes and cases of iris coloboma.5,6 Based on the dental examination, the clinical entity was diagnosed as hypomenarilized AI. The findings were in agreement with those previously reported for AI in JS patients.1 CRD is a rare group of progressive disorders that present during the first two decades of life. The symptoms are progressive loss of central visual acuity, color vision, photophobia, nystagmus, and associated night blindness in some cases.7,8 Macular involvement is seen in the majority of patients with JS; however, in a few cases, normal morphology has been reported.1,2 JS is a disorder where a single gene mutation in one protein affects two different tissues. Increased fluoride concentrations in groundwater may play a significant role in this mutation.8,9 Sociodemographic information indicates that both the patients and their families reside in regions of India with elevated fluoride levels in drinking water. Luder et al. have concluded that mutation of the CNNM4 gene, located on chromosome 2q11, may lead to premature amelogenesis, thus resulting in incompletely mineralized enamel. This gene plays a pivotal role in magnesium ion transport and homeostasis. Magnesium acts as a cofactor for several enzymes involved in retinal transduction mechanisms. A malfunction in cellular magnesium transport may be the shared factor behind both ocular and dental disorders, thus exhibiting pleiotropy.10 JS and Heimler syndrome share the hallmark features of AI and inherited retinal dystrophy (IRD), which can make differentiation challenging in the absence of genetic confirmation. However, certain clinical features help to distinguish between the two. JS, caused by mutations in CNNM4, presents as an autosomal recessive disorder characterized by early-onset CRD in association with enamel hypoplasia, with typical findings of macular atrophy and central outer retinal loss on optical coherence tomography (OCT). Importantly, systemic involvement is absent. In contrast, Heimler syndrome, resulting from mutations in PEX1 or PEX6, also follows an autosomal recessive pattern but manifests as a peroxisomal biogenesis disorder. It is usually associated with later-onset rod-cone dystrophy, peripheral retinal changes, relative foveal preservation on OCT, and systemic features such as sensorineural hearing loss and nail dysplasia.11 Recognition of these distinctions is critical in guiding diagnosis where molecular testing is not readily available. In our patient, the absence of hearing loss or systemic abnormalities, along with the presence of enamel hypoplasia and CRD, was consistent with a diagnosis of JS. Jalili classified this syndrome into two forms based on its phenotypic severity. The severe form of type A starts in infancy with the macular lesion, while type B, the milder form, starts in early childhood with a normal-appearing fundus.8 In our case report, both patients presented with reduced acuity and nystagmus in infancy with evidence of CRD on ERG. The fundus appearance varied between patients, ranging from bull’s eye maculopathy in the female to a normal retinal appearance in the male patient. JS lacks a strict genotype-phenotype correlation, with intrafamilial phenotypic variability, which we observed in our patients. Recognizing JS early is crucial for providing patients with comprehensive care. Early diagnosis allows to offer appropriate support for visual impairment, accurate prognosis, genetic counseling, and necessary dental interventions. Authors' contributions First author involved in concept, design, definition of intellectual content, literature search, manuscript preparation, manuscript editing, and manuscript review, and second author involved in definition of intellectual content, literature search, and manuscript preparation. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship: Nil. Conflicts of interest: There are no conflicts of interest.
Sharda et al. (Thu,) studied this question.