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Figure.  Cataract Morphology in an 18-Year-Old Man Diagnosed With Cerebrotendinous Xanthomatosis (CTX)
Cataract Morphology in an 18-Year-Old Man Diagnosed With Cerebrotendinous Xanthomatosis (CTX)

The patient (patient 3) had decreased distance vision and bilateral cataracts diagnosed at age 16 years. His ocular history included myopia, with spectacle correction beginning at approximately age 12 years and several changes in prescription over time. Slitlamp examination showed bilateral cataracts with anterior cortical opacities (A), posterior subcapsular opacities (B), and flecklike opacities throughout (C).

Table 1.  Demographic Characteristics
Demographic Characteristics
Table 2.  Clinical Characteristics of Patients With Cerebrotendinous Xanthomatosis
Clinical Characteristics of Patients With Cerebrotendinous Xanthomatosis
1.
Salen  G, Steiner  RD.  Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX).  J Inherit Metab Dis. 2017;40(6):771-781. doi:10.1007/s10545-017-0093-8PubMedGoogle Scholar
2.
Wong  JC, Walsh  K, Hayden  D, Eichler  FS.  Natural history of neurological abnormalities in cerebrotendinous xanthomatosis.  J Inherit Metab Dis. 2018;41(4):647-656. doi:10.1007/s10545-018-0152-9PubMedGoogle Scholar
3.
Mignarri  A, Gallus  GN, Dotti  MT, Federico  A.  A suspicion index for early diagnosis and treatment of cerebrotendinous xanthomatosis.  J Inherit Metab Dis. 2014;37(3):421-429. doi:10.1007/s10545-013-9674-3PubMedGoogle Scholar
4.
Tibrewal  S, Duell  PB, DeBarber  AE, Loh  AR.  Cerebrotendinous xanthomatosis: early diagnosis on the basis of juvenile cataracts.  J AAPOS. 2017;21(6):505-507. doi:10.1016/j.jaapos.2017.07.211PubMedGoogle Scholar
5.
Duell  PB, Salen  G, Eichler  FS,  et al.  Diagnosis, treatment, and clinical outcomes in 43 cases with cerebrotendinous xanthomatosis.  J Clin Lipidol. 2018;12(5):1169-1178. doi:10.1016/j.jacl.2018.06.008PubMedGoogle Scholar
6.
Lorincz  MT, Rainier  S, Thomas  D, Fink  JK.  Cerebrotendinous xanthomatosis: possible higher prevalence than previously recognized.  Arch Neurol. 2005;62(9):1459-1463. doi:10.1001/archneur.62.9.1459PubMedGoogle Scholar
7.
Appadurai  V, DeBarber  A, Chiang  PW,  et al.  Apparent underdiagnosis of cerebrotendinous xanthomatosis revealed by analysis of ~60,000 human exomes.  Mol Genet Metab. 2015;116(4):298-304. doi:10.1016/j.ymgme.2015.10.010PubMedGoogle Scholar
8.
Yahalom  G, Tsabari  R, Molshatzki  N, Ephraty  L, Cohen  H, Hassin-Baer  S.  Neurological outcome in cerebrotendinous xanthomatosis treated with chenodeoxycholic acid: early versus late diagnosis.  Clin Neuropharmacol. 2013;36(3):78-83. doi:10.1097/WNF.0b013e318288076aPubMedGoogle Scholar
9.
Stelten  BML, Huidekoper  HH, van de Warrenburg  BPC,  et al.  Long-term treatment effect in cerebrotendinous xanthomatosis depends on age at treatment start.  Neurology. 2019;92(2):e83-e95. doi:10.1212/WNL.0000000000006731PubMedGoogle Scholar
10.
Pitt  JJ.  High-throughput urine screening for Smith-Lemli-Opitz syndrome and cerebrotendinous xanthomatosis using negative electrospray tandem mass spectrometry.  Clin Chim Acta. 2007;380(1-2):81-88. doi:10.1016/j.cca.2007.01.016PubMedGoogle Scholar
11.
Haas  D, Gan-Schreier  H, Langhans  CD,  et al.  Differential diagnosis in patients with suspected bile acid synthesis defects.  World J Gastroenterol. 2012;18(10):1067-1076. doi:10.3748/wjg.v18.i10.1067PubMedGoogle Scholar
12.
Gillespie  RL, Urquhart  J, Anderson  B,  et al.  Next-generation sequencing in the diagnosis of metabolic disease marked by pediatric cataract.  Ophthalmology. 2016;123(1):217-220. doi:10.1016/j.ophtha.2015.06.035PubMedGoogle Scholar
13.
Musleh  M, Hall  G, Lloyd  IC,  et al.  Diagnosing the cause of bilateral paediatric cataracts: comparison of standard testing with a next-generation sequencing approach.  Eye (Lond). 2016;30(9):1175-1181. doi:10.1038/eye.2016.105PubMedGoogle Scholar
14.
Sheeladevi  S, Lawrenson  JG, Fielder  AR, Suttle  CM.  Global prevalence of childhood cataract: a systematic review.  Eye (Lond). 2016;30(9):1160-1169. doi:10.1038/eye.2016.156PubMedGoogle Scholar
15.
Berginer  VM, Gross  B, Morad  K,  et al.  Chronic diarrhea and juvenile cataracts: think cerebrotendinous xanthomatosis and treat.  Pediatrics. 2009;123(1):143-147. doi:10.1542/peds.2008-0192PubMedGoogle Scholar
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    Brief Report
    September 19, 2019

    Prevalence of Cerebrotendinous Xanthomatosis Among Patients Diagnosed With Acquired Juvenile-Onset Idiopathic Bilateral Cataracts

    Author Affiliations
    • 1Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina
    • 2Formerly at Retrophin, Inc, San Diego, California
    • 3Molecular Vision Laboratory, Hillsboro, Oregon
    • 4Department of Physiology and Pharmacology, Oregon Health & Science University, Portland
    • 5Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor
    • 6Knight Cardiovascular Institute, Oregon Health & Science University, Portland
    • 7Retrophin, Inc, San Diego, California
    JAMA Ophthalmol. 2019;137(11):1312-1316. doi:10.1001/jamaophthalmol.2019.3639
    Key Points

    Question  What is the prevalence of cerebrotendinous xanthomatosis (CTX) among patients with juvenile-onset idiopathic bilateral cataracts?

    Findings  In this multicenter study including 170 patients diagnosed as having early-onset idiopathic bilateral cataracts, from November 2015 through June 2017, 3 patients (1.8%) were diagnosed as having CTX, which is approximately 500-fold the currently estimated prevalence in the general population (3 to 5 per 100 000).

    Meaning  Juvenile-onset idiopathic bilateral cataracts may be an important screening marker for CTX that can facilitate early identification and treatment of CTX.

    Abstract

    Importance  Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive bile acid synthesis disorder caused by mutations in CYP27A1, the gene encoding sterol 27-hydroxylase, which results in elevated levels of plasma cholestanol and urinary bile alcohols. Clinical symptoms and signs may include early-onset chronic diarrhea, juvenile-onset bilateral cataracts, cholestatic jaundice, tendon xanthomas, and progressive neurological deterioration. Although initiation of treatment at a young age can prevent disease complications, diagnosis often occurs after the onset of permanent neurologic damage. Strategies are needed to facilitate early diagnosis.

    Objective  To evaluate the prevalence of CTX in a patient population diagnosed with early-onset idiopathic bilateral cataracts.

    Design, Setting, and Participants  This interim analysis of the Cerebrotendinous Xanthomatosis Prevalence Study was conducted in 26 active US sites from November 2015 to June 2017. The study included patients diagnosed as having idiopathic bilateral cataracts from ages 2 to 21 years. Potentially eligible study participants were identified through retrospective medical record review or on receiving care for cataracts at an active site. Data were analyzed from July 2017 to October 2018.

    Main Outcomes and Measures  Measurement of plasma cholestanol levels and optional urine bile alcohol screening were performed. A plasma cholestanol concentration of 0.4 mg/dL or greater or a positive urine bile alcohol result prompted CYP27A1 genetic testing to confirm the diagnosis of CTX.

    Results  Of 170 tested patients, 88 (51.8%) were male, and the median (range) age was 10 (2-49) years. A total of 3 patients (1.8%) had biochemical and genetic confirmation of newly diagnosed CTX (plasma cholestanol level greater than 1.0 mg/dL, positive urine bile alcohol result, and disease-causative mutations in CYP27A1). The mean (range) age at cataract diagnosis for patients with CTX was 12 (8-16) years. Reported symptoms included abnormal gait or balance (n = 3), learning disability (n = 2), cognitive decline (n = 2), seizures (n = 2), frequent bone fractures (n = 2), and chronic diarrhea (n = 1).

    Conclusions and Relevance  To date, 1.8% of patients in this study were diagnosed as having CTX, which is approximately 500-fold the currently estimated prevalence of CTX in the general population (3 to 5 per 100 000). These data suggest that juvenile-onset idiopathic bilateral cataracts may be useful as a screening marker for CTX and that ophthalmologists can play an important role in facilitating early identification of this condition.

    Introduction

    Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of lipid storage and bile acid synthesis.1 Bilateral cataracts are a clinical hallmark of CTX, reported in 76% to 88% of affected individuals.2,3 Childhood-onset bilateral cataracts are a common presentation in patients with CTX.3 Cerebrotendinous xanthomatosis–related cataracts have a characteristic morphology, presenting as diffuse flecks, seen best by retroillumination, with posterior capsular opacities.4

    In CTX, mutations in CYP27A1 cause impaired sterol 27-hydroxylase function, leading to decreased synthesis of chenodeoxycholic acid and accumulation of cholestanol in plasma, the lens, and other tissues (eg, brain and tendons).1 Diagnostic biochemical abnormalities include elevated plasma cholestanol and urinary bile alcohol concentrations.1 In addition to juvenile-onset bilateral cataracts, CTX symptoms and signs may include early-onset chronic diarrhea, neonatal cholestatic jaundice, tendon xanthomas, and progressive neurological deterioration.1,5 Although clinical manifestations of CTX vary considerably, there is a high probability of neurological disease progression over time in the absence of treatment.2

    The rarity of CTX in the United States (estimated prevalence, 3 to 5 per 100 0006; estimated incidence, 0.7 to 1.4 per 100 0007) and variability in phenotype are significant barriers to diagnosis.1 Latency between onset of symptoms and diagnosis of CTX can reach 20 to 25 years,3 often resulting in diagnosis after onset of permanent neurological damage.8,9 Strategies to improve early identification of CTX are needed, since earlier diagnosis and treatment may help to reduce or prevent permanent neurologic disability.8 We hypothesized that screening patients presenting for evaluation of juvenile-onset bilateral cataracts would enhance diagnosis and enable earlier treatment of CTX.

    Methods

    This observational, multicenter study was an interim analysis of the Cerebrotendinous Xanthomatosis Prevalence Study and evaluated the prevalence of CTX in patients diagnosed with juvenile-onset idiopathic bilateral cataracts. The study was approved by each site’s institutional review board. Patients 18 years and older provided written informed consent if willing to do so unless unable (ie, had diminished capacity owing to the illness), in which case parents or legal guardians provided written informed consent. For patients younger than 18 years, parents or legal guardians provided written informed consent and patients provided written assent.

    Patients

    Individuals potentially eligible for study participation were identified through retrospective medical record review or prospective screening after diagnosis of bilateral cataracts at 26 active US sites from November 2015 to June 2017. Eligible patients had been diagnosed as having idiopathic bilateral cataracts from ages 2 to 21 years. Patients were excluded if they had cataracts of known etiology, a prior diagnosis of CTX, had taken or were currently taking cholic acid or chenodeoxycholic acid, or had received an investigational product within the past 30 days.

    Assessments

    Blood samples were collected for quantitative gas chromatography–mass spectrometry analysis of plasma cholestanol. Urine samples were collected for semiquantitative tandem mass spectrometry analysis to determine if urinary bile alcohol levels were elevated.10,11 Plasma cholestanol levels of 0.4 mg/dL (to convert to micromoles per liter, multiply by 0.0257) or greater or a positive urinary bile alcohol result prompted CYP27A1 genetic testing. Genetic counseling was not provided prior to genetic testing. Biochemical and genetic testing was performed at Clinical Laboratory Improvement Amendment–certified laboratories (Molecular Vision Laboratory, Hillsboro, Oregon; OHSU Sterol Analysis Laboratory, Oregon Health & Science University, Portland). For cholestanol levels, the mean (SD) normal laboratory value was 0.23 (0.12) mg/dL, and the CTX diagnostic threshold was 1.0 mg/dL. Serious adverse events associated with study procedures (ie, blood draw) were recorded.

    Statistical Analysis

    Demographic information, plasma cholestanol concentrations, urinary bile alcohol results, and CTX genetic testing results were summarized using descriptive statistics and frequency counts with SAS, version 9.4 (SAS Institute Inc). Targeted medical histories were summarized for patients diagnosed with CTX.

    Results
    Patients and Demographic Characteristics

    A total of 170 patients aged 2 to 49 years (who were diagnosed as having cataracts between ages 2 and 21 years) were enrolled at 26 ophthalmology practices from November 2015 to June 2017 (Table 1). The patient aged 49 years was somewhat of an outlier, considering the mean age of 10 years in this population; however, this patient was diagnosed as having cataracts at approximately 10 years.

    Patients Diagnosed With CTX

    Of 170 patients enrolled, 16 (9.4%) met criteria for genetic testing, and 3 (1.8%; 95% CI, 0.37-5.07) had genetic confirmation of CTX (1 identified through medical record review; 2 prospectively identified after enrollment) (Table 2). Patients with CTX were aged 13 to 18 years at study entry, and the mean (range) age at cataract diagnosis was 12 (8-16) years (Figure). All 3 had plasma cholestanol levels of 3.17 mg/dL or greater and positive urinary bile alcohol results. Symptoms reported in more than 1 patient included abnormal gait or balance (n = 3), learning disability (n = 2), cognitive decline (n = 2), seizures (n = 2), and frequent bone fractures (n = 2). Patient 1 had additional symptoms of developmental delay, exotropia, and foot deformity; he also required assistance with activities of daily living. Patient 2 had abnormal electroencephalography findings and problems with fine motor control, which were not reported in the other 2 patients. Unlike patients 1 and 2, patient 3 did not have a learning disability or cognitive decline. There was no reported family history of consanguinity. One patient had a family history of xanthomas; another had a family history of unexplained chronic diarrhea. None had a family history of congenital or juvenile cataracts, developmental delay, or known genetic disorders. Additional details, including genetic variants for each patient, are provided in Table 2.

    Discussion

    As of November 2017, the prevalence of CTX in this study was 1.8%, approximately 500-fold the estimated prevalence in the general population (3 to 5 per 100 000).6 Although the academic and specialty settings of the participating sites may have led to some degree of selection bias in this study, this finding corroborates previous reports indicating a relatively high prevalence of CTX (2%12 to approximately 4%13) among patients with bilateral juvenile-onset cataracts (the prevalence of bilateral childhood cataracts in the general population is estimated at 3 to 68 per 100 00014).

    Other clinical features of CTX observed included abnormal gait and balance, learning disability, developmental delay, cognitive decline, seizures, and frequent bone fractures. The diagnosis of juvenile-onset bilateral cataracts should prompt ophthalmologists to consider CTX as a potential underlying cause, particularly when other clinical manifestations of CTX are present (eg, hepatobiliary disease, unexplained chronic diarrhea, learning disability, or seizures). Inquiring about clinical symptoms of CTX in the patient or siblings may be helpful in this endeavor. Additional family history may be informative, although none of the siblings in this study had features of CTX. There was no reported family history of consanguinity in the patients with CTX in this study, but case reports of patients with CTX do include a number of individuals from consanguineous families. The absence of true homozygosity in our study is further evidence that consanguinity was a not contributor to CTX. Biochemical testing for CTX should be considered for patients with symptoms or signs of CTX. In addition, use of next-generation sequencing for genes associated with congenital and developmental cataracts may improve diagnosis of underlying causes of cataracts.13

    Early diagnosis of CTX is important because initiation of treatment with chenodeoxycholic acid early in the disease process is associated with better outcomes, particularly with respect to neurological complications.5,8,9,15 One study of 16 patients with CTX8 found that patients starting treatment when younger than 25 years had significantly better outcomes with ambulation, dysarthria, pyramidal dysfunction, cerebellar dysfunction, and cognitive deterioration. A separate report of 2 siblings found that early initiation of long-term treatment prevented the onset of neurologic symptoms over 14 years of follow-up.15 Thus, early diagnosis of CTX is essential to facilitate initiation of treatment that may prevent or slow progression of irreversible neurological damage, and ophthalmologists are uniquely positioned to aid in early recognition and diagnosis of this disease.

    Limitations

    The findings of this study must be viewed in light of its limitations, including the use of a relatively small interim sample to assess a rare event. Further, we cannot ensure that the cases of acquired bilateral idiopathic cataracts in this study represent the same diagnostic categories as those at centers not participating in this study. In addition, despite attempts of participating centers to identify and recall patients identified as eligible based on retrospective medical record review, there may be some bias in terms of which patients actually returned for CTX testing. However, our results do appear to support prevalence results from previous studies and highlight an opportunity for earlier diagnosis of this disease.

    Conclusions

    These data suggest that juvenile-onset idiopathic bilateral cataracts may be an important marker that can facilitate early identification of CTX, a disease that can cause devastating neurological damage if left untreated. Eye care clinicians, including pediatric ophthalmologists, may be able to play an important role in promoting early diagnosis of CTX by ordering or recommending testing for this disease in patients with idiopathic bilateral juvenile-onset cataracts.

    Back to top
    Article Information

    Accepted for Publication: July 14, 2019.

    Published Online: September 19, 2019. doi:10.1001/jamaophthalmol.2019.3639

    Open Access: This article is published under the JN-OA license and is free to read on the day of publication.

    Corresponding Author: Sharon F. Freedman, MD, Department of Ophthalmology, Duke University Medical Center, 2351 Erwin Rd, Durham, NC 27710 (sharon.freedman@duke.edu).

    Author Contributions: Mr Fiorito and Dr Marshall had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Study concept and design: Brennand, Duell, Marshall.

    Acquisition, analysis, or interpretation of data: Freedman, Chiang, DeBarber, Del Monte, Duell, Fiorito, Marshall.

    Drafting of the manuscript: Brennand, Duell, Fiorito.

    Critical revision of the manuscript for important intellectual content: All authors.

    Administrative, technical, or material support: Brennand, DeBarber, Duell, Marshall.

    Study supervision: Duell, Marshall.

    Conflict of Interest Disclosures: Ms Brennand was a former employee of Retrophin, Inc, and was responsible for the operationalization of the study. Dr Chiang is a minority owner of Molecular Vision Laboratory. Dr DeBarber has received grants, personal fees, and nonfinancial support from Retrophin, Inc, paid to her institution as well as personal fees from Leadiant Biosciences and has patent 14/401,427 issued. Dr Del Monte has received grants from Retrophin, Inc, paid to his institution. Dr Duell has received grants and personal fees from Esperion, Regeneron, Regenxbio, and Retrophin, Inc, and personal fees from Akcea and AstraZeneca. Mr Fiorito is an employee of Retrophin, Inc. Dr Marshall is a former employee of Retrophin, Inc. No other disclosures were reported.

    Funding/Support: This study was funded by Retrophin, Inc.

    Role of the Funder/Sponsor: Retrophin, Inc, consulted with advisors and study investigators on the design of the study; provided financial and material support for the study; and, with the assistance of study investigators, monitored the conduct of the study, collected data from the investigative centers, and analyzed the data. Ms Brennand and Dr Marshall, former employees of Retrophin, Inc, and Mr Fiorito, a current employee of Retrophin, Inc, are authors of this article and were involved in the interpretation of the data and the preparation and review of the manuscript. The funding sources had no role in the approval of the manuscript or the decision to submit the manuscript for publication.

    Meeting Presentation: Data from this article were presented in part as a poster at the 2018 joint meeting of the International Strabismological Association and the American Association for Pediatric Ophthalmology & Strabismus; March 18-22, 2018; Washington, DC.

    Additional Contributions: We thank the patients and their parents for granting permission to publish this information. Medical writing and editorial support were provided by Sherri D. Jones, PharmD, and Donald Fallon, ELS, of MedVal Scientific Information Services, Princeton, New Jersey. They were funded by Retrophin, Inc.

    References
    1.
    Salen  G, Steiner  RD.  Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX).  J Inherit Metab Dis. 2017;40(6):771-781. doi:10.1007/s10545-017-0093-8PubMedGoogle Scholar
    2.
    Wong  JC, Walsh  K, Hayden  D, Eichler  FS.  Natural history of neurological abnormalities in cerebrotendinous xanthomatosis.  J Inherit Metab Dis. 2018;41(4):647-656. doi:10.1007/s10545-018-0152-9PubMedGoogle Scholar
    3.
    Mignarri  A, Gallus  GN, Dotti  MT, Federico  A.  A suspicion index for early diagnosis and treatment of cerebrotendinous xanthomatosis.  J Inherit Metab Dis. 2014;37(3):421-429. doi:10.1007/s10545-013-9674-3PubMedGoogle Scholar
    4.
    Tibrewal  S, Duell  PB, DeBarber  AE, Loh  AR.  Cerebrotendinous xanthomatosis: early diagnosis on the basis of juvenile cataracts.  J AAPOS. 2017;21(6):505-507. doi:10.1016/j.jaapos.2017.07.211PubMedGoogle Scholar
    5.
    Duell  PB, Salen  G, Eichler  FS,  et al.  Diagnosis, treatment, and clinical outcomes in 43 cases with cerebrotendinous xanthomatosis.  J Clin Lipidol. 2018;12(5):1169-1178. doi:10.1016/j.jacl.2018.06.008PubMedGoogle Scholar
    6.
    Lorincz  MT, Rainier  S, Thomas  D, Fink  JK.  Cerebrotendinous xanthomatosis: possible higher prevalence than previously recognized.  Arch Neurol. 2005;62(9):1459-1463. doi:10.1001/archneur.62.9.1459PubMedGoogle Scholar
    7.
    Appadurai  V, DeBarber  A, Chiang  PW,  et al.  Apparent underdiagnosis of cerebrotendinous xanthomatosis revealed by analysis of ~60,000 human exomes.  Mol Genet Metab. 2015;116(4):298-304. doi:10.1016/j.ymgme.2015.10.010PubMedGoogle Scholar
    8.
    Yahalom  G, Tsabari  R, Molshatzki  N, Ephraty  L, Cohen  H, Hassin-Baer  S.  Neurological outcome in cerebrotendinous xanthomatosis treated with chenodeoxycholic acid: early versus late diagnosis.  Clin Neuropharmacol. 2013;36(3):78-83. doi:10.1097/WNF.0b013e318288076aPubMedGoogle Scholar
    9.
    Stelten  BML, Huidekoper  HH, van de Warrenburg  BPC,  et al.  Long-term treatment effect in cerebrotendinous xanthomatosis depends on age at treatment start.  Neurology. 2019;92(2):e83-e95. doi:10.1212/WNL.0000000000006731PubMedGoogle Scholar
    10.
    Pitt  JJ.  High-throughput urine screening for Smith-Lemli-Opitz syndrome and cerebrotendinous xanthomatosis using negative electrospray tandem mass spectrometry.  Clin Chim Acta. 2007;380(1-2):81-88. doi:10.1016/j.cca.2007.01.016PubMedGoogle Scholar
    11.
    Haas  D, Gan-Schreier  H, Langhans  CD,  et al.  Differential diagnosis in patients with suspected bile acid synthesis defects.  World J Gastroenterol. 2012;18(10):1067-1076. doi:10.3748/wjg.v18.i10.1067PubMedGoogle Scholar
    12.
    Gillespie  RL, Urquhart  J, Anderson  B,  et al.  Next-generation sequencing in the diagnosis of metabolic disease marked by pediatric cataract.  Ophthalmology. 2016;123(1):217-220. doi:10.1016/j.ophtha.2015.06.035PubMedGoogle Scholar
    13.
    Musleh  M, Hall  G, Lloyd  IC,  et al.  Diagnosing the cause of bilateral paediatric cataracts: comparison of standard testing with a next-generation sequencing approach.  Eye (Lond). 2016;30(9):1175-1181. doi:10.1038/eye.2016.105PubMedGoogle Scholar
    14.
    Sheeladevi  S, Lawrenson  JG, Fielder  AR, Suttle  CM.  Global prevalence of childhood cataract: a systematic review.  Eye (Lond). 2016;30(9):1160-1169. doi:10.1038/eye.2016.156PubMedGoogle Scholar
    15.
    Berginer  VM, Gross  B, Morad  K,  et al.  Chronic diarrhea and juvenile cataracts: think cerebrotendinous xanthomatosis and treat.  Pediatrics. 2009;123(1):143-147. doi:10.1542/peds.2008-0192PubMedGoogle Scholar
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