Methods

Medical Sciences Institutional Review Board A at the University of Miami Miller School of Medicine approved the retrospective review of patient records from January 1, 2000, through October 15, 2012, with waiver of consent and authorization. After 2 index cases were identified in 2004, HLA class II typing was part of routine diagnostic evaluation in children with bilateral panuveitis of unknown cause. Consecutive patients were included in the review if they were 16 years of age or younger at onset of uveitis and had panuveitis or a history of tubulointerstitial nephritis. Patients with chronic anterior uveitis, or uveitis associated with known disorders such as juvenile idiopathic arthritis, generally did not receive class II typing and were excluded from data collection. One girl with recalcitrant, atypical anterior uveitis without chorioretinal lesions was HLA typed. She was found to have the TINU alleles without evidence of renal disease and was excluded from analysis of the panuveitis patients. During the study period, 2 adult patients, one with TINU, were typed and had the TINU alleles, but were excluded from analysis based on age. Because typing was conducted for clinical purposes, there is no concurrent control group. Demographics, medical history, ocular findings, clinical course, ocular complications, and laboratory results were recorded from pre-existing medical records.

Low-resolution HLA-DR, DQ class II DNA typing was performed in a commercial reference lab (Quest Diagnostics, Madison, New Jersey, USA) by polymerase chain reaction using sequence-specific oligonucleotides to detect HLA-DRB1*01 and HLA-DQB1*05, 2 key elements of the TINU haplotype. Low-resolution 2-digit typing is considered equivalent to older serologic methods and is used for disease associations and for screening transplant recipients and donors for compatibility before conducting more detailed evaluations. Four-digit testing was available for some patients. HLA-DQA testing and high-resolution testing with sequence-based typing were not ordered to reduce the cost of testing to the patient. Patients with the HLA-DRB1 and HLA-DQB1 markers associated with TINU were referred for medical evaluation for renal disease.

The Fisher exact test ( www.graphpad.com ; accessed November 8, 2013) compared the frequency of the HLA-DRB1*01–DQB1*05 haplotypes in cases versus North American European, Hispanic, and African American populations ( www.allelefrequencies.net ; accessed November 8, 2013); data were available from 5909 population controls, 10.4% of whom had the haplotype and all of whom were assumed not to have panuveitis because it is a rare disease. Descriptive statistics of sensitivity, specificity, likelihood ratios, and predictive values were calculated for HLA-DR class II DNA typing if used as a screening test for suspected TINU in pediatric panuveitis ( www.medCalc.org ; accessed November 8, 2013). A positive likelihood ratio was defined as sensitivity divided by 100 minus specificity. An historical control group of 112 published noninfectious pediatric patients from our institution from 1996 through 2002 also was used for statistical calculations by assuming that the haplotype would be found in 2 TINU patients (true-positive results), 10 idiopathic panuveitis (false-positive results), and 10.4% percent of the remaining 100 patients (false-positive results).

Results

Twenty-one pediatric uveitis patients met inclusion criteria: 6 with definite TINU and 15 with unexplained panuveitis. Demographics and clinical course are tabulated in Table 1 . Age at the time of diagnosis uveitis was a median of 11 years (range, 4 to 14 years) in the definite TINU group and a median of 10 years (range, 4 to 15 years) in the panuveitis group. Twenty were white or Hispanic; Patient 18 was black. Two (33%) of 6 children with definite TINU were female versus 9 (60%) of 15 children with panuveitis. Patients with definite TINU were diagnosed with renal disease before uveitis by a median of 3 months (range, 0 to 12 months). In the panuveitis group, detection of the TINU risk alleles occurred a median of 6 months (range, 1.4 to 33 months) after onset of uveitis. Most of the panuveitis patients initially were diagnosed with bilateral iridocyclitis and were referred because of recurrent or uncontrolled uveitis. Evaluation by pediatric specialists of the panuveitis patients after identification of the TINU risk alleles did not reveal evidence of tubulointerstitial nephritis.

There were 2 sibling pairs. The index sisters, Patients 9 and 10, were diagnosed simultaneously with bilateral panuveitis ( Figure 1 ); the younger sister had a remote history of abnormal urinalyses as her only medical illness and was believed to have possible TINU. Neither girl had current renal or systemic disease based on examinations by a nephrologist and a rheumatologist. The second sibling pair was 2 brothers, Patients 1 and 7. The younger brother had anterior and vitreous inflammation with mid-equatorial deep orange lesions at presentation. The elder recently had been treated for tubulointerstitial nephritis and was brought in for an eye examination and was diagnosed with panuveitis. Examinations of the younger sibling by a pediatric nephrologist, immunologist, and rheumatologist showed negative results for significant renal or other systemic disease, despite elevated creatinine and proteinuria. Clinically significant renal disease did not develop during follow-up.

Color fundus photograph of the left eye of the index Patient 9 showing the typical appearance of small atrophic chorioretinal lesions in pediatric panuveitis with risk alleles for tubulointerstitial nephritis and uveitis. There are small, peripheral, atrophic chorioretinal scars inferiorly. The appearance of the other eye was similar. Her younger sister had similar lesions in each eye that were more numerous but did not photograph well.

All 21 patients had anterior chamber and vitreous inflammation. Three (50%) of the 6 TINU patients and 11 (73.3%) of 15 panuveitis patients had small, sharply marginated chorioretinal inflammatory lesions, usually 200 to 300 μm, often located predominantly inferiorly, anterior to the equator, similar to those seen in Figure 1 and Figure 2 , Left. Clusters of larger, usually 500- to 750-μm, deep orange choroidal lesions, similar to those in Figure 3 , were seen in the 3 remaining TINU patients and the 4 remaining panuveitis patients. The deep orange lesions were observed to fade and enlarge during follow-up ( Figure 4 , Bottom left and Bottom right), but usually were without overlying RPE atrophy. Extensive vascular leakage was found in 4 of the panuveitis patients on fluorescein angiography ( Figure 2 , Right). There was optic nerve edema in 2 TINU patients and 4 panuveitis patients.

Punched-out chorioretinal lesions in pediatric panuveitis with tubulointerstitial nephritis and uveitis risk alleles with evidence of active retinal inflammation. (Left) Montage color photograph of the right fundus of Patient 16. There are multiple punched-out chorioretinal scars. The left eye had similar lesions. (Right) Montage mid-phase fluorescein angiogram of the right eye of Patient 16 showing optic nerve, macular, and peripheral small-vessel leakage.

Montage photograph of the right fundus of Patient 12 showing the typical appearance of the large orange choroidal lesions in pediatric panuveitis with tubulointerstitial nephritis and uveitis risk alleles. The large, orange, indistinctly bordered choroidal lesions are most visible temporally. The other eye also had clusters of orange lesions of the same size and location that were less numerous. No sharply demarcated areas of chorioretinal atrophy were present. The orange lesions remained stable after discontinuation of systemic immunosuppression.

New onset of focal choroidal lesions during treatment with methotrexate of pediatric panuveitis with tubulointerstitial nephritis and uveitis risk alleles. (Top left) Right macula at presentation of Patient 7, brother of Patient 1, who had confirmed tubulointerstitial nephritis and uveitis. There are no visible choroidal lesions. (Top right) Left macula of the same patient. There are small, faint orange lesions below the inferior arcade and in the temporal macula. (Bottom left) Same patient, right macula 13 months after presentation while being treated with methotrexate. There are new lesions in the inferior macula and also along the superotemporal arcade. (Bottom right) Same patient, left macula 13 months after presentation. There are new lesions in the central macula and an atrophic spot below the inferotemporal arcade. Some of the original orange lesions are no longer apparent.

Laboratory testing varied between patients and often was conducted before referral. Selected tests are tabulated in Table 2 . Typical biomarkers for iridocyclitis related to systemic disease were present in some children, but did not seem to have pathogenic significance based on the pattern of uveitis. Of 3 tested patients with definite TINU, 1 (33%) demonstrated positive results for HLA-B27, versus 3 (60%) of 5 tested panuveitis patients. None of 4 tested TINU patients (0%) had positive results for anti-nuclear antibodies (ANA) versus 3 (21%) of 14 tested panuveitis patients. Pediatric consultation results were negative for rheumatologic or renal disease in the panuveitis patients.

Table 2

HLA Class II DNA Typing and Laboratory Testing for Other Causes of Uveitis in Consecutive Patients with Pediatric Panuveitis

Patient No.	Class II HLA DNA Type a	Negative Test Results	Positive Test Results
Definite TINU
1	HLA-DRB1*0102,*0402-HLA-DQB1*03,*0501	ANA	ASO, CRP
2	HLA-DRB1*01,14-HLA-DQB1*05	ANA, ACE, ANCA, ESR	HLA-B27
3	HLA-DRB1*01-HLA-DQB1*05	Unknown	Unknown
4	Not done	Unknown	Unknown
5	Not done	ANA, ANCA, CCP, HLA-B27, RF	None
6	HLA-DRB1*01,*03-HLA-DQB1*02,*05	ACE, Bartonella, FTA-ABS, HSV, HLA-B27, Lyme, Lysozyme, Varicella	None
Panuveitis with TINU haplotype
7	HLA-DRB1*01-HLA-DQB1*05	ANA, ACE, Bartonella, HLA-B27, HSV, Lyme, RPR, VZV	ASO, serum creatinine, proteinuria, leukocytosis
8	HLA-DRB1*01-HLA-DQB1*05	ANA, ACE, ANCA, CRP, Bartonella, CMV, hepatitis B, rubella, toxoplasmosis	ASO, urine calcium oxalate crystals
9	HLA-DRB1*01,*07-HLA-DQB1*02,*05	ACE, CRP, ESR, HLA-B27, RF, toxoplasmosis	ANA
10	HLA-DRB1*01-HLA-DQB1*05	ANA	Remote, recurrent pyuria
11	HLA-DRB1*0101,*0102-DQB1*0501	ANA, ACE, ESR, lyme, RF	HLA-B27
12	HLA-DRB1*01-HLA-DQB1*05	ANA, ACE, CRP, lyme, lysozyme, UA	HLA-B27
13	HLA-DRB1*01-HLA-DQB1*05	Creatinine	ANA, HTN
14	HLA-DRB1*0103-HLA-DQB1*0501	Creatinine	β-thalassemia
15	HLA-DRB1*01-HLA-DQB1*05	ANA	None
16	HLA-DRB1*0102,*1302-HLA-DQB1*0501	ANA, ACE, β2 microglobulin, creatinine, RF	None
17	HLA-DRB1*01-HLA-DQB1*05	ANA	HLA-B27
18	HLA-DRB*01,*11-HLA-DQB1*05,*09	ANA	None
19	HLA-DRB1*01-HLA-DQB1*05	ANA, creatinine, CRP, ESR, RF	None
20	HLA-DRB1*01,*12-HLA-DQB1*03,*05	Creatinine, HLA-B27, urinalysis	ANA
21	HLA-DRB1*01-HLA-DQB1*01,*04	ANA, ACE, β2 microglobulin, CRP, FTA-ABS, HLA-B27, RF, toxoplasmosis	Proteinuria

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

1. Conjunctival Flora Antibiotic Resistance Patterns After Serial Intravitreal Injections Without Postinjection Topical Antibiotics
2. Eight-Year Follow-up of Posterior Chamber Phakic Intraocular Lens Implantation for Moderate to High Myopia
3. Comparison of Refractive Stability After Non-toric Versus Toric Intraocular Lens Implantation During Cataract Surgery
4. Effect of Nepafenac Eye Drops on Intraocular Pressure: A Randomized Prospective Study

Stay updated, free articles. Join our Telegram channel

Join