Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect.

Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins.

Ophthalmic Manifestations of Xeroderma Pigmentosum: A Perspective from the United Kingdom.

PURPOSE: To document the ocular manifestations of xeroderma pigmentosum (XP), presenting via the United Kingdom (UK) XP service, and to analyze the correlations between XP genotype and ophthalmic phenotype. DESIGN: Prospective observational case series. SUBJECTS: Eighty-nine patients seen by the UK Nationally Commissioned XP Service, from April 2010 to December 2014, with a genetically confirmed diagnosis of XP. METHODS: Patients underwent a full ophthalmic examination at each visit. Clinical features from both eyes were recorded on a standard proforma. The most recent assessments were analyzed. A 2-tailed Fisher exact test was used to assess for differences in ocular features between patients in XP subgroups with impaired transcription coupled nucleotide excision repair (TC-NER) (category 1: XP-A, B, D, F, and G) and preserved TC-NER (category 2: XP-C, E, and V). MAIN OUTCOME MEASURES: Lid and periocular abnormalities, ocular surface pathologies, neuro-ophthalmologic abnormalities, lens and retinal abnormalities, and visual acuity (VA). RESULTS: Ninety-three percent of XP patients in our cohort had ocular involvement, with 65% describing photophobia. The most common abnormalities were in the periocular skin and ocular surface, including interpalpebral conjunctival melanosis (44%) and conjunctival injection (43%). Eleven percent of patients had required treatment for periocular cancers and 2% for ocular surface cancers. The most common neuro-ophthalmologic finding was minimal pupillary reaction to light (25%). Patients in category 2 had significantly more ocular surface abnormalities than patients in category 1, including a greater proportion of conjunctival injection (P = 0.003), conjunctival corkscrew vessels (P < 0.001), corneal scarring (P = 0.01) and pingueculae under the age of 50 (P = 0.02). Meanwhile, patients in category 1 had a higher proportion of poorly reactive pupils (P < 0.001) and abnormal ocular movements (P = 0.03) compared with those in category 2. Five patients (6%) presented to ophthalmologists with ocular surface signs related to XP, before any formal diagnosis of XP was made. CONCLUSIONS: A large proportion of XP patients have ocular involvement. Regular examination by an ophthalmologist is essential, especially in screening for eyelid and ocular surface tumors. The ocular phenotype-genotype segregation within XP patients suggests that XP is a heterogeneous and complex disease. With further study, we hope to offer these patients more individualized patient care.

Master/slave optical coherence tomography imaging of eyelid basal cell carcinoma.

Optical coherence tomography (OCT) is fast emerging as an additional non-interventional modality for skin tumor detection and diagnosis. A master/slave flying spot OCT configuration was assembled to detect periocular basal cell carcinomas (BCC). A swept source at 1300 nm and sweeping speed of 50 kHz were used. A three-step process was involved. First, 384 channeled spectra using a mirror were stored for 384 optical path differences at the master stage. Then, the stored channeled spectra (masks) were correlated with the channeled spectrum from the BCC tissue to produce 384 en face OCT images (200×200 pixels) for the optical path difference values used to acquire the masks. Finally, these en face slices were stacked to form a volume to cross-reference BCC tumor margins in the orthogonal plane. Per each eyelid sample, several en face images of 200×200 lateral pixels are produced in the time to scan laterally a complete raster of 1.6 s. Combination of the en face views with the cross-sectioning views allow for better discrimination of BCCs comparable to using cross-sectional imaging alone, as previously reported using the conventional fast-Fourier-transform-based OCT techniques.

Intraocular pressure changes following topical ocular hypotensive medications washout.

BACKGROUND: To review the changes in intraocular pressure (IOP) following topical hypotensive medications washout in patients with primary open angle glaucoma (POAG), ocular hypertension (OHT) and uveitic glaucoma (UG)/OHT. METHODS: The study included 120 patients with POAG, OHT and UG recruited from prospective clinical trials between February 2013 and July 2017. We excluded 20 eyes with IOP of ≤21 mm Hg, 11 eyes with previous incisional surgery and 17 eyes with incomplete data. UG eyes with active inflammation and on steroid treatment were excluded. Participants underwent a 1-month washout period from topical ocular hypotensive medications before IOP phasing. Comparisons were made between pre/post-washout IOP, and highest-recorded (peak) and post-washout IOP. RESULTS: A total of 110 eyes with POAG, 33 eyes with OHT and 43 eyes with UG were included for analysis. The mean pre-washout IOP was 18.1±3.3 mm Hg in POAG, 18.8±3.3 mm Hg in OHT and 17.9±8.8 mm Hg in UG; the mean post-washout IOP was 26.6±4.8 mm Hg, 26.4±3.9 mm Hg, 23.1±10.1 mm Hg in POAG, OHT and UG, respectively. The mean increase in IOP after washout was significantly lower in UG compared with POAG and OHT eyes (p=0.01). The percentage of eyes with post-washout IOP <22 mm Hg was 12.7% in POAG, 6.1% in OHT and 51.2% in UG. CONCLUSION: Active inflammation and steroid treatment contributes to elevated IOP in uveitis. Therefore, IOP may revert to normal once inflammation subsides. We recommend ocular hypotensive treatment washout to be considered in UG eyes that have IOP under control in the absence of recurrence of uveitis.

The intracellular localisation and mobility of Type Igamma phosphatidylinositol 4P 5-kinase splice variants.

There are three known splice variants of Type Igamma phosphatidylinositol 4-phosphate 5-kinase (PIPkin Igamma): PIPkins Igamma87, Igamma90, and the most recently cloned (Giudici, M.L., Emson, P.C. and Irvine, R.F. (2004) A novel neuronal-specific splice variant of Type I phosphatidylinositol 4-phosphate 5-kinase isoform gamma. Biochem. J. 379, 489-496) PIPkin IgammaC (here called PIPkin Igamma93). Here, we have explored the subcellular localisation and mobility of Type I PIPkins in transfected cells by confocal microscopy and flourescence recovery after photobleaching. The unique behaviour shown by PIPkin Igamma93 is consistent with its suggested distinct function. Moreover, the markedly different localisation and mobility of active versus inactive PIPkin Igamma93 provide insights into the factors that dictate cellular targeting of Type Igamma PIPkins.

Progressive outer retinal necrosis: manifestation of human immunodeficiency virus infection.

We present the case of a 54-year-old man who developed progressive outer retinal necrosis (PORN) as an initial manifestation of HIV infection without any significant risk factors for infection with HIV. PORN is usually found as a manifestation of known AIDS late in the disease. Our patient presented with transient visual loss followed by decrease in visual acuity and facial rash. Subsequent investigation revealed anterior chamber tap positive for varicella zoster virus (VZV), as well as HIV positivity, with an initial CD4 count of 48 cells/µL. Systemic and intravitreal antivirals against VZV, and highly active antiretroviral therapy against HIV were started, which halted further progression of retinal necrosis. This case highlights the importance of suspecting PORN where there is a rapidly progressive retinitis, and also testing the patient for HIV, so appropriate treatment can be started.

Long-term stability of keratometric astigmatism after limbal relaxing incisions.

PURPOSE: To study the keratometric stability of limbal relaxing incisions (LRIs) performed during cataract surgery. SETTING: Princess Royal University Hospital, Kent, United Kingdom. DESIGN: Retrospective case series. METHODS: Medical notes of patients who had small-incision cataract surgery combined with LRIs between November 2006 and December 2010 were reviewed. Keratometric astigmatism was measured using Scheimpflug pachymetry (Pentacam). Surgically induced astigmatism (SIA) was calculated using the Astig Plot application. RESULTS: Twenty eyes of 20 patients were evaluated. The median keratometric astigmatism preoperatively and 2 weeks, 10 weeks, and 3 years postoperatively was 2.1 diopters (D) (interquartile range [IQR], 1.7 to 2.4 D), 1.3 D (IQR, 0.9 to 2.1 D), 1.2 D (IQR, 0.5 to 1.7 D), and 1.0 D (IQR, 0.7 to 1.4 D), respectively. There were no significant differences in keratometric astigmatism between 2 weeks and 10 weeks postoperatively (P=.35) or between 10 weeks and 3 years postoperatively (P=.72). The median SIA 2 weeks, 10 weeks, and 3 years postoperatively was 2.2 D (IQR, 1.6 to 4.1 D), 2.1 D (IQR, 1.2 to 2.7 D), and 1.8 D (IQR, 1.2 to 2.5 D), respectively. There was a statistically significant difference in SIA between 2 weeks and 10 weeks postoperatively (P=.002) but not between 10 weeks and 3 years postoperatively (P=.72). CONCLUSION: The keratometric effects of LRIs were stable from 10 weeks to 3 years postoperatively. FINANCIAL DISCLOSURE: Dr. Borasio is the creator of Astig Plot. No other author has a financial or proprietary interest in any material or method mentioned.