Gil Binenbaum

Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database

Renal coloboma syndrome, also known as papillorenal syndrome is an autosomal‐dominant disorder characterized by ocular and renal malformations. Mutations in the paired‐box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus‐specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating in this collaboration contributed 28 novel variations in 68 individuals in 33 families, which represent a 50% increase in the number of variations, patients, and families published in the medical literature. An LSDB was created using the Leiden Open Variation Database platform: www.lovd.nl/PAX2. The most common findings reported in this series were abnormal renal structure or function (92% of individuals), ophthalmological abnormalities (77% of individuals), and hearing loss (7% of individuals). Additional clinical findings and genetic counseling implications are discussed. Hum Mutat 33:457–466, 2012.

A Clinical Prediction Model to Stratify Retinopathy of Prematurity Risk Using Postnatal Weight Gain

OBJECTIVE: To develop an efficient clinical prediction model that includes postnatal weight gain to identify infants at risk of developing severe retinopathy of prematurity (ROP). Under current birth weight (BW) and gestational age (GA) screening criteria, <5% of infants examined in countries with advanced neonatal care require treatment. PATIENTS AND METHODS: This study was a secondary analysis of prospective data from the Premature Infants in Need of Transfusion Study, which enrolled 451 infants with a BW < 1000 g at 10 centers. There were 367 infants who remained after excluding deaths (82) and missing weights (2). Multivariate logistic regression was used to predict severe ROP (stage 3 or treatment). RESULTS: Median BW was 800 g (445–995). There were 67 (18.3%) infants who had severe ROP. The model included GA, BW, and daily weight gain rate. Run weekly, an alarm that indicated need for eye examinations occurred when the predicted probability of severe ROP was >0.085. This identified 66 of 67 severe ROP infants (sensitivity of 99% [95% confidence interval: 94%–100%]), and all 33 infants requiring treatment. Median alarm-to-outcome time was 10.8 weeks (range: 1.9–17.6). There were 110 (30%) infants who had no alarm. Nomograms were developed to determine risk of severe ROP by BW, GA, and postnatal weight gain. CONCLUSION: In a high-risk cohort, a BW-GA-weight-gain model could have reduced the need for examinations by 30%, while still identifying all infants requiring laser surgery. Additional studies are required to determine whether including larger-BW, lower-risk infants would reduce examinations further and to validate the prediction model and nomograms before clinical use.

The CHOP Postnatal Weight Gain, Birth Weight, and Gestational Age Retinopathy of Prematurity Risk Model

OBJECTIVE To develop a birth weight (BW), gestational age (GA), and postnatal-weight gain retinopathy of prematurity (ROP) prediction model in a cohort of infants meeting current screening guidelines. METHODS Multivariate logistic regression was applied retrospectively to data from infants born with BW less than 1501 g or GA of 30 weeks or less at a single Philadelphia hospital between January 1, 2004, and December 31, 2009. In the model, BW, GA, and daily weight gain rate were used repeatedly each week to predict risk of Early Treatment of Retinopathy of Prematurity type 1 or 2 ROP. If risk was above a cut-point level, examinations would be indicated. RESULTS Of 524 infants, 20 (4%) had type 1 ROP and received laser treatment; 28 (5%) had type 2 ROP. The model (Childrens Hospital of Philadelphia [CHOP]) accurately predicted all infants with type 1 ROP; missed 1 infant with type 2 ROP, who did not require laser treatment; and would have reduced the number of infants requiring examinations by 49%. Raising the cut point to miss one type 1 ROP case would have reduced the need for examinations by 79%. Using daily weight measurements to calculate weight gain rate resulted in slightly higher examination reduction than weekly measurements. CONCLUSIONS The BW-GA-weight gain CHOP ROP model demonstrated accurate ROP risk assessment and a large reduction in the number of ROP examinations compared with current screening guidelines. As a simple logistic equation, it can be calculated by hand or represented as a nomogram for easy clinical use. However, larger studies are needed to achieve a highly precise estimate of sensitivity prior to clinical application.

A controlled study of topical 0.25% timolol maleate gel for the treatment of cutaneous infantile capillary hemangiomas.

Purpose: To evaluate the efficacy of topical 0.25% timolol maleate gel for the treatment of cutaneous infantile capillary hemangiomas. Methods: A retrospective, consecutive, nonrandomized, comparative single-masked cohort study of all patients presenting with nonvision-threatening periocular infantile capillary hemangiomas between August 2007 and January 2011 was performed. Parents chose twice daily topical 0.25% timolol maleate gel or observation. Photographs were taken at all visits and subsequently evaluated by masked examiners for change in lesion size, color, and thickness. Lesions were clinically defined as superficial, mixed, or deep. The primary outcome was response to treatment at 2 months, categorized as good (size decreased >50%), moderate (decrease 0–50%), or poor (enlarged or caused visually significant ptosis or induced astigmatism). The secondary outcome was response at latest follow-up visit. Results: Thirteen children received timolol, and 10 children were observed, with mean ages at presentation of 4.8 and 3.7 months (p = 0.31), respectively. In the treated group, good response was observed in 8 (61.5%) infants, moderate response was seen in 4 (30.8%), and poor response was seen in one patient (7.7%). In the observed group, 0 (0%) demonstrated good response, one (10%) demonstrated moderate response, and 9 demonstrated poor response (90%) (p < 0.001). Responses were consistent on long-term follow-up (range 3–41 months). Both superficial (n = 5; 100% good response) and mixed (n = 7; 43% good, 57% moderate) lesions responded well to timolol; the one deep lesion did not. No adverse ocular or systemic effects were observed. Conclusions: Topical timolol maleate gel 0.25% is effective in treatment of nonvision-threatening infantile capillary hemangiomas with a superficial component. Response at 2 months is stable over time.

Odds of abuse associated with retinal hemorrhages in children suspected of child abuse

PURPOSE To describe the prevalence of retinal hemorrhages in children being evaluated for abusive head trauma and quantify the association between the likelihood of abuse and the presence and severity of retinal hemorrhages. METHODS Retrospective cross-sectional study of 110 children aged 15 months or younger who were evaluated for abusive head trauma and received an ophthalmological examination. The child abuse specialists diagnosis was categorized as definite accident, probable accident, probable abuse, or definite abuse, according to an algorithm that excluded eye findings. Retinal hemorrhage severity was scored on a 12-point scale (6 points per eye) based on type, size, location, and extent. Higher scores indicated greater severity of eye findings. RESULTS Seventy-four percent of children were younger than 6 months old. Forty-five percent of cases were definite abuse and 37% were definite accident. The prevalence of retinal hemorrhages was 32%. Across all subjects, the presence of retinal hemorrhage was highly associated with definite or probable abuse versus definite or probable accident (age-adjusted odds ratio 5.4 [95% CI, 2.1-13.6]). The odds ratio in children younger than 6 months (n = 81) was 11.7 (95% CI, 2.9-66.8). Retinal hemorrhage severity was higher in abuse versus accident (p < 0.0001) and correlated positively with abuse (Spearman r = 0.406, p < 0.0001). Scores above 8 (n = 13) were only present in abused children. CONCLUSIONS Retinal hemorrhages are highly associated with abusive head trauma, particularly in children younger than 6 months of age. Increasing retinal hemorrhage severity is correlated with increasing likelihood of abuse.

Algorithms for the Prediction of Retinopathy of Prematurity Based on Postnatal Weight Gain

Current ROP screening guidelines represent a simple risk model with two dichotomized factors, birth weight and gestational age at birth. Pioneering work has shown that tracking postnatal weight gain, a surrogate for low insulin-like growth factor 1, may capture the influence of many other ROP risk factors and improve risk prediction. Models including weight gain, such as WINROP, ROPScore, and CHOP ROP, have demonstrated accurate ROP risk assessment and a potentially large reduction in ROP examinations, compared to current guidelines. However, there is a need for larger studies, and generalizability is limited in countries with developing neonatal care systems.

Sclerocornea associated with the chromosome 22q11.2 deletion syndrome

Reported ocular findings in the 22q11.2 deletion syndrome (which encompasses the phenotypes of DiGeorge, velocardiofacial, and Takao (conotruncal‐anomaly‐face) syndromes) have included posterior embryotoxon (prominent, anteriorly displaced Schwalbes line at the corneal limbus or edge), retinal vascular tortuosity, eyelid hooding, strabismus, and astigmatism. We present seven 22q11.2 patients from multiple centers with sclerocornea, an eye finding previously unreported in the literature. Four boys and three girls were identified with sclerocornea, systemic DGS/VCFS findings, and fluorescence in situ hybridization (FISH)‐confirmed microdeletion at chromosome 22q11.2. FISH diagnosis was perinatal in six patients but at 2 years of age in one child. Sclerocornea was bilateral in five patients. Findings included descemetocele (five eyes), microophthalmos (one eye), iridocorneal adhesions (one bilateral case), and severe anterior segment dysgenesis (one eye). Two patients underwent bilateral corneal transplantation; another two were scheduled for possible unilateral transplant. Sclerocornea is a static congenital condition in which the cornea is opaque and vascularized and resembles the sclera. The novel finding of sclerocornea suggests that a genetic locus at 22q11.2 may be involved in anterior segment embryogenesis. In most of our patients, the diagnostic process was underway, but in one patient 22q11.2 deletion was not suspected until after the child had already been undergoing treatment for sclerocornea for 2 years. Sclerocornea should be added to the clinical manifestations of the 22q11.2 deletion syndrome. Ophthalmologists diagnosing sclerocornea in children with systemic findings suggestive of 22q11.2 deletion should ensure appropriate genetic referral.

Patterns of Retinal Hemorrhage Associated With Increased Intracranial Pressure in Children

OBJECTIVE: Raised intracranial pressure (ICP) has been proposed as an isolated cause of retinal hemorrhages (RHs) in children with suspected traumatic head injury. We examined the incidence and patterns of RHs associated with increased ICP in children without trauma, measured by lumbar puncture (LP). METHODS: Children undergoing LP as part of their routine clinical care were studied prospectively at the Childrens Hospital of Philadelphia and retrospectively at Nationwide Children’s Hospital. Inclusion criteria were absence of trauma, LP opening pressure (OP) ≥20 cm of water (cm H2O), and a dilated fundus examination by an ophthalmologist or neuro-ophthalmologist. RESULTS: One hundred children were studied (mean age: 12 years; range: 3–17 years). Mean OP was 35 cm H2O (range: 20–56 cm H2O); 68 (68%) children had OP >28 cm H2O. The most frequent etiology was idiopathic intracranial hypertension (70%). Seventy-four children had papilledema. Sixteen children had RH: 8 had superficial intraretinal peripapillary RH adjacent to a swollen optic disc, and 8 had only splinter hemorrhages directly on a swollen disc. All had significantly elevated OP (mean: 42 cm H2O). CONCLUSIONS: Only a small proportion of children with nontraumatic elevated ICP have RHs. When present, RHs are associated with markedly elevated OP, intraretinal, and invariably located adjacent to a swollen optic disc. This peripapillary pattern is distinct from the multilayered, widespread pattern of RH in abusive head trauma. When RHs are numerous, multilayered, or not near a swollen optic disc (eg, elsewhere in the posterior pole or in the retinal periphery), increased ICP alone is unlikely to be the cause.

Microsurgical lab testing is a reliable method for assessing ophthalmology residents’ surgical skills

Background: Formal assessment of clinical competencies is necessary to ensure that all residents are acquiring important skills and, in the United States, will soon become a requirement for residency programme accreditation by the Accreditation Council for Graduate Medical Education (ACGME). The Eye Surgical Skills Assessment Test (ESSAT), a laboratory-based surgical skills obstacle course, was developed in response to the need for improved tools for the assessment of surgical skills during residency. The ESSAT has previously been shown to have face and content validity, and in this study we sought to determine its inter-rater reliability and, to some extent, its construct validity. Methods: Twenty-seven content experts (residency programme directors and faculty members involved with resident surgical training) watched videos of a junior resident and senior resident completing the three ESSAT stations (skin suturing, muscle recession, and phacoemulsification: wound construction & suturing technique) and completed assessment forms, both task-specific checklists and a global rating scale of performance. Results: The ESSAT showed strong inter-rater reliability for determining whether a resident “passed” a threshold of competency at each station for both the checklists and global rating scale. In addition, for each station, the senior resident was consistently rated above a “passing” threshold using either assessment form, whereas the junior resident was more often rated below (94% vs 30% passing on completed forms). Conclusion: These results, along with the findings of our face and content validity analysis, support the reliability and validity of the ESSAT, and indicate that it could be a useful tool for improving the assessment of surgical skill during residency. The ESSAT is a tool that all residency programmes could implement as a part of their ophthalmic surgical curriculum and competency assessment, and may be useful to set a threshold of competence that all residents would need to achieve prior to entering the operating room.

The eye in child abuse: Key points on retinal hemorrhages and abusive head trauma

This review presents an up-to-date overview of ocular injuries resulting from child abuse, with a spotlight on abusive head trauma. Retinal hemorrhage is a principle finding of inflicted head trauma. The specific pattern of hemorrhages holds valuable diagnostic information, which can help to guide multidisciplinary assessments of the likelihood of abuse. Indirect ophthalmoscopy through dilated pupils by an ophthalmologist is necessary for adequate examination and documentation of retinal findings. Initial pediatrician evaluation of the eye and indications for ophthalmological consultation are reviewed. Focus is then placed upon understanding retinal hemorrhage patterns, their diagnostic significance and likely pathophysiological mechanisms. The differential diagnosis of retinal hemorrhage in young children is discussed, highlighting key distinctions among retinal hemorrhage patterns, severity and frequencies, as well as other ocular findings. The most common cause of retinal hemorrhage in an infant is trauma, and most other causes can be identified by considering the hemorrhage pattern, ocular or systemic signs and the results of laboratory and imaging tests, when indicated.