CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects.

BACKGROUND: Primary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level. METHODS: 7 patients with newly identified mutations in CDK5RAP2 (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions. RESULTS: All patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases. CONCLUSION: This is the first report indicating that CDK5RAP2 not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential. TRIAL REGISTRATION NUMBER: NCT01565005.

Evaluation of the Spot Vision Screener for children with limited access to ocular health care.

PURPOSE: To compare the sensitivity, specificity, and referral rate of the Spot Vision Screener (Welch Allyn Inc, Skaneateles Falls, NY) with the gold standard cycloplegic measurements acquired using the Retinomax in a population of underprivileged children and teenagers with limited access to medical care. METHODS: Children were recruited for the study by social workers in the vicinity of Robert Debre Hospital, Paris, France. Refractive errors (hyperopia of ≥ +2.00 D spherical equivalent [SE]; myopia of ≤ -0.50 D SE; astigmatism of ≥1.00 D between the two main meridians; anisometropia of ≥1.00 D SE difference between eyes) were assessed using the Spot Vision Screener and the Retinomax. Sensitivity (true positive rate), specificity (true negative rate), and referral rate of this Spot Vision screening program were evaluated. RESULTS: A total of 82 eyes of 41 subjects (19 males) were included; mean age was 126 months of age (range, 48-246). The sensitivity of the Spot Vision Screener for the detection of refractive errors was 82.35%; specificity was 91.67%. The sensitivity of the Spot Vision Screener to detect hyperopia, myopia, astigmatism, and anisometropia was 27.27%, 84.61%, 78.57%, and 66.67%, respectively. Its specificity to detect hyperopia, myopia, astigmatism, and anisometropia was 100%, 98.55%, 89.71% and 94.29%, respectively. CONCLUSIONS: The specificity of the Spot Vision Screener to detect refractive errors was found to be relatively high (>90%). However, its low sensitivity for hyperopia seems to remain a major limitation of the device, because hyperopia is particularly important to detect in children given its high prevalence and possible adverse consequences. Global programs using cycloplegic measurements should be considered an alternative.

In vivo confocal microscopic evaluation of corneal changes in chronic Stevens-Johnson syndrome and toxic epidermal necrolysis.

PURPOSE: To describe corneal changes visible on in vivo confocal microscopy, in patients with debilitating ocular sequelae because of toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS). PATIENTS AND METHODS: Forty-one eyes of 25 consecutive patients suffering from chronic TEN or SJS were studied using in vivo confocal microscopy. RESULTS: Severe dry eye syndrome with no associated limbal stem cell deficiency (25 eyes, 16 patients, 61%) was the most frequent clinical pattern. Limbal stem cell deficiency was noted in 16 eyes (12 patients, 39%). Three patients had asymmetric disease. Confocal microscopy showed a consistent change in the superficial epithelial cells in both clinical presentations. Patients with dry eye syndrome had frequent pathological nerve damages, and the presence of dendritic cells was prevalent (65%). Inflammatory cells were observed in a large number in 4 of the 12 patients presenting neovascularization of the cornea. CONCLUSIONS: The corneas of patients with chronic ocular sequelae linked to SJS and TEN present a number of abnormalities. In vivo confocal microscopy is a potentially useful tool for therapeutic indications and for follow-up of the debilitating chronic ocular problems associated with these diseases.