Development of a multidisciplinary clinic of neurofibromatosis type 1 and other neurocutaneous disorders in Greece. A 3-year experience.

Given the complexity of neurocutaneous syndromes, a multidisciplinary approach has been advocated in order to provide optimum care. Subjects and Methods: Retrospective analysis of a cohort of 157 patients during a 3-year period, seen at a newly developed neurocutaneous clinic in a pediatric tertiary care hospital in Athens (Greece); and systematic chart review of the patients diagnosed with neurofibromatosis type 1 during this time period. Results: The most frequent neurocutaneous syndromes were neurofibromatosis type 1 (NF1) in 89 patients and tuberous sclerosis complex in 17. In 20.38% of patients a neurocutaneous syndrome was not confirmed. Approximately 2/3 of the NF1 patients underwent genetic analysis, and for 76.67% of them, a pathogenic mutation on the NF1 gene was revealed. Eighty-one patients manifested with generalized NF1 and eight with mosaic NF1. Dermatological manifestations included café-au-lait macules in all patients, followed by axillary and/or inguinal freckling (n = 57), external plexiform neurofibromas (n = 17), and cutaneous and subcutaneous neurofibromas (n = 11). Approximately half of patients had learning disabilities and attention deficit hyperactivity disorder, followed by mental retardation (n = 9), autistic spectrum disorders (n = 4), headaches (n = 3) and seizures (n = 2). Neuroimaging showed characteristic areas of hyperintensity on T2-weighted images in 74.07% of patients and optic pathway glioma in 19.75%. Two patients developed malignant peripheral sheath nerve tumor. Conclusions: Neurocutaneous syndromes are clinically heterogeneous and the surveillance of potential clinical complications is challenging. The availability of genetic diagnosis and novel imaging methods in this group of disorders is likely to further expand their clinical spectrum. Guidelines for assessment and management will need to be modified based on new available data.

Isolated Medial Orbital Wall Fracture Associated with Enophthalmos in a Paediatric Patient: An Unusual Presentation.

PURPOSE: To report a case of isolated medial orbital wall fracture with enophthalmos in a paediatric patient and describe the clinical presentation and findings by means of computed tomography (CT) of the head and eyes. METHODS: We looked at the patient's medical and ophthalmologic history, and an ophthalmologic examination and a CT of the head were performed at baseline. RESULTS: A 14-year-old boy was admitted to the emergency department of our institution with ecchymosis of his right eyelids secondary to a sport accident. Physical examination revealed a moderate limitation of upgaze without diplopia. CT showed a medial orbital wall fracture without haemorrhage and a gross accumulation of air in the right eyelid with pressure exertion over the right globe and enophthalmos. The patient was treated conservatively with oral antibiotics and steroids showing dramatic improvement within 1 week. Enophthalmos and periorbital emphysema were completely resolved within 3 months after the accident as indicated by CT. CONCLUSIONS: We conclude that surgical intervention and intravenous treatment are not warranted in similar cases of medial orbital wall fracture. Medical history, clinical and paraclinical evaluations, and a regular follow-up, including CT, are needed though to avoid complications such as painful abduction, horizontal diplopia, pseudo sixth nerve paresis, or pseudo Duane.

Cohen syndrome resulting from a novel large intragenic COH1 deletion segregating in an isolated Greek island population.

Cohen syndrome, caused by mutations in the COH1 gene, is an autosomal recessive disorder consisting of mental retardation, microcephaly, growth delay, severe myopia, progressive chorioretinal dystrophy, facial anomalies, slender limbs with narrow hands and feet, tapered fingers, short stature, kyphosis and/or scoliosis, pectus carinatum, joint hypermobility, pes calcaneovalgus, and, variably, truncal obesity. Here, we describe the clinical and molecular findings in 14 patients from an isolated Greek island population. The clinical phenotype was fairly homogeneous, although microcephaly was not constant, and some patients had severe visual disability. All patients were homozygous for a novel intragenic COH1 deletion spanning exon 6 to exon 16, suggesting a founder effect. The discovery of this mutation has made carrier detection and prenatal diagnosis possible in this population.

Visual cycle: Dependence of retinol production and removal on photoproduct decay and cell morphology.

The visual cycle is a chain of biochemical reactions that regenerate visual pigment following exposure to light. Initial steps, the liberation of all-trans retinal and its reduction to all-trans retinol by retinol dehydrogenase (RDH), take place in photoreceptors. We performed comparative microspectrophotometric and microfluorometric measurements on a variety of rod and cone photoreceptors isolated from salamander retinae to correlate the rates of photoproduct decay and retinol production. Metapigment decay rate was spatially uniform within outer segments and 50-70 times faster in the cells that contained cone-type pigment (SWS2 and M/LWS) compared to cells with rod-type pigment (RH1). Retinol production rate was strongly position dependent, fastest at the base of outer segments. Retinol production rate was 10-40 times faster in cones with cone pigments (SWS2 and M/LWS) than in the basal OS of rods containing rod pigment (RH1). Production rate was approximately five times faster in rods containing cone pigment (SWS2) than the rate in basal OS of rods containing the rod pigment (RH1). We show that retinol production is defined either by metapigment decay rate or RDH reaction rate, depending on cell type or outer segment region, whereas retinol removal is defined by the surface-to-volume ratio of the outer segment and the availability of retinoid binding protein (IRBP). The more rapid rates of retinol production in cones compared to rods are consistent with the more rapid operation of the visual cycle in these cells.

Treatment of metastatic tumors of the choroid with proton beam irradiation.

OBJECTIVE: To describe the clinical outcomes of patients treated by proton beam irradiation for choroidal metastatic tumors. DESIGN: Noncomparative case series. PARTICIPANTS: A retrospective chart review was performed on a series of 63 patients (76 eyes) with choroidal metastases treated with proton beam therapy between December 1989 and September 2000. METHODS: Patients were treated with 2 fractions of 14 cobalt gray equivalents (CGEs) (CGE = proton Gy x relative biological effectiveness 1.1), each using a nonoperative "light-field" technique. Ophthalmologic follow-up was available for 46 patients (55 eyes), with a mean follow-up time of 10 months. The medical record or the Social Security Death Index was used to obtain survival status, which was available in 94% of cases. MAIN OUTCOME MEASURES: Tumor regression, recurrence, treatment-associated complications, and visual acuity were evaluated by ophthalmologic examination and ultrasonography. Eye retention and length of survival also were assessed. RESULTS: At the time of ocular diagnosis, 49 patients reported a history of a primary cancer. Median survival time after ocular diagnosis was 16 months through May 2003. Most choroidal metastases were dome shaped (62%) and located at the posterior pole (95%). Mean tumor height was approximately 3.5 mm, and serous retinal detachment was seen in 63% of cases. Eighty-four percent of treated tumors regressed completely within 5 months of treatment, and none of these recurred. Retinal detachment resolved in 82% of patients within 3.8 months after treatment, and visual acuity was preserved or improved in 47% of the patients. Complications occurred in 56% of cases and included madarosis, keratitis, dry eye syndrome, cataract, neovascular glaucoma, chorioretinal atrophy, radiation papillopathy, and radiation maculopathy. None of the treated eyes required enucleation. CONCLUSIONS: Proton beam irradiation is a useful therapeutic approach for choroidal metastases; it allows retention of the globe, achieves a high probability of local tumor control, and helps to avoid pain and visual loss. Although complications occur in most cases, many of these are minor and are not associated with a change in function. This modality is accurate and efficient, because it only entails 2 treatment fractions and does not require surgery for tumor localization.

Reduction of all-trans retinal to all-trans retinol in the outer segments of frog and mouse rod photoreceptors.

The first step in the Visual Cycle, the series of reactions that regenerate the vertebrate visual pigment rhodopsin, is the reduction of all-trans retinal to all-trans retinol, a reaction that requires NADPH. We have used the fluorescence of all-trans retinol to study this reduction in living rod photoreceptors. After the bleaching of rhodopsin, fluorescence (excitation, 360 nm; emission, 457 or 540 nm) appears in frog and wild-type mouse rod outer segments reaching a maximum in 30-60 min at room temperature. With this excitation and emission, the mitochondrial-rich ellipsoid region of the cells shows strong fluorescence as well. Fluorescence measurements at different emission wavelengths establish that the outer segment and ellipsoid signals originate from all-trans retinol and reduced pyridine nucleotides, respectively. Using outer segment fluorescence as a measure of all-trans retinol formation, we find that in frog rod photoreceptors the NADPH necessary for the reduction of all-trans retinal can be supplied by both cytoplasmic and mitochondrial metabolic pathways. Inhibition of the reduction reaction, either by retinoic acid or through suppression of metabolic activity, reduced the formation of retinol. Finally, there are no significant fluorescence changes after bleaching in the rod outer segments of Rpe65(-/-) mice, which lack 11-cis retinal.

Physiological and microfluorometric studies of reduction and clearance of retinal in bleached rod photoreceptors.

The visual cycle comprises a sequence of reactions that regenerate the visual pigment in photoreceptors during dark adaptation, starting with the reduction of all-trans retinal to all-trans retinol and its clearance from photoreceptors. We have followed the reduction of retinal and clearance of retinol within bleached outer segments of red rods isolated from salamander retina by measuring its intrinsic fluorescence. Following exposure to a bright light (bleach), increasing fluorescence intensity was observed to propagate along the outer segments in a direction from the proximal region adjacent to the inner segment toward the distal tip. Peak retinol fluorescence was achieved after approximately 30 min, after which it declined very slowly. Clearance of retinol fluorescence is considerably accelerated by the presence of the exogenous lipophilic substances IRBP (interphotoreceptor retinoid binding protein) and serum albumin. We have used simultaneous fluorometric and electrophysiological measurements to compare the rate of reduction of all-trans retinal to all-trans retinol to the rate of recovery of flash response amplitude in these cells in the presence and absence of IRBP. We find that flash response recovery in rods is modestly accelerated in the presence of extracellular IRBP. These results suggest such substances may participate in the clearance of retinoids from rod photoreceptors, and that this clearance, at least in rods, may facilitate dark adaptation by accelerating the clearance of photoproducts of bleaching.