Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome.

Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome (OMIM 604168) is an autosomal recessive developmental disorder that occurs in an endogamous group of Vlax Roma (Gypsies; refs. 1-3). We previously localized the gene associated with CCFDN to 18qter, where a conserved haplotype suggested a single founder mutation. In this study, we used recombination mapping to refine the gene position to a 155-kb critical interval. During haplotype analysis, we found that the non-transmitted chromosomes of some unaffected parents carried the conserved haplotype associated with the disease. Assuming such parents to be completely homozygous across the critical interval except with respect to the disease-causing mutation, we developed a new 'not quite identical by descent' (NQIBD) approach, which allowed us to identify the mutation causing the disease by sequencing DNA from a single unaffected homozygous parent. We show that CCFDN is caused by a single-nucleotide substitution in an antisense Alu element in intron 6 of CTDP1 (encoding the protein phosphatase FCP1, an essential component of the eukaryotic transcription machinery), resulting in a rare mechanism of aberrant splicing and an Alu insertion in the processed mRNA. CCFDN thus joins the group of 'transcription syndromes' and is the first 'purely' transcriptional defect identified that affects polymerase II-mediated gene expression.

Must screening examinations for retinopathy of prematurity necessarily be painful?

PURPOSE: This study investigates the impact of the length of the examination, the insertion of eyelid specula, and the indentation of the globe on the pain and stress sensation of premature infants. METHODS: Ninety-two premature infants in three neonatal wards were included. In two wards, the patients were examined using eyelid specula and scleral indentation as recommended in the official guidelines. In the third ward, the investigation time was minimized and ophthalmoscopy was performed without eyelid specula and scleral indentation. Physical and mental disturbance of the patients was assessed by the Neonatal Infant Pain Score and by monitoring the heart rate. The results were divided into two groups: in the one, eyelid specula and scleral indentation were used, whereas in the other one, they were not used. An independent-samples t-test was performed, which allowed us to calculate the correlation between the way the examination was executed and the condition of the patients. RESULTS: Demographic data and baseline values of heart rate and pain score did not differ between the two groups. Heart rate and pain score during and after the investigation were significantly higher and increased significantly with the duration of the examination for the patients who were investigated using lid specula and scleral indentation. CONCLUSION: Our study shows that indirect ophthalmoscopy without specula causes significantly less stress to infants than screening with lid specula and scleral indentation.

Refining clinical phenotypes in septo-optic dysplasia based on MRI findings.

Septo-optic dysplasia (SOD) is a heterogeneous brain midline anomaly associated with ophthalmological, endocrinological, and/or neurodevelopmental symptoms. The clinical phenotype correlates with abnormal brain magnetic resonance imaging (MRI) findings. However, variations of the septum pellucidum (SP) appearance and their clinical impact have not been studied in depth. Sixty-eight patients with optic nerve hypoplasia (ONH) were investigated for the presence of associated SP anomalies and correlations between clinical findings and their MRI abnormalities established. Thirty patients had either complete (n = 22) or partial (n = 8) absence of the SP. Pituitary hormone deficiencies were present in 64% or 25% of the cases, respectively. Neurological symptoms did not occur in patients with SP remnants or unilateral ONH. Hippocampus abnormalities (43%) that have not been described before in SOD and falx abnormalities (17%) correlated significantly with neurological symptoms and developmental delay (p < 0.05 and p < 0.01, respectively). Maternal age at birth was low (21.2 years) and drug abuse during pregnancy was reported in 27% of the patients. Twelve patients with pituitary anomaly and ONH but normal SP showed similar clinical and MRI features, and were classified as SOD-like. The remaining 26 patients were not assigned to SOD. We conclude that unilateral ONH and SP remnants are associated with a milder SOD phenotype. Hippocampus abnormalities and falx abnormalities seem to constitute important features of severe clinical disease, irrespective of SP appearance. Our anamnestic data support the hypothesis of vascular disruption during embryogenesis.

Increase in 6-hydroxymelatonin excretion in humans during ascent to high altitudes.

Melatonin (MLT), the pineal gland hormone involved in the regulation of circadian rhythms, shows characteristic diurnal variation. Its physiological role in humans is not clear. Exposure to high altitudes may disrupt the circadian rhythm and lead to various endocrine changes. MLT in humans has not been studied under these conditions. Urinary 6-hydroxy-MLT sulfate (aMT6s) excretion was analyzed during the day (0700-2200 h) and night (2200-0700 h) phases. A cohort of 33 healthy volunteers, aged 19-65 yr, was studied during an ascent to a high altitude in the Himalayas on three occasions (at a lower altitude, at 3400 m, and after reaching maximal altitudes of 5600-6100 m). aMT6s excretion during the daytime remained unchanged during exposure to high altitudes. As expected, nocturnal values were higher than diurnal values at each point in time. However, there was a significant increase in nocturnal MLT excretion after the ascent to high altitudes. Ascent to high altitudes is associated with increased nocturnal excretion of aMT6s. The mechanism and physiological significance of this MLT increase are unclear.

Morphological and functional results of AcrySof intraocular lens implantation in children: prospective randomized study of age-related surgical management.

PURPOSE: To evaluate the prevalence and severity of posterior capsule opacification (PCO) in pediatric eyes with a foldable acrylic AcrySof (Alcon) intraocular lens (IOL) and age-related surgical methods. SETTING: Department of Ophthalmology, University of Vienna, Medical School, Vienna, Austria. METHODS: This prospective randomized study comprised 50 eyes of 34 children aged between 2 and 16 years. Eyes of children between 2 and 5.9 years were consecutively randomized to Group 1a (primary posterior capsulotomy and anterior vitrectomy) or Group 1b (optic capture in addition). Eyes of children between 6 and 16 years were consecutively randomized to Group 2a (primary posterior capsulotomy without anterior vitrectomy), Group 2b (optic capture in addition), or Group 2c (in-the-bag IOL implantation without opening the posterior capsule). Main outcome parameters were the incidence and severity of PCO formation, early postoperative complications, pigmented cell deposits on the IOL surface, and cataract morphology. RESULTS: The visual axis was clear at the last follow-up in all eyes in Groups 1a, 1b, 2a, and 2b except in 1 eye in Group 1a. Sixty-percent of eyes in Group 2c had PCO. The incidence of early postoperative complications was significantly higher in eyes that developed PCO than in those that maintained a clear visual axis. There was no evidence that cataract morphology influenced PCO rates. CONCLUSIONS: The AcrySof IOL was well tolerated in pediatric eyes. Optic capture was not necessary to ensure a clear visual axis. Primary posterior capsulotomy should be performed in preschool and uncooperative children and in eyes expected to have relatively high postoperative inflammation. Implanting the AcrySof in the bag and leaving the posterior capsule intact is acceptable for school children and juveniles with isolated developmental cataract.

Surgery in unilateral congenital cataract caused by persistent fetal vasculature or minimal fetal vascular remnants: age-related findings and management challenges.

PURPOSE: To document in detail the surgical management challenges over the wide spectrum of persistent fetal vasculature syndrome (PFVS). SETTING: Department of Ophthalmology, University of Vienna, Medical School, Vienna, Austria. METHODS: As part of an ongoing prospective clinical trial of the treatment and etiology of pediatric cataract, a subgroup of 31 children with unilateral cataract was defined. Standard surgical techniques were used based on age. Group 1 comprised infants between 0 and 1.5 years; Group 2, preschool children between 1.6 and 5.9 years; and Group 3, school-aged children between 6 and 16 years. Additional surgical procedures were used based on the degree of PFVS. RESULTS: All 31 eyes with unilateral cataract showed signs of PFVS. Characteristic features were found in 75% of eyes in Group 1, 8% of eyes in Group 2, and 67% of eyes in Group 3. Minimal fetal vascular remnants were found in 92%, 25%, and 33%, respectively. Correct diagnosis of PFVS was made preoperatively in 56% of eyes in Group 1, 8% in Group 2, and 67% in Group 3. Surgical procedures in addition to standard age-related techniques were necessary in all eyes with unilateral cataract. CONCLUSIONS: Results indicate that varying degrees of PFVS are a frequent cause of unilateral congenital cataract. Most severe cases were in infants, and preschool children were usually mildly affected. Vitreoretinal complications may lead to challenges in the surgical management in infants. In preschool children, cataract surgery must be performed in a guarded fashion because of the high risk for preexisting posterior capsule breaks due to minimal fetal vascular remnants.

Neurofibromatosis 1: a novel NF1 mutation in an 11-year-old girl with a giant cell granuloma.

We report an 11-year-old girl who presented with a painless unilateral enlargement of the nasal bridge. Because of multiple café-au-lait spots and a positive family history, neurofibromatosis 1was diagnosed. On a computed tomographic scan, a unilocular radiolucency measuring 1.2 x 2 cm was seen in the anterior wall of the maxillary sinus, which was surgically removed. Histology revealed a central giant cell granuloma. Hyperparathyroidism, which can present with an osseous tumor and similar histology, was excluded. Molecular analysis uncovered a novel splice mutation (A4268G) in this neurofibromatosis 1 family, affecting our patient as well as her mother and brother. This article focuses on the variability of the neurofibromatosis 1 phenotype in this family and the possible relationship between central giant cell granuloma and neurofibromatosis 1.

Long-term follow-up in patients with CCFDN syndrome.

OBJECTIVE: We describe the 10-year follow-up in a cohort of 16 patients with genetically confirmed congenital cataracts, facial dysmorphism, and neuropathy (CCFDN) syndrome, providing new insights in the clinical course of the disease. METHODS: We performed a detailed clinical and paraclinical characterization and 10-year follow-up study in 16 patients with molecularly defined CCFDN syndrome, illustrating that CCFDN is a severe disabling disorder. RESULTS: All patients initially presented with congenital cataracts along with strabismus, facial dysmorphism, short stature, and demyelinating neuropathy. In all patients, paresis of small hand muscles and foot extensors worsened with disease progression, while ataxia scores remained stable or improved. Nerve conduction velocity was normal in early infancy up to 18 months, decreased to approximately 20 m/s around age 10 years, and then remained stable; distal motor latency was prolonged. Sensory nerve conduction velocities were slowed, and initially of normal amplitude. With disease progression, both sensory and motor nerves showed reduction of amplitudes indicating axonal loss. In 6 patients, acute severe proximal weakness and myalgia after febrile infections, along with rhabdomyolysis, myoglobinuria, and hyperCKemia, led to a less favorable outcome and permanent loss of ambulation in 3 patients. CONCLUSIONS: CCFDN should be classified as a recessive demyelinating sensory-motor neuropathy, and axonal loss is a major determinant of long-term outcomes and disability. Patients benefit from early and ongoing physiotherapy, and should be thoroughly counseled regarding virus-triggered rhabdomyolysis and the risk of malignant hyperthermia. Whether supplementation with liposoluble vitamins results in a therapeutic benefit should be evaluated in further studies.

Persistent fetal vasculature and minimal fetal vascular remnants: a frequent cause of unilateral congenital cataracts.

PURPOSE: To determine the significance of persistent fetal vasculature (PFV) and remnants of fetal vessels in the pathogenesis of pediatric unilateral cataracts. STUDY DESIGN: Prospective observational case series. PARTICIPANTS: Thirty-one children with unilateral cataract aged between 2 weeks and 15 years. METHODS: As part of an ongoing prospective clinical trial concerning treatment and etiology of pediatric cataracts, a subgroup of 31 children with unilateral cataracts was defined. The affected eyes received preoperative and intraoperative biomicroscopic examinations to identify characteristic features of PFV and even minimal fetal vascular remnants (MFVRs) at the level of the posterior lens capsule and anterior hyaloid face. In eyes with MFVRs, 3 different severity degrees were assumed, according to different posterior capsule abnormalities: mild, A; moderate, B; and severe, C. All observations were documented on video and analyzed in relation to age (group I, infants between 0 and 1.5 years; group II, preschool children between 1.6 and 5.9 years; group III, schoolchildren between 6 and 16 years). MAIN OUTCOME MEASURES: Frequency and morphology of characteristic features of PFV and MFVRs of the posterior lens capsule/anterior hyaloid face, lens clouding, and microphthalmos. RESULTS: All 31 eyes with unilateral congenital cataracts showed signs of PFV syndrome (100%). Characteristic features of PFV were found in 75% of group I eyes, in 8% of group II eyes, and in 67% of group III eyes. Minimal fetal vascular remnants were found in 25% of group I eyes (severity degree C in all eyes), in 92% of group II eyes (severity degree A in 36.4%, B in 27.2%, and C in 36.4%), and in 33% of group III eyes (severity degree A). Associated microphthalmos was found in all eyes in groups I and III and in 73% of group II, whereas axial lengths were equal in both eyes in 27% of group II children with MFVRs. CONCLUSIONS: Varying degrees of PFV seem to be a frequent cause of unilateral congenital cataracts. Although characteristic features of PFV occurred mainly in infants, eyes of preschool children were usually very mildly affected, showing MFVRs that were detected only by careful observation during surgery. Abnormalities of the central part of the posterior capsule, such as a translucent opacity or a lenticonic area leading to a spontaneous hole during lens aspiration, may be caused by minimal remnants of PFV.

Ocular features of the congenital cataracts facial dysmorphism neuropathy syndrome.

OBJECTIVE: To determine the nature and course of ophthalmologic abnormalities in congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome in a genetically verified group of 9 patients. STUDY DESIGN: Observational case series. PARTICIPANTS: Nine affected male individuals of 5 pedigrees aged 1.3 to 16.8 years were examined. Four individuals were recruited during an ongoing prospective study of congenital cataracts; 5 individuals could be assigned to the CCFDN group on the basis of our retrospective data. MAIN OUTCOME MEASURES: Linkage and haplotype analysis, neurologic examinations, bilateral cataracts, axial length, corneal diameter, pupil diameter and pupillary reactions, intraoperative and postoperative complications, lid changes, aphakic correction problems, refractive results, and visual function. RESULTS: All families originated from the eastern part of Serbia, close to the border with Romania. The 8 tested individuals were homozygous for the conserved ancestral CCFDN haplotype in the telomeric region of chromosome 18q. All patients showed a peripheral, demyelinating neuropathy and varying degrees of ataxia. In the older patients, muscular atrophy in distal muscles and facial dysmorphism was evident. Early-onset bilateral congenital cataracts associated with microcornea, microphthalmos, and micropupil could be found in all patients. All children had floppy eyelid syndrome and pseudoptosis. An increased inflammatory reaction to contact lenses and intraocular lenses could be documented in all. All patients had syndrome-associated nystagmus and congenital esotropia. Distant visual acuity could be classified as severe to moderate impairment, whereas near visual acuity was much better (mild to moderate impairment). CONCLUSIONS: Early-onset congenital cataracts associated with microcornea, microphthalmos, and micropupil are essential ocular features of the CCFDN syndrome and are the first recognizable signs during early infancy. Awareness of this syndrome by pediatric ophthalmologists is important, because these typical findings, combined with information on ethnic origin, may lead to very early diagnosis at an age when the nature and severity of nonophthalmologic features are not apparent. Affected individuals may benefit from careful ophthalmologic treatment and follow-up, as well as from early management of the neurologic problems and developmental delay. Affected families will benefit from genetic counseling and predictive testing.