Benign, Pathogenic and Copy Number Variations of Unknown Clinical Significance in Patients with Congenital Malformations and Developmental Delay.

The high frequency (3.0-5.0%) of congenital anomalies (CA) and intellectual disabilities (IDs), make them a serious problem, responsible for a high percentage (33.0%) of neonatal mortality. The genetic cause remains unclear in 40.0% of cases. Recently, molecular karyotyping has become the most powerful method for detection of pathogenic imbalances in patients with multiple CAs and IDs. This method is with high resolution and gives us the opportunity to investigate and identify candidate genes that could explain the genotype-phenotype correlations. This article describes the results from analysis of 81 patients with congenital malformations (CMs), developmental delay (DD) and ID, in which we utilized the CytoChip ISCA oligo microarray, 4 × 44 k, covering the whole genome with a resolution of 70 kb. In the selected group of patients with CAs, 280 copy number variations (CNVs) have been proven, 41 were pathogenic, 118 benign and 121 of unknown clinical significance (average number of variations 3.5). In six patients with established pathogenic variations, our data revealed eight pathogenic aberrations associated with the corresponding phenotype. The interpretation of the other CNVs was made on the basis of their frequency in the investigated group, the size of the variation, content of genes in the region and the type of the CNVs (deletion or duplication).

Peripheral and central delay in processing high spatial frequencies: reaction time and VEP latency studies.

Visually evoked potentials (VEP) and reaction time (RT) were recorded under stimulation with sinusoidal gratings. Grating spatial frequency (SF) was 0.5, 5 or 12 cd and grating contrast was varied. Consistent with previous findings, both VEP latency and RT increased with the increase of grating SF and with the decrease of grating contrast. It was found, in addition, that RT and VEP latency increased by approximately the same amount when SF increased from 0.5 to 5 cd, thus suggesting that the main source of the RT delay at 5 cd in comparison with RT at 0.5 cd is of peripheral origin. However, in comparison with the data at 0.5 and 5 cd, RT at 12 cd increased much more than VEP latency. We conclude that the RT delay at high SF involves a substantial central component in addition to the peripheral delay.

Surgical management of the anophthalmic orbit, part 1: congenital.

Congenital microphthalmos and anophthalmos are rare conditions in which orbital growth is deficient. Hypoplasia of the globe affects the bony orbit (micro-orbitism), the conjunctival sac, and eyelids (microblepharism), and it may be associated with abnormalities of the entire hemifacial skeleton (hemifacial microsomia). In the present article, the authors review a series of 19 patients with microphthalmos (nine had right-sided, one had bilateral, and nine had left-sided microphthalmos) who were treated in the Orbitopalpebral Unit at Hospital Foch over a period of 15 years (follow-up, 5 months to 18 years).Orbital expansion was achieved using spherical implants (n = 13), orbital osteotomies (n = 4), and orbital expanders (n = 2). Both expanders were removed within 6 months because of failure (one infection and one rupture). The current preferred method for orbital expansion is to use serial implants in the growing orbit and osteotomies in cases of late referral or insufficient orbital volume in the older child. The target proportions of the reconstructed orbit are not planned to mirror the healthy side exactly. The inferior orbital rim is kept higher to support the orbital implant, and the orbit is kept shallow to avoid a sunken appearance. Cranial bone grafts were used to augment deficient orbital contours; they were assisted by anterior transposition of the temporalis muscle (n = 5) when additional orbital volume was required. Conjunctival sac reconstruction was achieved by the use of serial conformers placed in the conjunctival sac during the neonatal period, followed by grafts of buccal mucosa and full-thickness skin maintained in place with a tarsorrhaphy for 3 to 6 months. Eyelid reconstruction using local flaps and skin grafts proved to be necessary in cases treated by osteotomy expansion, although reconstruction was not required after expansion using serial solid shapes. The results illustrate an evolution in approach and concepts of reconstruction of the microphthalmic orbit and emphasize the need for an integrated craniofacial approach for this complex deformity.

Surgical management of the anophthalmic orbit, part 2: post-tumoral.

Ablative surgery for tumors of the globe and its adnexal structures is frequently the cause of major orbitofacial deformity. Radiotherapy compounds the problem because it suppresses skeletal growth in the growing patient and induces a contraction of the remaining soft tissues in the orbit. Goals for reconstruction in these patients include the restoration of orbital structures to allow the fitting of an ocular prosthesis and the correction of distorted orbitofacial relationships. The authors present a series of 53 patients (mean age, 29 years; 28 male) who were treated over the past 18 years by composite reconstruction of the post-tumoral anophthalmic orbit. The follow-up ranged from 5 months to 18 years (mean, 7.75 years). Four patients were treated primarily (immediate reconstruction after tumor ablation), and 49 were treated secondarily (mean oncological follow-up since ablative surgery, 14.8 years). Twenty-eight patients underwent orbital enucleation (including three bilateral cases), 23 underwent orbital exenteration, and two underwent evisceration. Forty-two patients received radiotherapy, including 20 enucleation patients, 15 exenteration patients, and seven others in whom details of primary therapy were incomplete. A staged reconstruction was undertaken in each case; it considered, in turn, the bony orbital volume (orbital remodeling and cranial bone grafts), orbital contents (implant, temporalis muscle transposition, cranial bone grafts, and dermafat grafts), conjunctival sac (mucosal and skin grafts), ocular prosthesis, eyelids (local flaps and skin grafts), and additional procedures to restore orbitofacial symmetry. The authors conclude that the long-term results of post-tumoral orbital reconstruction are favorable, and they particularly recommend the use of autogenous tissues in irradiated orbits.

Effect of stimulus contrast uncertainty on simple reaction time.

Both reaction time (RT) and the latency of the visually evoked potentials (VEP) to grating onset increase with increasing stimulus spatial frequency (SF). At SF higher than 5 c/deg RT increases faster than VEP latency, the difference resulting in a "central delay" (Mihaylova et al., 1999). Due to the equipment limitations, RT and VEP experiments of Mihaylova et al. (1999) differed in constancy of stimulus contrast within a sequence of trials. The present experiments were aimed at testing the assumption that the central delay is a result of contrast uncertainty effect on RT. To this end, RT were measured in condition of both constant and variable grating contrast. The stimuli were sinusoidal gratings ranging in SF from 0.5 to 16 c/deg and in contrast from 2.5 to 50%. In addition, VEP were recorded to the same stimuli in blocks of fixed contrast and the latencies of the early VEP wave were subtracted from RT. Contrast uncertainty did not affect RT at low SF, 0.5 and 2 c/deg, while increasing RT at SF higher than 5 c/deg both at low and high stimulus contrast. The results showed that the central component of RT increase at high SF is reduced but not eliminated under constant contrast condition. The uncertainty effect at high SF might be due to contrast sensitivity reduction, reduced subjective stimulus probability and differences in response strategy adopted by the subjects when contrast was constant or variable. An alternative explanation is a larger ability of low SF stimuli compared to high SF stimuli to attract visual attention.