New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform.

This study aims to genetically characterize a two-year-old patient suffering from multiple systemic abnormalities, including skeletal, nervous and developmental involvements and Leber congenital amaurosis (LCA). Genetic screening by next-generation sequencing identified two heterozygous pathogenic variants in nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) as the molecular cause of the disease: c.439+5G>T and c.299+526_*968dup.This splice variant has never been reported to date, whereas pathogenic duplication has recently been associated with cases displaying an autosomal recessive disorder that includes a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and LCA (SHILCA), as well as some brain anomalies. Our patient presented clinical manifestations which correlated strongly with this reported syndrome. To further study the possible transcriptional alterations resulting from these mutations, mRNA expression assays were performed in the patient and her father. The obtained results detected aberrant alternative transcripts and unbalanced levels of expression, consistent with severe systemic involvement. Moreover, these analyses also detected a novel NMNAT1 isoform, which is variably expressed in healthy human tissues. Altogether, these findings represent new evidence of the correlation of NMNAT1 and SHILCA syndrome, and provide additional insights into the healthy and pathogenic expression of this gene.

Frontalis Muscle Flap Versus Maximal Anterior Levator Resection as First Option for Patients With Severe Congenital Ptosis.

PURPOSE: To compare 2 surgical techniques (frontalis flap versus maximal anterior levator resection) as first surgical options for the treatment of congenital ptosis with poor levator function in patients younger than 2 years of age with a follow up of 10 years. METHODS: A retrospective study of 58 patients (71 eyelids) with severe ptosis and poor levator function who underwent frontalis muscle flap (FMF = 47) or maximal anterior levator resection (ALR = 24) for correction of their ptosis. Eyelid measurements were taken at baseline, 1, 5, and 10 years after surgery. The presence of complications, need for reoperations, and palpebral contour were evaluated. RESULTS: Most patients in both groups required only one surgical procedure with a stable average margin-reflex distance 1 over the 10-year follow-up period in both groups, with no statistically significant difference between the 2 techniques in achieving an adequate palpebral height after one single procedure. Eleven eyelids treated with FMF (23%) and 12 treated with ALR (50%) needed a reoperation, with a statistically significant difference between the 2 techniques. Five ALR patients (21%) and 6 FMF patients (13%) had alterations of eyelid contour. Pop-eyelid and eyelash ptosis were observed in 8% of patients operated with FMF. CONCLUSION: Good functional and aesthetic results were obtained with both surgical techniques. FMF required fewer reoperations compared with maximal ALR, offering a better long-term result without residual ptosis.

Pseudonystagmus in trochlear nerve palsy.

We present the case report of a patient who presented with intermittent diplopia and left hypertropia associated with an apparent left superior oblique palsy. After dissociation with cover testing, he showed conjugate rhythmic vertical eye movements present in all gazes, thought to represent rapid rhythmically alternating fixation. The vertical rhythmic movement resolved after strabismus surgery.

Panel-based whole exome sequencing identifies novel mutations in microphthalmia and anophthalmia patients showing complex Mendelian inheritance patterns.

BACKGROUND: Microphthalmia and anophthalmia (MA) are congenital eye abnormalities that show an extremely high clinical and genetic complexity. In this study, we evaluated the implementation of whole exome sequencing (WES) for the genetic analysis of MA patients. This approach was used to investigate three unrelated families in which previous single-gene analyses failed to identify the molecular cause. METHODS: A total of 47 genes previously associated with nonsyndromic MA were included in our panel. WES was performed in one affected patient from each family using the AmpliSeqTM Exome technology and the Ion ProtonTM platform. RESULTS: A novel heterozygous OTX2 missense mutation was identified in a patient showing bilateral anophthalmia who inherited the variant from a parent who was a carrier, but showed no sign of the condition. We also describe a new PAX6 missense variant in an autosomal-dominant pedigree affected by mild bilateral microphthalmia showing high intrafamiliar variability, with germline mosaicism determined to be the most plausible molecular cause of the disease. Finally, a heterozygous missense mutation in RBP4 was found to be responsible in an isolated case of bilateral complex microphthalmia. CONCLUSION: This study highlights that panel-based WES is a reliable and effective strategy for the genetic diagnosis of MA. Furthermore, using this technique, the mutational spectrum of these diseases was broadened, with novel variants identified in each of the OTX2, PAX6, and RBP4 genes. Moreover, we report new cases of reduced penetrance, mosaicism, and variable phenotypic expressivity associated with MA, further demonstrating the heterogeneity of such disorders.