Fundus Autofluorescence and SD-OCT Document Rapid Progression in Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC) Associated with a c.256G > A Mutation in BEST1.

PURPOSE: To report the variability of clinical findings, rapid concentric progression, and successful treatment of macular edema in autosomal dominant vitreoretinochoroidopathy (ADVIRC) associated with a heterozygous c.256G > A missense mutation in the bestrophin-1 (BEST1) gene. METHODS: Three affected members of a four-generation ADVIRC family were examined with fundus autofluorescence (FAF), near-infrared autofluorescence (NIA) and spectral domain optical coherence tomography (SD-OCT). Direct sequence analysis of coding and flanking intronic regions of the BEST1 gene was performed. RESULTS: Disease manifestations presented with high variability with visual problems manifesting between 10 and 40 years of age. Two probands showed marked signs of peripheral degeneration, while this retinal area was not noticeably affected in the third. Cystoid macular edema was present in one proband, which responded to long-term treatment with topic dorzolamide with improved visual acuity. FAF and NIA revealed mid-peripheral retinal degeneration in areas that appeared normal on ophthalmoscopy. The full-field ERG was markedly reduced in two probands. Within a 5-year period a marked increase in concentric progression of degeneration including the posterior pole was documented with FAF, NIA and SD-OCT in one proband after the age of 63 years. Direct sequence analysis of the BEST1 gene revealed a heterozygous c.256G > A missense mutation in the three affected probands. CONCLUSION: The findings in this family emphasize the previously noted variability of clinical manifestations in BEST1-associated ADVIRC and the relevance of FAF and NIA imaging. Cystoid macular edema and vascular leakage can be successfully treated using dorzolamide.

Anti-Fas/CD95 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) differentially regulate apoptosis in normal and neoplastic human basophils.

Basophilia is associated with allergic and parasitic diseases and advanced chronic myeloid leukemia. In the present study, we characterized the expression and function of the death receptors Fas/CD95 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors in basophils from healthy donors compared to neoplastic basophils. Peripheral blood basophils obtained from healthy donors (HD-PBB) and from patients with chronic myeloid leukemia (CML-PBB) were found to express high levels of Fas/CD95 and low levels of TRAIL-R2, whereas the basophil-like chronic myeloid leukemia cell line KU-812 expressed significant levels of TRAIL-R1 and TRAIL-R2. HD-PBB underwent apoptosis in response to anti-Fas/CD95, but showed resistance to TRAIL, unless they were co-treated with actinomycin D. Interestingly, CML-PBB and KU-812 cells exhibited the opposite response pattern with resistance to anti-Fas/CD95, but significant susceptibility to TRAIL-induced apoptosis. Our data show that anti-Fas/CD95 and TRAIL differentially regulate apoptosis of normal and neoplastic human basophils, which may direct the development of novel therapeutic strategies.

Gyrate atrophy: clinical and genetic findings in a female without arginine-restricted diet during her first 39 years of life and report of a new OAT gene mutation.

We report the clinical and genetic data obtained at a 17-year follow-up examination of a patient with gyrate atrophy, without an arginine-restricted diet. Patient examinations included visual acuity (VA), perimetry, biomicroscopy, funduscopy, fundus photography, fundus autofluorescence (FAF), spectral-domain optical coherence tomography (OCT), and standard full-field electroretinography (ERG). Blood samples were taken for measurement of serum ornithine level and molecular genetic analysis of the OAT gene. The female was 22 years of age when gyrate atrophy was diagnosed based on peripheral chorioretinal atrophy and an increased ornithine level. Reexamination after 17 years revealed a reduced VA (0.25 OU), dense cataract, extensive peripheral chorioretinal atrophy, a further increased ornithine level, but only slow progression of visual field constriction, and still detectable ERG amplitudes. FAF was absent in the atrophic periphery and almost homogeneous at the posterior pole except parafoveally. OCT showed interruption of the foveal inner/outer segment junction and parafoveal microcystoid spaces. After cataract surgery, VA increased to the same values as those found at the age of 22 years (0.5 OD, 0.6 OS). Molecular analysis revealed a new deletion c.532_536delTGGGG (p.Trp178X) and a known mutation c.897C>G (p.Tyr299X) in the OAT gene. Although the patient had refused to diet during her first 39 years of life, the gyrate atrophy showed a very slow progression. FAF allows evaluating the integrity of the retinal pigment epithelium and may help to delimit gyrate atrophy from choroideremia. Interruption of foveal inner/outer segment junction and cystoid macula edema appears in gyrate atrophy.

Systemic epidermal nevus with involvement of the oral mucosa due to FGFR3 mutation.

BACKGROUND: Epidermal nevi (EN) represent benign congenital skin lesions following the lines of Blaschko. They result from genetic mosaicism, and activating FGFR3 and PIK3CA mutations have been implicated. CASE PRESENTATION: We report a female patient with a systemic keratinocytic nevus also involving the oral mucosa. Molecular genetic analysis revealed a mosaicism of the FGFR3 hotspot mutation R248C in the EN lesions of the skin and of the oral mucosa. The detection of the R248C mutation in a proportion of blood leukocytes and a slight scoliosis suggest an EN syndrome. CONCLUSIONS: Our results show that activating FGFR3 mutations can also affect the oral mucosa and that extracutaneous manifestations of EN syndrome can be subtle. We highlight the theoretical risk of the patient having an offspring with thanatophoric dysplasia as gonadal mosaicism for the R248C mutation cannot be excluded.

Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders.

Impaired fetal movement causes malformations, summarized as fetal akinesia deformation sequence (FADS), and is triggered by environmental and genetic factors. Acetylcholine receptor (AChR) components are suspects because mutations in the fetally expressed gamma subunit (CHRNG) of AChR were found in two FADS disorders, lethal multiple pterygium syndrome (LMPS) and Escobar syndrome. Other AChR subunits alpha1, beta1, and delta (CHRNA1, CHRNB1, CHRND) as well as receptor-associated protein of the synapse (RAPSN) previously revealed missense or compound nonsense-missense mutations in viable congenital myasthenic syndrome; lethality of homozygous null mutations was predicted but never shown. We provide the first report to our knowledge of homozygous nonsense mutations in CHRNA1 and CHRND and show that they were lethal, whereas novel recessive missense mutations in RAPSN caused a severe but not necessarily lethal phenotype. To elucidate disease-associated malformations such as frequent abortions, fetal edema, cystic hygroma, or cardiac defects, we studied Chrna1, Chrnb1, Chrnd, Chrng, and Rapsn in mouse embryos and found expression in skeletal muscles but also in early somite development. This indicates that early developmental defects might be due to somite expression in addition to solely muscle-specific effects. We conclude that complete or severe functional disruption of fetal AChR causes lethal multiple pterygium syndrome whereas milder alterations result in fetal hypokinesia with inborn contractures or a myasthenic syndrome later in life.

Gross rearrangements in BRCA1 but not BRCA2 play a notable role in predisposition to breast and ovarian cancer in high-risk families of German origin.

A total of 226 index cases from high-risk hereditary breast and ovarian cancer families of German origin who had tested negative for small nucleotide alterations in BRCA1 and BRCA2 were analyzed for gross genomic rearrangements at the two gene loci by the multiplex ligation-dependent probe amplification technique. Six large genomic alterations were identified in BRCA1, while no gross rearrangements were found in BRCA2. The six BRCA1 mutations included two novel mutations including a deletion of exon 5, and a deletion comprising exons 5-7, as well as three distinct gross alterations previously reported, including a deletion of exons 1A, 1B, and 2, two duplications of exon 13, and a deletion of exon 17. To understand the mechanisms underlying the genomic rearrangements within the BRCA1 gene and to provide a simple PCR-based assay for further diagnostic applications, we have defined the molecular breakpoints of the deletion/insertion mutations. In all cases, our data point to a mechanism by which illegitimate crossing over between stretches of direct repeat sequences as small as 9 base pairs (bp) and up to 188 bp may have occurred. Overall, we provide evidence that gross rearrangements within the BRCA1 gene locus may be as frequent as 3% in primarily mutation-negative tested high-risk familial breast and ovarian cancer of German ancestry, while large alterations involving the BRCA2 locus do not appear to play a significant role in disease etiology. These findings have important implications for genetic counseling and testing of high-risk breast and ovarian cancer families.