Biallelic CPAMD8 variants are a frequent cause of childhood and juvenile open-angle glaucoma

Purpose: Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Design: Retrospective, multicenter case series. Participants: A total of 268 probands and their relatives with a diagnosis of childhood or juvenile open-angle glaucoma. Methods: Patients underwent a comprehensive ophthalmic assessment, with DNA from patients and their relatives subjected to genome, exome, or capillary sequencing. CPAMD8 RNA expression analysis was performed on tissues dissected from cadaveric human eyes. Main outcome measures: Diagnostic yield within a cohort of childhood and juvenile open-angle glaucoma, prevalence and risk of ophthalmic phenotypes, and relative expression of CPAMD8 in the human eye. Results: We identified rare (allele frequency -5) biallelic CPAMD8 variants in 5.7% (5/88) of probands with childhood glaucoma and 2.1% (2/96) of probands with juvenile open-angle glaucoma. When including family members, we identified 11 individuals with biallelic variants in CPAMD8 from 7 unrelated families. Nine of these individuals were diagnosed with glaucoma (9/11, 81.8%), with a mean age at diagnosis of 9.22±14.89 years, and all individuals with glaucoma required 1 or more incisional procedures to control high intraocular pressure. Iris abnormalities were observed in 9 of 11 individuals, cataract was observed in 8 of 11 individuals (72.7%), and retinal detachment was observed in 3 of 11 individuals (27.3%). CPAMD8 expression was highest in neural crest-derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation or obstruction of key drainage structures. Conclusions: Biallelic CPAMD8 variation was associated with a highly heterogeneous phenotype and in our cohorts was the second most common inherited cause of childhood glaucoma after CYP1B1 and juvenile open-angle glaucoma after MYOC. CPAMD8 sequencing should be considered in the investigation of both childhood and juvenile open-angle glaucoma, particularly when associated with iris abnormalities, cataract, or retinal detachment

A Dutch guideline for the treatment of scoliosis in neuromuscular disorders

<p>Abstract</p> <p>Background</p> <p>Children with neuromuscular disorders with a progressive muscle weakness such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy frequently develop a progressive scoliosis. A severe scoliosis compromises respiratory function and makes sitting more difficult. Spinal surgery is considered the primary treatment option for correcting severe scoliosis in neuromuscular disorders. Surgery in this population requires a multidisciplinary approach, careful planning, dedicated surgical procedures, and specialized after care.</p> <p>Methods</p> <p>The guideline is based on scientific evidence and expert opinions. A multidisciplinary working group representing experts from all relevant specialties performed the research. A literature search was conducted to collect scientific evidence in answer to specific questions posed by the working group. Literature was classified according to the level of evidence.</p> <p>Results</p> <p>For most aspects of the treatment scientific evidence is scarce and only low level cohort studies were found. Nevertheless, a high degree of consensus was reached about the management of patients with scoliosis in neuromuscular disorders. This was translated into a set of recommendations, which are now officially accepted as a general guideline in the Netherlands.</p> <p>Conclusion</p> <p>In order to optimize the treatment for scoliosis in neuromuscular disorders a Dutch guideline has been composed. This evidence-based, multidisciplinary guideline addresses conservative treatment, the preoperative, perioperative, and postoperative care of scoliosis in neuromuscular disorders.</p

Kant’s epigenesis: specificity and developmental constraints

In this paper, I argue that Kant adopted, throughout his career, a position that is much more akin to classical accounts of epigenesis, although he does reject the more radical forms of epigenesis proposed in his own time, and does make use of preformationist sounding terms. I argue that this is because Kant (1) thinks of what is pre-formed as a species, not an individual or a part of an individual; (2) has no qualm with the idea of a specific, teleological principle or force underlying generation, and conceives of germs and predispositions as specific constraints on such a principle or force. Neither of these conceptions of what is “preformed”, I argue, is in strict opposition to classical epigenesis. I further suggest that Kant’s lingering use of preformationist terminology is due to (1) his belief that this is required to account for the specificity of the specific generative force; (2) his resistance towards the unrestricted plasticity of the generative force in radical epigenesis, which violates species-fixism; and (3) his insistence on the internal, organic basis of developmental plasticity and variation within species. I conclude by suggesting that this terminological and interpretative peculiarity is partly due to a larger shift in the natural philosophical concerns surrounding the debate on epigenesis and preformation. Specifically, it is a sign that the original reasons for resisting epigenesis, namely its use of specific, teleological principles and its commitment to the natural production of biological structure, became less of a concern, whereas unrestricted plasticity and its undermining of fixism became a real issue, thereby also becoming the focal point of the debate

Simultaneous Subconjunctival Triamcinolone and Bevacizumab Injections for Management of Blepharokeratoconjunctivitis in Children.

Purpose: To report the efficacy of subconjunctival triamcinolone (Kenalog A-40, Alcon) and bevacizumab (Avastin, Genentech) injections in fraternal twins with blepharokeratoconjunctivitis (BKC) causing progressive, bilateral corneal neovascularization and scarring. Methods: In this retrospective observational case series, two three-year-old male twins with BKC had presented with bilateral red eyes, photophobia, and frequent blinking. Examination of each child showed bilateral deep stromal and superficial corneal neovascularization, corneal infiltrates, multiple follicles on the palpebral conjunctiva bilaterally with blepharitis, and thick turbid sebum expressed from the Meibomian glands. Their disease progressed despite conventional treatment. Both twins were managed with subconjunctival triamcinolone injection and subconjunctival bevacizumab injection of each eye. Results: The treatment resulted in improvement of symptoms, and examination over an 8-10-month period postinjections showed fading stromal corneal infiltrates, partially regressed corneal neovascularization, and reduced conjunctival injection without complications. Conclusion: This case series highlights the potential vision threatening complications of BKC. In addition to conventional management options, this report is the first published use of subconjunctival triamcinolone and bevacizumab injections for BKC in children in an attempt to minimize and improve corneal neovascularization and scarring and subsequently to retain useful vision