Kristien Hoornaert

Stickler syndrome caused by COL2A1 mutations: Genotype-phenotype correlation in a series of 100 patients

Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation-dependent amplification analysis was used for the detection of intragenic deletions. We identified 77 different COL2A1 mutations in 100 affected individuals. Analysis of the splice site mutations showed unusual RNA isoforms, most of which contained a premature stop codon. Vitreous anomalies and retinal detachments were found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group (P<0.01). Overall, 20 of 23 sporadic patients with a COL2A1 mutation had either a cleft palate or retinal detachment with vitreous anomalies. The presence of vitreous anomalies, retinal tears or detachments, cleft palate and a positive family history were shown to be good indicators for a COL2A1 defect. In conclusion, we confirm that Stickler syndrome type 1 is predominantly caused by loss-of-function mutations in the COL2A1 gene as >90% of the mutations were predicted to result in nonsense-mediated decay. On the basis of binary regression analysis, we developed a scoring system that may be useful when evaluating patients with Stickler syndrome.

A report on 10 new patients with heterozygous mutations in the COL11A1 gene and a review of genotype–phenotype correlations in type XI collagenopathies

A series of 44 unrelated patients in whom COL2A1 screening demonstrated normal results but whose phenotype was nevertheless highly suggestive of either Stickler syndrome (with ocular involvement) or Marshall syndrome were investigated for mutations in the COL11A1 gene. Heterozygous COL11A1 mutations were found in 10 individuals. A splice site alteration (involving introns 47–55) was present in seven cases, with one in intron 50 (c.3816 + 1G > A) occurring in three patients. Two patients had a different deletion, and a missense mutation (Gly1471Asp) was observed in one case. In 4/10 patients the phenotype was classified as Marshall syndrome because of early‐onset severe hearing loss and characteristic facial features. These four patients were all heterozygous for a splice site mutation in intron 50. One of these cases had a type 1 vitreous anomaly despite the presence of a COL11A1 mutation. The remaining 6/10 patients had an overlapping Marshall–Stickler phenotype with less pronounced facial features. None of these had a mutation in the hot spot region of intron 50.

Czech dysplasia metatarsal type: another type II collagen disorder

Czech dysplasia metatarsal type is an autosomal-dominant disorder characterized by an early-onset, progressive spondyloarthropathy with normal stature. Shortness of third and/or fourth toes is a frequently observed clinical feature. Similarities between individuals with this dysplasia and patients with an R275C mutation in the COL2A1 gene, prompted us to analyze the COL2A1 gene in the original families reported with Czech dysplasia. Targeted sequencing of exon 13 of the COL2A1 gene was performed, followed by sequencing of the remaining exons in case the R275C mutation was not identified. We identified the R275C substitution in two of the original patients reported with Czech dysplasia and three additional patients. All affected individuals had a similar phenotype characterized by normal height, spondyloarthropathy, short postaxial toes and absence of ocular and orofacial anomalies. The R275C mutation was excluded in a third patient reported with Czech dysplasia. However, the identification of the Y1391C mutation in this patient with disproportionate short stature made the diagnosis of spondyloperipheral dysplasia (SPD) more probable. The Y1391C mutation is located in the C-propeptide of the procollagen chain and has been reported before in a patient with the Torrance type of lethal platyspondylic skeletal dysplasia (PLSD-T). Our observation of the same Y1391C mutation in an additional unrelated patient with SPD further supports the evidence that PLSD-T and SPD represent a phenotypic continuum. The R275C mutation in the COL2A1 gene causes a specific type II collagen disorder that was recently delineated as Czech dysplasia.

A Study of the Clinical and Radiological Features in a Cohort of 93 Patients with a COL2A1 Mutation Causing Spondyloepiphyseal Dysplasia Congenita or a Related Phenotype

Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n = 64), others having SEMD (n = 5), Kniest dysplasia (n = 7), spondyloperipheral dysplasia (n = 2), or Torrance‐like dysplasia (n = 2). The remaining 13 patients had normal stature with mild SED, Stickler‐like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38–74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto‐axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10–54) in whom flexion‐extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35–56), and retinal detachment had occurred in 12% (95% CI 6–21; median age 14 years; youngest age 3.5 years). Thirty‐two patients complained of hearing loss (37%, 95% CI 27–48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype–phenotype correlations in this cohort, we propose guidelines for the management and follow‐up in this group of disorders.

Do not turn a blind eye to alkyl nitrite (poppers)

(r = 0.38, p = 0.02, Fig. 1B). The reason why vitrectomy is effective in reducing periostin has not been determined. Because the level of periostin protein was reduced in a time-dependent manner (Fig. 1B), one possible explanation is that there is an increase in the diffusion of periostin away from the retina by the replacement of the vitreous gel with less viscous saline. Another reason for the quieting effects of vitrectomymay be the removal of FVMs because we have shown that the smooth muscle cells and M2 macrophages in FVMs actively produce periostin as well as a variety of adhesionmolecules (Yoshida et al. 2011). Anti-VEGF therapy is being used to treat neovascular diseases of the eye, and its use has led to significant advances in the management of PDR. However, this treatment turns on an ‘angiofibrotic switch’ to favour a fibrotic phase, and tractional retinal detachment have been reported in PDR patients following the administration of anti-VEGF agents in spite of the neovascular inhibition (Sohn et al. 2012). This indicates that anti-VEGF therapy is not effective in inhibiting fibrotic proliferation. Our findings that successful vitrectomy can reduce both periostin and VEGF for a long time (Yoshida et al. 2012; Fig. 1B) suggest that a successful vitrectomy may inhibit both angiogenesis and subsequent fibrosis by reducing the level of these molecules.

Retinal nerve fiber layer thickening in ARSACS carriers.

PURPOSE Two Caucasian Belgian families were diagnosed with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The ophthalmological findings in both ARSACS disease and carriers are described. METHODS In addition to a complete ophthalmological assessment, in both patients and carriers, spectral-domain Optical Coherence Tomography scans of the peri-papillary retinal nerve fiber layer were performed. RESULTS Molecular analysis revealed a missense mutation which has not been reported before. Besides patients with ARSACS, who also presented additional ophthalmological abnormalities i.e. eye movement problems, ARSACS carriers demonstrated thickening of the retinal nerve fiber layer. CONCLUSION The most conspicuous ophthalmological feature of ARSACS is an increased thickness of the peri-papillary retinal nerve fiber layer. Retinal striation and thickening of the nerve fiber layer on spectral-domain Optical Coherence Tomography appeared also in carriers of the ARSACS-gene. Other ophthalmological features encountered, were gaze-evoked nystagmus and rebound nystagmus.

Age-dependent ocular phenotype in hereditary hyperferritinaemia cataract syndrome (HHCS)

Chew EY, Benson WE, Remaley NA et al. (1999): Results after lens extraction in patients with diabetic retinopathy; Early Treatment Diabetic Retinopathy Study report number 25. Arch Ophthalmol 117: 1600–1606. Gibbens MV, Goel R & Smith SE (1989): Effect of cataract extraction on the pupil response to mydriatics. Br J Ophthalmol 73: 563–565. Hayashi K & Hayashi H (2004): Pupil size before and after phacoemulsification in nondiabetic and diabetic patients. J Cataract Refract Surg 30: 2543–2550. Suto C, Hori S & Kato S (2008): Management of type 2 diabetics requiring panretinal photocoagulation and cataract surgery. J Cataract Refract Surg 34: 1001–1006.

Bilateral Choroidal Metastases from Endobronchial Carcinoid Treated with Somatostatin Analogues.

Objective: To describe a patient with bilateral multifocal choroidal metastases from an endobronchial carcinoid treated with a somatostatin analogue. Method: A 60-year-old woman presenting with photopsia in the left eye underwent an extensive ophthalmic examination, including fluorescein angiography, OCT and ultrasound. Results: Fundoscopy revealed a small retinal tear in the left eye, for which she received laser treatment. In addition, choroidal masses were detected in both eyes. Her medical history of a pneumectomy for a bronchial carcinoid six years earlier together with recent elevated chromogranin A blood levels prompted a diagnosis of choroidal metastases. Subsequently, a Gallium-68 DOTANOC positron emitting tomography/computer tomography scan revealed a spinal cord metastasis and mediastinal as well as mesenterial lymph node invasion. Systemic treatment with Sandostatin®, a somatostatin analogue was started. Up until two years after the initial presentation and treatment, these choroidal lesions remained stable without any signs of growth. Conclusion: Endobronchial carcinoid tumors have an indolent nature and long-term follow-up is recommended for early detection of metastases. Although treatment with somatostatin analogues rarely induces complete tumor regression, tumor stabilization and prevention of symptoms related to hormone secretion is achieved. This well-tolerated systemic treatment provides a worthy alternative treatment for choroidal metastasis compared to classic radiotherapy without any risk of radiation or laser-related visual loss.

Prominent Mittendorf Spot

Remnant of the hyaloid artery in the left eye of an asymptomatic man in his early 60s. It supplies blood to the developing lens during embryological development and usually regresses during fetal life. In rare cases, its anterior part remains as an occluded, cicatricial tuft. A, Diffuse illumination. B and C, Narrow-slit illumination. D, Retroillumination. JAMA Ophthalmol. 2015;133(1):e141817. doi:10.1001/jamaophthalmol.2014.1817