Retinitis pigmentosa (RP) is an inherited retinal dystrophy caused by the loss of photoreceptors and characterized by retinal pigment deposits visible on fundus examination. Prevalence of non syndromic RP is approximately 1/4,000. The most common form of RP is a rod-cone dystrophy, in which the first symptom is night blindness, followed by the progressive loss in the peripheral visual field in daylight, and eventually leading to blindness after several decades. Some extreme cases may have a rapid evolution over two decades or a slow progression that never leads to blindness. In some cases, the clinical presentation is a cone-rod dystrophy, in which the decrease in visual acuity predominates over the visual field loss. RP is usually non syndromic but there are also many syndromic forms, the most frequent being Usher syndrome. To date, 45 causative genes/loci have been identified in non syndromic RP (for the autosomal dominant, autosomal recessive, X-linked, and digenic forms). Clinical diagnosis is based on the presence of night blindness and peripheral visual field defects, lesions in the fundus, hypovolted electroretinogram traces, and progressive worsening of these signs. Molecular diagnosis can be made for some genes, but is not usually performed due to the tremendous genetic heterogeneity of the disease. Genetic counseling is always advised. Currently, there is no therapy that stops the evolution of the disease or restores the vision, so the visual prognosis is poor. The therapeutic approach is restricted to slowing down the degenerative process by sunlight protection and vitaminotherapy, treating the complications (cataract and macular edema), and helping patients to cope with the social and psychological impact of blindness. However, new therapeutic strategies are emerging from intensive research (gene therapy, neuroprotection, retinal prosthesis).

Retinitis pigmentosa

This review provides an updated summary of the state of our knowledge of the genetic contributions to the pathogenesis of congenital heart disease. Since 2007, when the initial American Heart Association scientific statement on the genetic basis of congenital heart disease was published, new genomic techniques have become widely available that have dramatically changed our understanding of the causes of congenital heart disease and, clinically, have allowed more accurate definition of the pathogeneses of congenital heart disease in patients of all ages and even prenatally. Information is presented on new molecular testing techniques and their application to congenital heart disease, both isolated and associated with other congenital anomalies or syndromes. Recent advances in the understanding of copy number variants, syndromes, RASopathies, and heterotaxy/ciliopathies are provided. Insights into new research with congenital heart disease models, including genetically manipulated animals such as mice, chicks, and zebrafish, as well as human induced pluripotent stem cell-based approaches are provided to allow an understanding of how future research breakthroughs for congenital heart disease are likely to happen. It is anticipated that this review will provide a large range of health care-related personnel, including pediatric cardiologists, pediatricians, adult cardiologists, thoracic surgeons, obstetricians, geneticists, genetic counselors, and other related clinicians, timely information on the genetic aspects of congenital heart disease. The objective is to provide a comprehensive basis for interdisciplinary care for those with congenital heart disease.

https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000606

Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association.

Alagille syndrome (ALGS), also known as arteriohepatic dysplasia, is a multisystem disorder due to defects in components of the Notch signalling pathway, most commonly due to mutation in JAG1 (ALGS type 1), but in a small proportion of cases mutation in NOTCH2 (ALGS type 2). The main clinical and pathological features are chronic cholestasis due to paucity of intrahepatic bile ducts, peripheral pulmonary artery stenosis, minor vertebral segmentation anomalies, characteristic facies, posterior embryotoxon/anterior segment abnormalities, pigmentary retinopathy, and dysplastic kidneys. It follows autosomal dominant inheritance, but reduced penetrance and variable expression are common in this disorder, and somatic/germline mosaicism may also be relatively frequent. This review discusses the clinical features of ALGS, including long-term complications, the clinical and molecular diagnosis, and management.

/pdf/alagille-syndrome-pathogenesis-diagnosis-and-management-1kk2lgjfnh.pdf

Alagille syndrome: pathogenesis, diagnosis and management

This case is submitted by Drs. Francisco J. Ascaso, Maria Rojo, and Enrique Minguez from the Department of Ophthalmology, “Lozano Blesa” University Clinic Hospital, Zaragoza, Spain, for the Diagnostic and Therapeutic Challenges Section of Retina; and commented by Dr. Steven M. Cohen, Clearwater, Flo

/pdf/diagnostic-and-therapeutic-challenges-3ami9htzlk.pdf

Diagnostic and therapeutic challenges.

Macular and cone/cone-rod dystrophies (MD/CCRD) demonstrate a broad genetic and phenotypic heterogeneity, with retinal alterations solely or predominantly involving the central retina. Targeted next-generation sequencing (NGS) is an efficient diagnostic tool for identifying mutations in patient with retinitis pigmentosa, which shows similar genetic heterogeneity. To detect the genetic causes of disease in patients with MD/CCRD, we implemented a two-tier procedure consisting of Sanger sequencing and targeted NGS including genes associated with clinically overlapping conditions. Disease-causing mutations were identified in 74% of 251 consecutive MD/CCRD patients (33% of the variants were novel). Mutations in ABCA4, PRPH2 and BEST1 accounted for 57% of disease cases. Further mutations were identified in CDHR1, GUCY2D, PROM1, CRX, GUCA1A, CERKL, MT-TL1, KIF11, RP1L1, MERTK, RDH5, CDH3, C1QTNF5, CRB1, JAG1, DRAM2, POC1B, NPHP1 and RPGR. We provide detailed illustrations of rare phenotypes, including autofluorescence and optical coherence tomography imaging. Targeted NGS also identified six potential novel genotype-phenotype correlations for FAM161A, INPP5E, MERTK, FBLN5, SEMA4A and IMPDH1. Clinical reassessment of genetically unsolved patients revealed subgroups with similar retinal phenotype, indicating a common molecular disease cause in each subgroup.

/pdf/clinical-and-genetic-characteristics-of-251-consecutive-4mcov0tpqm.pdf

Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy

Ocular abnormalities in Alagille syndrome

Sir, There have now been a number of reports highlighting the association between adenocarcinoma of the breast and meningioma.1-3 Breast cancer is the commonest fatal malignant neoplasm of women,4 and meningioma is one of the commoner intracranial tumours, accounting for 19% of all central nervous system tumours.2 Carcinoma of the breast is also the second commonest source of intracranial metastases (after carcinoma of the bronchus)3 and the most frequent source of choroidal metastases.5'6 We present a patient with advanced carcinoma of the breast whose signs of intracranial mass with cranial nerve involvement were initially ascribed to a metastasis but subsequently found to be due to a meningioma. Detailed ophthalmic examination revealed the presence of an associated choroidal metastasis. Case Report A 71-year-old woman with known disseminated adenocarcinoma of the breast was referred to the eye unit by the radiotherapy department with a short history of diplopia. She had initially presented 5 years earlier with a large fungating tumour of the right breast and had subsequently received several courses of chemotherapy and radiotherapy for her metastatic disease, which included multiple bony secondaries and malignant pleural and pericardial effusions. Her initial symptoms consisted of migrainous headaches in the morning, 'trouble focusing' and photopsia in the left eye. Two weeks later she developed diplopia on upgaze and was referred for ophthalmic assessment. Her vision was 6/6 in both eyes but she had a mild left ptosis, an enlarged and unresponsive left pupil and a small left hypotropia (7A) and exotropia (5A). Elevation of the left eye was limited, particularly in abduction. A Hess chart confirmed this and also revealed a small limitation of adduction supporting the clinical diagnosis of a partial third nerve palsy (Fig. 1). On dilated funduscopy, a pale elevated lesion approximately 3 disc diameters in size with indistinct borders was noted inferonasal to the optic disc in the left eye (Fig. 2). Fluorescein angiography (Fig. 3) showed a diffuse leak and this lesion was thought to be a choroidal metastatic deposit with an overlying serous retinal detachment. An initial computed tomography (CT) scan of the head revealed a suspicious area adjacent to the pituitary which was thought to represent a secondary deposit. However, whilst the bone scan showed secondaries in the vault, there were no 'hot-spots' in the orbit or base of the skull. Therefore, a repeat CT scan with contrast was performed which showed a well-defined, hyperdense mass which enhanced uniformly, characteristic of a meningioma of the right sphenoidal ridge (Figs. 4, 5). Soon after the onset of diplopia, the patient also required decarubicin and then 3-M (mitomycin C, mitosantrone and methotrexate) chemotherapy as well as radiotherapy for progressive local and metastatic breast carcinoma. In the ensuing months her ophthalmoplegia remained stable and her ocular symptoms were satisfactorily controlled by a Fresnel prism alone. During this time there was no clinically obvious progression of the left choroidal metastasis. Unfortunately, her general condition continued to deteriorate and she died in a hospice 19 months after the onset of her eye problems. Discussion The unusually high rate of coexistence of breast carcinoma and intracranial meningioma was first reported by Schoenberg et al. in 19751 and since then a number of case reports have supported this.2'3'7-9 It has been postulated that the link between the two neoplasms is a sensitivity to female sex hormones. The risk of developing breast cancer is known to be influenced by circulating levels of free oestradiol10 and the presence of active oestrogen receptors is used as a guide to the likely responsiveness of the tumour to hormonal therapy.11 There are a number of persuasive reasons to believe that meningiomas are under hormonal influence. There is a female preponderance (women constitute two-thirds of patients with intracranial meningiomas)212 and there are several published reports of the symptoms and the size of meningiomas being reversibly increased in pregnancy and during the follicular phase of the menstrual cycle.13-15 The risk of meningioma is reduced in postmenopausal women16 but is increased in severe obesity where oestrogen levels are raised.11 Finally, the presence of oestrogen and progesterone receptors within tumour tissue has been documented '12 and there is preliminary evidence that hormonal therapy may be helpful in the treatment of meningiomas.17 However, this theory is by no means universally accepted as there is evidence that the changes in meningioma size in pregnancy are related to alterations in water content or vascularity rather than a true increase in tumour mass.15 In addition, many studies have failed to show significant oestrogen receptor numbers and activity in meningioma tissue18'19 or any growth modulation with hormonal treatment.20 This case illustrates several important issues in the investigation and management of neurological or visual symptoms in patients with a history of carcinoma of the breast. Firstly, the assumption that an intracranial mass lesion equates with a cerebral secondary may not always be correct, particularly if there is no other evidence of disseminated carcinoma. Relatively benign or treatable space-occupying lesions, such as chronic sub-dural haematoma and astrocytoma,8 as well as meningioma, need to be excluded by investigations such as CT with contrast, angiography and magnetic resonance imaging (MRI). Meningiomas have a characteristic appearance on CT, being well-defined, high-density and homogeneously enhancing lesions found in characteristic locations, whereas metastases show poor definition, low density, marked perilesional oedema and non-homogeneous enhancement.9 Meningiomas are potentially curable by surgery alone and may not be responsive to the radiotherapy which would be instigated for the treatment of metastases.21 It should be noted that the appearance of multiple intracranial masses does not exclude the diagnosis of coexistent meningiomata since they are multiple in 10% of cases.3 Secondly, patients with a history of neoplastic disease, particularly of the breast or bronchus, who develop visual symptoms should have a complete ophthalmic examination. In this particular case, an assessment of the ocular motility alone would have missed the choroidal metastasis. In retrospect the history of photopsia before the onset of diplopia may have been caused by the choroidal lesion and perhaps should have prompted an earlier ophthal-mological referral, although the outcome would not have been affected in this patient. A high index of suspicion coupled with a thorough ophthalmic examination including dilated funduscopy may reveal choroidal secondaries which can be the first sign of disseminated diseases6'22 and indeed may even be noted before the primary tumour is diagnosed.23'24 Choroidal metastases are usually radiosensitive and palliative treatment can improve the vision by shrinking the lesion and promoting absorption of subretinal fluid.24'25 Such treatment may prevent further ophthalmic complications and improve the patient's quality of life during a terminal illness.

/pdf/the-eye-and-adenocarcinoma-of-the-breast-metastases-and-5mux5c8ak7.pdf

The eye and adenocarcinoma of the breast: Metastases and meningiomas

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Ocular abnormalities in Alagille syndrome

The eye and adenocarcinoma of the breast: Metastases and meningiomas