The eye
Angus Clarke, Alex Murray, Julian Sampson in Harper's Practical Genetic Counselling, 2019
Microphthalmos and anophthalmos constitute an extremely heterogeneous group. Unilateral cases are frequently non-genetic but cannot be securely distinguished from genetic forms. Rubella, toxoplasmosis, maternal thalidomide and other drug exposures are possible causes of bilateral disease. Mental retardation is frequently associated, and microphthalmos is a feature of several chromosomal defects as well as Mendelian syndromes. The X-linked Lenz syndrome of microphthalmos with cataract, mental retardation and digital and genitourinary abnormalities must be considered. Microphthalmos with coloboma is usually autosomal dominant (in the absence of known external causes) and is heterogeneous. Complete bilateral anophthalmia can be difficult to distinguish from extreme microphthalmos and may result from environmental factors. Cryptophthalmos, with absent palpebral fissures, may be part of the previously mentioned disorders, or may occur with relatively normal eye development, usually following autosomal recessive inheritance. Some cases are part of the more general Fraser syndrome (autosomal recessive), where renal agenesis and laryngeal atresia may be major features, and where a specific developmental gene defect is known.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow in Fetal and Perinatal Skeletal Dysplasias, 2012
Prenatal US features: Mild ventriculomegaly, mild cerebellar hypoplasia and dysplastic choroid plexus are early prenatal signs. Bilateral semicircular canal hypoplasia/ agenesis, and arhinencephaly may also be demonstrated on fetal MRI. The ears are low set, asymmetric with a small or absent lobe, posteriorly rotated and triangular or square shaped. Four-dimensional ultrasound of the ears may be helpful. Coloboma affecting the retina or the choroid segment are present. Microphthalmia may be seen. Choanal atresia and a cleft lip and/or palate may be present. Congenital heart defects include complex malformations, atrial and/or ventricular septal defects and malformations of the aortic arch. Congenital renal anomalies may be identified. There may be polyhydramnios.
Hyperthermia and Teratogenicity
Leopold J. Anghileri, Jacques Robert in Hyperthermia In Cancer Treatment, 2019
Fraser and Skelton69 studied case histories of 479 children with congenital malformations, cerebral palsy, mental retardation, or convulsive disorders. The presence or absence of febrile episodes during pregnancy had been recorded. In 36 cases, fever occurred during the first 5 months of gestation. Microphthalmia occurred significanly more often (p ⩽0.001) when fever was reported than when it was not. The authors concluded that the findings support the hypothesis that fever during pregnancy increases the probability of developmental disorders, particularly microphthalmia, in humans.
Aplasia of the Optic Nerve: A Report of Seven Cases
Published in Neuro-Ophthalmology, 2020
Yujia Zhou, Maura E. Ryan, Marilyn B. Mets, Hawke H. Yoon, Bahram Rahmani, Sudhi P. Kurup
ONA is typically associated with other ocular abnormalities1 as seen here, too (Table 1). All of our patients clinically demonstrated microphthalmia and various involvements of both anterior and posterior segments in their affected eye(s) (n = 7, 100%). Microphthalmia usually indicates anatomic alterations of the eye and is a feature of many ocular diseases.12 In Case 4, no pathogenic variant was detected in four genes known to cause microphthalmia, indicating that other genes, epigenetic, or environmental factors may be contributory.6 It has been suggested that ONA may be underdiagnosed in the setting of severe microphthalmia due to difficulties of examining the eyes via funduscopy.13 Anomalous retina, as seen in all of our patients (n = 7, 100%), is another prominent feature of ONA, which indicates a close relationship between the optic nerve and retinal development. Neovascularization of the posterior segment has been reported, which was attributed to retinal ischaemia.14 In contrast, the neovascularization of our patients occurred in the anterior segment (n = 2, 29%). Other common ocular features in our patients included persistent pupillary membrane (n = 4, 57%), coloboma (n = 3, 43%), cataract (n = 3, 43%), posterior synechiae (n = 3, 43%), corneal abnormalities (n = 2, 29%), and elevated IOP (n = 2, 29%).
Clinical diagnosis of presumed SOX2 gonadosomatic mosaicism
Published in Ophthalmic Genetics, 2021
Malena Daich Varela, Robert B. Hufnagel, Bin Guan, Delphine Blain, Julie C. Sapp, Andrea L. Gropman, Ramakrishna Alur, Jennifer J. Johnston, Leslie G. Biesecker, Brian P. Brooks
Microphthalmia (OMIM #309700) is a developmental malformation in which the eyes are small (axial length <20 mm). It can appear simple (also called pure or primary, where the eye is otherwise structurally normal) or complex (where it is combined with other ocular abnormalities, most frequently microcornea and coloboma) (1). It has an estimated prevalence of 1 per 7,000 live births (2). Up to 80% of the individuals with microphthalmia have a syndromic form, associated with non-ocular malformations (3). Microphthalmia is considered part of a larger phenotypic continuum (i.e., the Microphthalmia-Anophthalmia-Coloboma (MAC) spectrum), where the mildest end is represented by forme fruste coloboma. The latter can appear as pigment loss in the inferior quadrant of the iris (sectoral transillumination defects), atypical optic disc cupping, and/or mild, flat choroidal lesions along the six o’clock meridian (4,5). The etiology of most cases of MAC remains unknown, although environmental (infection, nutritional deficiency or drug intake during the first trimester of the pregnancy) and genetic causes have been described (6). Among the last, pathogenic variants in the transcription factor gene SOX2 have been reported as causative in 10–20% of the individuals with anophthalmia or severe microphthalmia, and in up to 40% of those affected bilaterally (7,8).
Identification of a novel de novo variant in OTX2 in a patient with congenital microphthalmia using targeted next-generation sequencing followed by prenatal diagnosis
Published in Ophthalmic Genetics, 2022
Maryam Rafati, Faezeh Mohamadhashem, Koosha Jalilian, Fatemeh Hoseininasab, Laya Fakhri, Azadeh Hoseini, Hosna Amiri, Zeinab Barati, Somayeh Darzi Ramandi, Nioosha Mostofinezhad, Amir Hosein Mahmoudi, Saeed Reza Ghaffari
Regarding the etiology of microphthalmia and anophthalmia, both environmental and genetic causes have been reported. The best known examples of the environmental causes, accounting for the minority of cases, consist of vitamin A deficiency, exposure to X-ray, solvent misuse, exposure to drugs such as thalidomide, as well as gestational acquired infections related to toxoplasmosis, rubella and cytomegalovirus. Genetic causes include chromosomal abnormalities, copy number variations and monogenic disorders (1,6,10). Currently A/M can be traced to a genetic cause in about 20–30% of cases; although this figure rises among cases of severe and/or bilateral A/M as well as in systemic/syndromic cases of A/M (7).
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