Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy.

Eukaryotic initiation factor-4A2 (EIF4A2) is an ATP-dependent RNA helicase and a member of the DEAD-box protein family that recognizes the 5' cap structure of mRNAs, allows mRNA to bind to the ribosome, and plays an important role in microRNA-regulated gene repression. Here, we report on 15 individuals from 14 families presenting with global developmental delay, intellectual disability, hypotonia, epilepsy, and structural brain anomalies, all of whom have extremely rare de novo mono-allelic or inherited bi-allelic variants in EIF4A2. Neurodegeneration was predominantly reported in individuals with bi-allelic variants. Molecular modeling predicts these variants would perturb structural interactions in key protein domains. To determine the pathogenicity of the EIF4A2 variants in vivo, we examined the mono-allelic variants in Drosophila melanogaster (fruit fly) and identified variant-specific behavioral and developmental defects. The fruit fly homolog of EIF4A2 is eIF4A, a negative regulator of decapentaplegic (dpp) signaling that regulates embryo patterning, eye and wing morphogenesis, and stem cell identity determination. Our loss-of-function (LOF) rescue assay demonstrated a pupal lethality phenotype induced by loss of eIF4A, which was fully rescued with human EIF4A2 wild-type (WT) cDNA expression. In comparison, the EIF4A2 variant cDNAs failed or incompletely rescued the lethality. Overall, our findings reveal that EIF4A2 variants cause a genetic neurodevelopmental syndrome with both LOF and gain of function as underlying mechanisms.

Pathogenic variants in CDH11 impair cell adhesion and cause Teebi hypertelorism syndrome.

Teebi hypertelorism syndrome (THS; OMIM 145420) is a rare craniofacial disorder characterized by hypertelorism, prominent forehead, short nose with broad or depressed nasal root. Some cases of THS have been attributed to SPECC1L variants. Homozygous variants in CDH11 truncating the transmembrane and intracellular domains have been implicated in Elsahy-Waters syndrome (EWS; OMIM 211380) with hypertelorism. We report THS due to CDH11 heterozygous missense variants on 19 subjects from 9 families. All affected residues in the extracellular region of Cadherin-11 (CHD11) are highly conserved across vertebrate species and classical cadherins. Six of the variants that cluster around the EC2-EC3 and EC3-EC4 linker regions are predicted to affect Ca2+ binding that is required for cadherin stability. Two of the additional variants [c.164G > C, p.(Trp55Ser) and c.418G > A, p.(Glu140Lys)] are also notable as they are predicted to directly affect trans-homodimer formation. Immunohistochemical study demonstrates that CDH11 is strongly expressed in human facial mesenchyme. Using multiple functional assays, we show that five variants from the EC1, EC2-EC3 linker, and EC3 regions significantly reduced the cell-substrate trans adhesion activity and one variant from EC3-EC4 linker results in changes in cell morphology, focal adhesion, and migration, suggesting dominant negative effect. Characteristic features in this cohort included depressed nasal root, cardiac and umbilical defects. These features distinguished this phenotype from that seen in SPECC1L-related hypertelorism syndrome and CDH11-related EWS. Our results demonstrate heterozygous variants in CDH11, which decrease cell-cell adhesion and increase cell migratory behavior, cause a form of THS, as termed CDH11-related THS.

Mitochondrial Disorder: Maternally Inherited Diabetes and Deafness.

Patients with maternally inherited diabetes and deafness (MIDD) have insulin-dependent diabetes with relatively low BMI; usually the onset of the diabetes is during the third or fourth decade of life and it is associated with progressive neurosensory deafness. The fundus shows circumferentially oriented but discontinuous patches of RPE and choriocapillaris (CC) atrophy around the macula, within the arcades (Figs. 31.1 and 31.2). Sometimes even hyperpigmentation can be seen, also around the optic nerve, or pattern-like dystrophy may occur. Vision is usually good, about 20/40 or better. Fundus autofluorescence (FAF) shows decreased AF in the areas of RPE atrophy, surrounded by a zone of speckled AF. No generalized retinal dysfunction is seen on full-field electroretinography (ERG), but pattern ERG or multifocal ERG shows abnormal function. Asymptomatic maternal relatives harboring the mutation may show pigmentary changes, hearing loss, and in some, diabetes. Another disorder associated with the same A3243G mitochondrial DNA (mtDNA) mutation as MIDD is Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes (MELAS). The stroke-like episode (such as hemiplegia) occurs at about 5-15 years of age, and severe encephalopathy may cause death at a young age. Patients may also experience headache, vomiting, visual field defects, or cortical blindness.

Ciliopathy: Bardet-Biedl Syndrome.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disease with a prevalence of about 1/125,000. The syndrome involves mixed rod-cone dystrophy (which becomes obvious by 6 years of age). About two thirds of patients have postaxial polydactyly, and sometimes syndactyly, brachydactyly, and/or clinodactyly may be present. Hypogonadism and renal involvement occur in about 40%, mental retardation in about 50%, and truncal obesity in about 70%; it is present early, along with insulin resistance, type 2 diabetes, dyslipidemia, and hypertension. Vision becomes markedly impaired by about age 30 years. The BBS is genetically heterogeneous entity with considerable phenotypic variability. Other associated problems include CNS-related ataxia, abnormal gait, and facial hypotonia, as well as anomalies such as high palate, hearing loss, and cardiac malformations. In males, there is oligospermia, leading to infertility. Around 50–80% of BBS patients have renal malformations (like cyst, agenesis or scarring) and renal dysfunction leading to end-stage renal disease. There are no pigmentary changes before the age of 1–2 years. Later, subtle pigmentary changes appear in the macula or peripapillary area. Several years later, pigments appear in the equatorial region, along with attenuation of retinal blood vessels and waxy pallor of the optic disc. Eventually, the macula may show atrophic changes (Figs. 33.1, 33.2 and 33.3). Electroretinography (ERG) shows involvement of rods and cones and is abnormal even before the fundus shows changes. A perimacular hyperfluorescent ring can be seen.

Ciliopathy: Senior-Løken Syndrome.

Senior-Løken syndrome is a rare autosomal recessive disease with a prevalence of 1:1,000,000. Retinopathy may progress as Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), or sector RP (Figs. 34.1 and 34.2). Onset of photophobia, nystagmus, and hyperopia can occur in the first few years of life or later in childhood. Patients experience nephronophthisis, characterized by cystic kidney disease (medullary cystic kidney disease), reduced concentrating ability, and chronic tubulointerstitial nephritis, which progresses to end-stage renal disease. Hypertension is common.

Mitochondrial Disorder: Kearns-Sayre Syndrome.

Mitochondrial diseases are multisystem disorders: anemia, myopathy, lactic acidosis, CNS abnormality, endocrine abnormalities, renal disease, sensorineural deafness, and retinal involvement. The clinical abnormalities are heterogeneous, and they usually begin in childhood. Premature death occurs because of cardiac conduction defects. The onset is usually before 20 years of age. The fundus shows pigmentary retinopathy, with a salt-and-pepper appearance (Fig. 30.1), but vision remains good in most patients. Systemic involvement includes chronic progressive external ophthalmoplegia (CPEO), with ptosis being the most common complaint, and cardiomyopathy. Other variable features are short stature; cerebellar symptoms; weakness of muscles of the face, pharynx, trunk, or extremities; and progressive hearing loss. Full-field ERG does show evidence of generalized retinal dysfunction, involving both rods and cones. Skeletal muscle biopsy shows ragged red fibers and abnormal mitochondria.

Ciliopathy: Alström Syndrome.

Alström syndrome is an autosomal recessive disease with multisystem involvement, including cone-rod dystrophy, hearing loss, type 2 diabetes, insulin resistance with hyperinsulinemia, dilated cardiomyopathy, and progressive hepatic and renal failure. Patients present in childhood with photophobia and nystagmus, and mimic Leber congenital amaurosis (LCA). The fundus shows pigmentary retinopathy with peau d'orange appearance and some fine white dots like drusen around the macula; the disc is pale, with attenuated retinal vessels (Fig. 35.1). Patients have short stature; boys have hypogonadotropic hypogonadism and girls have polycystic ovary syndrome (PCOS). Obesity is always present, with markedly increased triglyceride and VLDL-C levels; arterial hypertension is diagnosed as early as 2 years of age. There is no polydactyly or syndactyly. About half have developmental delay, but intelligence is usually normal.

Ciliopathy: Sjögren-Larsson Syndrome.

Glistening yellow-white crystalline inclusions in foveal and parafoveal areas are almost pathognomonic (Fig. 36.1). These inclusions are evident at 1-2 years old and increase with age. Patients may have corneal stromal opacities, punctate keratitis, myopia, and astigmatism. About 50% have pigmentary degeneration of the retina, with decreased visual acuity and marked photophobia. Patients have dry, scaly skin (ichthyosis). Affected infants tend to be born prematurely. They also have neurological problems due to leukoencephalopathy (affecting the white matter of the brain). Intellectual disability varies from mild to severe, along with dysarthria and delayed speech.

Ciliopathy: Usher Syndrome.

Ciliopathies are a group of disorders caused by a defect in ciliogenesis, ciliary protein trafficking. Because nearly every cell in the body (including the photoreceptors) contains cilia, defects in ciliary proteins typically affect multiple organ systems. Usher syndrome is the most common syndromic cause of retinitis pigmentosa (RP) and accounts for 10-20% of cases of RP Inheritance is autosomal recessive, and the retinal dystrophy is usually rod-cone dystrophy (Figs. 32.1 and 32.2). These patients have RP with sensorineural hearing loss (partial or complete) since birth; some may have vestibular dysfunction. Most patients retain central vision of about 20/40 until about age 40. Usher Syndrome 1 (USH1): Profound congenital sensorineural hearing loss on audiometry, absent vestibular function, and typical RP (onset by 10 years of age); accounts for about 70% of all Usher cases. Patient may benefit from a cochlear implant. The retinitis pigmentosa occurs at an early age (childhood onset) and progress slowly. Usher Syndrome 2 (USH2): Moderate to severe congenital sensorineural hearing loss on audiometry (predominantly for higher frequencies), normal vestibular function, and typical RP (onset by 20 years of age); accounts for about 26% of all Usher cases. Usher Syndrome 3 (USH3): Progressive sensorineural hearing loss and typical RP (onset in second decade); accounts for about 4% of all Usher cases. Vestibular function is normal in about half of patients, but abnormal in the other half.

Inborn Errors of Metabolism: Gyrate Atrophy.

Gyrate atrophy is an autosomal recessive dystrophy in which night blindness starts early in the first decade of life. In the early stages, large areas of retinal pigment epithelium (RPE) and choriocapillaris (CC) atrophy in the far periphery (lobular shape, Fig. 37.1). (In choroideremia, atrophy appears in the mid periphery.) Later, these areas coalesce to form a characteristic scalloped border at the junction of healthy and diseased RPE. Myopia and subcapsular cataract are common by the end of second or third decade. Unlike in choroideremia (which is X-linked), patients with gyrate atrophy show areas of hyperpigmentation of the remaining RPE (Fig. 37.2). Patients with gyrate atrophy do not show the choroidal atrophy (as seen in choroideremia) until the late stages. Treatment includes a low-protein, arginine-restricted diet for all patients. In some cases, vitamin B6 (pyridoxine) may help in lowering plasma ornithine levels.

Incision and Curettage Versus Steroid Injection for the Treatment of Chalazia: A Meta-Analysis.

PURPOSE: To compare the efficacy of the chalazia treatment modalities of incision and curettage (I&C) and intralesional steroid injections (SI). METHODS: Full publications of randomized controlled trials that compared I&C with SI were identified. Aggregated success rate, weighted summary proportions, and weighted pooled relative risk for success were calculated for each method. RESULTS: Data were extracted from 8 publications that met these criteria, between 1984 and 2013. There were 288 patients treated by SI with aggregate success rate of 60.4% with 1 injection and 72.5% with 1 or 2 injections. The range of the success rate was 8.7 to 86.7% for 1 injection. The success rate for the second SI was 19.0%, with a range of 0% to 53.8%. There were 264 patients treated by I&C with a larger aggregate success rate of 78.0% with 1 procedure and 86.7% with 1 or 2 procedures (p < 0.05 for both comparisons). The range of the success rates was 60.0% to 92.0% for 1 I&C. The success rate for the second I&C was 90.65%, with a range of 83.3% to 100%. Compared with I&C, the overall relative risk for SI with 1 procedure was 0.77 (p = 0.05), while the overall relative risk for 1 or 2 procedures was 0.89 (p = 0.002). CONCLUSIONS: This analysis shows that I&C is more effective than SI with 1 procedure. This benefit is reduced when comparing 1 or 2 attempts of I&C and SI. Studies failed to show a difference in the incidence of complications with either procedure.