MYB insufficiency disrupts proteostasis in hematopoietic stem cells, leading to age-related neoplasia.

MYB plays a key role in gene regulation throughout the hematopoietic hierarchy and is critical for the maintenance of normal hematopoietic stem cells (HSC). Acquired genetic dysregulation of MYB is involved in the etiology of a number of leukemias, although inherited noncoding variants of the MYB gene are a susceptibility factor for many hematological conditions, including myeloproliferative neoplasms (MPN). The mechanisms that connect variations in MYB levels to disease predisposition, especially concerning age dependency in disease initiation, are completely unknown. Here, we describe a model of Myb insufficiency in mice that leads to MPN, myelodysplasia, and leukemia in later life, mirroring the age profile of equivalent human diseases. We show that this age dependency is intrinsic to HSC, involving a combination of an initial defective cellular state resulting from small effects on the expression of multiple genes and a progressive accumulation of further subtle changes. Similar to previous studies showing the importance of proteostasis in HSC maintenance, we observed altered proteasomal activity and elevated proliferation indicators, followed by elevated ribosome activity in young Myb-insufficient mice. We propose that these alterations combine to cause an imbalance in proteostasis, potentially creating a cellular milieu favoring disease initiation.

Glaucoma following Infant Lensectomy: 2021 Update.

PURPOSE: To review information pertaining to glaucoma following infant lensectomy surgery and to provide evidence to support the responsible mechanism of this condition. METHODS AND RESULTS: Described risk factors and proposed mechanisms for infantile aphakic glaucoma were assessed. The clinical evidence observed in affected glaucoma patients was analyzed, and evidence of postoperative anterior chamber fibrosis was reviewed and interpreted. CONCLUSION: The review and assessment of laboratory and clinical evidence support the proposal that infantile aphakic glaucoma is caused, in part, by postoperative anterior chamber fibroization related to lens cell dispersion and active epithelial-mesenchymal transition with resultant filtration angle tissue injury and loss of function.

Congenital Corneal Staphyloma: A Comprehensive Histopathologic Assessment Including Associated Anterior Segment Abnormalities.

Congenital corneal staphyloma is a rare congenital malformation with guarded visual potential. The cornea is opaque, markedly ectatic, and lined by uveal tissue with a variety of associated anterior segment abnormalities. In this case report, the detailed histopathology of this condition is highlighted with an unusual finding of the malformed lens. [J Pediatr Ophthalmol Strabismus. 2024;61(3):e28-e32.].

Case report: Extending the spectrum of clinical and molecular findings in FOXC1 haploinsufficiency syndrome.

FOXC1 is a ubiquitously expressed forkhead transcription factor that plays a critical role during early development. Germline pathogenic variants in FOXC1 are associated with anterior segment dysgenesis and Axenfeld-Rieger syndrome (ARS, #602482), an autosomal dominant condition with ophthalmologic anterior segment abnormalities, high risk for glaucoma and extraocular findings including distinctive facial features, as well as dental, skeletal, audiologic, and cardiac anomalies. De Hauwere syndrome is an ultrarare condition previously associated with 6p microdeletions and characterized by anterior segment dysgenesis, joint instability, short stature, hydrocephalus, and skeletal abnormalities. Here, we report clinical findings of two unrelated adult females with FOXC1 haploinsufficiency who have ARS and skeletal abnormalities. Final molecular diagnoses of both patients were achieved using genome sequencing. Patient 1 had a complex rearrangement involving a 4.9 kB deletion including FOXC1 coding region (Hg19; chr6:1,609,721-1,614,709), as well as a 7 MB inversion (Hg19; chr6:1,614,710-8,676,899) and a second deletion of 7.1 kb (Hg19; chr6:8,676,900-8,684,071). Patient 2 had a heterozygous single nucleotide deletion, resulting in a frameshift and a premature stop codon in FOXC1 (NM_001453.3): c.467del, p.(Pro156Argfs*25). Both individuals had moderate short stature, skeletal abnormalities, anterior segment dysgenesis, glaucoma, joint laxity, pes planovalgus, dental anomalies, hydrocephalus, distinctive facial features, and normal intelligence. Skeletal surveys revealed dolichospondyly, epiphyseal hypoplasia of femoral and humeral heads, dolichocephaly with frontal bossin gand gracile long bones. We conclude that haploinsufficiency of FOXC1 causes ARS and a broad spectrum of symptoms with variable expressivity that at its most severe end also includes a phenotype overlapping with De Hauwere syndrome.

Infantile Aphakic Glaucoma: A Proposed Mechanism.

PURPOSE: To review information pertaining to secondary glaucoma following infant lensectomy and provide evidence to support the mechanism responsible for this condition. METHODS: Reported risk factors and proposed mechanisms for infantile aphakic glaucoma are reviewed. Laboratory studies and clinical observations in affected patients with glaucoma are described. Evidence of postoperative anterior chamber fibrosis is reviewed and interpreted. RESULTS: Clinical evidence demonstrated the development of anterior chamber fibrosis following infant cataract surgery. Laboratory studies showed liberated lens epithelial cell transition to fibroblasts. CONCLUSIONS: The review and assessment of laboratory and clinical evidence support the proposal that infantile aphakic glaucoma is caused, in part, by postoperative anterior chamber fibroization related to lens cell dispersion, cytokine activation, and epithelial-mesenchymal transition with resultant filtration angle fibrosis and secondary loss of filtration function. [J Pediatr Ophthalmol Strabismus. 2022;59(4):236-242.].

Congenital pupillary-iris-lens membrane with goniodysgenesis: histopathologic findings in an enucleated eye.

A 10-year-old boy with clinically confirmed congenital pupillary-iris-lens membrane with goniodysgenesis underwent light microscopic examination of the enucleated eye. The anterior segment changes consisted of the absence of the iridial pupillary sphincter muscle and dilator muscle processes. Endothelialization and descemetization of the anterior chamber angle and the anterior surface of the iris covered the original eccentric pupillary opening (occlusio pupillae), but grew around the fibrotic edges of the surgically created, patent pseudopupil, probably secondary responses to surgery. The anterior chamber findings in this case establish a localized syndrome that includes absence of the pupillary sphincter and dilator muscle processes. Incomplete development of the iris may be partly attributable to an abnormality of stromal development and inductions by the anterior neuroectodermal layer, together with anomalies of the pupillo-iridial vasculature.

Failure of Goniosurgery for Glaucoma Associated With Sturge-Weber Syndrome.

PURPOSE: To report the surgical results of goniosurgery for children with glaucoma associated with Sturge-Weber syndrome. METHODS: Retrospective review of medical records of patients who had initial goniosurgery for glaucoma associated with Sturge-Weber syndrome. RESULTS: A total of 46 eyes of 42 patients who had glaucoma associated with Sturge-Weber syndrome and were treated with initial goniosurgery were identified to determine the efficacy of therapeutic goniotomy and trabeculotomy (goniosurgery). The average age at the time of goniosurgery was 1.5 years (range: 1 month to 23 years). Office intraocular pressure (IOP) measurements before goniosurgery were recorded in 76% of patients (32 of 42 patients) with an average measurement of 35 mm Hg (range: 25 to 50 mm Hg). The average interval to failure was 4 months (range: 1 to 48 months). Forty-six eyes underwent goniosurgery with a rate of failure of 98% (45 of 46 eyes) and a qualified success rate of 2% (1 of 46 eyes). Fifty-one goniotomy and 11 trabeculotomy procedures were performed. On gonioscopy, the filtration angles were all abnormal with variable width and visibility of the ciliary body band and less visible scleral spur. The trabecular meshwork was seen preoperatively in 100% of eyes (41 of 41 eyes) examined, all of which underwent goniosurgery. Five eyes underwent goniosurgery without documented gonioscopy. The ciliary body band was seen in 39% of eyes (16 of 41 eyes) and the scleral spur was visible in 10% of eyes (4 of 41 eyes). CONCLUSIONS: Goniosurgery is not an effective initial glaucoma surgery for glaucoma associated with Sturge-Weber syndrome. It can be used to temporize the IOP, but ultimately other forms of glaucoma surgery must be considered when indicated. [J Pediatr Ophthalmol Strabismus. 2020;57(6):384-387.].

Angle-closure glaucoma: the role of the lens in the pathogenesis, prevention, and treatment.

Primary angle-closure glaucoma is a major cause of blindness worldwide. It is a disease of ocular anatomy that is related to pupillary-block and angle-crowding mechanisms of filtration angle closure. Eyes at increased risk for primary angle-closure are small with decreased axial length, anterior chamber depth, and filtration angle width, associated with a proportionately large lens. Angle-closure glaucoma afflicts Asian and Eskimo eyes more frequently than eyes in other races with similar predisposing dimensions. The treatment of primary angle closure addresses its causal mechanisms. Laser peripheral iridotomy equalizes the anterior and posterior pressures and widens the filtration angle by reducing the effect of pupillary block. Argon laser peripheral iridoplasty contracts the iris stroma to reduce angle crowding and is helpful for some affected eyes. Lensectomy dramatically widens the angle and eliminates pupillary block. Clinical reports of lensectomy with posterior chamber intraocular lens implantation in the treatment of acute, chronic, and secondary angle-closure glaucoma describe very favorable results. The appropriate role for lensectomy in the management of primary angle closure, however, remains unproven. Prospective, randomized clinical trials are ongoing to determine the value and comparative risks and efficacy of lensectomy versus medical therapy, laser peripheral iridotomy, laser iridoplasty, and filtration procedures for the treatment of acute and chronic primary angle closure and for the prevention of chronic angle-closure glaucoma, both after and in place of laser peripheral iridotomy.

Optic neuropathy in a patient with pyruvate dehydrogenase deficiency.

Pyruvate dehydrogenase (PDH) deficiency is a genetic disorder of mitochondrial metabolism. The clinical manifestations range from severe neonatal lactic acidosis to chronic neurodegeneration. Optic neuropathy is an uncommon clinical sequela and the imaging findings of optic neuropathy in these patients have not previously been described. We present a patient with PDH deficiency with bilateral decreased vision in whom MRI demonstrated bilateral optic neuropathy and chiasmopathy.

The spontaneous resolution of primary congenital glaucoma.

PURPOSE: To describe the ocular findings in a series of children with spontaneous resolution of primary congenital glaucoma (PCG). METHODS: The medical records of 356 patients with PCG were reviewed. Nine patients with spontaneous resolution of PCG were studied. Fourteen of 18 eyes possessed evidence of early glaucoma, were found to have normal intraocular pressures, and were clinically classified as having spontaneous resolution of PCG. None of the eyes with spontaneous resolution received surgery or any glaucoma medication. RESULTS: Spontaneous resolution of PCG in all nine patients was recognized after 4 months of age. At the time of diagnosis, large corneas were observed in all affected eyes and Haab's striae in 10 of 14 eyes. Intraocular pressures were normal in 14 eyes. In all 14 eyes, the anterior chambers were deep, the lenses were clear, and the angles were abnormal with the typical appearance of PCG. The eyes with spontaneous resolution of PCG possessed angle abnormalities that were less severe compared to three fellow eyes that required glaucoma treatments. CONCLUSION: The occurrence of spontaneous resolution of PCG in these patients is supported by objective clinical evidence. The explanation for this spontaneous resolution is unknown. Its mechanism could be related to continued postnatal development of the angle structures in eyes possessing milder angle abnormalities. The anterior segment findings in patients with spontaneous resolution of PCG are similar to those of patients with treated PCG, the intraocular pressures are normal, the optic nerve damage is stable, and the filtration angles possess mild or moderate abnormalities.

Corneal anomalies in newborn primary congenital glaucoma.

This report describes the corneal pathology in an infant with newborn primary congenital glaucoma and discusses whether these findings could be due to a developmental anomaly. The corneal specimen of a 4-month-old infant with newborn primary congenital glaucoma and cloudy corneas who had undergone penetrating keratoplasty was evaluated by light and electron microscopy. Light microscopy showed a thinned epithelium, areas of thickened Bowman's layer (approximately 27 mum thick) interspersed with nuclei, and a thickened and disorganized stroma. Descemet's membrane was intact, and the endothelium was mildly attenuated. The corneal changes seen in this patient may be specific to primary congenital glaucoma and may contribute to the corneal clouding seen so frequently in these patients.

Dependence on Myb expression is attenuated in myeloid leukaemia with N-terminal CEBPA mutations.

Mutations at the N- or C-terminus of C/EBPα are frequent in acute myeloid leukaemia (AML) with normal karyotype. Here, we investigate the role of the transcription factor Myb in AMLs driven by different combinations of CEBPA mutations. Using knockdown of Myb in murine cell lines modelling the spectrum of CEBPA mutations, we show that the effect of reduced Myb depends on the mutational status of the two Cebpa alleles. Importantly, Myb knockdown fails to override the block in myeloid differentiation in cells with biallelic N-terminal C/EBPα mutations, demonstrating for the first time that the dependency on Myb is much lower in AML with this mutational profile. By comparing gene expression following Myb knockdown and chromatin immunoprecipitation sequencing data for the binding of C/EBPα isoforms, we provide evidence for a functional cooperation between C/EBPα and Myb in the maintenance of AML. This co-dependency breaks down when both alleles of CEBPA harbour N-terminal mutations, as a subset of C/EBPα-regulated genes only bind the short p30 C/EBPα isoform and, unlike other C/EBPα-regulated genes, do so without a requirement for Myb.

Prognostic significance of high GFI1 expression in AML of normal karyotype and its association with a FLT3-ITD signature.

Growth Factor Independence 1 (GFI1) is a transcriptional repressor that plays a critical role during both myeloid and lymphoid haematopoietic lineage commitment. Several studies have demonstrated the involvement of GFI1 in haematological malignancies and have suggested that low expression of GFI1 is a negative indicator of disease progression for both myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). In this study, we have stratified AML patients into those defined as having a normal karyotype (CN-AML). Unlike the overall pattern in AML, those patients with CN-AML have a poorer survival rate when GFI1 expression is high. In this group, high GFI1 expression is paralleled by higher FLT3 expression, and, even when the FLT3 gene is not mutated, exhibit a FLT3-ITD signature of gene expression. Knock-down of GFI1 expression in the human AML Fujioka cell line led to a decrease in the level of FLT3 RNA and protein and to the down regulation of FLT3-ITD signature genes, thus linking two major prognostic indicators for AML.

Anterior axial lens subluxation, progressive myopia, and angle-closure glaucoma: recognition and treatment of atypical presentation of ectopia lentis.

PURPOSE: To describe the clinical features of an atypical presentation of ectopia lentis consisting of primary anterior axial lens subluxation in childhood, associated progressive myopia, and complicating angle-closure glaucoma; to facilitate early diagnosis of this triad; and to report the results of lensectomy for treatment. METHODS: A retrospective case review of eight patients. Clinical course, visual acuity, gonioscopy, axial length, refraction, fundus examination, associated systemic features, and results of treatment are provided. RESULTS: This subgroup of patients with ectopia lentis is at risk for progressive, synechial, angle-closure glaucoma. Identification of a clinical triad consisting of rapidly increasing myopia, normal axial length, and progressive axial subluxation leads to earlier diagnosis. Prophylactic lensectomy provides a safe and sight-saving treatment that arrests and, at times, reverses the progression of angle-closure glaucoma. CONCLUSIONS: Ectopia lentis with anterior axial subluxation and progressive myopia can be a sight-threatening condition when significant forward mobilization of the lens results in synechial angle-closure glaucoma. Recognition of this clinical entity can expedite diagnosis and prevent irreversible loss of vision secondary to glaucoma. Because the primary mechanism of angle closure is angle crowding, peripheral iridotomy does little to control the rise in intraocular pressure. Prophylactic lensectomy has proven to be the most reliable treatment in our experience.

Infantile glaucoma associated with cranio-cerebello-cardiac syndrome.

We report the second case of infantile glaucoma associated with cranio-cerebello-cardiac (3C) syndrome. An infant with systemic features consistent with 3C syndrome presented with glaucoma and underwent a goniotomy for each eye. Patients with 3C syndrome should be evaluated for glaucoma.

Risk factors for the development of aphakic glaucoma after congenital cataract surgery.

BACKGROUND: It is well-known that lensectomy surgery during the first year of life increases one's risk of aphakic glaucoma. However, it is controversial whether there is a specific time period during the first year of life after which performing lensectomy surgery has a lower risk of aphakic glaucoma development. PATIENTS AND METHODS: A retrospective chart review was performed of all patients seen by a pediatric glaucoma specialist from 1970 to 2003. Patients were included in the study if they underwent congenital cataract surgery. Cataracts were defined as congenital if they were identified within the first 6 months of life, were dominantly inherited, or were of the lamellar type. Aphakic glaucoma was defined as having repeated intraocular pressures > 25 mm Hg after congenital cataract surgery. Patients were excluded if they had any conditions that were independently associated with glaucoma. RESULTS: A total of 368 eyes of 258 patients were included in the study. Of these, 216 (58.7%) eyes of 150 patients developed aphakic glaucoma. Risk factors of greatest significance (P < .0001) included having lensectomy within the first year of life and the development of postoperative complications. CONCLUSIONS: No specific age for lensectomy during the first year of life was associated with a decreased risk for development of aphakic glaucoma. Surgery for congenital cataracts should not be delayed if the only reason for delay is to prevent the development of aphakic glaucoma.

Glaucoma with the oculocerebrorenal syndrome of Lowe.

PURPOSE: To further describe the glaucoma with the oculocerebrorenal syndrome of Lowe (OCRL) including the responsible filtration angle abnormalities and response to treatment. METHODS: The scientific literature regarding the glaucoma associated with OCRL from 1952, when the first report of the syndrome appeared, to the present was reviewed. The medical records of 7 patients with OCRL were studied. The occurrence of glaucoma, corneal changes secondary to glaucoma, gonioscopic abnormalities, iris features, and response to glaucoma surgery were recorded. RESULTS: Signs of glaucoma are defining abnormalities leading to recognition of OCRL. The OCRL medical literature reports the frequency of glaucoma, secondary clinical signs of increased intraocular pressure (IOP), and results of glaucoma surgery, but little information related to the responsible filtration angle abnormalities. Glaucoma was present in 71% (5 of 7) of patients studied, and was recognized in infancy in 9 of their 10 eyes. Gonioscopy was performed in 6 OCRL patients and revealed the constant presence of open angles, primary filtration angle anomalies, and defects considered secondary to previous infantile lens extractions. The observed anomalies were anterior insertion of the iris, narrowing of the ciliary body band, and decreased visibility of the scleral spur. The angle defects felt to be acquired following lens surgery included a more anterior insertion of the iris on to the trabecular meshwork, pigment dusting of the angle tissues, and iris synechial abnormalities related to the surgery. Bilateral goniotomies were unsuccessful in 4 of 4 patients. The fundi of 6 of 7 patients showed normal optic disc development with variable abnormalities secondary to glaucoma, and normal retinal vessels. Minimal evidence of macular development was observed in a single patient from 1 month of age to his most recent examination at 14 months of age. CONCLUSION: A primary X-linked infantile glaucoma is a defining and frequent component of OCRL and is secondary to expression of a primary filtration angle anomaly. Goniotomy was unsuccessful in all (8) operated eyes. The adverse effects of cataract surgery on the filtration angle structures may influence the results of goniotomy surgery by superimposing a secondary aphakic glaucoma component that may explain the need for alternative glaucoma surgery.

Complications of pediatric lensectomy in 193 eyes.

BACKGROUND AND OBJECTIVE: To better define late complications and long-term visual outcomes associated with lensectomy surgery for pediatric cataracts. PATIENTS AND METHODS: Retrospective review of all patients seen by a pediatric ophthalmologist from 1970 to 2002. Patients were seen at a university-based clinical practice setting. This study defines the incidence of late post-lensectomy complications. Final long-term visual acuities were correlated with specific surgical complications and ocular and systemic anomalies. RESULTS: There were 193 eyes of 138 patients who had lensectomy for pediatric cataracts. The average follow-up time was 10.8 +/- 6.7 years (range, 3 months to 31.3 years). The most common postoperative complication was aphakic glaucoma (20.2%) at an average of 3.4 +/- 3.7 years after lensectomy surgery. At last follow-up, the median visual acuity was 20/40 in eyes without complications and 20/80 in eyes with complications. CONCLUSIONS: Aphakic glaucoma was the most common postoperative complication (20.2%). Most eyes with associated ocular and systemic anomalies and postoperative complications have poorer visual outcomes.

Glaucoma in retinoblastoma.

The association between retinoblastoma and secondary glaucoma is well known. The most common cause of secondary glaucoma in retinoblastoma is iris neovascularization (NVI) followed by pupillary block and tumor seeding of the anterior chamber. Although glaucoma is a secondary clinical issue in retinoblastoma (RB) management and care, awareness of its presence, revealed by a thorough ocular exam of the anterior segment, can guide the clinician in assessing the overall condition of the affected eye.