The Descemet Membrane in Primary Congenital Glaucoma.

PURPOSE: To evaluate Descemet membrane (DM) morphology in eyes with primary congenital glaucoma (PCG) in vivo using high-definition anterior segment optical coherence tomography (ASOCT) and on histopathology. METHODS: Corneal scans of patients with PCG (22 eyes of 15 patients) were evaluated for DM morphology and anterior chamber angle using ASOCT. The DM thickness in PCG eyes was compared with fellow eyes (8 eyes) of unilateral patients with PCG and healthy controls (12 eyes) on ASOCT. The DM morphology was also compared on the histopathology of corneal tissues (9) obtained from PCG eyes after keratoplasty and enucleated eyes of retinoblastoma (6 controls) on light microscopy with immunostaining for collagen IV. RESULTS: On ASOCT, all affected eyes showed the presence of either a thickened DM complex or a hyper-reflective double layer representing the thickened DM and pre-Descemet layer (PDL), unlike a single membrane in the controls and fellow eyes. On ASOCT, among patients with PCG, the DM showed significant thickening (32.0 ± 11.2 µm) versus fellow eyes (14.4 ± 3.3 µm) and controls (11.5 ± 1 µm) (P < 0.001; analysis of variance). The thickened DM complex continued peripherally into the trabecular meshwork as an abnormal membrane in 16/22 affected eyes. On histopathology, thickening of DM was also more among PCG eyes (median: 67.9 µm range: 27.2-214.9) versus controls (median: 27.7 µm, range: 22.1-36.1; P = 0.005) as also of PDL (median: 14 µm, range: 5.9-30.5) of PCG versus (median 3.5, range: 1.3-6.7 µm) in controls; P = 0.014. CONCLUSIONS: Thickening of DM and PDL occurs in eyes with PCG and is seen to have a peripheral extension upto the angle recess.

Iridotrabecular contact observed using anterior segment three-dimensional OCT in eyes with a shallow peripheral anterior chamber.

PURPOSE: To evaluate the prevalence and range of iridotrabecular contact (ITC) in eyes with a shallow peripheral anterior chamber (AC) by using anterior segment swept-source optical coherence tomography (AS-SS-OCT) and to compare the results with those obtained with ultrasound biomicroscopy (UBM) and gonioscopy. METHODS: Forty-three shallow peripheral AC eyes in 43 consecutive patients underwent gonioscopy. Cross-sectional images throughout the angle circumference (i.e., 360°) were obtained with AS-SS-OCT (SS-1000 noncontact, noninvasive three-dimensional imaging system) and those of the peripheral AC at the 3, 6, 9, and 12 o'clock positions were obtained with UBM (UD-1000). RESULTS: ITC evaluated with AS-SS-OCT included all gonioscopically identified peripheral anterior synechia (PAS) in the area. With AS-SS-OCT, at least one ITC was found in 40 (93.0%) and 42 (97.7%) of the 43 eyes under light and dark conditions, respectively, whereas with UBM, at least one ITC was found in 22 (51.1%) and 36 (83.7%) of the 43 eyes under light and dark conditions. The prevalence of ITC in eyes with AS-SS-OCT was significantly higher than that with UBM under light conditions, but not under dark conditions (P = 0.0001, 0.07, respectively, sign test). The PAS-positive eyes had a significantly greater ITC range than the PAS-negative eyes under light conditions (P = 0.006), but not under dark conditions (P = 0.08). CONCLUSIONS: AS-SS-OCT detected all PAS and the prevalence of ITC detected by AS-SS-OCT in narrow angle eyes was markedly higher than previously thought. A relationship between the ITC range under light conditions and future PAS formation was suggested.

Genotype and phenotype correlations in congenital glaucoma: CYP1B1 mutations, goniodysgenesis, and clinical characteristics.

PURPOSE: To determine whether there is a correlation among mutations in the cytochrome P4501B1 gene (CYP1B1), the degree of angle dysgenesis observed histologically, and disease severity in congenital glaucoma. DESIGN: Interventional case series. METHODS: Direct DNA sequencing was used to screen six unrelated children with congenital glaucoma, each set of parents, and all siblings for CYP1B1 mutations. Specimens of the anterior chamber angle obtained at trabeculectomy were examined histologically to identify abnormalities of the aqueous outflow pathway. CYP1B1 mutations were correlated with both the degree of angle dysgenesis and the patients' disease severity (age at diagnosis, difficulty in achieving intraocular pressure [IOP]) control. RESULTS: Four (66.7%) of the six patients were compound heterozygotes for mutations in the CYP1B1 gene. Seven of the eight CYP1B1 mutations were identified, including two novel mutations (R117P, C209R) and five others previously described (G61E, R368H, R390H, E229K, 4340delG). The cases were divided on the basis of histological phenotype into categories of (1) severe goniodysgenesis highlighted by the agenesis of the canal of Schlemm (two patients), (2) moderate goniodysgenesis characterized by the presence of a band of collagenous tissue (CT) in the trabecular meshwork (TM) and/or the juxtacanalicular tissues (JXT) (three patients), and (3) mild goniodysgenesis with deposition of a mucopolysaccharide material in the JXT (one patient). CYP1B1 mutations were identified in both cases of severe angle dysgenesis and two of three cases of moderate dysgenesis. Disease severity closely correlated with the degree of angle dysgenesis. CONCLUSIONS: Most patients in our cohort had compound heterozygous CYP1B1 mutations. Specific CYP1B1 mutations may be associated with severe or moderate angle abnormalities.

[Congenital glaucoma and trabeculodysgenesis. Clinical and genetic aspects]. / Glaucomes congénitaux et trabéculodysgénésies: aspects cliniques et génétiques.

Congenital glaucoma is generally related to an iridocorneal angle malformation, with an obstacle to aqueous humor outflow. This spectrum of diseases can involve the angle, the iris and the cornea. The diagnosis relies on characteristic signs and is confirmed by an examination under general anaesthesia and paraclinical examinations (especially echography). An early diagnosis is essential for beginning surgical treatment. Several filtering surgery techniques with equivalent intraocular pressure results are available, but visual function must be protected in all cases. In many cases, genetic counseling relies on a careful clinical analysis and sometimes on a molecular analysis. A number of ocular and/or general abnormalities can be accompanied by glaucoma in infants and children. They must be screened in case of associated signs, but the existence of these abnormalities leads to suspicion of associated glaucoma.

Genotype and phenotype correlations in congenital glaucoma.

PURPOSE: To determine whether there is a correlation among mutations in the cytochrome P450 1B1 gene (CYP1B1), the degree of angle dysgenesis observed histologically, and disease severity in congenital glaucoma. METHODS: Direct DNA sequencing was utilized to screen six unrelated children with congenital glaucoma, each set of parents, and all siblings for CYP1B1 mutations. Specimens of the anterior chamber angle obtained at trabeculectomy were examined histologically to identify abnormalities of the aqueous outflow pathway. CYP1B1 mutations were correlated with both the degree of angle dysgenesis and the patient's disease severity (age at diagnosis, difficulty in achieving intraocular pressure control). RESULTS: Four of the six patients (66.7%) were compound heterozygotes for mutations in the CYP1B1 gene. Seven of the eight CYP1B1 mutations were identified, including two novel mutations (R117P, C209R) and five others previously described (G61E, R368H, R390H, E229K, 4340delG). The cases were divided based on histological phenotype into categories of (1) severe goniodysgenesis highlighted by the agenesis of Schlemm's canal (two patients), (2) moderate goniodysgenesis characterized by the presence of a band of collagenous tissue in the trabecular meshwork and/or the juxtacanalicular tissues (three patients), and (3) mild goniodysgenesis with deposition of a mucopolysaccharide material in the juxtacanalicular tissue (one patient). CYP1B1 mutations were identified in both cases of severe angle dysgenesis and two of three cases of moderate dysgenesis. Disease severity closely correlated with the degree of angle dysgenesis. CONCLUSION: The majority of cases in the cohort had compound heterozygous CYP1B1 mutations. Specific CYP1B1 mutations may be associated with severe or moderate angle abnormalities.

Congenital microcoria associated with late-onset developmental glaucoma.

PURPOSE: To demonstrate that developmental glaucoma (instead of the term goniodysgenetic glaucoma is used in this paper), defined as glaucoma with goniodysgenesis resulting from a fetal maldevelopment of the iridocorneal angle, develops in association with congenital microcoria. METHODS: Three subjects descended from a family with autosomal dominant congenital microcoria and goniodysgenesis were followed up for more than 25 years. RESULTS: The extended family consisted of 3 generations including 8 males and 10 females. In the second generation, 2 of 7 subjects who presented with a history of congenital microcoria had late-onset goniodysgenetic glaucoma. In the third generation, all 3 descendants of the second generation subjects with congenital microcoria had congenital microcoria with goniodysgenesis. Two of these subjects developed late-onset goniodysgenetic glaucoma in both eyes during the 25-years follow-up period. They were both treated with a trabeculectomy in both eyes to control the glaucoma. Histologically, the iridocorneal angle tissues from the patients showed thick juxtacanalicular connective tissue with accumulations of a basement membrane-like extracellular matrix. CONCLUSION: Congenital microcoria are considered to be frequently associated with the incidence of late-onset goniodysgenetic glaucoma.

Primary trabeculodysgenesis in association with neonatal Marfan syndrome.

We present the clinical and ophthalmological findings in two infants with neonatal Marfan syndrome (nMFS) and primary trabeculodysgenesis (PT). Fibrillin 1 (FBN1) mutations were confirmed in both cases. Numerous eye anomalies have been recognized in infants with nMFS, but PT has not been reported previously. Our report expands the phenotype of nMFS, and highlights the importance of early and careful ophthalmological assessment of these infants.

Modification of ocular defects in mouse developmental glaucoma models by tyrosinase.

Mutations in the cytochrome P450 family 1, subfamily B, polypeptide 1 (CYP1B1) gene are a common cause of human primary congenital glaucoma (PCG). Here we show that Cyp1b1-/- mice have ocular drainage structure abnormalities resembling those reported in human PCG patients. Using Cyp1b1-/- mice, we identified the tyrosinase gene (Tyr) as a modifier of the drainage structure phenotype, with Tyr deficiency increasing the magnitude of dysgenesis. The severe dysgenesis in eyes lacking both CYP1B1 and TYR was alleviated by administration of the tyrosinase product dihydroxyphenylalanine (l-dopa). Tyr also modified the drainage structure dysgenesis in mice with a mutant Foxc1 gene, which is also involved in PCG. These experiments raise the possibility that a tyrosinase/l-dopa pathway modifies human PCG, which could open new therapeutic avenues.

Infusion misdirection syndrome during trabeculectomy for primary trabeculodysgenesis.

PURPOSE: To report a case of infusion misdirection syndrome, simulating an intraoperative suprachoroidal hemorrhage, in an eye undergoing trabeculectomy for primary trabeculodysgenesis. METHODS: A 21-year-old woman underwent trabeculectomy for primary trabeculodysgenesis. Congenitally abnormal intraocular anatomy led to intraoperative and postoperative complications. RESULTS: Intraoperative anterior chamber irrigation was followed by vitreous prolapse. Eye pain, globe hardening, and shallowing of the anterior chamber were caused by infusion misdirection into the posterior segment. The eye was rapidly closed after a limited wound-site vitrectomy. Intraoperative and postoperative management led to a successful outcome. CONCLUSION: Altered intraocular anatomy set the stage for infusion misdirection syndrome, a rare but manageable complication that mimicked an expulsive suprachoroidal hemorrhage.

Late-onset unilateral primary developmental glaucoma associated with iridotrabecular dysgenesis, congenital ectropion uveae and thickened corneal nerves: a new neural crest syndrome?

The association of unilateral primary developmental glaucoma with iridotrabecular dysgenesis and congenital ectropion uveae has been well documented in the literature. The glaucoma in this entity may present at birth, infancy or may develop at a later stage in life. I report the case of a child with late-onset unilateral primary developmental glaucoma due to iridotrabecular dysgenesis, congenital ectropion uveae, and who had a previously undescribed association with ipsilateral thickened corneal nerves in the stroma.

CHARGE association with congenital glaucoma due to maldevelopment of the anterior chamber angle.

PURPOSE: We examined the clinicopathologic features of a male infant with the CHARGE association and bilateral congenital glaucoma. METHODS: Trabeculectomy specimens were obtained from the anterior chamber angle and examined by light and electron microscopy. RESULTS: Histopathologic examination of the trabeculectomy specimens showed immature development of the trabecular meshwork that was covered by the ciliary muscles. There were few intertrabecular spaces because the meshwork was almost completely filled with cells and extracellular substances. Deposition of a granular and/or homogeneous substance was observed in the subendothelial area of Schlemm's canal. CONCLUSIONS: Our patient exhibited features typical of the CHARGE association, but also had congenital glaucoma. We hypothesize that these clinical findings are all mediated by a neurocristopathic mechanism. Our findings suggest that the CHARGE association may predispose to anterior chamber angle maldevelopment, which can lead to congenital glaucoma.

Ultrastructural studies of primary congenital glaucoma in rabbits.

BACKGROUND: The cause of congenital glaucoma is unknown. METHODS: To determine whether the site of impaired aqueous outflow is the entrance to the trabecular meshwork (TM), within the TM, the aqueous drainage plexus, or a combination thereof, the process of TM development was examined by scanning and transmission electron microscopy on postnatal day 3 and weeks 1, 2, 3, 4, and 6 in New Zealand rabbits homozygous for the buphthalmic (bu/bu) gene compared with age-matched controls. RESULTS: Openings to the entrance of the TM in congenital glaucoma were observed, and there was no evidence of an endothelial membrane occluding aqueous flow to the TM. The morphology of the congenital glaucoma TM was abnormal in all bu/bu rabbits by 2 weeks and was characterized by a smaller entrance to the TM at the iris base, smaller intertrabecular openings within and between the trabecular lamellae, and at 6 weeks, iris pillars with extensive lateral extensions in the angle recess. Most intertrabecular spaces were open, however, the inner intertrabecular spaces adjacent to the aqueous plexus were compressed. CONCLUSION: These results suggest the development of congenital glaucoma, which involves a mutation in an autosomal recessive gene and leads to loss of function of a gene(s) required for the differentiation of the TM.

Autosomal dominant iridogoniodysgenesis anomaly maps to 6p25.

Autosomal dominant iridogoniodysgenesis anomaly (IGDA) is characterized by iris hypoplasia and goniodysgenesis with frequent juvenile glaucoma. IGDA is the result of aberrant migration or terminal induction of the neural crest cells involved in the formation of the anterior chamber of the eye. After eliminating candidate regions for other ocular disorders, a genome-wide scan for IGDA was performed using linkage analysis. Approximately 95% of the genome was excluded with >300 microsatellite markers before significant linkage was demonstrated between IGDA and chromosome 6 markers in two families. From haplotype analysis and identification of recombinants, the IGDA locus is mapped to an 8.3-cM interval distal to D6S477, at 6p25. Our linkage results are consistent with the ocular findings in rare cases of individuals with chromosomal anomalies involving deletions of 6p. This suggests that there is a major gene involved in eye anterior segment development at 6p25.

Efecto del etanol sobre la osificación membranosa en embriones de pollo: análisis histológico e histoquímico / Ethanol effect on membranous ossification of chicken embryo: histological and histochemical analysis

El presente estudio pretende analizar microscópicamente los defectos inducidos por el etanol cuando la exposición ocurre durante los primeros estadios de desarrollo en el pollo. En este estudio se emplearon huevos fecundados de gallina (White Leghorn). Los huevos fueron tratados con etanol en el día 0 (29, 40 y 60 por ciento) mediante instilación en la cámara de aire. El grupo control fue instilado con 0,1 ml de NaCI al 0,9 por ciento. Los huevos se incubaron a 37,8 ºC. Los embriones fueron extraídos, desde los huevos, después de 11 días de incubación y examinados con lupa esteroscópica. Las muestras obtenidas fueron fijadas en formol al 10 por ciento , fotografiadas y procesadas de acuerdo a las técnicas histológicas corrientes y por el método de picrosirius. El análisis microscópico por medio del método de picrosirius, reveló que el proceso de osificación membranosa presenta un menor desarrollo, además, una menor cantidad de colágeno tipo I en el hueso trabecular en los embriones postexposición a etanol con respecto al control

Autosomal dominant inheritance of iridogoniodysgenesis and cataract.

BACKGROUND: There has been only one report in the literature of iridogoniodysgenesis associated with cataracts in two brothers. In that report, the authors conclude that the condition was inherited by autosomal recessive transmission. METHODS: The authors evaluated 10 members in three generations of a family in which there is a striking prevalence of pre-senile hypermature cataract formation and iridogoniodysgenesis. In addition, historical information regarding two deceased members of the family was studied. RESULTS: Six of 10 family members evaluated have iridogoniodysgenesis. Four of five siblings have had pre-senile hypermature cataracts. Despite the iridogoniodysgenesis, there appears to be no association with glaucoma in any of these patients. CONCLUSION: The inheritance pattern of this syndrome appears to be that of autosomal dominance with variable penetrance. The authors believe that this report helps to clarify the inheritance pattern of this previously described hereditary syndrome.