[TGC Repeats in Intron 2 of the TCF4 Gene have a Good Predictive Power Regarding to Fuchs Endothelial Corneal Dystrophy]. / TGC-Repeats im Intron 2 des TCF4-Gens haben eine große Vorhersagekraft bezüglich Fuchs-Hornhautendotheldystrophie.

BACKGROUND: Fuchs endothelial corneal dystrophy (FECD) is one of the most common indications for corneal transplants. FECD is associated with various genes, e.g., COL8A2 or SLC4A11. Among other things a TGC trinucleotide repeat expansion in intron 2 of the TCF4 gene has been characterised in FECD patients and the allele G of the polymorphism rs613872 in intron 3 of the same gene has been associated with this disease. Our intention was to investigate sources in molecular genetics in the German population and to calculate the odds ratio as indicator for the chance to suffer from FECD. PATIENTS AND METHOD: 42 unrelated FECD patients, 93 unrelated controls and 17 members of a family with four FECD affected patients have been examined for the described changes in the TCF4 gene. After amplification of the TGC repeats with specific PCR the obtained products were electrophoretically divided according to their length and investigated with a triplet-primed PCR. Polymorphism rs613872 was analysed by Sanger sequencing. All coding exons of the adjacent genes TCF4 and LOXHD1 were sequenced in six patients in order to exclude potential disease associated mutations. RESULTS: 33 out of 42 unrelated analysed patients (79 %) had a TGC repeat expansion (> 50 TGC repeats) in intron 2 of the TCF4 gene. Out of 93 controls only 10 (10.8 %) showed an expanded allele. In the family the four diseased and four healthy subjects of the 17 examined family members had an expanded allele. Analysis of the polymorphism rs613872 in intron 3 of the TCF4 gene exhibited 33 of 42 unrelated patients (78.6 %) heterozygous TG and four homozygous GG (9.5 %). 65 of 93 controls were homozygous TT (69.9 %) and only 21 heterozygous TG (22.6 %). Of the 17 family members nine had the genotype TG, including the four FECD patients. Sequencing of the coding exons of TCF4 and LOXHD1 in six patients showed no variant described with FECD. The odds ratio as indicator for being affected by FECD in our data for the expanded TGC allele is 30. The chance of being affected is thus 30 times higher when someone exhibits the expanded allele. For a carrier of the risk allele G the chance is 16.5 times higher. DISCUSSION: An expanded TGC allele with more than 50 TGC repeats in intron 2 and the described risk allele G of the polymorphism rs613872 in intron 3 of the TCF4 gene appear as an association to FECD. The chance to be affected by FECD is up to 30 times higher. With molecular genetics also donors with clinically unknown FECD may be detected.

[Mutational analysis of VSX-1 in one patient with posterior polymorphous corneal dystrophy and in three families with hereditary Fuchs endothelial dystrophy]. / Mutationsanalyse im VSX1-Gen bei einem Patienten mit posteriorer polymorpher Hornhautdystrophie und drei Familien mit autosomal-dominant vererbter Fuchs'scher Hornhautendotheldystrophie.

BACKGROUND: Fuchs endothelial corneal dystrophy is the most common disease of the corneal endothelium. Besides some sporadic cases, an autosomal dominant inheritance is frequently described. Mutations in the VSX-1 gene are identified as the underlying gene defect for a rarer kind of endothelial dystrophy, posterior polymorphous endothelial dystrophy. We report on mutational analysis of the VSX-1 gene in affected and non-affected family members of three families with autosomal dominant inherited Fuchs endothelial corneal dystrophy and one male patient showing posterior polymorphous endothelial dystrophy. PATIENTS/MATERIALS AND METHODS: From one patient with posterior polymorphous endothelial dystrophy and 10 affected and 15 non-affected family members of three families with autosomal dominant inherited Fuchs endothelial corneal dystrophy DNA was extracted from leukocytes of the peripheral blood and mutational analysis was performed by direct sequencing of the VSX-1 gene. RESULTS: Screening of the VSX-1 gene did not reveal sequence variants in any affected or non-affected individuals from the three families with Fuchs endothelial corneal dystrophy or the patient with posterior polymorphous endothelial dystrophy. CONCLUSIONS: The absence of pathogenic mutations in the VSX-1 gene in affected family members of 3 pedigrees indicates that other genetic factors are involved in the development of familial Fuchs endothelial corneal dystrophy. In addition, VSX-1 seems unlikely to be the crucial gene in our patient with posterior polymorphous endothelial dystrophy.

TGFBI (BIGH3) gene mutations in German families: two novel mutations associated with unique clinical and histopathological findings.

BACKGROUND: To report the clinical, histopathological and immunohistochemical findings of two novel mutations within the TGFBI gene. METHODS: The genotype of 41 affected members of 16 families and nine sporadic cases was investigated by direct sequencing of the TGFBI gene. Clinical, histological and immunohistochemical characteristics of corneal opacification were reported and compared with the coding region changes in the TGFBI gene. RESULTS: A novel mutation Leu509Pro was detected in one family with a geographic pattern-like clinical phenotype. Histopathologically we found amyloid together with non-amyloid deposits and immunohistochemical staining of Keratoepithelin (KE) KE2 and KE15 antibodies. In two families and one sporadic case the novel mutation Gly623Arg with a late-onset, map-like corneal dystrophy was identified. Here amyloid and immunohistochemical staining of only KE2 antibodies occurred. Further, five already known mutations are reported: Arg124Cys Arg555Trp Arg124His His626Arg, Ala546Asp in 13 families and five sporadic cases of German origin. The underlying gene defect within the TBFBI gene was not identified in any of the four probands with Thiel-Behnke corneal dystrophy. CONCLUSIONS: The two novel mutations within the TGFBI gene add another two phenotypes with atypical immunohistochemical and histopathological features to those so far reported.

["Loose eye"]. / "Loses Auge". Diagnose: Akzidentelle Selbstenukleation (Avulsio bulbi) mit typischen Dissektionsebenen.

An extremely rare type of injury is presented: unintentional traumatic self-enucleation.

[Molecular genetic and histopathological examinations for genotype-phenotype analysis in patients with TGFBI-linked corneal dystrophy]. / Molekulargenetische und histopathologische Untersuchungen zur Genotyp-Phänotyp-Analyse bei Patienten mit TGFBI-gekoppelten Hornhautdystrophien.

PURPOSE: Different missense mutations in the TGFBI gene cause granular (Groenouw CDGG1, Avellino CDA, Reis-Bücklers CDB1) and lattice (Type I; Biber-Haab-Dimmer; CDL1) corneal dystrophies and, in some reports, corneal dystrophy Thiel-Behnke (CDB2). We report on the mutation spectrum and the genotype-phenotype correlations on the basis of clinical and histopathological examinations of 13 German families with TGFBI-linked corneal dystrophies. METHODS: In 31 patients with different corneal dystrophies, DNA was extracted from leukocytes of the peripheral blood and mutation analysis was performed by direct sequencing of the TGFBI gene. Clinical and histopathological findings were compared with the molecular genetic findings for genotype-phenotype correlations. RESULTS: In 6 patients (2 families/one single person) with clinical and histopathological CDL1 we found a Missense mutation Arg124Cys and in 7 patients (3 families/one single person) with clinical and histopathological CDA we found a Missense mutation Arg124His in the exon 4 of the TGFBI gene. In 12 patients (4 families/2 single persons) with clinical and histopathological CDGG1 we found a Missense mutation Arg555Trypt in the codon 12 of the TGFBI gene. In all five patients (1 family/4 single persons) with clinical and histopathological CDB2 we could not find any mutation in the TGFBI gene. In one patient with exceptional clinical and histopathological findings we found a Missense mutation Ala546Asp, which was reported before only twice in connection with polymorphous corneal amyloidosis. CONCLUSIONS: In comparison of our clinical and histopathological findings and the molecular genetic results we found a strong genotype-phenotype correlation in patients with TGFBI-linked corneal dystrophies. Rare mutations can lead to exceptional clinical and histopathological findings which cannot be classified into the different groups of corneal dystrophies. In our patients with CDB2 we could not find any molecular genetic correlation to the TGFBI gene.

[Molecular genetic analysis of the BIGH3 gene in lattice type I (Biber-Haab-Dimmer) and granular type II (Avellino) corneal dystrophy: is indirect mutation analysis for hot spots recommended?]. / Molekulargenetische Analyse des BIGH3-Gens bei gittriger Hornhautdystrophie Typ I (Biber-Haab-Dimmer) und bei bröckliger Hornhautdystrophie Typ II (Avellino): Erlauben Hot Spots einen indirekten Mutationsnachweis?

BACKGROUND: Mutations of the BIGH3 gene were delineated as the underlying gene defect for corneal dystrophy Lattice Type I (CDL1) and corneal dystrophy Avellino type (CDA) in families with different regional provenance. Missense mutations in exon 4 with single base pair substitution which result in amino acid alterations Arg124Cys (CDL1) and ARG124His are described as hot spots. We report on histopathological and molecular genetic investigations in 2 German families and a single patient with CDL1 and CDA. METHOD: In 3 affected family members and 1 unaffected family member and in one single patient with CDL1 and in 3 affected family members and 1 unaffected family member of a family with CDA mutation analysis in exon 4 of BIGH3 gene by direct sequencing of genomic DNA from peripheral blood was performed. Histopathological examination of corneal tissue of both index patients was performed after penetrating keratoplasty. RESULTS: We revealed a heterozygous single base pair substitution 417C-->T in family A and patient B (CDL1) and a heterozygous single base pair substitution 418G-->A in family C (CDA). In all index patient's diagnosis was confirmed by histopathological examination of corneal tissue. The sequencing results were confirmed by restriction digestion with HpyCH4V (NEB; CDL1) restriction endonuclease site and AvaII (NEB; CDA) restriction endonuclease site. The heterozygous 417C-->T transition in family A and patient B alters the amino acid sequence from Arg124Cys while the heterozygous 418G-->A transition in family C alters the amino acid sequence from Arg124His in the keratoepithelin. COMMENT: Codon 124 of the BIGH3 gene appears as a mutation hot spot also in German families with CDL1 and CDA. Indirect mutation analysis with restriction digestion is suggested as first step investigation in families with relevant corneal dystrophies. Direct sequencing of all exons is recommended as a second step if there are no results in restriction digestion.

[Honeycomb-shaped corneal dystrophy of Thiel and Behnke. Reclassification and distinction from reis-Bücklers' corneal dystrophy]. / Die wabenförmige Hornhautdystrophie (Thiel-Behnke). Neubewertung und Abgrenzung gegenüber der Reis-Bücklers'schen Hornhautdystrophie.

BACKGROUND: The honeycomb-shaped dystrophy of Thiel and Behnke has been misunderstood for a long time and has erroneously been classified as Reis-Bücklers' dystrophy. The mistake originates in historical misunderstandings concerning the interpretation of the original Reis-Bücklers' dystrophy which results in a nonuniform nomenclature and a permanent confusion in the evaluation of the superficial stroma dystrophies. This paper intends to clarify the original identity of the honeycomb corneal dystrophy and to distinguish it from the Reis-Bücklers' dystrophy. PATIENTS AND METHODS: We examined seven patients of the original family of Thiel and Behnke. Five of them were newly detected, two of them were reexamined. The histological findings were reevaluated, and the diagnosis was proved by electron microscopic study of corneal specimens. RESULTS: The honeycomb dystrophy is characterized by: (1) dominant inheritance, (2) early manifestation, (3) slow progression, (4) painful erosions during childhood, (5) subepithelial corneal opacities with a clear limbal zone, (6) honeycomb-shaped opacity pattern, (7) recurrence in the graft following keratoplasty, (8) subepithelial fibrous tissue in wave-like accumulation in histologic sections, (9) curly filaments observed by electron microscopy. The clinical symptoms hardly differ from those of Reis-Bücklers' dystrophy. The histological appearance, however, is clearly distinct and curly filaments are the pathognomonic ultrastructural features. CONCLUSIONS: The honeycomb dystrophy represents a definite corneal disease. The terms "Reis-Bücklers' dystrophy" and "ring dystrophy" used for it up to now are wrong and should be eliminated in this context. The only correct term of the disease is honeycomb-shaped dystrophy (Thiel-Behnke) according to its first description and major clinical features. The eponym Reis-Bücklers' dystrophy should only be used for the corneal dystrophy described by Reis and Bücklers.

Complete occlusion of the anterior capsular opening after intact capsulorhexis: clinicopathologic correlation.

PURPOSE: To report histopathologic findings of capsule contraction syndrome with complete occlusion of the capsulorhexis opening. METHODS: Case report. In an 81-year-old woman, a complete occlusion of the anterior capsulorhexis opening developed 2 months after phacoemulsification and intraocular lens implantation. We surgically removed the contracted anterior capsule and analyzed the membrane by standard light microscopy and actin immunohistology. RESULTS: Light microscopic analysis of the membrane showed fibrous tissue subcapsularly with metaplastic lens epithelial cells. The contracted capsulorhexis opening was filled completely with proliferated actin-positive lens epithelial cells. CONCLUSIONS: Complete occlusion of the capsulorhexis opening can be attributed to excessive shrinkage of the capsule, probably caused by actin filaments found in the residual lens epithelial cells together with weak zonular support, and to the occlusion of the remaining central defect by massive proliferation of metaplastic lens epithelial cells.

Traumatic wound dehiscence after penetrating keratoplasty.

BACKGROUND: Traumatic wound dehiscence after penetrating keratoplasty is probably underestimated. PATIENTS: From the files of the University Eye Hospital Tübingen (1981-1993), 15 patients with a traumatic wound dehiscence after penetrating keratoplasty were investigated. RESULTS: Latency between corneal grafting and wound rupture ranged from 1 month to 25 years (mean 6.2 years). Wound dehiscence was quite evenly distributed over the circle. Intraocular tissue was lost to a variable extent. Three eyes were primarily or secondarily enucleated. Seven eyes (47%) with an originally reduced but useful vision became blind or were removed. Most (67%) of the resutured grafts lost transparency. CONCLUSIONS: Traumatic wound dehiscence is a serious and not very rare complication after penetrating keratoplasty. Functional results are poor.

[Rifabutin-induced hypopyon iritis in HIV infection]. / Rifabutin-induzierte Hypopyoniritis bei HIV-Infektion.

BACKGROUND: Rifabutin is a new semisynthetic rifamycin which is approved in Germany for clinical application since 1/15/95. The drug is used for prophylaxis and treatment of Mycobacterium avium intracellulare (MAI) infection in patients with AIDS. In 1994 it was reported that rifabutin can cause anterior uveitis. This side effect is dose-dependent and aggravated, when the drug is combined with clarithromycin and/or fluconazol. PATIENT: A 32-year-old woman suffered from acquired immunodeficiency syndrome and systemic MAI. She was treated with a combination of rifabutin (450 mg/day), clarithromycin (750 mg/day) and ethambutol (800 mg/day). 78 days later she developed a unilateral hypopyon iritis. RESULTS: Rifabutin was discontinued and topical steroids and mydriatics were given. The uveitis disappeared within two weeks. CONCLUSIONS: The ophthalmologist should be aware of this new potential etiology of anterior uveitis. Rifabutin should be withdrawn immediately. Anti-inflammatory eye drops might be helpful.

Retrospective long-term follow-up of the triple procedure (combined keratoplasty and cataract surgery).

PURPOSE: Combined keratoplasty and cataract surgery has been performed at the University Eye Clinic in Tübingen since the nineteen-seventies. The present study was carried out to evaluate the long-term efficacy of this procedure. MATERIAL AND METHODS: Only grafts that had been followed for at least 4 years (6.5 +/- 2.3) were included. We studied the clinical outcome and final visual acuity of 19 patients (mean age 70 +/- 8.4 years) who had undergone "triple procedure surgery" on 23 eyes at the University Eye Clinic in Tübingen between 1983 and 1991. RESULTS: The keratoplasty was the first for 20 eyes and a regraft procedure in three. The mean diameter of the donor buttons was 7.31 +/- 0.4 mm, that of the host transplants 7.17 +/- 0.4 mm. Intra-operative complications included four vis a tergo reactions and one instance of bleeding in the anterior chamber. The most frequent postoperative complications were astigmatism (61%) and secondary glaucoma (4.3%). Postoperatively, six of the affected eyes required additional surgery. Preoperative visual acuity (0.06 +/- 0.08) improved postoperatively to 0.4 +/- 0.26, which was statistically significant. The postoperative retinal vision was 0.5 +/- 0.2. CONCLUSION: The results demonstrate the long-term success of the triple procedure. It can be especially recommended for patients in reduced general health who require rapid visual rehabilitation.

[Congenital familial cornea plana with ptosis, peripheral sclerocornea and conjunctival xerosis]. / Kongenitale familiäre Cornea plana mit Ptosis, peripherer Sklerokornea und Bindehaut-Xerose.

BACKGROUND: Cornea plana is an extremely rare, congenital hereditary malformation of the corneo-scleral shape. The curvatures of cornea and sclera are nearly equal with an indistinct limbus. In addition to the flatness, there is a peripheral sclerocornea that produces a pseudomicrocornea. The low corneal refraction and the short anterior segment often result in hyperopia. Myopia is also described. Usually the posterior segment is not involved. MATERIALS AND METHODS: A young man of 22 years, his three- and five-year-old sons, and his newborn daughter showed this hereditary abnormality of the cornea. In this uncommon anomaly we measured corneal curvature, refraction, diameter and in three of the four patients echographical length of the bulbi. RESULTS: The family showed an autosomal dominant inheritance of the cornea plana. The corneal refraction was less than 32 diopters. The scleral encroachment caused an oval cornea measuring horizontally between 5 and 6.5 mm, vertically 4 to 5 mm. Additionally a pseudoblepharoptosis and a conjunctival xerosis of the father and his sons was observed, which is not regularly found. A-scan measuring of the bulbi revealed age-related normal values. CONCLUSIONS: There is no evidence for progression of this anomaly during life. No therapeutical consequences are necessary. To preserve a satisfactory function a conscientious orthoptical maintainance should be guaranteed.

[Corneal manifestations in Vitamin A deficiency]. / Hornhautmanifestationen bei Vitamin-A-Mangel.

BACKGROUND: Vitamin A, the fat soluble vitamin, must be supplied orally before resorption in the mucosa of the small intestine and storage in the liver. Vitamin A deficiency can cause alterations in the anterior segment of the eye, from Bitot spots, which are reversible, to irreversible keratomalacia. PATIENTS AND METHODS: 5 patients suffering from manifestations at the cornea underwent ophthalmological, general and dermatological investigation and measurements of the vitamin A, retinol-binding protein and, in one patient, zinc were performed. 4 patients suffered from cornea manifestations, reaching from almost a reactive ulceration to spontaneous perforation. One patient had relapsing episcleritis. All patients were alcoholics, had hepatopathies and dermatological diseases. Vitamin A and retinol-binding protein were decreased and in one patient a highly decreased zinc was measured. In one patient a systemical and local substitution of vitamin A increased the clinical findings significantly. Two eyes had to undergo a keratoplasty à chaud, one evisceration had to be done. CONCLUSION: Vitamin A deficiency can be the reason for bilateral painless cornea manifestations. An interdisciplinary cooperation is essential for the elaboration of the diagnosis and the treatment.

[Unilateral type III (Hida) lattice stromal corneal dystrophy]. / Einseitige gittrige stromale Hornhautdystrophie Typ III (Hida).

BACKGROUND: All three types of lattice stromal dystrophy of the cornea use to appear bilaterally. We report on two patients with an unilateral manifestation of type III. PATIENTS: A 54 and a 87-years-old man presented a strictly unilateral atypical lattice dystrophy of the cornea and suffered from corneal erosion. Strikingly thickened lattice lines were predominantly orientated radially, almost reached to the corneoscleral limbus and were located in the anterior and midstroma. Both patients had no affected family members and there was no indication on general amyloidosis. RESULTS: After successful penetrating keratoplasty histological examination showed remarkably large amyloid deposits predominantly located close to Bowman's layer or in the midstroma and a discontinuous band of amorphous material beneath the intact Bowman's layer. Electron microscopy disclosed that the deposits were composed of typical amyloid fibrils. Four years later the younger of the two patients developed a corneal opacification being suggestive of early stage of lattice dystrophy in the other eye. CONCLUSIONS: Lattice corneal dystrophy type III, as described by Hida et al. in 1987, is easily diagnosed at the slit lamp. It may manifest itself unilaterally. In contrast to Meretoja's syndrome, there is no systemic involvement.

[Detection of phosphoglucomutase in the cornea and corneal cell cultures using isoelectric focusing and enzymatic stain methods]. / Nachweis der Phosphoglukomutase in der Kornea und in Korneazellkulturen mit Hilfe der isoelektrischen Fokussierung und enzymatischer Färbemethoden.

PGM-1 and its isoenzymes had been studied in the human cornea, in cornea cell cultures, in erythrocytes and lymphocytes. Qualitative and quantitative comparisons between cornea of healthy persons and cornea cell cultures of patients with cornea dystrophies showed differences between certain phenotypes and their signals of activity.

[Surgical treatment of hyperplastic persistent pupillary membrane]. / Zur operativen Behandlung der hyperplastisch persistierenden Pupillarmembran.

Clinical findings of two patients with persisting pupillary membranes are described and therapy is discussed. The indication for excision of the pupillary membrane was constituted in one patient (age 6 weeks) by complete occlusion of the optic axis, in the second (age 4 months) by absence of any recordable fixation. In both cases the pupillary membrane could be separated from the anterior lens capsule without lens damage. No strabismus or lens opacification were detected postoperatively. Surgery was undertaken with the intention of avoiding primary lentectomy, since pupillary membranes can usually be separated easily from the anterior lens capsule with viscoelastic substances.

A new, band-shaped and whorled microcystic dystrophy of the corneal epithelium.

Five family members and three unrelated patients (four women, four men, 23 to 71 years old) had a dystrophy of the corneal epithelium. Direct slit-lamp examination showed bilateral or unilateral, gray, band-shaped, and feathery opacities that sometimes appeared in whorled patterns. Retroillumination showed intraepithelial, densely crowded, clear microcysts. Light and electron microscopy disclosed diffuse vacuolization of the cytoplasm of epithelial cells in the affected area. Visual acuity was so reduced in three patients that abrasion of the corneal epithelium was performed. The corneal abnormalities recurred within months, with the same reduction in visual acuity as before. The corneal opacities were progressive in two patients but diminished noticeably in another after he began using a hard contact lens. We found no other ophthalmic irregularities or associated systemic abnormalities and no indication of drug-induced keratopathy.