Case 2 -

Cornea, Left, Keratectomy: - Granular Dystrophy Patricia Chevez-Barrios - The Methodist Hospital, Houston, TX

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Clinical History The patient is a 56 year-old female with history of slowly decrease in visual acuity for several years with a sister that had similar symptomas and necessitated a corneal graft. Visual acuity in both eyes was 20/200. On slit lamp examination the cornea shows bilateral central white deposits in the stroma that are granular with clear spaces in between. No epithelial defects or endothelial lesions were seen. The patient also had 1+ subcapsular lens opacities. The remainder of the ocular examination was within normal limits. She underwent keratectomy (corneal graft) of the left eye. Case 2 - Figure 1 Clinical picture of cornea with well-defined deposits in the stroma with clear spaces. Case 2 - Figure 2 H&E stain of keratectomy specimen with eosinophilic deposits in stroma and Bowman's layer. Case 2 - Figure 3 Trichrome Masson stain of keratectomy specimen showing bright red deposits in stroma and Bowman's layer. Introduction: Corneal dystrophies are primary, inherited, bilateral disorders and generally characterized by the layer of the cornea most involved. It is a group of heterogenous conditions that are characterized by the progressive loss of corneal transparency that results from the accumulation of deposits within the different corneal layers. Corneal dystrophies were (until recently) classified according to their clinical slit lamp appearance, the morphology of the deposits, the depth of the corneal involvement and their histopathological features. However, there are some challenges for the classification based on morphologic criteria, including: 1) significant inter-and intra- familial variability in phenotypic expression; 2) overlapping characteristics between the different types, and 3) stypical characteristics that involve multiple corneal layers or are associated with extraocular involvement. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: Macroscopic findings: Received in formalin and labeled partial layer corneal button left eye is a 9 x 9 x 1 mm gray translucent corneal button. Two paramedial sections are performed, embedded in histogel and submitted entirely on edge. Microscopic findings: The sections show a keratectomy specimen with irregular epithelium. The Bowman's layer shows focal eosinophilic deposits. The stroma is irregular with irregular hyalin eosinophilic deposits. Vascularization or cellular infiltrates are not seen. Special stains (Trichrome Masson, Alcian blue with and without hyaluronidase, and Congo red) show that the deposits are strongly positive with Trichrome Masson staining bright red. PAS stain show the deposits negatively staining. Descemet's membrane and endothelium and unremarkable. The findings are consistent with Granular dystrophy. Differential Diagnoses: Stromal corneal dystrophies includes macular corneal dystrophy (MCD), granular corneal dystrophy (GCD) type I, the lattice corneal dystrophies (LCD), Schnyder corneal dystrophy (SCD), fleck corneal dystrophy (FCD), congenital stromal corneal dystrophy (CSCD) and posterior amorphous corneal dystrophy (PACD). Final Diagnosis: Cornea, left, keratectomy: - Granular dystrophy Case Discussion: The term corneal dystrophy refers to a heterogenous group of genetically determined corneal diseases that are restricted to the cornea. The designation corneal dystrophy is imprecise but remains in vogue because of its clinical value. Typically, the conditions are bilateral spontaneous corneal disorders that vary in clinical severity and in their signs and symptoms. Most corneal dystrophies have no systemic manifestations and present with variable shaped corneal opacities in a clear or cloudy cornea and they affect visual acuity to different degrees. Diagnoses can be established on clinically and this may be confirmed and better defined with studies on keratectomy specimens and in some cases with molecular genetic analyses. The management options and outcomes following therapy vary with the condition under consideration. Clinically, the corneal dystrophies are classified with respect to the layer of cornea involved and can be divided into three groups based on the sole or predominant anatomical location of the abnormalities. Some affect primarily the corneal epithelium and its basement membrane or Bowman layer and the superficial corneal stroma (anterior or superficial corneal dystrophies), the corneal stroma (stromal corneal dystrophies), or Descemet membrane and the corneal endothelium (posterior corneal dystrophies). Most of the corneal dystrophies are of Mendelian inheritance (autosomal dominant, autosomal recessive or X-linked recessive) with some phenotype diversity and a variable degree of penetrance. The age of onset of the different types of corneal dystrophies is variable and reflects different underlying defects. A few corneal dystrophies are congenital and represent developmental anomalies. In a recent study, records of almost 8 million enrollees in a national managed-care network throughout the United States who had an eye care visit in 2001 to 2009 were searched for a recording of corneal dystrophy on a claim submitted by an ophthalmologist or optometrist from January 1, 2001, through December 31, 2007. Unique individuals (n = 27,372) received two or more diagnoses of any type of corneal dystrophy, for an overall corneal dystrophy prevalence rate of 897 per million (10⁶) covered lives. Endothelial and anterior corneal dystrophies accounted for most of the reported dystrophies, and granular corneal dystrophy was the least common, being reported in 167 enrollees. Age, sex, and race variations among the various corneal dystrophies were observed. The mean age of those with macular corneal dystrophy (47.3 years) was 15 years younger than the age of those with endothelial dystrophy (62.9 years), and females were most highly represented (68.5%) among those with lattice corneal dystrophy. Hispanics and blacks were underrepresented relative to enrollees undergoing eye care for reasons other than corneal dystrophy. Keratoplasty was most frequently coded among those with lattice dystrophy. Granular corneal dystrophy (GCD) type I (classic GCD, corneal dystrophy Groenouw type I, MIM #121900) is characterized by multiple small white discrete irregular- shaped sharply demarcated spots that resemble bread crumbs or snowflakes become apparent beneath Bowman zone in the superficial central corneal stroma. These deposits appear in the first decade of life and may be evident by 3 years of age. The opaque spots are often arranged in lines and with time they gradually enlarge and become more numerous. Some patients have only a few corneal granules, others eventually have many and the cornea becomes markedly opaque. Visual acuity is more or less normal. By the end of a second decade, many opacities are present in the central and superficial cornea but rarely in the deep stroma. Intervening tissue between the opacities and in the peripheral 2–3 mm of the cornea usually remains crystal clear. The opaque spots eventually extend throughout the central two-thirds of the cornea. GCD1 seems to be most prevalent in Europe, but GCD2 is more common in Japan, Korea and the USA. The ancestry of some families with GCD2 have been traced to the Avellino district of Italy (hence the synonym Avellino corneal dystrophy). Histologic features The light microscopic appearance and staining attributes of the corneal deposits in GCD are diagnostic. The corneal opacities consist predominantly of an extracellular deposition of mutant transforming growth factor beta induced protein (TGFBIp), which stains with eosin as pink deposits with H&E and a brilliant red with the Masson trichrome stain. The deposits react with histochemical methods for protein as well as with antibodies to TGFBIp. Transmission electron microscopy shows characteristic electron dense, discrete, rod-shaped or trapezoid bodies in the stroma and occasionally intercellularly in the epithelium. Clinical course In most cases of GCD, visual acuity remains good until late in the course of the disease. After a penetrating keratoplasty, the graft usually remains free of recurrence for at least 30 months, but the opacities may recur in the grafts within a year, usually superficial to the donor tissue, even with lamellar grafts, or at the host-graft interface Molecular genetics GCD usually has an autosomal dominant mode of inheritance, but rarely occurs sporadically due to de novo mutations or mosaicism. In some families the mutant gene is completely penetrant, but in others the penetrance is incomplete. When both parents have GCD their offspring may be homozygous for the TGFBI mutation and develop an unusually severe corneal dystrophy with larger corneal opacities and an earlier onset than heterozygous cases. Molecular genetics have resulted in new insights into the pathogenesis of corneal dystrophies which now require a new classification. Clinical evidence, the results of histopathological and electron-microscopical examinations, especially in cases of recurrence which reflect early disease, and the immunohistochemical analysis of the deposits have already aroused the suspicion that the "old" classification dividing the dystrophies into those of the epithelium, of the so-called anterior membrane, of the stroma and of the endothelium may no longer be adequate. The detection of the BIGH 3 gene which is mainly expressed in the corneal epithelium, and its gene product keratoepithelin, have led to the insight that the so-called anterior membrane dystrophies (Reis-Bücklers, Thiel-Behnke) as well as the more common "classical" stromal dystrophies (granular dystrophies Types I and II, lattice dystrophies Types I and IIIA) are caused by different mutations of the above mentioned BIGH3 gene and are thus to be regarded as epithelial in origin. Lattice dystrophy Type II is part of the Meretoja syndrome, a systemic amyloidosis, and is caused by a mutation of the gelsoline gene on chromosome 9 (9q34). Gelsoline is also predominantly expressed in the corneal epithelium. In addition, the responsible genes, their gene-products and the mutations are known for Meesmann's epithelial dystrophy and for the so-called gelatinous drop-like dystrophy, while in other dystrophies only the location on a certain chromosome can be given, namely: 16q22 for the macular dystrophy, 1p36 for the central crystalline dystrophy of Schnyder and 20p11.2-q11.2 for the congenital hereditary endothelial and for Schlichting's posterior polymorphous dystrophies. As the production rate of new results in molecular genetics is very fast, the proposed new classification can only be of preliminary character. Conclusion(s): Adequate orientation and embedding of cornea is important for evaluation of location of dystrophy Of all types of classification, the morphologic/histological is the most used Special stains useful in differencing between stromal dystrophies are: Congo red, trichrome Masson and Alcian blue with and without digestion The three types of deposits in stromal dystrophies are: amyloid (lattice), hyaline(granular) and mucopolysacharides (macular). Mutations in the Tissue Growth factor beta inducible (TGFBI) responsive gene, BIGH3, is found in the group of corneal dystrophies (granular, Avellino, lattice and Reis Bucklers) . References: Musch DC, Niziol LM, Stein JD, Kamyar RM, Sugar A. Prevalence of corneal dystrophies in the United States: estimates from claims data. Invest Ophthalmol Vis Sci. 2011 Sep 1;52(9):6959-63. Print 2011 Aug. PubMed PMID: 21791583; PubMed Central PMCID: PMC3175990. Møller HU. Granular corneal dystrophy Groenouw type I (GrI) and Reis-Bücklers' corneal dystrophy (R-B). One entity? Acta Ophthalmol (Copenh) 1989;67:678–684. doi: 10.1111/j.1755 3768.1989.tb04401.x Rodrigues MM, Gaster RN, Pratt MV. Unusual superficial confluent form of granular corneal dystrophy. Ophthalmology. 1983;90:1507–1511. Klintworth GK. The molecular genetics of the corneal dystrophies—current status. Front Biosci. 2003 May 1;8:d687-713. Review. PubMed PMID: 12700042.