Genetic epidemiological study of keratoconus: evidence for major gene determination.

Keratoconus (KC) is a noninflammatory corneal thinning disorder and the major cause of cornea transplantation in the Western world. Genetic factors have been suggested in the cause of KC. We conducted a family study to investigate genetic contributions to the development of KC by evaluating familial aggregation and testing genetic models with segregation analysis. KC was diagnosed based on clinical criteria. Familial aggregation of KC was evaluated using both clinical status and three videokeratography indices generated by the Topographic Modeling System (TMS-1). The estimated KC prevalence in first-degree relatives was 3.34% (41/1,226, 95% CI: 3. 22-3.46%), which is 15 to 67 times higher than that in the general population (0.23-0.05%). For all three videokeratography indices, CK, IS, and KISA, KC propositi had significantly higher mean values than controls (all P < 0.0001). Clinically unaffected parents also had significantly higher values for these indices than controls (all P < 0.016). The correlation of KISA in sib and parent-offspring pairs (r = 0.30 and 0.22, respectively, both P < 0.0005) was significantly greater than that in marital pairs (r = 0.14), and the latter was not significantly different from zero. We performed segregation analysis on KISA in 95 families ascertained through KC propositi. Hypotheses of both sporadic and environmental models were rejected (P < 0.001); a major gene model was not rejected (P > 0.1). Additionally, the most parsimonious model was autosomal recessive. In conclusion, we observed strong evidence of familial aggregation in KC and its subclinical indices and this aggregation is likely due to a major gene effect.

Computer-assisted corneal topography in family members of patients with keratoconus.

In about 6% of patients with keratoconus, there is a history of familial disease. High keratometric astigmatism and mildly irregular mires observed by placidois disc have been suggested to represent variable forms of expression of a gene in family members of patients with keratoconus. We used a computer-assisted digital videophotokeratoscope to map the corneas of 28 family members of 5 patients with keratoconus. Abnormalities observed in family members included central steepening, greater steepening of the cornea inferior to the apex, and substantial asymmetry in the central dioptric power between the two eyes of the same individual. These findings were similar to, but less severe than, those found in patients with keratoconus and may represent the variable expression of a gene contributing to the development of keratoconus. Pedigree analysis in these families suggests an autosomal dominant mode of inheritance.

Keratoconus.

Keratoconus is a bilateral noninflammatory corneal ectasia with an incidence of approximately 1 per 2,000 in the general population. It has well-described clinical signs, but early forms of the disease may go undetected unless the anterior corneal topography is studied. Early disease is now best detected with videokeratography. Classic histopathologic features include stromal thinning, iron deposition in the epithelial basement membrane, and breaks in Bowman's layer. Keratoconus is most commonly an isolated disorder, although several reports describe an association with Down syndrome, Leber's congenital amaurosis, and mitral valve prolapse. The differential diagnosis of keratoconus includes keratoglobus, pellucid marginal degeneration and Terrien's marginal degeneration. Contact lenses are the most common treatment modality. When contact lenses fail, corneal transplant is the best and most successful surgical option. Despite intensive clinical and laboratory investigation, the etiology of keratoconus remains unclear. Clinical studies provide strong indications of a major role for genes in its etiology. Videokeratography is playing an increasing role in defining the genetics of keratoconus, since early forms of the disease can be more accurately detected and potentially quantified in a reproducible manner. Laboratory studies suggest a role for degradative enzymes and proteinase inhibitors and a possible role for the interleukin-1 system in its pathogenesis, but these roles need to be more clearly defined. Genes suggested by these studies, as well as collagen genes and their regulatory products, could potentially be used as candidate genes to study patients with familial keratoconus. Such studies may provide the clues needed to enable us to better understand the underlying mechanisms that cause the corneal thinning in this disorder.

Tangential vs sagittal videokeratographs in the "early" detection of keratoconus.

PURPOSE: To illustrate the difference between tangential and sagittal videokeratographs in the "early" (subclinical) detection of keratoconus. METHODS: The clinically normal fellow eye of a patient with unilateral keratoconus was studied with a topographer, which can display both a sagittal and a tangential map on the same page using the same color scale. RESULTS: The tangential map depicted a pattern more consistent with keratoconus and provided a maximum power of 51 diopters compared with the 46 diopters of the sagittal map. CONCLUSIONS: Tangential videokeratographs, derived from instantaneous radius of curvature algorithms, may be more useful than sagittal displays for detecting subtle corneal topographic abnormalities.

Fluorescein test for the detection of striae in the corneal flap after laser in situ keratomileusis.

PURPOSE: To report a technique for detecting striae in the corneal flap after laser in situ keratomileusis. METHODS: Fluorescein dye was instilled in the eye, and the patient was asked to blink. The tear film was examined at the slit lamp with the cobalt filter 1 or 2 seconds after blinking. RESULTS: The uneven pattern of pooling in the tear film was a sensitive indicator of the presence of striae in the flap. CONCLUSION: This technique may be useful in detecting minimal striae in the corneal flap in patients with unexplained suboptimal visual acuity after laser in situ keratomileusis.

Surgical correction of incomplete cryptophthalmos in Fraser syndrome.

PURPOSE: To demonstrate favorable long-term visual outcome after ocular reconstruction in an infant with Fraser syndrome and with complete left cryptophthalmos. METHODS: Reconstruction of incomplete right cryptophthalmos in our patient was accomplished in a stepwise manner, beginning in the third week of life, by dissecting the eyelids from the cornea, reconstructing the conjunctival fornices with buccal mucosa, and repairing the upper lid coloboma in a flap reconstruction using the inferior eyelid margin. RESULTS: At age 3 years, the patient currently has good movement of the right eyelids when blinking, reasonable right tear function, and a visual acuity in the right eye between 20/200 and 20/360 on forced preferential looking. CONCLUSION: In selected cases of incomplete cryptophthalmos, oculoplastic and corneal surgery may result in useful vision and in good eyelid movement when blinking.

Cosegregation of X-linked retinitis pigmentosa and hemophilia A.

We examined a family pedigree in which retinitis pigmentosa and hemophilia A were inherited in an X-linked manner. Six female carriers were identified by electroretinography. Results of ophthalmoscopic examination were normal in two women, while four displayed marked variability in phenotypic expression. Six of seven males identified with retinitis pigmentosa had hemophilia A. One asymptomatic boy had a markedly abnormal electroretinogram despite normal ophthalmoscopic examination. Pedigree analysis showed a high recombination rate, which would be expected as these two genes are known to be at opposite arms of the X chromosome.

Corneal transplantation in a patient with mucopolysaccharidosis type VII (Sly disease).

PURPOSE: To illustrate a good visual outcome following penetrating keratoplasty in a patient with Sly disease, a rare mucopolysaccharidosis (MPS) caused by a deficiency of beta-glucuronidase. METHODS: A 15-year-old male with progressive bilateral corneal opacification had a complete medical, genetic, and ophthalmic evaluation followed by a penetrating keratoplasty. RESULTS: The cornea has remained clear for two years following surgery. Histopathology of the corneal button demonstrated vacuoles and granular inclusions consistent with this lysosomal storage disease. CONCLUSION: While research is ongoing in the fields of enzyme replacement and bone marrow transplantation, these treatments may not alleviate or reverse the corneal clouding. This case illustrates that cornea transplantation may be a valuable treatment option for visually rehabilitating such patients.

Videokeratography of keratoconus in monozygotic twins.

PURPOSE: To determine the corneal topographic appearance in a pair of monozygotic twins and family members of the twins because one of the twins had keratoconus and the other appeared normal by clinical examination. METHODS: Clinical examination and videokeratography (Topographic Modeling System, Tomey) of the patient, his monozygotic twin brother, an older brother, and his parents were performed. The I-S values (difference in the average dioptric powers of symmetrical points between the inferior and superior cornea) were calculated. RESULTS: The patient, a 28-year-old man, had clinical keratoconus confirmed with videokeratography. Clinical examination of family members including a twin brother, an older brother and both parents revealed no corneal abnormalities. Videokeratography of the clinically normal twin brother showed inferior steepening with progression over time. The I-S value of the clinically normal brother was 1.36 (right eye) (greater than 2.00 SD of normal controls), which progressed to 1.69 (right eye), 1.32 (left eye) 5 months later and to 1.87 (right eye), 1.43 diopters (D) (left eye) 14 months later. Minimal asymmetric inferior steepening was noted in an older brother who had an I-S value of 0.81 (right eye), 1.27 (left eye). The mother appeared topographically normal. CONCLUSIONS: This study lends support to the existence of subclinical keratoconus detectable by videokeratography only.

Keratoconus detected by videokeratography in candidates for photorefractive keratectomy.

BACKGROUND: Patients with corneal shape abnormalities should be identified prior to photorefractive keratectomy (PRK). We used videokeratography screening to detect subclinical corneal abnormalities, including keratoconus, which might have been missed by conventional clinical evaluation. METHODS: One hundred forty-six apparently normal myopic eyes (-1.00 to -7.00 diopters [D] with less than 1.50 D of cylinder) of 91 consecutive patients who were candidates for PRK were screened by videokeratography. RESULTS: In 6 of 91 patients (7 of 146 eyes), unsuspected corneal shape abnormalities were detected by videokeratography. Two patients had definite keratoconus and three were classified as keratoconus suspects by inferior corneal steepening (Rabinowitz I-S index ranging from 1.62 to 6.20 D). One patient had early pellucid marginal degeneration. CONCLUSIONS: Keratoconus suspects and contact lens-induced changes resembling keratoconus are present in the "normal" myopic population that presents for refractive surgery. Videokeratographic screening is the only effective means of identifying these and other corneal shape abnormalities.

Interobserver and intraobserver reliability of a classification scheme for corneal topographic patterns.

AIMS: To determine the interobserver and the intraobserver reliability of a published classification scheme for corneal topography in normal subjects using the absolute scale. METHOD: A prospective observational study was done in which 195 TMS-1 corneal topography maps in the absolute scale were independently classified twice by three classifiers--a cornea fellow, an ophthalmic technician, and an optometrist. From these observations the interobserver reliability for each category and the intraobserver reliability for each observer were determined in terms of the median weighted kappa statistic for each category and for each observer. RESULTS: For interobserver reliability, the median weighted kappa statistic for each category varied from 0.72 to 0.97 and for intraobserver reliability the range was 0.79 to 0.98. CONCLUSION: This classification scheme is extremely robust and even in the hands of less experienced observers with minimal training it can be relied upon to provide consistent results.

Videokeratography database of normal human corneas.

AIM: To form a database of videokeratography patterns and quantitative indices describing normal human corneas using the absolute scale. METHODS: Both eyes of 195 normal subjects were examined with a TMS-1 videokeratoscope. Videokeratographs were divided into 10 categories based on a classification scheme devised from the absolute scale and analysed with 10 quantitative indices devised to describe phenotypic features of keratoconus videokeratographs. Correlations were sought between videokeratograph patterns and quantitative indices. Additionally, data were analysed for differences in age, sex, and ethnicity. RESULTS: For symmetric videokeratography patterns, analysis in the absolute scale was similar to a previous study done in the normalised scale. In the asymmetric categories, analyses differed markedly. Using the absolute scale and our classification scheme more variation in normal videokeratography patterns could be appreciated. There was good correlation between quantitative indices and videokeratography patterns. Neither videokeratography patterns nor indices differed significantly between sex, ethnic groups, or age using two way analysis of variance. CONCLUSIONS: Pattern analysis of videokeratographs in the absolute scale using, a standard classification scheme, may be more useful in trying to determine whether a cornea is normal or represents subtle early disease than analysis in the normalised scale. Quantitative indices could remove the subjectivity from the decision making process thus facilitating universal reproducibility of videokeratography data interpretation.

KISA% index: a quantitative videokeratography algorithm embodying minimal topographic criteria for diagnosing keratoconus.

PURPOSE: To formulate and test an algorithm using minimal topographic criteria for accurately diagnosing clinical keratoconus. SETTING: Subspecialty cornea practice and Keratoconus Genetic Research Project. METHODS: Both eyes of 86 keratoconic patients who had never worn contact lenses and 195 normal participants were studied with the TMS-1 videokeratoscope to evaluate the KISA% index, an algorithm that topographically quantifies the phenotypic features of keratoconus. The diagnostic efficacy of the KISA% index was compared with that of the modified Rabinowitz/McDonnell (K- and I-S values) and the Maeda/Klyce (KCI% and KPI) indices. The same indices were calculated for an additional 8 eyes with keratoconus-suspect topography and 12 eyes with early keratoconus. RESULTS: The mean KISA% was significantly greater in the keratoconus group (10,382%) than in the normal control group (20.44%) with minimal overlap. At a cutoff point for KISA% of 100, 280 of 281 participants (99.6%) were correctly classified. In contrast, the correct classification rate for the other indices were KCI%, 274 of 281 (97.5%); KPI, 249 of 281 (88.6%); K, 272 of 281 (96.8%); I-S, 269 of 281 (95.7%). Six of the 8 eyes with keratoconus-suspect topography had a KISA% between 60% and 100%, and 11 of the 12 eyes with early keratoconus had a KISA% greater than 100%. CONCLUSIONS: The KISA% index set at 100 was highly sensitive and specific for diagnosing keratoconus; a range of 60% to 100% may be useful for designating suspects. This index is more useful than any of the other currently available tools for classifying patients with keratoconus for computerized segregation analysis and for distinguishing eyes with keratoconus from normal eyes in topographic screening of refractive surgical candidates.

Superficial lamellar keratectomy using an automated microkeratome to excise corneal scarring caused by photorefractive keratectomy.

Corneal haze is a recognized complication of excimer laser photorefractive keratectomy. When severe, it can result in the formation of a dense corneal scar, with a reduction in best corrected visual acuity. In extreme cases, medical treatment and repeated phototherapeutic excimer ablations may fail to restore corneal transparency. In these patients, penetrating keratoplasty (PKP) has been used to restore visual function. We describe a technique for excising a superficial corneal scar using an automated microkeratome. The resultant corneal surface is quite smooth, and good visual acuity may be restored without resorting to PKP.

Method for safer penetrating keratoplasty in patients with low scleral rigidity.

In eyes with low scleral rigidity, penetrating keratoplasty (PKP) is a high-risk procedure because forward movement of the lens-iris diaphragm can result in prolapse of intraocular contents, expulsive choroidal hemorrhage, and damage to the crystalline lens. We developed a method for safer PKP in eyes with low scleral rigidity. In this technique, the host cornea is incompletely excised and remains attached at the 6 and 12 o'clock positions while the cardinal sutures to secure the donor button over the host are placed. Donor endothelium is protected by an intervening layer of viscoelastic material. After the first 3 cardinal sutures are placed, the host button is completely excised and removed and the donor cornea is sutured. This technique prevents the unopposed forward movement of the lens-iris diaphragm and may reduce the risk of expulsive choroidal hemorrhage and spontaneous extrusion or damage to the crystalline lens during PKP in patients with low scleral rigidity.

Accuracy of ultrasonic pachymetry and videokeratography in detecting keratoconus.

PURPOSE: To compare the accuracy of ultrasonic pachymetry measurements and videokeratography-derived indices in distinguishing keratoconus patients from those with normal eyes. SETTING: A subspecialty cornea practice (Los Angeles, California, USA) and the Keratoconus Genetics Research Project. METHODS: Corneal thickness was measured by ultrasonic pachymetry at the center and inferior margins of the pupil of 142 normal and 99 keratoconus patients The corneal surface topography of patients was studied with the Topographic Modeling System (TMS-1). The videokeratographs obtained were analyzed with a computer program that automatically calculates two indices derived from data points in the central and paracentral cornea: central K and I-S values. Linear discriminant analysis was used to determine the correct classification percentages using pachymetry measurements and indices derived from videokeratography as the independent variables. RESULTS: The range of corneal thickness in normal and keratoconic eyes overlapped considerably. In the discriminant analysis, videokeratography indices provided a 97.5% correct classification rate and pachymetry data, an 86.0% rate (P < .01, McNemar's test). CONCLUSION: Keratoconus is more accurately distinguished from the normal population by videokeratography-derived indices than by ultrasonic pachymetry measurements. This may be due to the large variation in corneal thickness in the normal population or the inability of ultrasonic pachymetry to accurately detect the location of corneal thinning in keratoconus by measuring standard points on the cornea. Pachymetry should not be relied on to exclude or diagnose keratoconus because the false-negative and false-positive rates are unacceptably higher than those obtained by videokeratography.

Keratoconus and bilateral lattice-granular corneal dystrophies.

The occurrence of lattice and granular corneal dystrophies in the same eye has been reported in individuals who trace their families to the province of Avellino in Italy. We present the first histopathologic report of keratoconus and bilateral lattice-granular corneal dystrophies occurring in the same patient. This individual's family also originated in Avellino, Italy.

Molecular genetic analysis in autosomal dominant keratoconus.

Members in three generations of a family whose propositus had keratoconus were examined by biomicroscopy, with a corneoscope and a computer-assisted videophoto-keratoscope. Keratoconus was detected in eight of 15 family members with vertical transmission consistent with autosomal dominant inheritance. Affected individuals displayed variable topographic features. Abortive "nipple-type" cones were identified in some individuals in successive generations using the computer-assisted videophotokeratoscope and more advanced nipple-type cones detected on biomicroscopy of other family members. We selected a COL6A1 cDNA (the gene encoding the alpha 1 chain of type VI collagen) as a "candidate gene" to determine cosegregation with the disease locus. Linkage analysis excluded a gene locus for keratoconus on the most telomeric region of chromosome 21 in this family.