Journal of Pediatric Ophthalmology and Strabismus

Leber Congenital Amaurosis and Its Association With Keratoconus and Keratoglobus

Mark J Elder, FRACO, FRACS

Abstract

ABSTRACT

Leber congenital amaurosis has been associated with keratoconus and it has been postulated that this is due to eye rubbing, the oculo-digital sign, because of poor vision. Six schools for the blind were visited, and 174 children with a visual acuity of less than 3/60 examined. Thirty-five children had Leber amaurosis, and 10 of these had keratoconus (29%) and one had keratoglobus (3%). The six pedigrees of the cases with Leber amaurosis and keratoconus are presented in detail. Only 3 of the 139 other blind children had keratoconus (P<.05) and 1 had keratoglobus. Keratoconus seems specifically associated with Leber amaurosis, probably due to genetic factors, rather than poor visual acuity per se.

Abstract

ABSTRACT

Leber congenital amaurosis has been associated with keratoconus and it has been postulated that this is due to eye rubbing, the oculo-digital sign, because of poor vision. Six schools for the blind were visited, and 174 children with a visual acuity of less than 3/60 examined. Thirty-five children had Leber amaurosis, and 10 of these had keratoconus (29%) and one had keratoglobus (3%). The six pedigrees of the cases with Leber amaurosis and keratoconus are presented in detail. Only 3 of the 139 other blind children had keratoconus (P<.05) and 1 had keratoglobus. Keratoconus seems specifically associated with Leber amaurosis, probably due to genetic factors, rather than poor visual acuity per se.

INTRODUCTION

Leber congenital amauroeie hae previouely been associated with keratoconue and keratoglobue, but the interconnecting factore are unknown.1'6 Leber amauroeie ie regarded ae an autoeomal receeeive dieeaee.1 By comparieon, eome keratoconue ie probably autoeomal dominant with low penetrance,711 and eome keratoconue ie probably due to eye rubbing.1214 Eye rubbing, the oculo-digital eign, ie aleo known to occur in any eevere blinding dieeaee in childhood15 and it hae been poetulated that thie ie the link between Leber amauroeie and keratoconue.16 Thie communication preeente eix pedigreee with Leber amaurosis and keratoconus and comparée the prevalence of keratoconus and keratoglobue in Leber amauroeie to that found in other blind children from the same location.17

PATIENTS AND METHODS

All eix academic blind schools of Jerusalem's West Bank and Gaza Strip were visited and the children were examined. There were 174 children aged 5 to 25 yeare with vieual acuitiee leee than 3/60. Seven children were unavailable for examination; otherwiee there were no exclueion criteria.

Each school was visited by the "Outreach" facility of the St John Ophthalmic Hospital, Jerusalem, which ie a well-equipped mobile clinic. A complete hietory wae taken, with particular reference to the family history, and the previous medical records were reviewed. A full examination was conducted including best corrected visual acuity with Sheridan-Gardner test charte, color vision assessment, visual field teeting by confrontation, elit-lamp biomicroecopy, retinoecopy, cycloplegic refraction, and funduscopy. When indicated, children were eent to the baee hoepital for further inveetigatione such ae ultrasound, Goldmann visual fields, Farnsworth-Munsell tests, and electrodiagnostic testing. Where possible, family members were examined on the eame day.

The criterion for inclusion within thie etudy wae a visual acuity of less than 3/60 according to the standard World Health Organization (WHO) definition of childhood blindness. The diagnosis of keratoconus was made based on standard slit-lamp biomicroscopy and retinoscopy appearances.1820 This included central or paracentral corneal thinning and protrusion and the associated clinical signs such as Munson sign, Vogt striae, Fleischer ring, apical scarring, and prominent corneal nerves.18'20 Keratoglobus was distinguished from keratoconus by the global corneal contour and the peripheral and central thinning.18·20 All patients with keratoconus and keratoglobus were examined by the author. Leber amaurosis was diagnosed based on the retinal and optic nerve appearances, a flat or markedly reduced electroretinogram, and an absence of any other cause for the clinical signs. All patients in both arms of the study were examined using the same methods, techniques, and instruments and the same diagnostic criteria were applied to each. Keratometry and/or computerized corneal topographic analysis was not used as a diagnostic tool because it would have been technically very difficult due to the nystagmus and lack of fixation that was present in all patients with Leber amaurosis and many of the other patients.

Statistical analysis used chi-square with Yates correction.

RESULTS

One hundred and seventy-four patients had a visual acuity of less than 3/60. Thirty-five patients had Leber amaurosis of whom 10 patients also had bilateral keratoconus and one had bilateral keratoglobus. None of these 35 patients had clinical signs of atopy, trisomy 21, EhlersDanlos syndrome, or osteogenesis imperfecta. The mean age of those with Leber amaurosis was 13.49 ± 5.48 years with a range from 5 to 24 years. Patients with both Leber amaurosis and keratoconus were older, with a mean age of 18.2 ± 4.0 years with a range from 12 to 24 years. Those patients with keratoconus represented six pedigrees.

Table

TABLEDiagnosis of the Cause of Blindness and the Association with Keratoconus and Keratoglobus

TABLE

Diagnosis of the Cause of Blindness and the Association with Keratoconus and Keratoglobus

There were 139 patients without Leber amaurosis, of whom three had bilateral keratoconus and one had bilateral keratoglobus. The patient with keratoglobus also had bilateral congenital cataracts (age 16 years). One of the patients with keratoconus also had severe myopic chorioretinal degeneration (age 14 years), one had bilateral severe amblyopia due early onset keratoconus (now age 20 years), and one had severe irregular astigmatism and was referred for corneal grafting (age 11 years). The mean age of these 139 patients was 11.8 ± 5.2 years with a range from 5 to 25 years. The common diagnoses are listed in the Table.

Statistically, there was a significant difference between the prevalence of keratoconus in Leber amaurosis and those children with a visual acuity of less than 3/60 (10/35 vs 3/139, P < .001, odds ratio 18.13, 95% confidence limits 4.2-90). There is also a significant difference between the prevalence of keratoconus in Leber amaurosis and that found in optic atrophy and retinitis pigmentosa, the two most common conditions (10/35 vs 0/23 and 0/19, P < .05).

PEDIGREES OF LEBER AMAUROSIS AND KERATOCONUS

Pedigree I

Of four siblings, two brothers (ages 20 and 24 years) each had Leber amaurosis and keratoconus, and had visual acuities of perception of light (PL). A medical report claimed that one sister was blind from birth from Leber amaurosis but the patient was unavailable for examination. One brother had normal vision, as did both parents and grandparents. The parents were first cousins.

Pedigree II

Of four siblings, one sister (age 21 years) had Leber amaurosis and keratoconus, and PL vision. Another sister (age 17 years) with Leber amaurosis had keratoglobus and PL vision. One brother and one sister had normal vision, as did both parents and grandparents. There was no history of parental consanguinity.

Pedigree III

Of seven siblings, one sister and one brother (ages 14 and 18 years) had Leber amaurosis and keratoconus, and hand movement and PL vision, respectively. One sister (age 16 years) with Leber amaurosis had a normal cornea and 2/60 vision. Medical records showed that one brother was blind from birth with Leber amaurosis but he was unavailable for examination. Two sisters and two brothers had normal vision, as did the mother and grandparents. The father had Leber amaurosis but with normal corneas. There was no parental consanguinity or any other family history of visual problems.

Pedigree IV

Of nine siblings, one sister (age 12 years) had Leber amaurosis and keratoconus, and PL vision. One brother (age 16 years) had Leber amaurosis but had normal corneas, and PL vision. Four sisters and three brothers had normal vision, as did both parents and grandparents. The parents were first cousins.

Pedigree V

Of three siblings, two sisters (ages 19 and 23 years) had Leber amaurosis and keratoconus, PL and 1/60 vision. Medical records revealed that one brother was blind from birth with Leber amaurosis but he was unavailable for examination. Both parents and grandparents had normal vision, and the parents were unrelated.

Pedigree VI

Of two siblings, both sisters (ages 14 and 17 years) had keratoconus and Leber amaurosis, and PL vision. Both parents and grandparents had normal vision, and the parents were first cousins.

DISCUSSION

This article presents two sets of data; that of the patients with Leber amaurosis and keratoconus and that of the comparison of the prevalence of keratoconus in childhood blindness of various causes.

Alstrom and Olson's study1 of Leber amaurosis found that keratoconus occurred in 2% of 0- to 14-year-olds and 30% of 15- to 45-year-olds. Other series show a prevalence of 9% to 39%,3,4 and one report aesociated this with macular coloboma in two pedigrees.5 Keratoglobus has also been associated with Leber amaurosis, with Gillespie2 reporting two pedigrees spanning two and three generations and Waardenburgs 1957 series6 reporting 8 of 32 patients with Leber amaurosis having "keratoglobus-like keratoconue." Unfortunately, no definition of keratoglobue wae given.

Leber amauroeie has been well-documented to be an autosomal recessive disease,1 and the patients in this series follow that pattern. Of the six pedigrees with keratoconus, there are more than one sibling affected in each, 7 of 10 were female and in only one instance was Leber amaurosis present in two generations. Parental consanguinity was present in 50%. However, an association with keratoconus may be either genetic or environmental in nature, and siblings often share both factors.

The exact hereditary patterns of keratoconus are not clear although 7% to 20% of patients have a blood relative with keratoconus.7·21 Hammerstein and Friedburgs prospective study7 concluded that keratoconus is autosomal dominant with 20% penetrance, and this is also suggested by other reports.711 There are also reports of isolated keratoconus after consanguineous relationships, implying a recessive inheritance pattern,22 and in identical twins.7·2325 Keratoconus is sometimes associated with atopy, trisomy 21, Ehlers-Danlos syndrome, osteogenesis imperfecta, and eye rubbing.13·20 Eye rubbing occurs in 66% to 73% of patients with keratoconus and this has been considered the major etiological factor by some authors.1214 Therefore, the etiology of keratoconus may have a genetic and an environmental component.

Within the pedigrees with Leber amaurosis, the relationship to keratoconus is not clear-cut. In 3 of 6 pedigrees, one sibling had keratoconus and the other did not. Pedigree G? is most unusual in that two siblings had keratoconus and another had keratoglobus, yet the father had Leber amaurosis but with normal corneas. The genetic relationship between keratoconus and keratoglobus is uncertain although Cavara26 reports a pedigree (not with Leber amaurosis) where the father had keratoglobus and the son had keratoconus.

The occurrence of keratoconus is much higher in Leber amaurosis than with other blinding childhood diseases, and this suggests a genuine link between the two. This putative link is probably genetic rather than due to poor visual acuity perse.

REFERENCES

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25. Woillez M, Razemon PH, Constantinides G. A propos d'un nouveau cas de keratocone ches des juneaux univitellins. Bull Soc Opthalmol Fr. 1976;76:279-281.

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TABLE

Diagnosis of the Cause of Blindness and the Association with Keratoconus and Keratoglobus

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