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Characterization of optical coherence topography findings in Kenny-Caffey Syndrome
Characterization of optical coherence topography findings in Kenny-Caffey Syndrome Peter Timoney, MBBCh,a Fiona Darcy, MBBCh,a Kathryn McCreery, MB, FRCOpth, FRCSI,b William Reardon, MD, MRCPI, DCH FRCPCH, FRCP (Lond) CFH,b and Donal Brosnahan, MB, DCH, FRCS, FRCOptha
An unusual congenital syndrome was first reported in 1966 by Kenny and Linarelli, who described two patients with dwarfism, cortical thickening of the long bones, transient hypocalcemia, and normal intelligence,1 the radiological features in the condition being reported by Caffey.2 The constellation of dwarfism, medullary stenosis, transient hypocalcemia, and ophthalmologic abnormalities has been classically recognized as Kenny-Caffey syndrome with additional manifestations ranging from hypoplastic nails, persistent neutropenia, abnormal T-cell function, and neonatal liver disease.3 Ocular findings range from uncomplicated nanophthalmos with hypermetropia to extreme pseudopapilloedema, vascular tortuosity, and macular crowding. Other reported ophthalmic findings include bilateral band keratopathy,4 bilateral optic atrophy,5 and myelinated nerve fibers.6 We report two cases of Kenny-Caffey syndrome with an ellipsoid macular fold orientated horizontally involving the fovea and document this unusual feature with optical coherence topography (OCT ).
Case Reports Case 1 six-year-old white boy was referred to the ophthalmology outpatient clinic for difficulty in reading at school. He was the product of a dizygotic twin pregnancy born to nonconsanguineous parents in their late twenties by normal vaginal delivery weighing 2 pounds and 12 ounces at 28 weeks gestation. Postnatally he presented to the Neonatal Intensive Care Unit with twitching movements of his limbs and was subsequently treated for transient hypocalcemia. He had an otherwise uncomplicated neonatal period. No dysmorphic features were present at birth. The family history and examination of his parents and twin sister were noncontributory; they did not display any dysmorphic features and ophthalmologic examinations were normal. At first visit he was noted to have an expressionless face, prominent forehead, micrognathia, and proportionate short stature. At 9 years of age he measured 126 cm (3rd
A
a
Royal Victoria Eye and Ear Hospital, Dublin, Ireland; bOur Lady’s Hospital for Sick Children, Dublin, Ireland. No financial interests/conflicts are associated with this article. Submitted December 27, 2005. Revision accepted September 11, 2006. Published online March 20, 2007. Reprint requests: Peter Timoney, Department of Ophthalmology, Kentucky Clinic, University of Kentucky, Lexington, Kentucky 40536-0284 (email: [email protected]) J AAPOS 2007;11:291-293. Copyright © 2007 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2007/$35.00 ⫹ 0 doi:10.1016/j.jaapos.2006.09.020
Journal of AAPOS
centile), and his occipito-frontal head circumference measured 53.9 cm (25th centile). He has no evidence of low intelligence as evidenced by his attendance and progression in a mainstream classroom environment. Uncorrected visual acuity was 6/60 in each eye and best corrected visual acuity was 6/36 in each eye. Cycloplegic refraction revealed ⫹16.50 diopters sphere (D) in the right eye and ⫹18.00 D in the left eye. There was no evident hypertelorism with an inner canthal distance of 30 mm and an outer canthal distance of 85 mm. Pupils were equal and reacted normally. Color testing with Ishihara pseudoisochromatic test plates was normal. Visual fields were full to confrontation. Motility evaluation revealed orthotropia. Anterior segment examination revealed shallow anterior chambers and bilateral microcornea with each cornea measuring 9.5 mm in horizontal diameter. Intraocular pressures were normal. Dilated retinal examination revealed symmetrical pseudopapilloedema with indistinct margins and bilateral horizontal retinal folds emanating from the optic nerve head to the temporal margin of the macula. A diagnosis of hypermetropic pseudopapilloedema was based on there being no obscuration of peripapillary vessels by nerve fiber edema, no congestion of the disk microvasculature, and no microvascular abnormalities on the surface of the disk such as flame-shaped hemorrhages. There was associated minimal retinal vascular tortuosity (Figure 1A). Based on the ophthalmologic findings, the patient was referred for further evaluation. A skeletal survey study was within normal range and endocrinologic tests including serum calcium, thyroid function tests, and parathyroid hormone were normal. Genetic analysis revealed a normal fluorescent in situ hybridization study of chromosome 22q11, thereby excluding the possibility of DiGeorge syndrome, a rare congenital disorder classified as a deletion 22q11 syndrome in which hypocalcemia is a prominent feature. Although there was no biochemical evidence for continued calcium dysregulation since the neonatal period, and the skeletal examination did not show classical signs of Kenny-Caffey syndrome, this was deemed to be the most likely diagnosis. The diagnosis was reinforced by the fact that other causes of transient hypocalcemia were diagnostically excluded and in view of the ophthalmic findings which were central to the diagnosis. A-scan ultrasonography demonstrated nanophthalmia in both eyes with an axial length of 14.67 mm in the right eye and 14.73 mm in the left eye. OCT illustrated elevation of the neural retina in the central macular region with
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FIG 1. (A) Fundus photograph displaying the right elevated swollen disk with blurred margins along with the horizontal macular fold emanating from the optic disk margin and extending temporally. (B) Optical coherence tomography (OCT ) illustrating the chorioretinal elevation in the central macular region with an underlying empty vaulted space.
an empty, vaulted space between the choroid and sclera. There were no retinal pigment epithelial detachments or any cystic macular changes evident. The overlying retina was of normal thickness (Figure 1B). Case 2 A 12-year-old white boy was referred to the ophthalmology clinic with bilateral decreased visual acuity. His family history was noncontributory; he was the offspring to nonconsanguineous parents in their early thirties; his parents and siblings were without any medical issues, and general and ophthalmologic examination of his parents was normal. He was proportionately small in stature, measuring 122 cm (third centile), had a featureless face with a prominent forehead and microagnathia, and his mental development was normal. His best corrected visual acuity was 6/24 in each eye. Cycloplegic refraction was ⫹16.00 D in the right eye and ⫹16.00 D in the left eye. The inner and outer canthal distances were within normal range. Anterior segment examination revealed early bilateral band keratopathy and bilateral microcornea with each cornea
Volume 11 Number 3 / June 2007
FIG 2. (A) Fundus image of the left swollen optic disk with indistinct margins and the macular fold extending temporally. (B) OCT showing the elevated chorioretinal fold of normal thickness with an underlying empty vaulted area.
measuring 10 mm in horizontal diameter. Fundus examination revealed minimal tortuous retinal vasculature, pseudopapilloedema, and bilateral horizontal elevated macular folds extending from the disk margin temporally (Figure 2A). Bilateral nanophthalmia was demonstrated by A-scan ultrasonography with an axial length of 14.29 mm in the right eye and 14.27 in the left eye. OCT imaging portrayed chorioretinal elevation in the central macular area with an underlying empty, vaulted space (Figure 2B). On further evaluation, he suffered from hypoparathyroidism requiring daily 1-alpha vitamin D supplementation, and skeletal studies were within normal range.
Comment Early reports of Kenny-Caffey syndrome were predicated upon “classical” radiological findings of medullary stenosis and excessive thickening of the cortex in addition to delayed closure of the anterior fontanelle.1 However, the identification of gene mutations has shown a much wider phenotype associated with the syndrome than was previously recognized,7 and, as noted by Winter and Baraitser
Journal of AAPOS
Volume 11 Number 3 / June 2007
in their commentary on the condition, “radiological findings are not constant features” in Kenny-Caffey syndrome.8 Accordingly, the absence of classical, absolute radiological findings as reported by Majewski et al9 is not surprising nor does this absence contradict the diagnosis, particularly in a case with documented hypocalcemia for whom other causes of that condition have been excluded and whose ophthalmic findings were so strongly suggestive of the diagnosis. Molecular testing for confirmation of the diagnosis was not performed in either of the two cases. These two cases appear to be sporadic and suggest either a new mutation or a possible autosomal-recessive inheritance (Kenny-Caffey syndrome, type 1). Despite the lack of radiological findings, the ophthalmologic features were invaluable in establishing the diagnosis in these two cases. Ocular anomalies are present in 73% of Kenny-Caffey syndrome patients with extreme hypermetropia and nanophthalmos being the most prevalent.5 Visual morbidity is secondary to angle closure glaucoma in association with nanophthalmos, anomalous macular anatomy, and ammetropic/anisometropic ambylopia. Previous studies have indicated the association of nanophthalmos with Kenny-Caffey syndrome and have clearly documented the various retinal findings with nanophthalmos.10 The sole histopathological evaluation of enucleated nanophthalmic eyes from a patient with Kenny-Caffey syndrome demonstrated swollen discs with lateral displacement of the peripapillary retina due to bulging of the edge of the disk.4 Notwithstanding the documented clinical variability, certain clinical manifestations, including growth retardation, atypical facial features, and ocular anomalies, such as nanophthalmos and a papillomacular retinal fold, along with calcium dysregulation are central in considering a clinical diagnosis of Kenny-Caffey syndrome.
Journal of AAPOS
Timoney et al
293
This is the first time that OCT analysis of the characteristic papillomacular retinal fold of Kenny-Caffey syndrome has been performed. This new clinical tool provides a detailed anatomical picture of the fold and demonstrates that it involves both the choroid and the retina but spares the sclera. This supports the hypothesis that the fold is a result of the crowding effect of extreme nanophthalmos.
References 1. Kenny FM, Linarelli L. Dwarfism and cortical thickening of tubular bones. Am J Dis Child 1966;111:201-7. 2. Caffey J. Congenital stenosis of medullary spaces in tubular bones and calvaria in two proportionate dwarfs—mother and son; coupled with transitory hypocalcemia. Am J Roentgenol 1967;100:111. 3. Bergada I, Schiffrin A, Srair HA, et al. Kenny syndrome: Description of additional abnormalities and molecular studies. Hum Genet 1988; 80:39-42. 4. Boynton JR, Pheasant TR, Johnson BL, et al. Ocular findings in Kenny’s Syndrome. Arch Ophthalmol 1979;97:896-900. 5. Fernandez GR, Negrete FJ, Martin BG, et al. Bilateral optic atrophy in Kenny’s Syndrome. Acta Ophthalmologica 1992;70:135-8. 6. Larsen JL, Kivlin J, Odell WD. Unusual cause of short stature. Am J Med 1985;78:1025-32. 7. Parvari R, Hershkovitz E, Grossman N, et al. Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey Syndrome. Nat Genet 2002;32:44852. 8. Winter RM, Baraitser M. Kenny-Caffey Syndrome [computer program]. Winter-Baraitser Dysmorphology Database. London Medical Database; 2006. 9. Majewski F, Rosendahl W, Ranke M, et al. The Kenny syndrome, a rare type of growth deficiency with tubular stenosis, transient hypoparathyroidism and anomalies of refraction. Eur J Pediatr 1981;136: 21-30. 10. Serrano JC, Hodgkins PR, Taylor DSI, et al. The nanophthalmic macula. Br J Ophthalmol 1998;82:276-9.
An unusual congenital syndrome was first reported in 1966 by Kenny and Linarelli, who described two patients with dwarfism, cortical thickening of the long bones, transient hypocalcemia, and normal intelligence,1 the radiological features in the condition being reported by Caffey.2 The constellation of dwarfism, medullary stenosis, transient hypocalcemia, and ophthalmologic abnormalities has been classically recognized as Kenny-Caffey syndrome with additional manifestations ranging from hypoplastic nails, persistent neutropenia, abnormal T-cell function, and neonatal liver disease.3 Ocular findings range from uncomplicated nanophthalmos with hypermetropia to extreme pseudopapilloedema, vascular tortuosity, and macular crowding. Other reported ophthalmic findings include bilateral band keratopathy,4 bilateral optic atrophy,5 and myelinated nerve fibers.6 We report two cases of Kenny-Caffey syndrome with an ellipsoid macular fold orientated horizontally involving the fovea and document this unusual feature with optical coherence topography (OCT ).
Case Reports Case 1 six-year-old white boy was referred to the ophthalmology outpatient clinic for difficulty in reading at school. He was the product of a dizygotic twin pregnancy born to nonconsanguineous parents in their late twenties by normal vaginal delivery weighing 2 pounds and 12 ounces at 28 weeks gestation. Postnatally he presented to the Neonatal Intensive Care Unit with twitching movements of his limbs and was subsequently treated for transient hypocalcemia. He had an otherwise uncomplicated neonatal period. No dysmorphic features were present at birth. The family history and examination of his parents and twin sister were noncontributory; they did not display any dysmorphic features and ophthalmologic examinations were normal. At first visit he was noted to have an expressionless face, prominent forehead, micrognathia, and proportionate short stature. At 9 years of age he measured 126 cm (3rd
A
a
Royal Victoria Eye and Ear Hospital, Dublin, Ireland; bOur Lady’s Hospital for Sick Children, Dublin, Ireland. No financial interests/conflicts are associated with this article. Submitted December 27, 2005. Revision accepted September 11, 2006. Published online March 20, 2007. Reprint requests: Peter Timoney, Department of Ophthalmology, Kentucky Clinic, University of Kentucky, Lexington, Kentucky 40536-0284 (email: [email protected]) J AAPOS 2007;11:291-293. Copyright © 2007 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2007/$35.00 ⫹ 0 doi:10.1016/j.jaapos.2006.09.020
Journal of AAPOS
centile), and his occipito-frontal head circumference measured 53.9 cm (25th centile). He has no evidence of low intelligence as evidenced by his attendance and progression in a mainstream classroom environment. Uncorrected visual acuity was 6/60 in each eye and best corrected visual acuity was 6/36 in each eye. Cycloplegic refraction revealed ⫹16.50 diopters sphere (D) in the right eye and ⫹18.00 D in the left eye. There was no evident hypertelorism with an inner canthal distance of 30 mm and an outer canthal distance of 85 mm. Pupils were equal and reacted normally. Color testing with Ishihara pseudoisochromatic test plates was normal. Visual fields were full to confrontation. Motility evaluation revealed orthotropia. Anterior segment examination revealed shallow anterior chambers and bilateral microcornea with each cornea measuring 9.5 mm in horizontal diameter. Intraocular pressures were normal. Dilated retinal examination revealed symmetrical pseudopapilloedema with indistinct margins and bilateral horizontal retinal folds emanating from the optic nerve head to the temporal margin of the macula. A diagnosis of hypermetropic pseudopapilloedema was based on there being no obscuration of peripapillary vessels by nerve fiber edema, no congestion of the disk microvasculature, and no microvascular abnormalities on the surface of the disk such as flame-shaped hemorrhages. There was associated minimal retinal vascular tortuosity (Figure 1A). Based on the ophthalmologic findings, the patient was referred for further evaluation. A skeletal survey study was within normal range and endocrinologic tests including serum calcium, thyroid function tests, and parathyroid hormone were normal. Genetic analysis revealed a normal fluorescent in situ hybridization study of chromosome 22q11, thereby excluding the possibility of DiGeorge syndrome, a rare congenital disorder classified as a deletion 22q11 syndrome in which hypocalcemia is a prominent feature. Although there was no biochemical evidence for continued calcium dysregulation since the neonatal period, and the skeletal examination did not show classical signs of Kenny-Caffey syndrome, this was deemed to be the most likely diagnosis. The diagnosis was reinforced by the fact that other causes of transient hypocalcemia were diagnostically excluded and in view of the ophthalmic findings which were central to the diagnosis. A-scan ultrasonography demonstrated nanophthalmia in both eyes with an axial length of 14.67 mm in the right eye and 14.73 mm in the left eye. OCT illustrated elevation of the neural retina in the central macular region with
291
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Timoney et al
FIG 1. (A) Fundus photograph displaying the right elevated swollen disk with blurred margins along with the horizontal macular fold emanating from the optic disk margin and extending temporally. (B) Optical coherence tomography (OCT ) illustrating the chorioretinal elevation in the central macular region with an underlying empty vaulted space.
an empty, vaulted space between the choroid and sclera. There were no retinal pigment epithelial detachments or any cystic macular changes evident. The overlying retina was of normal thickness (Figure 1B). Case 2 A 12-year-old white boy was referred to the ophthalmology clinic with bilateral decreased visual acuity. His family history was noncontributory; he was the offspring to nonconsanguineous parents in their early thirties; his parents and siblings were without any medical issues, and general and ophthalmologic examination of his parents was normal. He was proportionately small in stature, measuring 122 cm (third centile), had a featureless face with a prominent forehead and microagnathia, and his mental development was normal. His best corrected visual acuity was 6/24 in each eye. Cycloplegic refraction was ⫹16.00 D in the right eye and ⫹16.00 D in the left eye. The inner and outer canthal distances were within normal range. Anterior segment examination revealed early bilateral band keratopathy and bilateral microcornea with each cornea
Volume 11 Number 3 / June 2007
FIG 2. (A) Fundus image of the left swollen optic disk with indistinct margins and the macular fold extending temporally. (B) OCT showing the elevated chorioretinal fold of normal thickness with an underlying empty vaulted area.
measuring 10 mm in horizontal diameter. Fundus examination revealed minimal tortuous retinal vasculature, pseudopapilloedema, and bilateral horizontal elevated macular folds extending from the disk margin temporally (Figure 2A). Bilateral nanophthalmia was demonstrated by A-scan ultrasonography with an axial length of 14.29 mm in the right eye and 14.27 in the left eye. OCT imaging portrayed chorioretinal elevation in the central macular area with an underlying empty, vaulted space (Figure 2B). On further evaluation, he suffered from hypoparathyroidism requiring daily 1-alpha vitamin D supplementation, and skeletal studies were within normal range.
Comment Early reports of Kenny-Caffey syndrome were predicated upon “classical” radiological findings of medullary stenosis and excessive thickening of the cortex in addition to delayed closure of the anterior fontanelle.1 However, the identification of gene mutations has shown a much wider phenotype associated with the syndrome than was previously recognized,7 and, as noted by Winter and Baraitser
Journal of AAPOS
Volume 11 Number 3 / June 2007
in their commentary on the condition, “radiological findings are not constant features” in Kenny-Caffey syndrome.8 Accordingly, the absence of classical, absolute radiological findings as reported by Majewski et al9 is not surprising nor does this absence contradict the diagnosis, particularly in a case with documented hypocalcemia for whom other causes of that condition have been excluded and whose ophthalmic findings were so strongly suggestive of the diagnosis. Molecular testing for confirmation of the diagnosis was not performed in either of the two cases. These two cases appear to be sporadic and suggest either a new mutation or a possible autosomal-recessive inheritance (Kenny-Caffey syndrome, type 1). Despite the lack of radiological findings, the ophthalmologic features were invaluable in establishing the diagnosis in these two cases. Ocular anomalies are present in 73% of Kenny-Caffey syndrome patients with extreme hypermetropia and nanophthalmos being the most prevalent.5 Visual morbidity is secondary to angle closure glaucoma in association with nanophthalmos, anomalous macular anatomy, and ammetropic/anisometropic ambylopia. Previous studies have indicated the association of nanophthalmos with Kenny-Caffey syndrome and have clearly documented the various retinal findings with nanophthalmos.10 The sole histopathological evaluation of enucleated nanophthalmic eyes from a patient with Kenny-Caffey syndrome demonstrated swollen discs with lateral displacement of the peripapillary retina due to bulging of the edge of the disk.4 Notwithstanding the documented clinical variability, certain clinical manifestations, including growth retardation, atypical facial features, and ocular anomalies, such as nanophthalmos and a papillomacular retinal fold, along with calcium dysregulation are central in considering a clinical diagnosis of Kenny-Caffey syndrome.
Journal of AAPOS
Timoney et al
293
This is the first time that OCT analysis of the characteristic papillomacular retinal fold of Kenny-Caffey syndrome has been performed. This new clinical tool provides a detailed anatomical picture of the fold and demonstrates that it involves both the choroid and the retina but spares the sclera. This supports the hypothesis that the fold is a result of the crowding effect of extreme nanophthalmos.
References 1. Kenny FM, Linarelli L. Dwarfism and cortical thickening of tubular bones. Am J Dis Child 1966;111:201-7. 2. Caffey J. Congenital stenosis of medullary spaces in tubular bones and calvaria in two proportionate dwarfs—mother and son; coupled with transitory hypocalcemia. Am J Roentgenol 1967;100:111. 3. Bergada I, Schiffrin A, Srair HA, et al. Kenny syndrome: Description of additional abnormalities and molecular studies. Hum Genet 1988; 80:39-42. 4. Boynton JR, Pheasant TR, Johnson BL, et al. Ocular findings in Kenny’s Syndrome. Arch Ophthalmol 1979;97:896-900. 5. Fernandez GR, Negrete FJ, Martin BG, et al. Bilateral optic atrophy in Kenny’s Syndrome. Acta Ophthalmologica 1992;70:135-8. 6. Larsen JL, Kivlin J, Odell WD. Unusual cause of short stature. Am J Med 1985;78:1025-32. 7. Parvari R, Hershkovitz E, Grossman N, et al. Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey Syndrome. Nat Genet 2002;32:44852. 8. Winter RM, Baraitser M. Kenny-Caffey Syndrome [computer program]. Winter-Baraitser Dysmorphology Database. London Medical Database; 2006. 9. Majewski F, Rosendahl W, Ranke M, et al. The Kenny syndrome, a rare type of growth deficiency with tubular stenosis, transient hypoparathyroidism and anomalies of refraction. Eur J Pediatr 1981;136: 21-30. 10. Serrano JC, Hodgkins PR, Taylor DSI, et al. The nanophthalmic macula. Br J Ophthalmol 1998;82:276-9.