Letters
The syndrome now known as microcephaly associated with congenital lymphedema and chorioretinopathy (MLCR) was first described in 1980 by Alzial et al.1 Microcephaly with chorioretinal dysplasia has been reported to be inherited in an autosomal dominant or autosomal recessive manner and has a variety of associations, including lymphedema and mental retardation. Our patient displayed all 4 of these clinical characteristics and appeared to manifest an autosomal dominant inheritance pattern.
optical coherence tomography (Heidelberg Engineering Inc) showed loss of the photoreceptor layers temporally and inferiorly (Figure 2), corresponding to the areas of chorioretinal atrophy visible by ophthalmoscopy. Examination of the extremities revealed pedal lymphedema. Based on the history and clinical findings, we suspected a mutation in KIF11. After obtaining written informed consent conforming to the tenets of the Declaration of Helsinki, molecular analysis of KIF11 was performed. This identified a heterozygous 2–base pair deletion (Thr65 del 2 base pair AT) in exon 2 that, to our knowledge, has not been previously reported. This mutation would be expected to cause 2 incorrect amino acids (codons 66 and 67 would be changed from Tyr-Thr to His-Phe) followed by a premature stop codon.
Report of a Case | A boy in his midteens was referred after failing his school vision test. He has a learning disability, first noted at age 3 years, and a family history of a learning disability in both his mother and maternal grandfather. Review of his medical records revealed that at age 2 days he had a head circumference that was in the fifth percentile and pedal edema. The patient was seen by the medical genetics service at age 9 years and was noted to have microcephaly, intellectual disability, and dysmorphic features including asymmetric facies and a single left palmar crease. Laboratory evaluation at that time included DNA fragile X syndrome testing and chromosome microarray analysis, both of which showed normal results. Our examination revealed best-corrected visual acuity of 20/80 OD and 20/40 OS. The patient had low hyperopia. The extraocular motility, pupils, and anterior segments were normal. Dilated fundus examination revealed optic disc pallor and gliosis, atrophic chorioretinal lesions inferior to the optic discs, and smaller scattered areas of chorioretinal atrophy temporally (Figure 1). Heidelberg retinal angiography (Spectralis) and
Discussion | The ocular findings of MLCR are peripheral retinal pigmentation, retinal folds, chorioretinopathy, and optic atrophy.2 Chorioretinopathy is the most common and highly specific finding in patients with KIF11 mutations.2 Lower limb features include pitting edema of the lower extremities, deep interphalangeal creases, small dysplastic nails, and wide-caliber veins. Lower limb lymphoscintigraphy studies have been used in some patients to confirm lymphatic vessel dysfunction.2 Facial features include broad, depressed nasal bridge, prominent nasal tip, full lips, and mild micrognathia. The facial features were first described by Opitz3 in 1986 as congenital lymphedema of the face. KIF11 encodes kinesin-5, which is a molecular motor protein essential for mitosis. It is also involved in central nervous system development and axonal cone outgrowth.4 Kinesin-5 is a nanomotor that moves along microtubule tracks in the cell. The function of this protein includes chromosome positioning, centrosome separation, and establishing a bipolar spindle during cell mitosis. Other gene products involved in centrosome function and intracellular transport, such as CEP290 and Bardet-Biedl
OBSERVATION
Autosomal Dominant Microcephaly Associated With Congenital Lymphedema and Chorioretinopathy Due to a Novel Mutation in KIF11
Figure 1. Color Fundus Photographs A
B
Color fundus photographs of the right (A) and left (B) eyes showing gliosis of the optic nerve and an inferior area of chorioretinal atrophy extending from the arcades to the periphery. jamaophthalmology.com
(Reprinted) JAMA Ophthalmology Published online March 12, 2015
Copyright 2015 American Medical Association. All rights reserved.
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Letters
Figure 2. Optical Coherence Tomographic Images A
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Katrina Mears, MD Benjamin Bakall, MD, PhD Lisa A. Harney, BA Jessica A. Penticoff, BA Edwin M. Stone, MD, PhD
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B
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syndrome proteins, are also involved in retinal diseases, likely based on their role in intraflagellar transport across the connecting cilium of photoreceptor cells. Because the eye phenotype observed in MLCR is considerably different from what is observed in these other disorders, the mechanism involved in disease associated with KIF11 mutation is likely not to be related to intraflagellar transport.
Author Affiliations: Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City (Mears, Bakall, Harney, Penticoff, Stone); Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City (Mears, Bakall, Harney, Penticoff, Stone); Howard Hughes Medical Institute, University of Iowa, Iowa City (Stone).
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Corresponding Author: Edwin M. Stone, MD, PhD, Stephen A. Wynn Institute for Vision Research, University of Iowa, 375 Newton Rd, 4111 MERF, Iowa City, IA 52242 ([email protected]).
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Published Online: March 12, 2015. doi:10.1001/jamaophthalmol.2015.199. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 200 µm
Funding/Support: This study was supported by grant R01-EY15569 from the National Eye Institute and by the Foundation Fighting Blindness, the Stephen A. Wynn Foundation, and the Howard Hughes Medical Institute.
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D
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 1. Alzial C, Dufier JL, Brasnu C, Aicardi J, de Grouchy J. “True” microcephaly with dominant-inheritance chorioretinal dysplasia [in French]. Ann Genet. 1980;23 (2):91-94.
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Horizontal (A and C) and vertical (B and D) optical coherence tomographic images of the right (A and B) and left (C and D) eyes showing thinning of the retina and loss of the ellipsoid zone in the perifoveal area. Green lines indicate the direction of the scan.
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2. Ostergaard P, Simpson MA, Mendola A, et al. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy. Am J Hum Genet. 2012;90(2):356-362. 3. Opitz JM. On congenital lymphedema. Am J Med Genet. 1986;24(1):127-129. 4. Myers KA, Baas PW. Kinesin-5 regulates the growth of the axon by acting as a brake on its microtubule array. J Cell Biol. 2007;178(6):1081-1091.
JAMA Ophthalmology Published online March 12, 2015 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a University of Georgia User on 05/28/2015
jamaophthalmology.com
The syndrome now known as microcephaly associated with congenital lymphedema and chorioretinopathy (MLCR) was first described in 1980 by Alzial et al.1 Microcephaly with chorioretinal dysplasia has been reported to be inherited in an autosomal dominant or autosomal recessive manner and has a variety of associations, including lymphedema and mental retardation. Our patient displayed all 4 of these clinical characteristics and appeared to manifest an autosomal dominant inheritance pattern.
optical coherence tomography (Heidelberg Engineering Inc) showed loss of the photoreceptor layers temporally and inferiorly (Figure 2), corresponding to the areas of chorioretinal atrophy visible by ophthalmoscopy. Examination of the extremities revealed pedal lymphedema. Based on the history and clinical findings, we suspected a mutation in KIF11. After obtaining written informed consent conforming to the tenets of the Declaration of Helsinki, molecular analysis of KIF11 was performed. This identified a heterozygous 2–base pair deletion (Thr65 del 2 base pair AT) in exon 2 that, to our knowledge, has not been previously reported. This mutation would be expected to cause 2 incorrect amino acids (codons 66 and 67 would be changed from Tyr-Thr to His-Phe) followed by a premature stop codon.
Report of a Case | A boy in his midteens was referred after failing his school vision test. He has a learning disability, first noted at age 3 years, and a family history of a learning disability in both his mother and maternal grandfather. Review of his medical records revealed that at age 2 days he had a head circumference that was in the fifth percentile and pedal edema. The patient was seen by the medical genetics service at age 9 years and was noted to have microcephaly, intellectual disability, and dysmorphic features including asymmetric facies and a single left palmar crease. Laboratory evaluation at that time included DNA fragile X syndrome testing and chromosome microarray analysis, both of which showed normal results. Our examination revealed best-corrected visual acuity of 20/80 OD and 20/40 OS. The patient had low hyperopia. The extraocular motility, pupils, and anterior segments were normal. Dilated fundus examination revealed optic disc pallor and gliosis, atrophic chorioretinal lesions inferior to the optic discs, and smaller scattered areas of chorioretinal atrophy temporally (Figure 1). Heidelberg retinal angiography (Spectralis) and
Discussion | The ocular findings of MLCR are peripheral retinal pigmentation, retinal folds, chorioretinopathy, and optic atrophy.2 Chorioretinopathy is the most common and highly specific finding in patients with KIF11 mutations.2 Lower limb features include pitting edema of the lower extremities, deep interphalangeal creases, small dysplastic nails, and wide-caliber veins. Lower limb lymphoscintigraphy studies have been used in some patients to confirm lymphatic vessel dysfunction.2 Facial features include broad, depressed nasal bridge, prominent nasal tip, full lips, and mild micrognathia. The facial features were first described by Opitz3 in 1986 as congenital lymphedema of the face. KIF11 encodes kinesin-5, which is a molecular motor protein essential for mitosis. It is also involved in central nervous system development and axonal cone outgrowth.4 Kinesin-5 is a nanomotor that moves along microtubule tracks in the cell. The function of this protein includes chromosome positioning, centrosome separation, and establishing a bipolar spindle during cell mitosis. Other gene products involved in centrosome function and intracellular transport, such as CEP290 and Bardet-Biedl
OBSERVATION
Autosomal Dominant Microcephaly Associated With Congenital Lymphedema and Chorioretinopathy Due to a Novel Mutation in KIF11
Figure 1. Color Fundus Photographs A
B
Color fundus photographs of the right (A) and left (B) eyes showing gliosis of the optic nerve and an inferior area of chorioretinal atrophy extending from the arcades to the periphery. jamaophthalmology.com
(Reprinted) JAMA Ophthalmology Published online March 12, 2015
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a University of Georgia User on 05/28/2015
E1
Letters
Figure 2. Optical Coherence Tomographic Images A
200 µm
Katrina Mears, MD Benjamin Bakall, MD, PhD Lisa A. Harney, BA Jessica A. Penticoff, BA Edwin M. Stone, MD, PhD
200 µm
B
200 µm
syndrome proteins, are also involved in retinal diseases, likely based on their role in intraflagellar transport across the connecting cilium of photoreceptor cells. Because the eye phenotype observed in MLCR is considerably different from what is observed in these other disorders, the mechanism involved in disease associated with KIF11 mutation is likely not to be related to intraflagellar transport.
Author Affiliations: Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City (Mears, Bakall, Harney, Penticoff, Stone); Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City (Mears, Bakall, Harney, Penticoff, Stone); Howard Hughes Medical Institute, University of Iowa, Iowa City (Stone).
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Corresponding Author: Edwin M. Stone, MD, PhD, Stephen A. Wynn Institute for Vision Research, University of Iowa, 375 Newton Rd, 4111 MERF, Iowa City, IA 52242 ([email protected]).
C
Published Online: March 12, 2015. doi:10.1001/jamaophthalmol.2015.199. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 200 µm
Funding/Support: This study was supported by grant R01-EY15569 from the National Eye Institute and by the Foundation Fighting Blindness, the Stephen A. Wynn Foundation, and the Howard Hughes Medical Institute.
200 µm
D
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 1. Alzial C, Dufier JL, Brasnu C, Aicardi J, de Grouchy J. “True” microcephaly with dominant-inheritance chorioretinal dysplasia [in French]. Ann Genet. 1980;23 (2):91-94.
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Horizontal (A and C) and vertical (B and D) optical coherence tomographic images of the right (A and B) and left (C and D) eyes showing thinning of the retina and loss of the ellipsoid zone in the perifoveal area. Green lines indicate the direction of the scan.
E2
2. Ostergaard P, Simpson MA, Mendola A, et al. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy. Am J Hum Genet. 2012;90(2):356-362. 3. Opitz JM. On congenital lymphedema. Am J Med Genet. 1986;24(1):127-129. 4. Myers KA, Baas PW. Kinesin-5 regulates the growth of the axon by acting as a brake on its microtubule array. J Cell Biol. 2007;178(6):1081-1091.
JAMA Ophthalmology Published online March 12, 2015 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a University of Georgia User on 05/28/2015
jamaophthalmology.com
