Diagnostic and Therapeutic Challenges
Edited by H. Richard McDonald
Drs. Kurt Spiteri Cornish, Aravind R. Reddy, Vikki A. MCBain, and Kimberly Stepien
T
delineated by current imaging techniques.1,2 This variability is like the result of the fact that albinism is not one disease but rather describes a group of genetically diverse disorders, each characterized by errors in melanin biosynthesis, resulting in absent or reduction in melanin pigmentation of the eye, and often hair and skin. Albinism can be further divided into ocular albinism or oculocutaneous albinism. Ocular albinism (OA1) is X-linked disorder because of mutations in the GPR143 gene (MIM 300808), which encodes a G protein-coupled receptor expressed by melanocytes and the retina pigment epithelium. Typically, affected males will have normal skin and hair pigmentation, but exhibit the ocular changes thought typical of albinism: iris transillumination defects, photosensitivity, reduced visual acuity, refractive error, macular translucency, astigmatism, nystagmus, and impaired stereopsis. Female carriers of X-linked albinism may have iris transillumination defects and have patchy pigmentary changes in the retina. Very rarely, females may have more significant findings of albinism because of skewed X-chromosome inactivation, monosomy of the X chromosome, or being homozygous for a GPR143 mutation.3 Although less likely, this could be the case for this patient. Individuals who never develop melanin pigment within the eye, skin, or hair have oculocutaneous albinism type 1 (OCA1: MIM 203100). Oculocutaneous albinism type 1 is an autosomal recessive disorder resulting from complete lack of tyrosinase enzyme function because of mutations in the tyrosinase (TYR) gene. Affected individuals will have white hair and skin from birth, iris transillumination defects, significantly reduced vision, infantile nystagmus, retinal hypopigmentation, foveal hypoplasia, and misrouting of optic nerve projections at the optic chiasm. OCA1B (MIM 606952), also caused by mutations in the TYR gene but with minimal tyrosinase enzyme activity, may
his case is submitted by Drs. Kurt Spiteri Cornish, Aravind R. Reddy, and Vikki A. McBain of the Eye Out-Patient Department, Aberdeen Royal Infirmary, Aberdeen, United Kingdom; commented by Dr. Kimberly Stepien, Milwaukee, Wisconsin. Case Report
An 8-year-old girl was referred with slightly reduced visual acuities (0.24 and 0.26 logarithm of the minimum angle of resolution in the right and left eyes, respectively). Visual acuity did not improve despite hypermetropic correction. Anterior segments were normal, ocular motility full and fundus examination revealed absent foveal reflexes. Full-field electroretinography, pattern electroretinography, and pattern visual evoked potentials were all within normal limits. Infrared reflectance (Figure 1), optical coherence tomography (OCT) (Figure 2), and autofluorescence (AF) (Figure 3) are presented for discussion of diagnosis and the etiology of the concentric reflex seen on the IRR.
Dr. Kimberly Stepien (Milwaukee, Wisconsin): Spiteri Cornish et al present an interesting case of an 8-year-old girl with slightly reduced visual acuity in both eyes and fundus findings remarkable for loss of foveal reflexes. Optical coherence tomography shows lack of inner retina interdigitation in both eyes, although some cone inner and outer segment lengthening is seen, especially in the left eye. Also given are infrared fundus images showing absence of typical foveal reflectance and fundus autofluorescence showing lack of typical hypofluorescence of the foveal area in the left eye, although a speckle appearance is seen, suggesting some macular pigment granularity. The information provided is very suggestive of an individual with albinism. Recent imaging research has shown a significant variability to foveal morphology in individuals with albinism, suggesting previously used terms of foveal hypoplasia or foveal plana do not adequately represent anatomical findings that can be 2311
2312 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2014 VOLUME 34 NUMBER 11
Fig. 1. Infrared reflectance (IRR) imaging of right (A) and left (B) eye. There is a lack of “bow-tie” reflex caused by Henle layer birefringence as seen in normal IRR (C) and highlighted with a marker (D). Concentric petalloid macular reflex is seen bilaterally in our case (A and B).
have minimal levels of pigmentation.4 Although not directly addressed, it does not appear that this patient had lack of skin and hair pigmentation, making a diagnosis of OCA1 less likely. Those individuals with features of albinism who develop some melanin pigment could have oculocutaneous albinism type 2 (OCA2) (MIM 611409), OCA3 (MIM 203290), OCA4 (MIM 606574), or Hermansky– Pudlak syndromes 1 to 7.5 OCA2, OCA3, and OCA4, all autosomal recessive disorders, are considered somewhat milder forms of oculocutaneous albinism and are because of mutations in OCA2, TYR2, and MATP genes, respectively.5 Individuals with OCA2 have been found to have lightly pigmented hair, ranging from yellow to light brown or even red.6 All have ocular findings consistent with albinism to varying degrees. It is very possible that the discussed patient could have a form of oculocutaneous albinism. To better define the etiology of this child’s unique examination findings, further history and examination could prove helpful. Information such as hair color
at birth and whether they tan may be helpful in distinguishing ocular albinism from oculocutaneous albinism. If the patient has siblings, it would be interesting to know if the patient is considered more fair complexed. A history of easy bruising, nosebleed, etc., could be possible indicators of Hermansky–Pudlak syndrome, and frequent infections along with findings of albinism could indicate Chediak–Higashi syndrome. A detailed family history, the ethnicity of the biologic parents, and inquiry to the possibility of consanguinity may be helpful. On examination, noting hair and skin color may be useful. Many patients with albinism have a positive angle k. Careful examination for nystagmus including looking for compensatory head tilt is important. On slit-lamp examination, careful checking for iris transillumination defects during an undilated examination and documenting a rudimentary annular reflex and macular pigmentation is useful. An indirect examination looking for subtle peripheral hypopigmentation is helpful.
DIAGNOSTIC AND THERAPEUTIC CHALLENGES
2313
coherence tomography imaging. The variability in optical coherence tomography findings may be explained by the heterogeneity of diseases falling under the title of “albinism.” She states that albinism represents a diverse group of genetic disorders, all characterized by errors in melanin synthesis. She reviews the types of albinism, starting with ocular albinism, an X-lined disorder because of mutations in the GPR143 gene. Males will usually have normal skin and hair, but have characteristic albinitic ocular changes, listed below.
Fig. 2. Optical coherence tomography of right (A) and left (B) eyes showing absence of foveal pit and continuity of all retinal layers throughout the fovea. C. Normal optical coherence tomography highlighting normal foveal dip (arrow).
Genetic testing is available for several variants of albinism. Family history, ethnicity of the parents, and better knowledge of the patient’s hair color and pigmentation may be helpful in targeting which tests may be more likely in revealing the underlying etiology for this specific patient.
Editor’s Note: Drs. Spiteri Cornish, Reddy, and McBain have presented an 8-year-old girl with reduced vision bilaterally and absent foveal reflexes. Dr. Stepien has consulted on this case and states that the testing results suggest a diagnosis of albinism. She states that our conventional descriptions of foveal findings in this entity (foveal hypoplasia) do not represent anatomical findings shown by current optical
1. 2. 3. 4. 5. 6. 7. 8.
Iris transillumination Photosensitivity Reduced visual acuity Refractive error Macular translucency Astigmatism Nystagmus Impaired stereopsis
Dr. Stepien states that female carriers may show some of these characteristics because of skewed X-chromosome inactivation, monosomy of the X-chromosome, or being homozygous for a GPR143 mutation. Oculocutaneous albinism type 1 is an autosomal recessive disorder resulting from complete lack of tyrosinase enzyme function. These patients have the following findings: 1. 2. 3. 4. 5. 6. 7.
White hair and skin from birth Iris transillumination defects Significantly reduced vision Infantile nystagmus Retinal hypopigmentation Foveal hypoplasia Misrouting of optic nerve projections at the optic chiasm
Fig. 3. Autofluorescence of the patient’s left eye (A) and a normal age-matched control (B). There is absence of hypoautofluorescence centrally in the patient’s eye (A) as opposed to the control.
2314 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2014 VOLUME 34 NUMBER 11
Fig. 4. Five-channel flash visual evoked potential of the patient showing optic nerve misrouting typical of ocular and oculocutaneous albinism.
She reviews those individuals with features of albinism who develop some melanin pigment, who could have oculocutaneous albinism type 2 or Hermansky– Pudlak syndrome. Patients with oculocutaneous type 2 may have lightly pigmented hair and varying degrees of ocular albinitic findings. Dr. Stepien would like information on hair color at birth and ability to tan, sibling history, history of easy brusing (Hermansky–Pudlak syndrome), and frequent infections (Chediak–Higashi syndrome). She notes that genetic testing is available for several variants of albinism. Follow-up From Presenters: This is a case of an 8-year-old girl with mildly reduced visual acuity despite refractive correction and lack of clinical signs except lack of foveal reflex. The diagnosis of foveal hypoplasia was made on optical coherence tomography because of the lack of foveal dip and the uninterrupted continuation of retinal layers through the macula (Figure 2). This prompted us to perform 5-channel visual evoked potentials, which are presented in Figure 4. Optic nerve misrouting was thus shown, and a diagnosis of ocular albinism made. The phenotypic presentation of ocular albinism has been described as a continuum of foveal immaturity (foveal hypoplasia) which ranges from mild to severe,7 as reflected in visual acuity and other clinical signs including nystagmus and iris transillumination. In all cases, however, there is lack of a normal foveal architecture which normally consists of thicker Henle layer in the fovea, responsible for the “bow-tie” reflex in normal infrared reflectance imaging.8 The underlying cause of the “concentric petaloid” reflex is hitherto not understood but has been confirmed in a series of patients with foveal hypoplasia. It is believed that a regular ring concentric of phase retardation is caused
by the radially symmetric orientation of the axons (Henle layer) and retinal nerve fiber layer around the fovea, as these layers form a continuous regular layer in cases of foveal hypoplasia. Further studies are needed to confirm this. We thank our Drs. Spiteri Cornish, Reddy, and McBain for their case and Dr. Stepien for her discussion. References 1. McAllister JT, Dubis AM, Tait DM, et al. Arrested development: high-resolution imaging of foveal morphology in albinism. Vision Res 2010;50:810–817. doi: 810.1016/j. visres.2010.1002.1003. 2. Mohammad S, Gottlob I, Kumar A, et al. The functional significance of foveal abnormalities in albinism measured using spectral-domain optical coherence tomography. Ophthalmology 2011;118:1645–1652. doi: 1610.1016/j.ophtha.2011.1601.1037. 3. Lewis RA. Ocular albinism, X-linked. 1993. 4. Lewis RA. Oculocutaneous albinism type 1. 1993. 5. Lewis RA. Oculocutaneous albinism type 2. 1993. 6. King RA, Willaert RK, Schmidt RM, et al. MC1R mutations modify the classic phenotype of oculocutaneous albinism type 2 (OCA2). Am J Hum Genet 2003;73:638–645. 7. Michaelides M, Jeffery G, Moore AT. Developmental macular disorders: phenotypes and underlying molecular genetic basis. Br J Ophthalmol 2012;96:917–924. 8. Charbel Issa P, Foerl M, Helb HM, et al. Multimodal fundus imaging in foveal hypoplasia: combined scanning laser ophthalmoscope imaging and spectral-domain optical coherence tomography. Arch Ophthalmol 2008;126:1463–1465.
RETINAÒ, The Journal of Retinal and Vitreous Diseases, encourages readers to submit Diagnostic and Therapeutic Challenges to [email protected]. Cases for the Diagnostic and Therapeutic Challenges section should include a detailed history of the patient, the diagnosis, the workup, the management, and finally, the question or questions that the submitter wishes to have answered by the consultants.
Edited by H. Richard McDonald
Drs. Kurt Spiteri Cornish, Aravind R. Reddy, Vikki A. MCBain, and Kimberly Stepien
T
delineated by current imaging techniques.1,2 This variability is like the result of the fact that albinism is not one disease but rather describes a group of genetically diverse disorders, each characterized by errors in melanin biosynthesis, resulting in absent or reduction in melanin pigmentation of the eye, and often hair and skin. Albinism can be further divided into ocular albinism or oculocutaneous albinism. Ocular albinism (OA1) is X-linked disorder because of mutations in the GPR143 gene (MIM 300808), which encodes a G protein-coupled receptor expressed by melanocytes and the retina pigment epithelium. Typically, affected males will have normal skin and hair pigmentation, but exhibit the ocular changes thought typical of albinism: iris transillumination defects, photosensitivity, reduced visual acuity, refractive error, macular translucency, astigmatism, nystagmus, and impaired stereopsis. Female carriers of X-linked albinism may have iris transillumination defects and have patchy pigmentary changes in the retina. Very rarely, females may have more significant findings of albinism because of skewed X-chromosome inactivation, monosomy of the X chromosome, or being homozygous for a GPR143 mutation.3 Although less likely, this could be the case for this patient. Individuals who never develop melanin pigment within the eye, skin, or hair have oculocutaneous albinism type 1 (OCA1: MIM 203100). Oculocutaneous albinism type 1 is an autosomal recessive disorder resulting from complete lack of tyrosinase enzyme function because of mutations in the tyrosinase (TYR) gene. Affected individuals will have white hair and skin from birth, iris transillumination defects, significantly reduced vision, infantile nystagmus, retinal hypopigmentation, foveal hypoplasia, and misrouting of optic nerve projections at the optic chiasm. OCA1B (MIM 606952), also caused by mutations in the TYR gene but with minimal tyrosinase enzyme activity, may
his case is submitted by Drs. Kurt Spiteri Cornish, Aravind R. Reddy, and Vikki A. McBain of the Eye Out-Patient Department, Aberdeen Royal Infirmary, Aberdeen, United Kingdom; commented by Dr. Kimberly Stepien, Milwaukee, Wisconsin. Case Report
An 8-year-old girl was referred with slightly reduced visual acuities (0.24 and 0.26 logarithm of the minimum angle of resolution in the right and left eyes, respectively). Visual acuity did not improve despite hypermetropic correction. Anterior segments were normal, ocular motility full and fundus examination revealed absent foveal reflexes. Full-field electroretinography, pattern electroretinography, and pattern visual evoked potentials were all within normal limits. Infrared reflectance (Figure 1), optical coherence tomography (OCT) (Figure 2), and autofluorescence (AF) (Figure 3) are presented for discussion of diagnosis and the etiology of the concentric reflex seen on the IRR.
Dr. Kimberly Stepien (Milwaukee, Wisconsin): Spiteri Cornish et al present an interesting case of an 8-year-old girl with slightly reduced visual acuity in both eyes and fundus findings remarkable for loss of foveal reflexes. Optical coherence tomography shows lack of inner retina interdigitation in both eyes, although some cone inner and outer segment lengthening is seen, especially in the left eye. Also given are infrared fundus images showing absence of typical foveal reflectance and fundus autofluorescence showing lack of typical hypofluorescence of the foveal area in the left eye, although a speckle appearance is seen, suggesting some macular pigment granularity. The information provided is very suggestive of an individual with albinism. Recent imaging research has shown a significant variability to foveal morphology in individuals with albinism, suggesting previously used terms of foveal hypoplasia or foveal plana do not adequately represent anatomical findings that can be 2311
2312 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2014 VOLUME 34 NUMBER 11
Fig. 1. Infrared reflectance (IRR) imaging of right (A) and left (B) eye. There is a lack of “bow-tie” reflex caused by Henle layer birefringence as seen in normal IRR (C) and highlighted with a marker (D). Concentric petalloid macular reflex is seen bilaterally in our case (A and B).
have minimal levels of pigmentation.4 Although not directly addressed, it does not appear that this patient had lack of skin and hair pigmentation, making a diagnosis of OCA1 less likely. Those individuals with features of albinism who develop some melanin pigment could have oculocutaneous albinism type 2 (OCA2) (MIM 611409), OCA3 (MIM 203290), OCA4 (MIM 606574), or Hermansky– Pudlak syndromes 1 to 7.5 OCA2, OCA3, and OCA4, all autosomal recessive disorders, are considered somewhat milder forms of oculocutaneous albinism and are because of mutations in OCA2, TYR2, and MATP genes, respectively.5 Individuals with OCA2 have been found to have lightly pigmented hair, ranging from yellow to light brown or even red.6 All have ocular findings consistent with albinism to varying degrees. It is very possible that the discussed patient could have a form of oculocutaneous albinism. To better define the etiology of this child’s unique examination findings, further history and examination could prove helpful. Information such as hair color
at birth and whether they tan may be helpful in distinguishing ocular albinism from oculocutaneous albinism. If the patient has siblings, it would be interesting to know if the patient is considered more fair complexed. A history of easy bruising, nosebleed, etc., could be possible indicators of Hermansky–Pudlak syndrome, and frequent infections along with findings of albinism could indicate Chediak–Higashi syndrome. A detailed family history, the ethnicity of the biologic parents, and inquiry to the possibility of consanguinity may be helpful. On examination, noting hair and skin color may be useful. Many patients with albinism have a positive angle k. Careful examination for nystagmus including looking for compensatory head tilt is important. On slit-lamp examination, careful checking for iris transillumination defects during an undilated examination and documenting a rudimentary annular reflex and macular pigmentation is useful. An indirect examination looking for subtle peripheral hypopigmentation is helpful.
DIAGNOSTIC AND THERAPEUTIC CHALLENGES
2313
coherence tomography imaging. The variability in optical coherence tomography findings may be explained by the heterogeneity of diseases falling under the title of “albinism.” She states that albinism represents a diverse group of genetic disorders, all characterized by errors in melanin synthesis. She reviews the types of albinism, starting with ocular albinism, an X-lined disorder because of mutations in the GPR143 gene. Males will usually have normal skin and hair, but have characteristic albinitic ocular changes, listed below.
Fig. 2. Optical coherence tomography of right (A) and left (B) eyes showing absence of foveal pit and continuity of all retinal layers throughout the fovea. C. Normal optical coherence tomography highlighting normal foveal dip (arrow).
Genetic testing is available for several variants of albinism. Family history, ethnicity of the parents, and better knowledge of the patient’s hair color and pigmentation may be helpful in targeting which tests may be more likely in revealing the underlying etiology for this specific patient.
Editor’s Note: Drs. Spiteri Cornish, Reddy, and McBain have presented an 8-year-old girl with reduced vision bilaterally and absent foveal reflexes. Dr. Stepien has consulted on this case and states that the testing results suggest a diagnosis of albinism. She states that our conventional descriptions of foveal findings in this entity (foveal hypoplasia) do not represent anatomical findings shown by current optical
1. 2. 3. 4. 5. 6. 7. 8.
Iris transillumination Photosensitivity Reduced visual acuity Refractive error Macular translucency Astigmatism Nystagmus Impaired stereopsis
Dr. Stepien states that female carriers may show some of these characteristics because of skewed X-chromosome inactivation, monosomy of the X-chromosome, or being homozygous for a GPR143 mutation. Oculocutaneous albinism type 1 is an autosomal recessive disorder resulting from complete lack of tyrosinase enzyme function. These patients have the following findings: 1. 2. 3. 4. 5. 6. 7.
White hair and skin from birth Iris transillumination defects Significantly reduced vision Infantile nystagmus Retinal hypopigmentation Foveal hypoplasia Misrouting of optic nerve projections at the optic chiasm
Fig. 3. Autofluorescence of the patient’s left eye (A) and a normal age-matched control (B). There is absence of hypoautofluorescence centrally in the patient’s eye (A) as opposed to the control.
2314 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
2014 VOLUME 34 NUMBER 11
Fig. 4. Five-channel flash visual evoked potential of the patient showing optic nerve misrouting typical of ocular and oculocutaneous albinism.
She reviews those individuals with features of albinism who develop some melanin pigment, who could have oculocutaneous albinism type 2 or Hermansky– Pudlak syndrome. Patients with oculocutaneous type 2 may have lightly pigmented hair and varying degrees of ocular albinitic findings. Dr. Stepien would like information on hair color at birth and ability to tan, sibling history, history of easy brusing (Hermansky–Pudlak syndrome), and frequent infections (Chediak–Higashi syndrome). She notes that genetic testing is available for several variants of albinism. Follow-up From Presenters: This is a case of an 8-year-old girl with mildly reduced visual acuity despite refractive correction and lack of clinical signs except lack of foveal reflex. The diagnosis of foveal hypoplasia was made on optical coherence tomography because of the lack of foveal dip and the uninterrupted continuation of retinal layers through the macula (Figure 2). This prompted us to perform 5-channel visual evoked potentials, which are presented in Figure 4. Optic nerve misrouting was thus shown, and a diagnosis of ocular albinism made. The phenotypic presentation of ocular albinism has been described as a continuum of foveal immaturity (foveal hypoplasia) which ranges from mild to severe,7 as reflected in visual acuity and other clinical signs including nystagmus and iris transillumination. In all cases, however, there is lack of a normal foveal architecture which normally consists of thicker Henle layer in the fovea, responsible for the “bow-tie” reflex in normal infrared reflectance imaging.8 The underlying cause of the “concentric petaloid” reflex is hitherto not understood but has been confirmed in a series of patients with foveal hypoplasia. It is believed that a regular ring concentric of phase retardation is caused
by the radially symmetric orientation of the axons (Henle layer) and retinal nerve fiber layer around the fovea, as these layers form a continuous regular layer in cases of foveal hypoplasia. Further studies are needed to confirm this. We thank our Drs. Spiteri Cornish, Reddy, and McBain for their case and Dr. Stepien for her discussion. References 1. McAllister JT, Dubis AM, Tait DM, et al. Arrested development: high-resolution imaging of foveal morphology in albinism. Vision Res 2010;50:810–817. doi: 810.1016/j. visres.2010.1002.1003. 2. Mohammad S, Gottlob I, Kumar A, et al. The functional significance of foveal abnormalities in albinism measured using spectral-domain optical coherence tomography. Ophthalmology 2011;118:1645–1652. doi: 1610.1016/j.ophtha.2011.1601.1037. 3. Lewis RA. Ocular albinism, X-linked. 1993. 4. Lewis RA. Oculocutaneous albinism type 1. 1993. 5. Lewis RA. Oculocutaneous albinism type 2. 1993. 6. King RA, Willaert RK, Schmidt RM, et al. MC1R mutations modify the classic phenotype of oculocutaneous albinism type 2 (OCA2). Am J Hum Genet 2003;73:638–645. 7. Michaelides M, Jeffery G, Moore AT. Developmental macular disorders: phenotypes and underlying molecular genetic basis. Br J Ophthalmol 2012;96:917–924. 8. Charbel Issa P, Foerl M, Helb HM, et al. Multimodal fundus imaging in foveal hypoplasia: combined scanning laser ophthalmoscope imaging and spectral-domain optical coherence tomography. Arch Ophthalmol 2008;126:1463–1465.
RETINAÒ, The Journal of Retinal and Vitreous Diseases, encourages readers to submit Diagnostic and Therapeutic Challenges to [email protected]. Cases for the Diagnostic and Therapeutic Challenges section should include a detailed history of the patient, the diagnosis, the workup, the management, and finally, the question or questions that the submitter wishes to have answered by the consultants.
