- Email: [email protected]
Nod2 mutation
Ocular Manifestations in Blau Syndrome Associated with a CARD15/Nod2 Mutation Toru Kurokawa, MD, PhD,1 Takanobu Kikuchi, PhD,2 Kouichi Ohta, MD, PhD,1 Hiroki Imai, MD,1 Nagahisa Yoshimura, MD, PhD1 Purpose: To report cases of Blau syndrome with a CARD15/Nod2 mutation. Design: Observational and interventional case report. Participants: A 10-year-old Japanese boy (proband) was seen with secondary angle-closure glaucoma (iris bombe), uveitis, skin rashes, and camptodactyly. His sister had posterior synechia and camptodactyly. She had iritis in both eyes during the follow-up period. Both eyes of the father were phthisical because of granulomatous uveitis and secondary glaucoma. The father also had camptodactyly. Methods: Surgery was performed to release the iris bombe. Ocular inflammation was treated by topical and systemic steroids. Biopsy specimens from the skin rash and from the iris (from iridectomy) were obtained from the proband. Genetic analyses were performed on the proband, his sister, and their mother for a CARD15/Nod2 mutation. Main Outcome Measures: Clinical features, pathologic findings of the skin and iris specimens, and genetic analysis of the CARD15/Nod2 gene. Results: Phacoemulsification, intraocular lens implantation, and peripheral iridectomy released the iris bombe. The biopsy specimen from the skin rash showed noncaseating, granulomatous infiltration with epithelioid cells and lymphocytes. The iridectomy specimen showed nonspecific inflammation. Systemic and topical steroid therapy partly reduced the ocular inflammation. Genetic analyses showed that the proband and his sister had an R334W mutation in the CARD15/Nod2 gene, but their mother was of the wild type. Conclusions: Blau syndrome should be considered in the differential diagnosis of childhood uveitis. Genetic analysis of the CARD15/Nod2 gene is helpful in the diagnosis. Ophthalmology 2003;110:2040 –2044 © 2003 by the American Academy of Ophthalmology.
Blau syndrome (MIM 186580) is a rare, autosomal-dominant disorder characterized by early-onset granulomatous arthritis, uveitis, skin rashes, and camptodactyly (flexion deformity at the proximal interphalangeal joint).1 The ocular manifestations, besides the uveitis, can include cataract, glaucoma, and retinal detachment.1,2 We present two siblings with Blau syndrome and describe their ocular manifestations. The presence of a recently described CARD15/Nod2 mutation3 was confirmed in these two siblings by genetic analyses.
Case Reports Case 1 A 10-year-old Japanese boy (proband) had ocular pain and visual loss in his right eye for 2 days. He was born at full term after an Originally received: August 26, 2002. Accepted: March 21, 2003.
Manuscript no. 220579.
1
Department of Ophthalmology, Shinshu University School of Medicine, Matsumoto, Japan.
2 Research Center for Instrumental Analysis, Shinshu University, Matsumoto, Japan. Supported in part by the Grant-in-Aid from the Ministry of Health, Labour, and Welfare of the Japanese Government, Tokyo, Japan. Reprint requests to Nagahisa Yoshimura, MD, PhD, Department of Ophthalmology, Shinshu University School of Medicine, Matsumoto 3908621, Japan. E-mail: [email protected].
2040
© 2003 by the American Academy of Ophthalmology Published by Elsevier Inc.
uncomplicated pregnancy, labor, and delivery. Both his father and mother are Japanese. He had a history of bilateral anterior uveitis since he was 6 years old, and his mother noticed swelling of his wrists and ankles at the same time as the ocular problems. At the initial examination, the best-corrected visual acuity was hand motions in the right eye and 10/20 in the left eye. The intraocular pressure was 38 mmHg in his right eye and 20 mmHg in his left eye. Ciliary injection was noted in both eyes. The cornea of his right eye was edematous, and granular subepithelial opacities and keratic precipitates were found in both eyes (Fig 1A, B). Posterior synechiae were present in both eyes, and an iris bombe was found in the right eye (Fig 1B). There were inflammatory cells in the anterior chamber of both eyes, and rubeosis iritis was found in the right eye. The right anterior chamber angle could not be observed by gonioscopy because of the corneal edema, but ultrasound biomicroscopy showed an iris bombe and a closed chamber angle. The fundus of the right eye could not be evaluated because of the hazy media, and the optic disc in the left eye was slightly hyperemic, and subretinal exudates were observed. In addition to the ocular findings, he had red skin rashes on his cheeks and arms, and his wrists were swollen and deformed (Fig 2A, B). He was afebrile and did not show any lymphadenopathy. The chest x-ray was normal. Complete blood cell counts were normal, and serum C-reactive protein and angiotensin-converting enzyme levels were also normal. Antinuclear antibody and rheumatoid factor were negative. The serum IgG was elevated to 1862 mg/dl. Systemic methylprednisolone (600 mg/day, 20 mg/kg body weight) was administered for 3 days, and topical corticosteroids and atropine were also started. The inflammation of the anterior chamber in both eyes responded immediately to the treatment. To ISSN 0161-6420/03/$–see front matter doi:10.1016/S0161-6420(03)00717-6
Kurokawa et al 䡠 Blau Syndrome release the iris bombe, cataract extraction by phacoemulsification with intraocular lens implantation and peripheral iridectomy were performed. After the surgery, the intraocular pressure of the right eye decreased to the middle teens. The right optic disc was slightly hyperemic. Multiple subretinal exudates that were similar to those seen in sarcoid uveitis were present (Fig 1C). Specimens obtained from peripheral iridectomy showed dilated vessels filled with neutrophils, but no giant cells or epithelioid cells were observed (Fig 1D). Skin biopsy specimens obtained from the right arm before the steroid therapy showed noncaseating granulomatous infiltration with epithelioid cells and lymphocytes. A few giant cells were also observed (Fig 2C, D). These changes are compatible with that found in sarcoidosis. Systemic prednisolone was tapered to 15 mg (0.5 mg/kg body weight) every other day, but it was difficult to reduce or stop the corticosteroids, because a relapse of the anterior and posterior uveitis occurred with 10 mg (0.3 mg/kg body weight) every other day. When the ocular inflammation was controlled, his vision was 15/20 in the right eye and 20/20 in the left eye. Throughout the course, the ocular inflammation and skin rashes waxed and waned in proportion to the amount of systemic prednisolone, but synovitis remained rather quiet.
Case 2 The proband’s 12-year-old sister had a history of iritis and had camptodactyly of the fourth distal interphalangeal joints of both hands. She was also born at term after an uncomplicated pregnancy and labor. She had anterior and posterior synechiae in the left eye (Fig 3A, B), but there were no inflammatory cells in the anterior chamber and vitreous at our initial examination. During the follow-up period, she had mild iritis in her right eye and moderate iritis and vitreous opacities that responded to systemic prednisolone (starting from 1 mg/kg body weight) in the left eye. The retinas were normal in both eyes. She is enjoying good vision of 30/20 in both eyes.
Case 3 The father of cases 1 and 2 was 51 years old and had camptodactyly since he was an infant. He lost his vision in both eyes at age 14 when he was diagnosed with tuberculous uveitis and glaucoma, and both eyes were phthisical. He has not been able to walk since he was 46 years old and had been diagnosed with chronic inflammatory demyelinating polyneuropathy.
Genetic Analysis From the history, the father’s parents did not have any visual problems, skin rashes, or synovitis. With written informed consent and institutional review board permission, peripheral blood was obtained from cases 1 and 2 and their mother. Because a recent report showed a CARD15/NOD2 gene mutation in French and German patients with Blau syndrome, 11 exons and the flanking intronic sequences of CARD15/NOD2 (EMBL accession number AJ303140) were amplified by polymerase chain reaction, and the nucleotide sequence was determined. Both cases 1 and 2 had a C to T transition (Fig 4B, C), with a change of an arginine at the 334th amino acid to a tryptophan (R334W), but their mother had the wild-type sequence (Fig 4A). In the flanking intron, case 2 and the mother did show a deletion and insertion, but case 1 was of the wild type.
Discussion Blau syndrome is a dominantly inherited disease and was first reported as a granulomatous disease of the skin, eyes, and joints in 1985.1 Arthritis is the most common manifestation of the disease and is usually manifested in the first decade of life as painful cystic swelling of the wrists, fingers, ankles, and elbows.1,2 The skin lesions are intermittent, red, and papular rashes.1 Uveitis is classified as granulomatous, and cataracts might occur.1,2 Recently, the susceptibility locus has been mapped to chromosome 16p12-q21,4 and CARD15/NOD2 mutations have been reported in Blau syndrome by a French group.3 Blau syndrome has been described mainly in pediatric or dermatologic journals. Until very recently, there was a serious debate whether Blau syndrome is a distinct disease or represents just a childhood sarcoidosis. Furthermore, it is not known whether Blau syndrome is a rare disease or a disease that is rarely diagnosed. Most likely it is both; Blau syndrome is a rare disease and is also rarely diagnosed. Recently, an article describing the clinical features of this syndrome has been published,5 but no data on genetic analysis have been provided. To the best of our knowledge, this is the first article to report on the clinical picture of Blau syndrome with genetic analysis. In Table 1, previously reported cases of Blau syndrome have been summarized. In the proband, the surgery relieved the iris bombe and secondary angle-closure glaucoma. The iridectomy specimen showed only nonspecific inflammation (Fig 2), and no pathologic findings compatible with sarcoidosis were found. However, the fundus changes (Fig 2) were similar to those found in sarcoid uveitis, and the pathology of the skin lesion was compatible with that found in sarcoidosis. In one study, “comma-shaped” or “wormlike” bodies were found in the cytoplasm of the epithelioid cells of granuloma in Blau syndrome on electron microscopic observation.6 Such organelles have not been described in sarcoidosis and are rather described in histiocytes seen in Hashimoto-Pritzker disease.6 Interestingly, CARD15/NOD2 is a homologue of Apaf-1/NOD1 found mainly in monocytes, and CARD15/ NOD2 is known to regulate apoptosis and/or activate nuclear factor B.7 The mutation found in cases 1 and 2 is located in the nucleotide-binding domain of CARD15/ NOD2, and the nucleotide-binding domain is thought to play an important role in the activation of nuclear factor B. Conversely, in Crohn’s disease, another granulomatous disease, mutations are usually found in the leucine-rich repeat of CARD15/NOD2.8 In our cases, the same mutation as reported by the French group (R334W) was identified. Determination of the genotype of the father was not possible, but from the history, both paternal and maternal grandparents of the proband did not show any signs of Blau syndrome. The mutation in this family might be a new one, and R334W mutation in CARD15/NOD2 might be a hot spot in this gene. It is also possible that the mutation found in our cases is a recurrent mutation resulting from the migration of a common founder chromosome to different populations. Because the ethnic background of our cases is Japanese and cases reported by Miceli-Richard et al are from French and German families,
2041
Kurokawa et al 䡠 Blau Syndrome Figure 1. The right ocular findings of case 1. A, The cornea is edematous, and dotlike subepithelial opacities (arrows) can be seen. Cataract and posterior synechiae are also present. B, The anterior chamber is shallow, forming an iris bombe. C, Slit-lamp photograph of the right fundus after the surgery. The optic disk is hyperemic, and subretinal exudates are present at the equatorial region (arrows). D, Histology of the iridectomy specimen. The vascular vessels are dilated, but there are no giant cells or epithelioid cells. Bar ⫽ 100 m. Figure 2. Systemic presentation of case 1. A, Butterfly-shaped skin rash on the cheeks. B, Deformed wrists and hands can be seen. C, Skin biopsy shows granulomatous inflammatory lesions with epithelioid cells and lymphocytes in the dermis (large and small arrows). Bar ⫽ 500 m. D, A giant epithelioid cell is visible at higher magnification (arrowhead). Bar ⫽ 50 m.
4™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™
Figure 3. Ocular findings in case 2. A, Posterior synechiae are present in the left eye. B, Peripheral anterior synechiae can be seen in the left eye.
such a possibility is not high. The proband had a severe phenotype, but his sister is rather mildly affected, and she is enjoying good vision. Because the proband and his sister have the same R334W mutation in the CARD15/NOD2 gene, it is difficult to explain the difference in the severity from the CARD15/Nod2 mutation. There is a possibility that another unknown gene plays a role in the determination of the severity of the clinical pictures. Although the initial response of case 1 to systemic steroids was good, it was not easy to taper the corticosteroids. Indeed, when prednisolone
Figure 4. Mutation analysis of CARD15/Nod2 gene. The mother shows a wild type (A). In both cases 1 (B) and 2 (C), an arginine-to-tryptophan substitution in the 344th amino acid of the CARD15/Nod2 gene (R344W) is present.
was tapered to 0.3 mg/kg body weight every other day, there was a relapse of uveitis. Although our follow-up period is not long enough, therapeutic regimens other than corticosteroids might be needed to stabilize ocular inflammation of Blau syndrome once anterior and posterior uveitis take place. Judging from the clinical manifestations, family history, and genetic analyses, our cases can be diagnosed as Blau syndrome. Genetic analysis for the father was not possible, but judging from his history, it is most likely that he had a severe form of Blau syndrome. Blau syndrome sometimes is
2043
Ophthalmology Volume 110, Number 10, October 2003 Table 1. Summary of Reported Cases
References
Number Reference of Number Patients
Incidence of Lesions Skin
Joints
Eye
Ophthalmologic Findings
11 4
3/11 0/4
9/11 4/4
3/11 3/4
Iritis, posterior uveitis, peripheral retinitis Multiple recurrences of anterior uveitis, cataract, secondary glaucoma Conjunctival erythema, cataract, anterior and posterior synechiae, uveitis, disc edema, perimacular wrinkle, peripheral pigmented choroidal scar Corneal stromal opacity, cataract, disc swelling Uveitis, multifocal choroidal lesions Panuveitis, cataract, disc swelling, secondary glaucoma, multifocal choroiditis Granulomatous anterior uveitis, disc edema, angleclosure glaucoma Uveitis Band keratopathy, anterior and posterior uveitis, disc edema, anterior ischemic optic neuropathy, glaucoma, cystoid macular edema Uveitis Subepithelial corneal opacities, granulomatous uveitis, anterior synechia, iris bombe, cataract, multifocal choroiditis
Blau Jabs et al
1
Pastores et al
2
3
2/3
2/3
2/3
de Chadare´ vian et al Tromp et al Scerri et al
6
2 16 2
2/2 8/16 2/2
2/2 13/16 2/2
2/2 6/16 2/2
9
4 10
Manouvrier-Hanu et al
11
4
2/4
4/4
2/4
Miceli-Richard et al Latkany et al
3
11 16
711 9/16
11/11 15/16
5/11 16/16
Ewida et al This report
12
4 3
4/4 2/3
4/4 3/3
2/4 3/3
76
41/76 (54%)
69/76 (91%)
46/76 (61%)
Total
5
Previously reported cases of Blau syndrome have been summarized in the table.
seen with severe neurologic manifestation as reported by Jabs et al.9 The corneal opacities found in the proband were not found in his sister, and the medical record of the proband at age 3 showed corneal opacities without anterior uveitis. Such corneal opacities have not been described in Blau syndrome and might be an incidental finding, or it might be a new finding. In conclusion, the ocular manifestations and the results of genetic analysis of Blau syndrome have been presented. Although rare or rarely diagnosed, Blau syndrome needs to be considered in the differential diagnosis of childhood uveitis.
References 1. Blau EB. Familial granulomatous arthritis, iritis, and rash. J Pediatr 1985;107:689 –93. 2. Pastores GM, Michels VV, Stickler GB, et al. Autosomal dominant granulomatous arthritis, uveitis, skin rash, and synovial cysts. J Pediatr 1990;117:403– 8. 3. Miceli-Richard C, Lesage S, Rybojad M, et al. CARD15 mutations in Blau syndrome. Nat Genet 2001;29:19 –20. 4. Tromp G, Kuivaniemi H, Raphael S, et al. Genetic linkage of familial granulomatous inflammatory arthritis, skin rash, and uveitis to chromosome 16. Am J Hum Genet 1996;59:1097– 107.
2044
5. Latkany PA, Jabs DA, Smith JR, et al. Multifocal choroiditis in patients with familial juvenile systemic granulomatosis. Am J Ophthalmol 2002;134:897–904. 6. de Chadare´ vian JP, Raphael SA, Murphy GF. Histologic, ultrastructural, and immunohistochemical features of the granulomas seen in a child with the syndrome of familial granulomatous arthritis, uveitis, and rash. Arch Pathol Lab Med 1993;117:1050 –2. 7. Ogura Y, Inohara N, Benito A, et al. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-B. J Biol Chem 2001;276:4812– 8. 8. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001;411:599 – 603. 9. Jabs DA, Houk JL, Bias WB, Arnett FC. Familial granulomatous synovitis, uveitis, and cranial neuropathies. Am J Med 1985;78:801– 4. 10. Scerri L, Cook LJ, Jenkins EA, Thomas AL. Familial juvenile systemic granulomatosis (Blau’s syndrome). Clin Exp Dermatol 1996;21:445– 8. 11. Manouvrier-Hanu S, Puech B, Piette F, et al. Blau syndrome of granulomatous arthritis, iritis, and skin rash: a new family and review of the literature. Am J Med Genet 1998;76:217– 21. 12. Ewida AS, Raphael SA, Abbasi JA, et al. Evaluation of Th-1 and Th-2 immune responses in the skin lesions of patients with Blau syndrome. Appl Immunohistochem Mol Morphol 2002; 10:171–7.
Blau syndrome (MIM 186580) is a rare, autosomal-dominant disorder characterized by early-onset granulomatous arthritis, uveitis, skin rashes, and camptodactyly (flexion deformity at the proximal interphalangeal joint).1 The ocular manifestations, besides the uveitis, can include cataract, glaucoma, and retinal detachment.1,2 We present two siblings with Blau syndrome and describe their ocular manifestations. The presence of a recently described CARD15/Nod2 mutation3 was confirmed in these two siblings by genetic analyses.
Case Reports Case 1 A 10-year-old Japanese boy (proband) had ocular pain and visual loss in his right eye for 2 days. He was born at full term after an Originally received: August 26, 2002. Accepted: March 21, 2003.
Manuscript no. 220579.
1
Department of Ophthalmology, Shinshu University School of Medicine, Matsumoto, Japan.
2 Research Center for Instrumental Analysis, Shinshu University, Matsumoto, Japan. Supported in part by the Grant-in-Aid from the Ministry of Health, Labour, and Welfare of the Japanese Government, Tokyo, Japan. Reprint requests to Nagahisa Yoshimura, MD, PhD, Department of Ophthalmology, Shinshu University School of Medicine, Matsumoto 3908621, Japan. E-mail: [email protected].
2040
© 2003 by the American Academy of Ophthalmology Published by Elsevier Inc.
uncomplicated pregnancy, labor, and delivery. Both his father and mother are Japanese. He had a history of bilateral anterior uveitis since he was 6 years old, and his mother noticed swelling of his wrists and ankles at the same time as the ocular problems. At the initial examination, the best-corrected visual acuity was hand motions in the right eye and 10/20 in the left eye. The intraocular pressure was 38 mmHg in his right eye and 20 mmHg in his left eye. Ciliary injection was noted in both eyes. The cornea of his right eye was edematous, and granular subepithelial opacities and keratic precipitates were found in both eyes (Fig 1A, B). Posterior synechiae were present in both eyes, and an iris bombe was found in the right eye (Fig 1B). There were inflammatory cells in the anterior chamber of both eyes, and rubeosis iritis was found in the right eye. The right anterior chamber angle could not be observed by gonioscopy because of the corneal edema, but ultrasound biomicroscopy showed an iris bombe and a closed chamber angle. The fundus of the right eye could not be evaluated because of the hazy media, and the optic disc in the left eye was slightly hyperemic, and subretinal exudates were observed. In addition to the ocular findings, he had red skin rashes on his cheeks and arms, and his wrists were swollen and deformed (Fig 2A, B). He was afebrile and did not show any lymphadenopathy. The chest x-ray was normal. Complete blood cell counts were normal, and serum C-reactive protein and angiotensin-converting enzyme levels were also normal. Antinuclear antibody and rheumatoid factor were negative. The serum IgG was elevated to 1862 mg/dl. Systemic methylprednisolone (600 mg/day, 20 mg/kg body weight) was administered for 3 days, and topical corticosteroids and atropine were also started. The inflammation of the anterior chamber in both eyes responded immediately to the treatment. To ISSN 0161-6420/03/$–see front matter doi:10.1016/S0161-6420(03)00717-6
Kurokawa et al 䡠 Blau Syndrome release the iris bombe, cataract extraction by phacoemulsification with intraocular lens implantation and peripheral iridectomy were performed. After the surgery, the intraocular pressure of the right eye decreased to the middle teens. The right optic disc was slightly hyperemic. Multiple subretinal exudates that were similar to those seen in sarcoid uveitis were present (Fig 1C). Specimens obtained from peripheral iridectomy showed dilated vessels filled with neutrophils, but no giant cells or epithelioid cells were observed (Fig 1D). Skin biopsy specimens obtained from the right arm before the steroid therapy showed noncaseating granulomatous infiltration with epithelioid cells and lymphocytes. A few giant cells were also observed (Fig 2C, D). These changes are compatible with that found in sarcoidosis. Systemic prednisolone was tapered to 15 mg (0.5 mg/kg body weight) every other day, but it was difficult to reduce or stop the corticosteroids, because a relapse of the anterior and posterior uveitis occurred with 10 mg (0.3 mg/kg body weight) every other day. When the ocular inflammation was controlled, his vision was 15/20 in the right eye and 20/20 in the left eye. Throughout the course, the ocular inflammation and skin rashes waxed and waned in proportion to the amount of systemic prednisolone, but synovitis remained rather quiet.
Case 2 The proband’s 12-year-old sister had a history of iritis and had camptodactyly of the fourth distal interphalangeal joints of both hands. She was also born at term after an uncomplicated pregnancy and labor. She had anterior and posterior synechiae in the left eye (Fig 3A, B), but there were no inflammatory cells in the anterior chamber and vitreous at our initial examination. During the follow-up period, she had mild iritis in her right eye and moderate iritis and vitreous opacities that responded to systemic prednisolone (starting from 1 mg/kg body weight) in the left eye. The retinas were normal in both eyes. She is enjoying good vision of 30/20 in both eyes.
Case 3 The father of cases 1 and 2 was 51 years old and had camptodactyly since he was an infant. He lost his vision in both eyes at age 14 when he was diagnosed with tuberculous uveitis and glaucoma, and both eyes were phthisical. He has not been able to walk since he was 46 years old and had been diagnosed with chronic inflammatory demyelinating polyneuropathy.
Genetic Analysis From the history, the father’s parents did not have any visual problems, skin rashes, or synovitis. With written informed consent and institutional review board permission, peripheral blood was obtained from cases 1 and 2 and their mother. Because a recent report showed a CARD15/NOD2 gene mutation in French and German patients with Blau syndrome, 11 exons and the flanking intronic sequences of CARD15/NOD2 (EMBL accession number AJ303140) were amplified by polymerase chain reaction, and the nucleotide sequence was determined. Both cases 1 and 2 had a C to T transition (Fig 4B, C), with a change of an arginine at the 334th amino acid to a tryptophan (R334W), but their mother had the wild-type sequence (Fig 4A). In the flanking intron, case 2 and the mother did show a deletion and insertion, but case 1 was of the wild type.
Discussion Blau syndrome is a dominantly inherited disease and was first reported as a granulomatous disease of the skin, eyes, and joints in 1985.1 Arthritis is the most common manifestation of the disease and is usually manifested in the first decade of life as painful cystic swelling of the wrists, fingers, ankles, and elbows.1,2 The skin lesions are intermittent, red, and papular rashes.1 Uveitis is classified as granulomatous, and cataracts might occur.1,2 Recently, the susceptibility locus has been mapped to chromosome 16p12-q21,4 and CARD15/NOD2 mutations have been reported in Blau syndrome by a French group.3 Blau syndrome has been described mainly in pediatric or dermatologic journals. Until very recently, there was a serious debate whether Blau syndrome is a distinct disease or represents just a childhood sarcoidosis. Furthermore, it is not known whether Blau syndrome is a rare disease or a disease that is rarely diagnosed. Most likely it is both; Blau syndrome is a rare disease and is also rarely diagnosed. Recently, an article describing the clinical features of this syndrome has been published,5 but no data on genetic analysis have been provided. To the best of our knowledge, this is the first article to report on the clinical picture of Blau syndrome with genetic analysis. In Table 1, previously reported cases of Blau syndrome have been summarized. In the proband, the surgery relieved the iris bombe and secondary angle-closure glaucoma. The iridectomy specimen showed only nonspecific inflammation (Fig 2), and no pathologic findings compatible with sarcoidosis were found. However, the fundus changes (Fig 2) were similar to those found in sarcoid uveitis, and the pathology of the skin lesion was compatible with that found in sarcoidosis. In one study, “comma-shaped” or “wormlike” bodies were found in the cytoplasm of the epithelioid cells of granuloma in Blau syndrome on electron microscopic observation.6 Such organelles have not been described in sarcoidosis and are rather described in histiocytes seen in Hashimoto-Pritzker disease.6 Interestingly, CARD15/NOD2 is a homologue of Apaf-1/NOD1 found mainly in monocytes, and CARD15/ NOD2 is known to regulate apoptosis and/or activate nuclear factor B.7 The mutation found in cases 1 and 2 is located in the nucleotide-binding domain of CARD15/ NOD2, and the nucleotide-binding domain is thought to play an important role in the activation of nuclear factor B. Conversely, in Crohn’s disease, another granulomatous disease, mutations are usually found in the leucine-rich repeat of CARD15/NOD2.8 In our cases, the same mutation as reported by the French group (R334W) was identified. Determination of the genotype of the father was not possible, but from the history, both paternal and maternal grandparents of the proband did not show any signs of Blau syndrome. The mutation in this family might be a new one, and R334W mutation in CARD15/NOD2 might be a hot spot in this gene. It is also possible that the mutation found in our cases is a recurrent mutation resulting from the migration of a common founder chromosome to different populations. Because the ethnic background of our cases is Japanese and cases reported by Miceli-Richard et al are from French and German families,
2041
Kurokawa et al 䡠 Blau Syndrome Figure 1. The right ocular findings of case 1. A, The cornea is edematous, and dotlike subepithelial opacities (arrows) can be seen. Cataract and posterior synechiae are also present. B, The anterior chamber is shallow, forming an iris bombe. C, Slit-lamp photograph of the right fundus after the surgery. The optic disk is hyperemic, and subretinal exudates are present at the equatorial region (arrows). D, Histology of the iridectomy specimen. The vascular vessels are dilated, but there are no giant cells or epithelioid cells. Bar ⫽ 100 m. Figure 2. Systemic presentation of case 1. A, Butterfly-shaped skin rash on the cheeks. B, Deformed wrists and hands can be seen. C, Skin biopsy shows granulomatous inflammatory lesions with epithelioid cells and lymphocytes in the dermis (large and small arrows). Bar ⫽ 500 m. D, A giant epithelioid cell is visible at higher magnification (arrowhead). Bar ⫽ 50 m.
4™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™
Figure 3. Ocular findings in case 2. A, Posterior synechiae are present in the left eye. B, Peripheral anterior synechiae can be seen in the left eye.
such a possibility is not high. The proband had a severe phenotype, but his sister is rather mildly affected, and she is enjoying good vision. Because the proband and his sister have the same R334W mutation in the CARD15/NOD2 gene, it is difficult to explain the difference in the severity from the CARD15/Nod2 mutation. There is a possibility that another unknown gene plays a role in the determination of the severity of the clinical pictures. Although the initial response of case 1 to systemic steroids was good, it was not easy to taper the corticosteroids. Indeed, when prednisolone
Figure 4. Mutation analysis of CARD15/Nod2 gene. The mother shows a wild type (A). In both cases 1 (B) and 2 (C), an arginine-to-tryptophan substitution in the 344th amino acid of the CARD15/Nod2 gene (R344W) is present.
was tapered to 0.3 mg/kg body weight every other day, there was a relapse of uveitis. Although our follow-up period is not long enough, therapeutic regimens other than corticosteroids might be needed to stabilize ocular inflammation of Blau syndrome once anterior and posterior uveitis take place. Judging from the clinical manifestations, family history, and genetic analyses, our cases can be diagnosed as Blau syndrome. Genetic analysis for the father was not possible, but judging from his history, it is most likely that he had a severe form of Blau syndrome. Blau syndrome sometimes is
2043
Ophthalmology Volume 110, Number 10, October 2003 Table 1. Summary of Reported Cases
References
Number Reference of Number Patients
Incidence of Lesions Skin
Joints
Eye
Ophthalmologic Findings
11 4
3/11 0/4
9/11 4/4
3/11 3/4
Iritis, posterior uveitis, peripheral retinitis Multiple recurrences of anterior uveitis, cataract, secondary glaucoma Conjunctival erythema, cataract, anterior and posterior synechiae, uveitis, disc edema, perimacular wrinkle, peripheral pigmented choroidal scar Corneal stromal opacity, cataract, disc swelling Uveitis, multifocal choroidal lesions Panuveitis, cataract, disc swelling, secondary glaucoma, multifocal choroiditis Granulomatous anterior uveitis, disc edema, angleclosure glaucoma Uveitis Band keratopathy, anterior and posterior uveitis, disc edema, anterior ischemic optic neuropathy, glaucoma, cystoid macular edema Uveitis Subepithelial corneal opacities, granulomatous uveitis, anterior synechia, iris bombe, cataract, multifocal choroiditis
Blau Jabs et al
1
Pastores et al
2
3
2/3
2/3
2/3
de Chadare´ vian et al Tromp et al Scerri et al
6
2 16 2
2/2 8/16 2/2
2/2 13/16 2/2
2/2 6/16 2/2
9
4 10
Manouvrier-Hanu et al
11
4
2/4
4/4
2/4
Miceli-Richard et al Latkany et al
3
11 16
711 9/16
11/11 15/16
5/11 16/16
Ewida et al This report
12
4 3
4/4 2/3
4/4 3/3
2/4 3/3
76
41/76 (54%)
69/76 (91%)
46/76 (61%)
Total
5
Previously reported cases of Blau syndrome have been summarized in the table.
seen with severe neurologic manifestation as reported by Jabs et al.9 The corneal opacities found in the proband were not found in his sister, and the medical record of the proband at age 3 showed corneal opacities without anterior uveitis. Such corneal opacities have not been described in Blau syndrome and might be an incidental finding, or it might be a new finding. In conclusion, the ocular manifestations and the results of genetic analysis of Blau syndrome have been presented. Although rare or rarely diagnosed, Blau syndrome needs to be considered in the differential diagnosis of childhood uveitis.
References 1. Blau EB. Familial granulomatous arthritis, iritis, and rash. J Pediatr 1985;107:689 –93. 2. Pastores GM, Michels VV, Stickler GB, et al. Autosomal dominant granulomatous arthritis, uveitis, skin rash, and synovial cysts. J Pediatr 1990;117:403– 8. 3. Miceli-Richard C, Lesage S, Rybojad M, et al. CARD15 mutations in Blau syndrome. Nat Genet 2001;29:19 –20. 4. Tromp G, Kuivaniemi H, Raphael S, et al. Genetic linkage of familial granulomatous inflammatory arthritis, skin rash, and uveitis to chromosome 16. Am J Hum Genet 1996;59:1097– 107.
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5. Latkany PA, Jabs DA, Smith JR, et al. Multifocal choroiditis in patients with familial juvenile systemic granulomatosis. Am J Ophthalmol 2002;134:897–904. 6. de Chadare´ vian JP, Raphael SA, Murphy GF. Histologic, ultrastructural, and immunohistochemical features of the granulomas seen in a child with the syndrome of familial granulomatous arthritis, uveitis, and rash. Arch Pathol Lab Med 1993;117:1050 –2. 7. Ogura Y, Inohara N, Benito A, et al. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-B. J Biol Chem 2001;276:4812– 8. 8. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001;411:599 – 603. 9. Jabs DA, Houk JL, Bias WB, Arnett FC. Familial granulomatous synovitis, uveitis, and cranial neuropathies. Am J Med 1985;78:801– 4. 10. Scerri L, Cook LJ, Jenkins EA, Thomas AL. Familial juvenile systemic granulomatosis (Blau’s syndrome). Clin Exp Dermatol 1996;21:445– 8. 11. Manouvrier-Hanu S, Puech B, Piette F, et al. Blau syndrome of granulomatous arthritis, iritis, and skin rash: a new family and review of the literature. Am J Med Genet 1998;76:217– 21. 12. Ewida AS, Raphael SA, Abbasi JA, et al. Evaluation of Th-1 and Th-2 immune responses in the skin lesions of patients with Blau syndrome. Appl Immunohistochem Mol Morphol 2002; 10:171–7.