n CASE 208
Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at www.rsna.org/rsnarights.
DIAGNOSIS PLEASE
Case 208: Alkaptonuria1
Thomas L. Mwambingu, MBChB, MRCP(UK) Geoff Hide, MBBS, MRCP(UK), FRCR
History
A 76-year-old woman presented after a fall with a history of progressively worsening mobility due to lower back and generalized joint pain. She had a longstanding history of arthritis since early adulthood that predominantly affected her weight-bearing joints. The small joints of her hands and feet were spared. Physical examination findings were notable for the presence of slate gray pigmented areas on the patient’s sclerae, ears, and hands. A urinary catheter sample was noted to turn dark on standing, and the patient reported a lifelong history of darkly discolored urine and dark brown staining of clothing at the axillae. Routine laboratory findings—including full blood count, bone profile, erythrocyte sedimentation rate, urea level, electrolyte levels, and ferritin level—were all within the normal range. Tests for rheumatoid factor and HLA-B27 antigen were negative. Radiographs of the lumbar spine and pelvis were requested to assess the possibility of degenerative changes and osteoporotic fractures.
Figure 1
Imaging Findings A lateral spine radiograph revealed vertebral body osteoporosis, disc space narrowing, and calcification without significant endplate osteophyte formation (Fig 1). A hip radiograph depicted extensive resorption and flattening of the femoral heads (Fig 2), with mild protrusion.
Part one of this case appeared 4 months previously and may contain larger images. Published online 10.1148/radiol.14121842 Content codes: Radiology 2014; 272:608–611 1 From the Department of Radiology, Freeman Hospital, Freeman Rd, Newcastle Upon Tyne NE7 7DN, England. Received August 14, 2012; revision requested September 14; revision received October 3; accepted October 10; final version accepted October 15. Address correspondence to T.L.M. (e-mail: [email protected]).
Conflicts of interest are listed at the end of this article. q RSNA, 2014
608
Discussion Alkaptonuria, a rare inborn error of amino acid metabolism, has an autosomal recessive inheritance pattern. Deficiency of homogentisate 1,2-dioxygenase (HGO) results in the urinary excretion of large amounts of homogentisic acid (HGA) and deposition of HGA and its metabolites in connective tissues (sclerae, ear cartilage, fingernails and toenails, buccal mucosa, and skin) (1). The human HGO gene locus has been mapped to chromosome 3q21q23 (2), and there is currently no diagnostic test with which to detect the car-
Figure 1: Lateral radiograph of the spine shows vertebral body osteoporosis (small arrow) and disc space narrowing, calcification, and ossification (large arrow).
radiology.rsna.org n Radiology: Volume 272: Number 2—August 2014
DIAGNOSIS PLEASE: Alkaptonuria
Mwambingu and Hide
Figure 2
Figure 3
Figure 3: Ochronotic pigmentation of, A, the first finger, B, ear cartilage, and, C, the sclera. Figure 2: Frontal radiograph of the lumbar spine and pelvis shows resorption and flattening of the femoral heads, with mild protrusion (arrow).
rier state. Widespread HGA tissue deposition can lead to joint destruction, nephrocalcinosis, and even cardiac valve degeneration. This pigmentous accumulation appears dark yellow or ochre at microscopic examination; hence, Virchow termed this condition ochronosis (Greek for yellow disease) (3). Aciduria causing darkly stained diapers can lead to this diagnosis in infancy; however, the diagnosis typically is not considered until the gradual development of ochronosis in young adulthood. Clinical features of ochronotic arthritis are typically delayed until the 4th decade of life because of reduced renal clearance of HGA with age (4); however, the patient described in this report experienced arthritis beginning in early adulthood. Ochronotic arthritis has a male preponderance, it principally affects the weight-bearing joints, and it can be severe. In contrast to rheumatoid arthritis, the small joints of the hands and feet are spared. Radiologic examination of the thoracolumbar spine often reveals changes, including vacuum phenomena and intervertebral calcification, at mul-
tiple levels (Fig 1). Flowing osteophytes may be seen and, if present, are usually small. Unlike radiologic changes seen in patients with ankylosing spondylitis, there is relative sparing of the sacroiliac joints and no association with bamboo spine, annular ossification, syndesmophytes, or erosion (5). Important differential diagnoses include atypical degenerative disc disease, as well as neuropathic arthropathy of the spine, which may manifest in a similar fashion. Other important differential diagnoses to be considered include exogenous ochronosis, which has similar radiologic and musculoskeletal consequences. However, this is not associated with the striking clinical features seen in this patient (Fig 3). In addition, the patient had no history of exposure to phenols, mercury, antimalarial drugs, or hydroquinone-containing skin creams, all of which are known causes of exogenous ochronosis (6). There are a range of other conditions that are associated with intervertebral disc calcification and that should be considered as differential diagnoses. These include calcium pyrophosphate deposition (pseudogout), hemochromatosis, hyperparathyroidism, acromegaly, and amyloidosis. However, none of these diseases manifest with the pigmentation abnormalities seen in patients with alkaptonuric ochronosis. In addition,
Radiology: Volume 272: Number 2—August 2014 n radiology.rsna.org
these differential diagnoses are associated with specific clinical and metabolic features that were not seen in this patient. The diagnosis is confirmed once it is determined that HGA is present in blood or urine. Currently, no available treatment has been conclusively shown to prevent the complications of alkaptonuria. Restriction of dietary protein in pediatric patients has been advocated, with the aim of reducing HGA excretion (7). Treatment with high-dose ascorbic acid occasionally has been shown to slow the progression of arthropathy (8). Administration of ascorbic acid was commenced in this patient; however, it was not possible to monitor the long-term clinical result of this intervention because the patient died of an unrelated cause soon after. Disclosures of Conflicts of Interest: T.L.M. disclosed no relevant relationships. G.H. disclosed no relevant relationships.
References 1. La Du BN, Seegmiller JE, Laster L, Zannoni V. Alcaptonuria and ochronotic arthritis. Bull Rheum Dis 1958;8(9):163–164. 2. Janocha S, Wolz W, Srsen S, et al. The human gene for alkaptonuria (AKU) maps to chromosome 3q. Genomics 1994;19(1):5–8. 3. Vijaikumar M, Thappa DM, Srikanth S, Sethuraman G, Nadarajan S. Alkaptonuric ochronosis presenting as palmoplantar pig-
609
DIAGNOSIS PLEASE: Alkaptonuria
mentation. Clin Exp Dermatol 2000;25(4): 305–307. 4. Hamdi N, Cooke TD, Hassan B. Ochro notic arthropathy: case report and review of the literature. Int Orthop 1999;23(2): 122–125. 5. Baeva M, Bueno A, Dhimes P. AIRP best cases in radiologic-pathologic correlation: ochronosis. RadioGraphics 2011;31(4):1163–1167. 6. Levin CY, Maibach H. Exogenous ochronosis: an update on clinical features, causative agents and treatment options. Am J Clin Dermatol 2001;2(4):213–217. 7. de Haas V, Carbasius Weber EC, de Klerk JB, et al. The success of dietary protein restriction in alkaptonuria patients is agedependent. J Inherit Metab Dis 1998;21(8): 791–798. 8. Morava E, Kosztolányi G, Engelke UF, Wevers RA. Reversal of clinical symptoms and radiographic abnormalities with protein restriction and ascorbic acid in alkaptonuria. Ann Clin Biochem 2003;40(Pt 1):108–111. Congratulations to the 258 individuals and 12 resident groups that submitted the most likely diagnosis (alkaptonuric ochronosis) for Diagnosis Please, Case 208. The names and locations of the individuals and resident groups, as submitted, are as follows: Individual responses Rifat F. Abdi, MD, Dhahran, Saudi Arabia Hisashi Abe, MD, Osaka, Japan Osamu Abe, MD, PhD, Itabashi-ku, Tokyo, Japan Bruna O. Aburjeli, MD, Sao Paulo, SP, Brazil Subathra Adithan, MD, Pondicherry, India Gholamali Afshang, MD, Tinley Park, Ill Anjali Agrawal, MD, Delhi, India Sunil K. Agrawal, MBBS, New Delhi, India Mobeen Ahmed, MBBS, Islamabad, Punjab, Pakistan Kelly E. Ainsworth, MD, Mount Hope, Ontario, Canada Tahleel Altaf, MBBS, MD, Srinagar, J&K, India Canan Altay, MD, Izmir, Turkey Albert J. Alter, MD, PhD, Blanchardville, Wis Nabil F. Ammouri, MD, Zahle, Lebanon Roger L. Antonelli, MD, Dayton, Ohio Roshan K. Arjal, MD, Wuhan, China Christopher W. Bailey, DO, Morgantown, WVa Dean E. Baird, MD, Potomac, Md Morteza Bajoghli, MD, Isfahan, Iran Kenneth F. Baliga, MD, Rockford, Ill Thomas J. Barloon, MD, Iowa City, Iowa Panagiotis Baroutas, MD, Athens, Greece Dhiraj Baruah, MD, Wauwatosa, Wis Patrick Battaglia, DO, Chesterfield, Mo Rupert Bauer, MD, Holzminden, Germany Richard J. Beedie, MBBCh, Auckland, New Zealand
610
Mwambingu and Hide
Sasha Bhan, Hamilton, Ontario, Canada Gustav A. Blomquist, MD, Lexington, Ky J. Scott Bolton, MD, Dothan, Ala Manon N. Braat, MD, Utrecht, the Netherlands Sebastian Bravo-Grau, MD, MSc, Santiago, Region Metropolitana, Chile Eric L. Bressler, MD, Minnetonka, Minn Ghislain Brousseau, MD, Charlesbourg, Quebec, Canada Douglas C. Brown, MD, Virginia Beach, Va Michael P. Buetow, MD, Okemos, Mich Ian A. Burgess, MD, Manly, New South Wales, Australia Tamara Y. Carroll, MD, Seattle, Wash Tirso Cascajares Murillo, MD, Hermosillo, Mexico Antonio A. Cavalcanti, MD, Sao Paulo, SP, Brazil Balasundaram Chandra-Sekar, MD, Birmingham, Ala Phillip M. Cheng, MD, MS, Culver City, Calif Michael H. Childress, MD, Washington, DC Christopher Chu, MBBS, FRANZC, Sydney, New South Wales, Australia Neal R. Conti, MD, Bellevue, Wash Francois Cornelis, MD, Bordeaux, France Theresa M. Corrigan, MD, Louisville, Ky Marco A. Cura, MD, Dallas, Tex Genta Dani, MD, Charleston, SC Anil K. Dasyam, MD, Pittsburgh, Pa Marc G. De Baets, MD, Collina d'Oro, Ticino, Switzerland Peter de Baets, MD, Damme, Belgium Kristof De Meerleer, MD, Sint Blasius Boekel-Zwalm, Belgium Mustafa K. Demir, MD, Istanbul, Turkey Thaworn Dendumrongsup, MD, Songkhla, Thailand Carlos R. Deragopyan, MD, Buenos Aires, Argentina Dionisios Drakopoulos, MD, Palaio Faliro, Athens, Greece Sjunne H. Duhnsen, MD, Zug, Switzerland Seyed A. Emamian, MD, PhD, Rockville, Md Edward J. Escott, MD, Lexington, Ky Susan M. Fanapour, DO, Lombard, Ill Brett D. Ferdinand, MD, Livingston, NJ Francis T. Flaherty, MD, Ridgefield, Conn Enrique Flores, MD, Santa Cristina, Oleiros, A Coruna, Spain Akira Fujikawa, MD, Tokyo, Japan Toshihiro Furuta, MD, Bunkyo-ku, Tokyo, Japan William H. Gallmann III, MD, Shreveport, La Ram P. Galwa, MD, Fredericton, New Brunswick, Canada Douglas J. Gardner, MD, Toronto, Ontario, Canada Bradley S. Gluck, MD, Southampton, NY Mark G. Goldshein, MD, Andover, Mass Antonio Carlos P. Gomes, MD, Sao Paulo, SP, Brazil Wataru Gonoi, MD, PhD, Bunkyo-ku, Tokyo, Japan Ruben F. Gonzalez Villaveiran, MD, Buenos Aires, Argentina
Philip Goodman, MD, Binghamton, NY Maria A. Gosein, MBBS, FRCR, Santa Cruz, Trinidad And Tobago Alex Grande Astorquiza, MD, Vigo, Pontevedra, Spain Navraj S. Grewal, MD, Rancho Cucamonga, Calif Michael Griffin, MD, PhD, Milwaukee, Wis Pramod K. Gupta, MD, Plano, Tex Akifumi Hagiwara, MD, Tokyo, Japan Ferris M. Hall, MD, Brookline, Mass Sameer H. Hanfi, MBBS, Karachi, Sindh, Pakistan Osamu Hasegawa, MD, Koriyama, Fukushima, Japan D. C. Heasley, Jr, MD, Dallas, Tex Christoph Hefel, Feldkirch, Austria Mateus A. Hernandes, MD, Ribeirao Preto, Sao Paulo, Brazil Yuusuke Hirokawa, MD, Kyoto, Japan Nerea Hormaza, MD, Barakaldo, Bizkaia, Spain Sodai Hoshiai, MD, Tsukuba, Ibaraki, Japan Brian H. Hu, MD, Hollis, NH Mark A. Hunter, MBBCh, FRCR, Paisley, Renfrewshire, United Kingdom Alberto C. Iaia, MD, Wilmington, Del Waleed M. Ibrahim, MD, Annandale, Va Noriatsu Ichiba, MD, Otsu, Shiga, Japan Mitsuru Ikeda, MD, Nagoya, Japan Takashi Ikeuchi, Moriyama, Shiga, Japan Akitoshi Inoue, MD, Otsu, Shiga, Japan Richard N. Irion, MD, Murray, Utah Nath G. Iyer, MD, FRANZCR, Perth, Western Australia, Australia Stephen F. Janas, MD, De Pere, Wis Sharada Jayagopal, MD, East Williston, NY Miral D. Jhaveri, MD, Chicago, Ill Colin D. Jones, MD, Calgary, Alberta, Canada Jennifer W. Jung, MD, Wyomissing, Pa Kenji Kachi, MD, Tsuchiura, Ibaraki, Japan Geoffrey Karjala, MD, Saskatoon, Saskatchewan, Canada Atman V. Kathiria, Surendranagar, Gujarat, India Koki Kato, MD, Utsunomiya, Tochigi, Japan Yasushi Kawata, MD, Yurihonjo City, Akita, Japan Shanigarn Keoplung, MD, Muang Nonthaburi, Nonthaburi, Thailand Patrick Kiely, MBBCh, Limerick, Ireland Takao Kiguchi, MD, Niigata, Japan Takuji Kiryu, MD, PhD, Gifu, Japan Osamu Kizu, MD, Ohtsu, Japan Mitchell A. Klein, MD, Mequon, Wis Masamichi Koyama, MD, PhD, Tokyo, Japan Richard E. Krauthamer, MD, Rolling Hills, Calif John J. Krol, MD, Portland, Ore Ryo Kuwahara, MD, Kyoto, Nakagyogu, Japan Anthony G. Laglia, MD, Piedmont, Calif Mario A. Laguna, MD, Milwaukee, Wis Luis A. Landeras, MD, Westlake, Ohio Alan Laorr, MD, Eden Prairie, Minn Martin Lecompte, MD, Manotick, Ontario, Canada
radiology.rsna.org n Radiology: Volume 272: Number 2—August 2014
DIAGNOSIS PLEASE: Alkaptonuria
Chee Hwee Lee, MD, Taipei, Taiwan Stefanie Lee, London, Ontario, Canada Karl J. Lehmann, MD, Karlsruhe, Germany Donald R. Lewis, Jr, MD, Huntington, WVa David A. Lisle, MBBS, Brisbane, Queensland, Australia Thomas B. Lloyd, MBBS, Brisbane, Queensland, Australia Rafael Maffei Loureiro, MD, Sao Paulo, Brazil Patrick D. Magoon, MD, Torrance, Calif Mark D. Mamlouk, MD, Foster City, Calif Stephen V. Manghisi, MD, Closter, NJ Douglas J. Martin, MD, Minneapolis, Minn Satoshi Matsushima, MD, Tokyo, Japan Edward J. Mauch, MD, Harrison Township, Mich Alan P. Mautz, MD, Presque Isle, Me Brian McNamee, MD, Coeur D Alene, Idaho Sunil L. Mehta, MD, Mississauga, Ontario, Canada Albert Mendelson, MD, Northbrook, Ill Steven J. Michel, MD, Bend, Ore Ralph A. Milillo, MD, Manhasset, NY Manabu Minami, MD, PhD, Yokohama, Japan Shunsuke Minami, Otsu, Japan Kenichi Mizuki, MD, Hamamatsu-shi, Shizuokaken, Japan Jose Mondello, MD, Buenos Aires, CA, Argentina Deirdre E. Moran, MBBCh, Brookline, Mass Tiago N. Morato, MD, Brasilia, DF, Brazil Toshio Moritani, MD, PhD, Iowa City, Iowa Sleiman Y. Naddaf, MD, Brooklyn, NY Kyoko Nagai, MD, Yokohama, Japan Ryusuke Nakamoto, MD, Kyoto, Japan Tammam N. Nehme, MD, Mattawan, Mich Tuan Duc Nguyen, MD, Ski, Norway Hironori Nishibori, MD, Minokamo City, Gifu, Japan Tomokazu Nishiguchi, MD, PhD, Osaka, Japan Mizuki Nishino, MD, Boston, Mass Hiroshi Nobusawa, MD, PhD, Ota, Tokyo, Japan Roque Oca, MD, Vigo, Pontevedra, Spain Laura Oleaga, Barcelona, Spain Resmiye Oral, MD, Iowa City, Iowa Sanford M. Ornstein, MD, Paradise Valley, Ariz Michael D. Orsi, MD, San Antonio, Tex Vishal Panchal, San Francisco, Calif David M. Panicek, MD, New York, NY Ioannis E. Papachristos, MD, Agrinio, Greece Patouras Paraskevas, MD, Agia Paraskevi, Attiki, Greece Narendrakumar P. Patel, MD, Newburgh, NY Prakash N. Patel, MD, New City, NY Satish D. Patel, MD, Shavertown, Pa Suresh K. Patel, MD, Chicago, Ill Aruna R. Patil, MD, FRCR, Bangalore, Karnataka, India Yeliz Pekcevik, Izmir, Turkey Francesco Pierazzoli, MD, Padua, PD, Italy John M. Plotke, MD, Naperville, Ill Rubem Pochaczevsky, MD, Bronx, NY Elias Primetis, MD, Athens, Greece
Mwambingu and Hide
Shawn P. Quillin, MD, Charlotte, NC Gary W. Radner, MD, La Canada Flintridge, Calif Keshav P. Raichurkar, MD, Mysore, Kamataka, India Daniel C. Rappaport, MD, Toronto, Ontario, Canada Ryan P. Rebello, MD, Dundas, Ontario, Canada Eric W. Robbins, MD, Denver, Colo Mathieu H. Rodallec, MD, Paris, France Jorge Rodriguez Antuna, MD, A Coruna, Spain Hugo Rodriguez Requena, MD, Madrid, Spain Simon Roh, MD, Iowa City, Iowa Daniel Romeu Vilar, MD, Bertamirans, A Coruna, Spain Stefan Roosendaal, MD, PhD, Amsterdam, the Netherlands Akihiko Sakata, MD, Kyoto, Japan Blake Saltaformaggio, MD, Franklin, Tenn Meir H. Scheinfeld, MD, PhD, Suffern, NY Pierre Schmit, MD, Halifax, Nova Scotia, Canada Steven M. Schultz, MD, Fort Worth, Tex Joel M. Schwartz, MD, Elmsford, NY Randall L. Scott, MD, Memphis, Tenn Anthony J. Scuderi, MD, Johnstown, Pa Matthew P. Shapiro, MD, Charlottesvle, Va Hussain H. Sharahili, MBBS, MD, Dharhan, Eastern Province, Saudi Arabia Hideki Shima, MD, Narita, Chiba, Japan Taro Shimono, MD, Osaka, Japan Ichiro Shirouzu, MD, Tokyo, Japan Paul J. Shogan, MD, Clarksville, Tenn Richard M. Shore, MD, Glenview, Ill Ho L. Sie, MD, Henderson, Nev Michael S. Siegfried, MD, Glencoe, Ill Andre Simoes, MD, Barcelos, Portugal Evan M. Sirc, MD, Santa Cruz, Calif Christopher L. Smoley, Dallas, Tex David F. Sobel, MD, La Jolla, Calif Luis A. Sosa, MD, Mexico City, DF, Mexico Isabel Sousa, MD, Lisboa, Portugal James D. Sprinkle, Jr, MD, Spotsylvania, Va Evan G. Stein, MD, PhD, New York, NY Peter M. Stroz, MD, Toronto, Ontario, Canada Jorge O. Suarez, MD, Bogota, Colombia Hongliang Sun, MD, Beijing, China Eliko Tanaka, MD, Yokohama, Japan Takashi Tanaka, MD, Okayama, Japan Bisher Tarabishy, MD, West Bloomfield, Mich Satoshi Tatsuno, MD, Ichikawa, Chiba, Japan Douglas L. Teich, MD, Brookline, Mass Yasuyo Teramura, MD, Tokorozawa, Saitama, Japan Craig B. Thayer, MD, Tucson, Ariz Christina M. Thuerl, MD, Freiburg, BadenWurttemberg, Germany Eugene Tong, MD, Austin, Tex Ulysses S. Torres, MD, Sao Paulo, SP, Brazil Joseph Z. Toutounji, MD, Beirut, Lebanon Jeffrey Tseng, MD, Menlo Park, Calif Meric Tuzun, MD, Ankara, Turkey Herminia Tyminski, MD, Manama, Bahrain Atsushi Uehara, Niigata, Japan
Radiology: Volume 272: Number 2—August 2014 n radiology.rsna.org
Piet K. Vanhoenacker, MD, Moorsel, Belgium Harsha Vardhan, MBBS, Chandigarh, Haryana and Punjab, India Bonny Varghese, MD, FRANZCR, Melbourne, Victoria, Australia Rajeev K. Varma, MD, Torrance, Calif Constantine P. Vassiliou, MD, Pallini, Greece Ricardo Videla, Cordoba, CB, Argentina Alexander Vidershayn, MD, Brooklyn, NY Pier Carlo Villani, MD, Bari, Italy Ainhoa Viteri, MD, Bilbao, Biscay, Spain Christopher P. Vittore, MD, Belvidere, Ill Lynne Voutsinas, MD, Staten Island, NY James S. Walsh, MD, Edinburgh, United Kingdom Garrett L. Walworth, MD, Milford, Mich Haruo Watanabe, MD, Gifu, Japan Noritaka Yamakawa, Kyoto, Japan Tatsuya Yamamoto, MD, Yoshida-gun, Fukui, Japan Yi Yang, MD, Suzhou, Jiangsu, China Koichiro Yasaka, MD, Tokyo, Japan Kurata Yasuhisa, MD, Kobe, Hyogo, Japan Hajime Yokota, MD, Kyoto, Japan Rika Yoshida, MD, Utsunomiya, Tochigi, Japan Kaneko You, Gifu, Japan Stanko Yovichevich, MD, Sydney, New South Wales, Australia Carlos A. Zamora, MD, PhD, Lutherville, Md Ahmed Zidan, MD, Barcelona, Spain
Resident group responses Hospital de Santa Maria Radiology Residents, Lisbon, Portugal Mater Dei Hospital, Msida, Malta Mie University Hospital Radiology Residents, MD, Tsu, Mie, Japan Montefiore Medical Center Radiology Residents, Bronx, NY Prince of Songkla University Radiology Residents, Songkla, Thailand Thomas Jefferson University Radiology Residents, MD, Philadelphia, Pa Tsukuba University Hospital Radiology Residents, Tsukuba, Ibaraki, Japan University of Pennsylvania Radiology Residents, Philadelphia, Pa University of Washington Radiology Residents, MD, Seattle, Wash UTHSC at San Antonio Radiology Residents, MD, San Antonio, Tex Virginia Commonwealth University Radiology Residents, Richmond, Va Yale University Radiology Residents, New Haven, Conn Kristof De Meerleer, MD, Sint Blasius Boekel-Zwalm, Begium, submitted the correct diagnosis (persistent hypertrophic primary vitreous) for Case 206.
611
Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at www.rsna.org/rsnarights.
DIAGNOSIS PLEASE
Case 208: Alkaptonuria1
Thomas L. Mwambingu, MBChB, MRCP(UK) Geoff Hide, MBBS, MRCP(UK), FRCR
History
A 76-year-old woman presented after a fall with a history of progressively worsening mobility due to lower back and generalized joint pain. She had a longstanding history of arthritis since early adulthood that predominantly affected her weight-bearing joints. The small joints of her hands and feet were spared. Physical examination findings were notable for the presence of slate gray pigmented areas on the patient’s sclerae, ears, and hands. A urinary catheter sample was noted to turn dark on standing, and the patient reported a lifelong history of darkly discolored urine and dark brown staining of clothing at the axillae. Routine laboratory findings—including full blood count, bone profile, erythrocyte sedimentation rate, urea level, electrolyte levels, and ferritin level—were all within the normal range. Tests for rheumatoid factor and HLA-B27 antigen were negative. Radiographs of the lumbar spine and pelvis were requested to assess the possibility of degenerative changes and osteoporotic fractures.
Figure 1
Imaging Findings A lateral spine radiograph revealed vertebral body osteoporosis, disc space narrowing, and calcification without significant endplate osteophyte formation (Fig 1). A hip radiograph depicted extensive resorption and flattening of the femoral heads (Fig 2), with mild protrusion.
Part one of this case appeared 4 months previously and may contain larger images. Published online 10.1148/radiol.14121842 Content codes: Radiology 2014; 272:608–611 1 From the Department of Radiology, Freeman Hospital, Freeman Rd, Newcastle Upon Tyne NE7 7DN, England. Received August 14, 2012; revision requested September 14; revision received October 3; accepted October 10; final version accepted October 15. Address correspondence to T.L.M. (e-mail: [email protected]).
Conflicts of interest are listed at the end of this article. q RSNA, 2014
608
Discussion Alkaptonuria, a rare inborn error of amino acid metabolism, has an autosomal recessive inheritance pattern. Deficiency of homogentisate 1,2-dioxygenase (HGO) results in the urinary excretion of large amounts of homogentisic acid (HGA) and deposition of HGA and its metabolites in connective tissues (sclerae, ear cartilage, fingernails and toenails, buccal mucosa, and skin) (1). The human HGO gene locus has been mapped to chromosome 3q21q23 (2), and there is currently no diagnostic test with which to detect the car-
Figure 1: Lateral radiograph of the spine shows vertebral body osteoporosis (small arrow) and disc space narrowing, calcification, and ossification (large arrow).
radiology.rsna.org n Radiology: Volume 272: Number 2—August 2014
DIAGNOSIS PLEASE: Alkaptonuria
Mwambingu and Hide
Figure 2
Figure 3
Figure 3: Ochronotic pigmentation of, A, the first finger, B, ear cartilage, and, C, the sclera. Figure 2: Frontal radiograph of the lumbar spine and pelvis shows resorption and flattening of the femoral heads, with mild protrusion (arrow).
rier state. Widespread HGA tissue deposition can lead to joint destruction, nephrocalcinosis, and even cardiac valve degeneration. This pigmentous accumulation appears dark yellow or ochre at microscopic examination; hence, Virchow termed this condition ochronosis (Greek for yellow disease) (3). Aciduria causing darkly stained diapers can lead to this diagnosis in infancy; however, the diagnosis typically is not considered until the gradual development of ochronosis in young adulthood. Clinical features of ochronotic arthritis are typically delayed until the 4th decade of life because of reduced renal clearance of HGA with age (4); however, the patient described in this report experienced arthritis beginning in early adulthood. Ochronotic arthritis has a male preponderance, it principally affects the weight-bearing joints, and it can be severe. In contrast to rheumatoid arthritis, the small joints of the hands and feet are spared. Radiologic examination of the thoracolumbar spine often reveals changes, including vacuum phenomena and intervertebral calcification, at mul-
tiple levels (Fig 1). Flowing osteophytes may be seen and, if present, are usually small. Unlike radiologic changes seen in patients with ankylosing spondylitis, there is relative sparing of the sacroiliac joints and no association with bamboo spine, annular ossification, syndesmophytes, or erosion (5). Important differential diagnoses include atypical degenerative disc disease, as well as neuropathic arthropathy of the spine, which may manifest in a similar fashion. Other important differential diagnoses to be considered include exogenous ochronosis, which has similar radiologic and musculoskeletal consequences. However, this is not associated with the striking clinical features seen in this patient (Fig 3). In addition, the patient had no history of exposure to phenols, mercury, antimalarial drugs, or hydroquinone-containing skin creams, all of which are known causes of exogenous ochronosis (6). There are a range of other conditions that are associated with intervertebral disc calcification and that should be considered as differential diagnoses. These include calcium pyrophosphate deposition (pseudogout), hemochromatosis, hyperparathyroidism, acromegaly, and amyloidosis. However, none of these diseases manifest with the pigmentation abnormalities seen in patients with alkaptonuric ochronosis. In addition,
Radiology: Volume 272: Number 2—August 2014 n radiology.rsna.org
these differential diagnoses are associated with specific clinical and metabolic features that were not seen in this patient. The diagnosis is confirmed once it is determined that HGA is present in blood or urine. Currently, no available treatment has been conclusively shown to prevent the complications of alkaptonuria. Restriction of dietary protein in pediatric patients has been advocated, with the aim of reducing HGA excretion (7). Treatment with high-dose ascorbic acid occasionally has been shown to slow the progression of arthropathy (8). Administration of ascorbic acid was commenced in this patient; however, it was not possible to monitor the long-term clinical result of this intervention because the patient died of an unrelated cause soon after. Disclosures of Conflicts of Interest: T.L.M. disclosed no relevant relationships. G.H. disclosed no relevant relationships.
References 1. La Du BN, Seegmiller JE, Laster L, Zannoni V. Alcaptonuria and ochronotic arthritis. Bull Rheum Dis 1958;8(9):163–164. 2. Janocha S, Wolz W, Srsen S, et al. The human gene for alkaptonuria (AKU) maps to chromosome 3q. Genomics 1994;19(1):5–8. 3. Vijaikumar M, Thappa DM, Srikanth S, Sethuraman G, Nadarajan S. Alkaptonuric ochronosis presenting as palmoplantar pig-
609
DIAGNOSIS PLEASE: Alkaptonuria
mentation. Clin Exp Dermatol 2000;25(4): 305–307. 4. Hamdi N, Cooke TD, Hassan B. Ochro notic arthropathy: case report and review of the literature. Int Orthop 1999;23(2): 122–125. 5. Baeva M, Bueno A, Dhimes P. AIRP best cases in radiologic-pathologic correlation: ochronosis. RadioGraphics 2011;31(4):1163–1167. 6. Levin CY, Maibach H. Exogenous ochronosis: an update on clinical features, causative agents and treatment options. Am J Clin Dermatol 2001;2(4):213–217. 7. de Haas V, Carbasius Weber EC, de Klerk JB, et al. The success of dietary protein restriction in alkaptonuria patients is agedependent. J Inherit Metab Dis 1998;21(8): 791–798. 8. Morava E, Kosztolányi G, Engelke UF, Wevers RA. Reversal of clinical symptoms and radiographic abnormalities with protein restriction and ascorbic acid in alkaptonuria. Ann Clin Biochem 2003;40(Pt 1):108–111. Congratulations to the 258 individuals and 12 resident groups that submitted the most likely diagnosis (alkaptonuric ochronosis) for Diagnosis Please, Case 208. The names and locations of the individuals and resident groups, as submitted, are as follows: Individual responses Rifat F. Abdi, MD, Dhahran, Saudi Arabia Hisashi Abe, MD, Osaka, Japan Osamu Abe, MD, PhD, Itabashi-ku, Tokyo, Japan Bruna O. Aburjeli, MD, Sao Paulo, SP, Brazil Subathra Adithan, MD, Pondicherry, India Gholamali Afshang, MD, Tinley Park, Ill Anjali Agrawal, MD, Delhi, India Sunil K. Agrawal, MBBS, New Delhi, India Mobeen Ahmed, MBBS, Islamabad, Punjab, Pakistan Kelly E. Ainsworth, MD, Mount Hope, Ontario, Canada Tahleel Altaf, MBBS, MD, Srinagar, J&K, India Canan Altay, MD, Izmir, Turkey Albert J. Alter, MD, PhD, Blanchardville, Wis Nabil F. Ammouri, MD, Zahle, Lebanon Roger L. Antonelli, MD, Dayton, Ohio Roshan K. Arjal, MD, Wuhan, China Christopher W. Bailey, DO, Morgantown, WVa Dean E. Baird, MD, Potomac, Md Morteza Bajoghli, MD, Isfahan, Iran Kenneth F. Baliga, MD, Rockford, Ill Thomas J. Barloon, MD, Iowa City, Iowa Panagiotis Baroutas, MD, Athens, Greece Dhiraj Baruah, MD, Wauwatosa, Wis Patrick Battaglia, DO, Chesterfield, Mo Rupert Bauer, MD, Holzminden, Germany Richard J. Beedie, MBBCh, Auckland, New Zealand
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Sasha Bhan, Hamilton, Ontario, Canada Gustav A. Blomquist, MD, Lexington, Ky J. Scott Bolton, MD, Dothan, Ala Manon N. Braat, MD, Utrecht, the Netherlands Sebastian Bravo-Grau, MD, MSc, Santiago, Region Metropolitana, Chile Eric L. Bressler, MD, Minnetonka, Minn Ghislain Brousseau, MD, Charlesbourg, Quebec, Canada Douglas C. Brown, MD, Virginia Beach, Va Michael P. Buetow, MD, Okemos, Mich Ian A. Burgess, MD, Manly, New South Wales, Australia Tamara Y. Carroll, MD, Seattle, Wash Tirso Cascajares Murillo, MD, Hermosillo, Mexico Antonio A. Cavalcanti, MD, Sao Paulo, SP, Brazil Balasundaram Chandra-Sekar, MD, Birmingham, Ala Phillip M. Cheng, MD, MS, Culver City, Calif Michael H. Childress, MD, Washington, DC Christopher Chu, MBBS, FRANZC, Sydney, New South Wales, Australia Neal R. Conti, MD, Bellevue, Wash Francois Cornelis, MD, Bordeaux, France Theresa M. Corrigan, MD, Louisville, Ky Marco A. Cura, MD, Dallas, Tex Genta Dani, MD, Charleston, SC Anil K. Dasyam, MD, Pittsburgh, Pa Marc G. De Baets, MD, Collina d'Oro, Ticino, Switzerland Peter de Baets, MD, Damme, Belgium Kristof De Meerleer, MD, Sint Blasius Boekel-Zwalm, Belgium Mustafa K. Demir, MD, Istanbul, Turkey Thaworn Dendumrongsup, MD, Songkhla, Thailand Carlos R. Deragopyan, MD, Buenos Aires, Argentina Dionisios Drakopoulos, MD, Palaio Faliro, Athens, Greece Sjunne H. Duhnsen, MD, Zug, Switzerland Seyed A. Emamian, MD, PhD, Rockville, Md Edward J. Escott, MD, Lexington, Ky Susan M. Fanapour, DO, Lombard, Ill Brett D. Ferdinand, MD, Livingston, NJ Francis T. Flaherty, MD, Ridgefield, Conn Enrique Flores, MD, Santa Cristina, Oleiros, A Coruna, Spain Akira Fujikawa, MD, Tokyo, Japan Toshihiro Furuta, MD, Bunkyo-ku, Tokyo, Japan William H. Gallmann III, MD, Shreveport, La Ram P. Galwa, MD, Fredericton, New Brunswick, Canada Douglas J. Gardner, MD, Toronto, Ontario, Canada Bradley S. Gluck, MD, Southampton, NY Mark G. Goldshein, MD, Andover, Mass Antonio Carlos P. Gomes, MD, Sao Paulo, SP, Brazil Wataru Gonoi, MD, PhD, Bunkyo-ku, Tokyo, Japan Ruben F. Gonzalez Villaveiran, MD, Buenos Aires, Argentina
Philip Goodman, MD, Binghamton, NY Maria A. Gosein, MBBS, FRCR, Santa Cruz, Trinidad And Tobago Alex Grande Astorquiza, MD, Vigo, Pontevedra, Spain Navraj S. Grewal, MD, Rancho Cucamonga, Calif Michael Griffin, MD, PhD, Milwaukee, Wis Pramod K. Gupta, MD, Plano, Tex Akifumi Hagiwara, MD, Tokyo, Japan Ferris M. Hall, MD, Brookline, Mass Sameer H. Hanfi, MBBS, Karachi, Sindh, Pakistan Osamu Hasegawa, MD, Koriyama, Fukushima, Japan D. C. Heasley, Jr, MD, Dallas, Tex Christoph Hefel, Feldkirch, Austria Mateus A. Hernandes, MD, Ribeirao Preto, Sao Paulo, Brazil Yuusuke Hirokawa, MD, Kyoto, Japan Nerea Hormaza, MD, Barakaldo, Bizkaia, Spain Sodai Hoshiai, MD, Tsukuba, Ibaraki, Japan Brian H. Hu, MD, Hollis, NH Mark A. Hunter, MBBCh, FRCR, Paisley, Renfrewshire, United Kingdom Alberto C. Iaia, MD, Wilmington, Del Waleed M. Ibrahim, MD, Annandale, Va Noriatsu Ichiba, MD, Otsu, Shiga, Japan Mitsuru Ikeda, MD, Nagoya, Japan Takashi Ikeuchi, Moriyama, Shiga, Japan Akitoshi Inoue, MD, Otsu, Shiga, Japan Richard N. Irion, MD, Murray, Utah Nath G. Iyer, MD, FRANZCR, Perth, Western Australia, Australia Stephen F. Janas, MD, De Pere, Wis Sharada Jayagopal, MD, East Williston, NY Miral D. Jhaveri, MD, Chicago, Ill Colin D. Jones, MD, Calgary, Alberta, Canada Jennifer W. Jung, MD, Wyomissing, Pa Kenji Kachi, MD, Tsuchiura, Ibaraki, Japan Geoffrey Karjala, MD, Saskatoon, Saskatchewan, Canada Atman V. Kathiria, Surendranagar, Gujarat, India Koki Kato, MD, Utsunomiya, Tochigi, Japan Yasushi Kawata, MD, Yurihonjo City, Akita, Japan Shanigarn Keoplung, MD, Muang Nonthaburi, Nonthaburi, Thailand Patrick Kiely, MBBCh, Limerick, Ireland Takao Kiguchi, MD, Niigata, Japan Takuji Kiryu, MD, PhD, Gifu, Japan Osamu Kizu, MD, Ohtsu, Japan Mitchell A. Klein, MD, Mequon, Wis Masamichi Koyama, MD, PhD, Tokyo, Japan Richard E. Krauthamer, MD, Rolling Hills, Calif John J. Krol, MD, Portland, Ore Ryo Kuwahara, MD, Kyoto, Nakagyogu, Japan Anthony G. Laglia, MD, Piedmont, Calif Mario A. Laguna, MD, Milwaukee, Wis Luis A. Landeras, MD, Westlake, Ohio Alan Laorr, MD, Eden Prairie, Minn Martin Lecompte, MD, Manotick, Ontario, Canada
radiology.rsna.org n Radiology: Volume 272: Number 2—August 2014
DIAGNOSIS PLEASE: Alkaptonuria
Chee Hwee Lee, MD, Taipei, Taiwan Stefanie Lee, London, Ontario, Canada Karl J. Lehmann, MD, Karlsruhe, Germany Donald R. Lewis, Jr, MD, Huntington, WVa David A. Lisle, MBBS, Brisbane, Queensland, Australia Thomas B. Lloyd, MBBS, Brisbane, Queensland, Australia Rafael Maffei Loureiro, MD, Sao Paulo, Brazil Patrick D. Magoon, MD, Torrance, Calif Mark D. Mamlouk, MD, Foster City, Calif Stephen V. Manghisi, MD, Closter, NJ Douglas J. Martin, MD, Minneapolis, Minn Satoshi Matsushima, MD, Tokyo, Japan Edward J. Mauch, MD, Harrison Township, Mich Alan P. Mautz, MD, Presque Isle, Me Brian McNamee, MD, Coeur D Alene, Idaho Sunil L. Mehta, MD, Mississauga, Ontario, Canada Albert Mendelson, MD, Northbrook, Ill Steven J. Michel, MD, Bend, Ore Ralph A. Milillo, MD, Manhasset, NY Manabu Minami, MD, PhD, Yokohama, Japan Shunsuke Minami, Otsu, Japan Kenichi Mizuki, MD, Hamamatsu-shi, Shizuokaken, Japan Jose Mondello, MD, Buenos Aires, CA, Argentina Deirdre E. Moran, MBBCh, Brookline, Mass Tiago N. Morato, MD, Brasilia, DF, Brazil Toshio Moritani, MD, PhD, Iowa City, Iowa Sleiman Y. Naddaf, MD, Brooklyn, NY Kyoko Nagai, MD, Yokohama, Japan Ryusuke Nakamoto, MD, Kyoto, Japan Tammam N. Nehme, MD, Mattawan, Mich Tuan Duc Nguyen, MD, Ski, Norway Hironori Nishibori, MD, Minokamo City, Gifu, Japan Tomokazu Nishiguchi, MD, PhD, Osaka, Japan Mizuki Nishino, MD, Boston, Mass Hiroshi Nobusawa, MD, PhD, Ota, Tokyo, Japan Roque Oca, MD, Vigo, Pontevedra, Spain Laura Oleaga, Barcelona, Spain Resmiye Oral, MD, Iowa City, Iowa Sanford M. Ornstein, MD, Paradise Valley, Ariz Michael D. Orsi, MD, San Antonio, Tex Vishal Panchal, San Francisco, Calif David M. Panicek, MD, New York, NY Ioannis E. Papachristos, MD, Agrinio, Greece Patouras Paraskevas, MD, Agia Paraskevi, Attiki, Greece Narendrakumar P. Patel, MD, Newburgh, NY Prakash N. Patel, MD, New City, NY Satish D. Patel, MD, Shavertown, Pa Suresh K. Patel, MD, Chicago, Ill Aruna R. Patil, MD, FRCR, Bangalore, Karnataka, India Yeliz Pekcevik, Izmir, Turkey Francesco Pierazzoli, MD, Padua, PD, Italy John M. Plotke, MD, Naperville, Ill Rubem Pochaczevsky, MD, Bronx, NY Elias Primetis, MD, Athens, Greece
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Shawn P. Quillin, MD, Charlotte, NC Gary W. Radner, MD, La Canada Flintridge, Calif Keshav P. Raichurkar, MD, Mysore, Kamataka, India Daniel C. Rappaport, MD, Toronto, Ontario, Canada Ryan P. Rebello, MD, Dundas, Ontario, Canada Eric W. Robbins, MD, Denver, Colo Mathieu H. Rodallec, MD, Paris, France Jorge Rodriguez Antuna, MD, A Coruna, Spain Hugo Rodriguez Requena, MD, Madrid, Spain Simon Roh, MD, Iowa City, Iowa Daniel Romeu Vilar, MD, Bertamirans, A Coruna, Spain Stefan Roosendaal, MD, PhD, Amsterdam, the Netherlands Akihiko Sakata, MD, Kyoto, Japan Blake Saltaformaggio, MD, Franklin, Tenn Meir H. Scheinfeld, MD, PhD, Suffern, NY Pierre Schmit, MD, Halifax, Nova Scotia, Canada Steven M. Schultz, MD, Fort Worth, Tex Joel M. Schwartz, MD, Elmsford, NY Randall L. Scott, MD, Memphis, Tenn Anthony J. Scuderi, MD, Johnstown, Pa Matthew P. Shapiro, MD, Charlottesvle, Va Hussain H. Sharahili, MBBS, MD, Dharhan, Eastern Province, Saudi Arabia Hideki Shima, MD, Narita, Chiba, Japan Taro Shimono, MD, Osaka, Japan Ichiro Shirouzu, MD, Tokyo, Japan Paul J. Shogan, MD, Clarksville, Tenn Richard M. Shore, MD, Glenview, Ill Ho L. Sie, MD, Henderson, Nev Michael S. Siegfried, MD, Glencoe, Ill Andre Simoes, MD, Barcelos, Portugal Evan M. Sirc, MD, Santa Cruz, Calif Christopher L. Smoley, Dallas, Tex David F. Sobel, MD, La Jolla, Calif Luis A. Sosa, MD, Mexico City, DF, Mexico Isabel Sousa, MD, Lisboa, Portugal James D. Sprinkle, Jr, MD, Spotsylvania, Va Evan G. Stein, MD, PhD, New York, NY Peter M. Stroz, MD, Toronto, Ontario, Canada Jorge O. Suarez, MD, Bogota, Colombia Hongliang Sun, MD, Beijing, China Eliko Tanaka, MD, Yokohama, Japan Takashi Tanaka, MD, Okayama, Japan Bisher Tarabishy, MD, West Bloomfield, Mich Satoshi Tatsuno, MD, Ichikawa, Chiba, Japan Douglas L. Teich, MD, Brookline, Mass Yasuyo Teramura, MD, Tokorozawa, Saitama, Japan Craig B. Thayer, MD, Tucson, Ariz Christina M. Thuerl, MD, Freiburg, BadenWurttemberg, Germany Eugene Tong, MD, Austin, Tex Ulysses S. Torres, MD, Sao Paulo, SP, Brazil Joseph Z. Toutounji, MD, Beirut, Lebanon Jeffrey Tseng, MD, Menlo Park, Calif Meric Tuzun, MD, Ankara, Turkey Herminia Tyminski, MD, Manama, Bahrain Atsushi Uehara, Niigata, Japan
Radiology: Volume 272: Number 2—August 2014 n radiology.rsna.org
Piet K. Vanhoenacker, MD, Moorsel, Belgium Harsha Vardhan, MBBS, Chandigarh, Haryana and Punjab, India Bonny Varghese, MD, FRANZCR, Melbourne, Victoria, Australia Rajeev K. Varma, MD, Torrance, Calif Constantine P. Vassiliou, MD, Pallini, Greece Ricardo Videla, Cordoba, CB, Argentina Alexander Vidershayn, MD, Brooklyn, NY Pier Carlo Villani, MD, Bari, Italy Ainhoa Viteri, MD, Bilbao, Biscay, Spain Christopher P. Vittore, MD, Belvidere, Ill Lynne Voutsinas, MD, Staten Island, NY James S. Walsh, MD, Edinburgh, United Kingdom Garrett L. Walworth, MD, Milford, Mich Haruo Watanabe, MD, Gifu, Japan Noritaka Yamakawa, Kyoto, Japan Tatsuya Yamamoto, MD, Yoshida-gun, Fukui, Japan Yi Yang, MD, Suzhou, Jiangsu, China Koichiro Yasaka, MD, Tokyo, Japan Kurata Yasuhisa, MD, Kobe, Hyogo, Japan Hajime Yokota, MD, Kyoto, Japan Rika Yoshida, MD, Utsunomiya, Tochigi, Japan Kaneko You, Gifu, Japan Stanko Yovichevich, MD, Sydney, New South Wales, Australia Carlos A. Zamora, MD, PhD, Lutherville, Md Ahmed Zidan, MD, Barcelona, Spain
Resident group responses Hospital de Santa Maria Radiology Residents, Lisbon, Portugal Mater Dei Hospital, Msida, Malta Mie University Hospital Radiology Residents, MD, Tsu, Mie, Japan Montefiore Medical Center Radiology Residents, Bronx, NY Prince of Songkla University Radiology Residents, Songkla, Thailand Thomas Jefferson University Radiology Residents, MD, Philadelphia, Pa Tsukuba University Hospital Radiology Residents, Tsukuba, Ibaraki, Japan University of Pennsylvania Radiology Residents, Philadelphia, Pa University of Washington Radiology Residents, MD, Seattle, Wash UTHSC at San Antonio Radiology Residents, MD, San Antonio, Tex Virginia Commonwealth University Radiology Residents, Richmond, Va Yale University Radiology Residents, New Haven, Conn Kristof De Meerleer, MD, Sint Blasius Boekel-Zwalm, Begium, submitted the correct diagnosis (persistent hypertrophic primary vitreous) for Case 206.
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