•
Early-Onset Gouty Arthritis
l
•
Diagnostic Radiology
Donald Resnick, M.D., Robert T. Reinke, M.D., and Richard M. Taketa, M.D. Five cases of early-onset gouty arthritis are presented, with roentgcnographic abnormalities evident in the first two decades of life. Three patients suffered from "primary" gout; classification of the other two patients was difficult because of associated mental retardation, hypothyroidism and psoriasis. Radiographic alterations included soft-tissue masses and calcification, with typical erosive abnormalities and predilection for the hands and feet. The sacroiliac joints were abnormal in two patients. INDEX TERMS:
Arthritis. Gout
Radiology 114:67-73, January 1975
•
•
ness, redness and swelling about the third proximal interphalangeal joint of the right hand and right knee which persisted for one week. Four months later he had recurrent and more exaggerated symptoms in the second and third metacarpophalangeal and fourth proximal interphalangeal joints of the right hand, and right wrist. He was hospitalized in Guam, and was treated with Benemid and Colchicine for gout. In 1969, in the United States, he began having episodic joint complaints in the right shoulder, both elbows, wrists, hands, feet, knees, ankles and metatarsophalangeal joints. He was admitted to the University Hospital in 1970 for evaluation of the joint disease. A family history revealed a mother with adult-onset gout, although three brothers and four sisters had no evidence of disease. Physical examination revealed a non tender subcutaneous nodule in the soft tissues of the right hand and swelling about several metacarpophalangeal and proximal interphalangeal joints. Additional swelling was noted in the right knee. Laboratory values included a scrum uric acid of 15.4 mg/lOO ml, blood urea nitrogen of 10 mg/lOO rnl, normal electrolytes, and an elevated sedimentation rate. A 24-hour urine for uric acid was ;:178 mg. Evaluation for the Lesch- ~ yhan syndrome was undertaken without evidence of enzymc deficiency, Right heart catheterization revealed mild mitral insufficiency. Radiographs of the right hand demonstrated soft-tissue and bony abnormalities mainly confined to the proximal interphalangeal and metacarpophalangeal joints (Fig. 1). The patient was treated with Bencmid and Colchicine with good response, Following discharge from the hospital, he has continued to have episodic joint complaints and a recent radiographic survey revealed progression of the disease. Comment: Reports have indicated a higher incidence of hyperuricemia in persons of the South Pacific (::1, ::17), particularly Filipinos (3,43). A high incidence of hemoglobin E has also been reported in the indigenous population of Southeast Asia (28). The homozygous state of E-hemoglobinopathy produces mild microcytic normochromic anemia with target cells and minimal signs of hemolysis. Splenomegaly may be present (51). Our patient was not anemic and had no evidence of splenomegaly.
OUT is predominantly a disease of the adult population, males being affected in 90-95% of cases. The peak age incidence has varied from the 30s through 50s (49), the age of onset being related in some instances to the serum urate level (13). Exceptional cases of gout in early (3, 4, 33) and advanced (44) age have been reported. In some large series (11) up to 5% of gouty individuals have had the onset of the disease prior to the age of twenty. Often, in these studies, it is not stated whether one is dealing with "chemical gout" (asymptomatic patients with elevation of serum uric acid levels), or symptomatic gout without roentgenographic abnormality, nor is a clear distinction made between primary and secondary gouty arthritis. The purpose of this paper is to record five cases of early-onset gouty arthritis in which radiographic alterations were evident prior to the age of twenty, and to define the location and type of these radiologic abnormalities.
G
MATERIAL AND METHODS The medical files of gouty patients at the U niversity of California Hospitals in San Diego and San Francisco were reviewed. Five patients with early-onset gout demonstrating radiologic abnormality were discovered (TABLE I). Clinical and roentgenographic records of these patients were studied and, when possible, follow-up examinations were performed. CASE REPORTS CASE I: The patient is a 23-year-old Guamanian man who was well until the age of 16 years when he noted heat, tender-
1 From the Departments of Radiology, University of California, San Diego (D. R., R. M. T.) and San Francisco (R. T. R.), Calif. Final revision accepted in July 1974. elk
67
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DONALD R ESNICK AND OTHERS
Januar y 1975
Fig. 1. CASE 1. A. Soft-tissue swelling about multiple proximal interphalangeal joints is associated with erosive abnormalit y, best noted in the proximal phalanx of the fifth finger. Flexion deformity at the second and third meta carpophalan geal joints is seen. B. Two years later progressive soft-ti ssue and osseous abnormality is evident. C. Soft-ti ssue swelling and underl ying erosive change (arrow) of th e olecranon are apparent.
CASE 11: T his white man presented at th e age of 14 in 1961 wit h complaints of arthritis. skin ailment, and small stature . He had been th e product of a full-term pregnancy compli cated by m aternal dysentery in th e eigh th munth , and was jaundiced following birth. As a child he had had scarlet fever a nd slow ph ysical devel opment. Hypothyroidism was diagnosed and trea ted with th yroid horm une. H e began walking a t the age of 2 1/, years. A skin ras h was noted on his legs a t the age of eight. In 1960, at the age of 1:3, pain began in the hip, elbow, feet , and hands. There was swelling without redness. Thyroid hormone and steroids gave some relief, although continued symptoms necessitated hospitalization. Family hist ory at t ha t time revealed a fath er with psoriasis and an
uncle with arthritis. On phys ical exa mina tion he was obese a nd aler t. He had generalized psoriasis a nd there was some rest riction of joint mot ion. Laboratory values included a sedimentation rate of 40 mm /hour and seru m uric acid levels varying frum 7-15 mg/ lOO m\. Electrolytes were norm al. R adioact ive iodine uptake was 9% at 24 hours. Radiographs demonstrated abnor malities of multiple joints in cluding th e elbows , ankles, feet and shoulder (Fig. 2). Biopsies of tophi on the ri ght arm and proximal interphalangeal joint of the right second toe were performed . Gouty arthritis was diagnosed and treatment with Colchicine begun. A dermatologist diagnosed psori asis and a pcdiatric cnd ocrinologist th ought the te st s for hypothyr oidism were equivocal.
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Fig. 2. CASE n. A. Destruction of the proximal interphalangeal joint of the second toe (arrow) is associated with a soft-tissue mass and periosteal proliferation. B. Cortical disruption and a large subchondral lucent lesion (arrow) in the olecranon are noted. Effusion is present.
The patient was discharged on Colchicine and has continued to have episodic joint complaints. At a recent visit to his physician, the patient had widespread psoriasis, a serum uric acid of 9.2 mg/lOO ml, and symptomatic involvement of the left wrist, both feet and elbows. CASE Ill: This patient, the brother of Patient Il, was evaluated in 1962 at the age of 13. At that time he was asymptomatic and evaluation was requested because of his brother's gouty arthritis. The boy was obese but radiographic studies were within normal limits. Serum uric acid level was 9.7 mg/lOO ml, Further evaluation in 1965 revealed a serum uric acid of 14 mg/IOO ml and a BUN of 13 mg/IOO ml. Roentgenographic surveys in 1963 and 1966 demonstrated increasing abnormalities of the left foot and ankle (Fig. 3). He was last seen in 1967 when the examiner noted increased obesity and no visible tophi. No serum uric acid level at this time was noted in the chart. The patient failed to keep his next appointment and was subsequently killed in an automobile accident. Comment: The etiology of the mental retardation in the older of the two brothers was not clear. The possibility of hypothyroidism was suggested although not firmly established. One cannot totally exclude a partial deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (see discussion). Elevated uric acid levels in the serum of rnyxedernatous patients have been noted (26,40). In a study of 28 hypothyroid individuals (26) most of the male patients and onethird of the females had hyperuricemia and decreased urinary excretion of uric acid. The youngest patient was 38 years old. No clinical or roentgenographic joint abnormality was noted. Patient Il had generalized psoriasis; the relationship between gout and psoriasis is well known, although of some debate. Hyperuricernia has been described in 25-5C% of patients with psoriasis. Arthritic manifestations in psoriatic patients are well documented and in some individuals urate crystals have been recovered from biopsy material. Psoriatic patients appear to have an increased turnover rate of nucleic acid (9).
Fig. 3. CASE Ill. A. A small erosion (arrow) of the posterior surface of the calcaneus is apparent. B. Two years later the lesion has enlarged substantially and a surrounding sclerotic rim is more evident.
CASE IV: The patient, a 27-year-old white man, had been in good health until the age of 19 when he experienced an episode of pain and swelling in his left foot and toes. Following this attack, he had several episodes of joint complaints of pain, redness and swelling. He was first found to have an elevated serum uric acid level at the age of 21 and was treated with Colchicine, Butazolidin, and Benemid with some control of the symptomatology. He had subsequent multiple hospitalizations for joint complaints and recurrent nephrolithiasis. Analysis of the stones revealed uric acid. From the ages of 24 through 28 serum uric acid levels varied from 9-16 rng/lOO ml, Medications included combinations of Allopurinol, Tndocin and Prednisone. He became overtly Cushinoid, depressed, somnolent and edematous. Family history revealed a maternal grandfather who died with
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index finger was amputated because of an infected tophus. Serum uric acid levels during this period were between 9-12 mg/100 ml. The attacks continued with widespread joint involvement, induding the hands, feet, ankles, knees, sacroiliacs, and temporomandibular joints. The metatarsophalangeal joints became involved at this stage. On one admission the patient was noted to have proteinuria, although the renal chemistries were normal. Mild and then moderate hypertension developed, although an intravenous pyelogram was normal. Gouty nephritis was diagnosed; no laboratory evidence of hyperparathyroidism was established. At further admissions in subsequent years roentgenographs demonstrated progressive joint disease and calcified tophi (Fig. 5). In 1961 a tophectomy of several fingers was accomplished; in 1962 a tophus was removed from the right heel. Medication during these years although variable, induded Colchicine, Benernid, and steroids. The patient was last seen in August 1963, failing to keep his next appointment. He died shortly thereafter at the age of 42, although details of his death are not available. DISCUSSION
Fig. 4. CASE IV. Flexion deformities and erosive abnormalities of several metatarsophalangeal joints may be seen.
"arthritis and renal stones." During hospitalization in 1967, at the age of 27, the patient had obvious tophi of the left ear, elbows and left great toe. Tenderness was noted in the right elbow, wrist, hand, left knee and ankles. Laboratory data included serum uric acid determinations of 12-13 mg/IOO ml and 24-hour urinary uric acid of I1GO mg. Electrolytes were normal. Roentgenographic evaluation of multiple joints demonstrated abnormalities of the hands, particularly on the right side. While in the hospital, the patient had a carpal tunnel release on his right hand, the pathologist noting uric acid crystals about the volar tendons. Following discharge from the hospital, the patient was seen in Hawaii and was hospitalized with acute gout, renal lithiasis and cholestasis. Serum uric acid determinations varied from 5-14 mg/lOO ml and medications induded Butazolidin and Demerol. Radiographs taken in 1971 demonstrated increasing abnormalities of the left hand and feet and sacroiliac erosions (Fig. 4). CASE V: The patient, a white man, was in good health until the age of 19 when he noticed the first onset of mild arthritic pain. In the next two years severe bouts of acute arthritis developed with pain, swelling and tenderness of both ankles. Complete remission lasted for approximately one or two years. In 1946, at the age of 24, the patient was admitted with increasing joint complaints. Family history induded a father with gout and a brother with several episodes of joint discomfort. An ear tophus was biopsied. Radiographic abnormalities of the ankles and intertarsal joints were demonstrated (Fig. 5). The patient was treated with Colchicine but the attacks became more severe. In 1952 the left
Primary symptomatic gouty arthritis is uncommon prior to the third decade of life; secondary gout related to underlying disease process may occur in younger individuals. In either case roentgenographic abnormality in the first two decades of life is distinctly unusual. Specific enzYme defects may be associated with "juvenile gout" (14). Glucose 6-phosphatase deficiency (glycogen storage disease, type I) may produce severe and deforming arthritis in the first and second decades of life (15, 16, 17, 20), although frequently hyperuricemia is present without arthritic complaints. Hypoxanthine-guaninephosphoribosyltransferase deficiency may be partial or complete and associated with the Lesch-Nyhan syndrome (27, 32, 34, 35, 3R) consisting of spasticity, choreoathetosis, mental retardation and selfmutilation. Overproduction and overexcretion of uric acid are associated with renal disease and lithiasis. Radiographic abnormalities resulting from self-mutilation include amputation of soft and osseous tissues of the hands (2). Additionally, one may see retarded skeletal maturation, coxa valga deformities, soft-tissue tophi (34, 35, 39) and gouty erosions (38). A partial deficiency of the same enzyme may be found in adult patients with overproduction of uric acid (21, 22). These individuals may present in the second or third decades of life with neurological disorders, including seizures, mental retardation, ataxia and quadriplegia, renal stones and gout (14). H yperuricernia and secondary gouty arthritis may be associated with many disorders, including blood dyscrasias (11, 36, 45, 48), multiple myeloma (5), polycythemia (46), leukemia and lymphoma (11, 12, 52), lead poisoning (10), drugs, hyperparathyroidism, and chronic renal insufficiency
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F ig . 5 . C ASE V. A. Vasc ular (cur ved ar rows ) and soft-t iss ue (st rai ght arrow ) calci ficatio n ar e pre sent ab out the ankle. B. M assi ve soft -t iss ue enlargem ent , destruc t ive changes and calc ifica t ion are present at t he distal int er ph alangeal joints (closed st ra igh t arrows ). Fusion of th e fou rth di st al interphalan geal joi nt was evi dent on additional vi ews. Prox im al interphalan geal a nd metacarpoph alangeal joint a bnor mal itie s and soft-t issue (open ar row ) a nd vascular (closed curved a rro w) calcificat ion may be not ed . The second ray had been previ ously amp utated . C . E ros ive and cystic changes (a rrows) , more prominent in t he ilium, invo lving the lower asp ects of bot h sacroiliac joints, are. see n . Si milar a bnormalit ies may be seen in hyperparathyroidism, althou gh no evi dence of the latter di sease was pre sent.
(7). In many of these disorders "gout " is reflected by elevat ion of serum uric acid alone, without evidence of joint sympto mato logy. Occasionall y, however, secondary gouty a rt h rit is may produce recognizable rad iographic ch anges in the first two decades of life (41). Gout in aleuke mic leukemi a (;jO) wa s described in a 5-year -old boy with a positive family history of gout . P ostmortem examination demon strated exten sive gouty tophi. "J uvenile" gout ha s also been associat ed with congeni tal hemoly ti c anemias (25), cyanotic con genital heart disease (42) and m yeloid metaplasia (45) . I solated case s of primar y juvenil e gout have appeared in the literature (3, 4, 8, 33); larger series of a rt hrit ic patients also contain occasional cases of early-onset gout (31). A review of the literature in 1971 revealed 66 cases of primary juvenile gout at which time two additio nal cases were reported (47). The ons et of disease in most of these
indi viduals was in th e second decade of life. The sex incidence in males and females was equal in those wit h gou t in the first decade ; in the second decade the males ou t numbered th e female s three to one. As compar ed to the paucity of the disease in adult women, th e young female doe s not appear immune. A family hi story of gout is often st riking in th ese young patients (47). The art icu lar symptoms are identical to those of th e adult, although rapid and seve re deformities ma y be noted (18, 23) and ea rly death ma y result (23) . R enal disease may be a complica ting factor (R) . It would appear that t hree of our patients (C ASE S I , IV, and V) suffered from early-on set primary gout as no associat ed etiologic factor could be appreciated . The two brothers (CASE S n and Ill) are more difficult to classify. The possibility of their having a partial enzyme deficienc y or a form e fruste of the Lesch- Nyhan
72
DONALD RESNICK AND OTHERS
TABLE I:
Patient
1
2 3 4 5
PATIENT ANALYSIS
DuraHon Age of Family of Onset History Disease (Yrs.) (Yrs.)
Classification of Disease
Feet
Ankles
+ + +? +
Primary ?Primary ?Primary Primary Primary
+ + + + +
+ + +
16 14 15 19 19
8 12 8* 14 23*
January 1975
Radiographs Knees
Hips
Sacroiliacs
N.A.
+
N.A.
+ +
Spine N.A. N.A. N.A. N.A.
Hands and Wrists
+ + + +
Elbows
Shoulders
+ +
+ +
N.A. N.A.
N.A. N.A.
* Expired. N.A. = Radiographs not available.
syndrome cannot be discarded, and complicating diseases such as psoriasis and hypothyroidism may be contributing factors. The radiographic manifestations of gout in these young patients did not differ significantly from those reported in adults (44). They were severe in one patient (CASE V) who had progressive gouty arthritis for 23 years and moderate in the others. Typical soft-tissue masses, bony erosions with overhanging edges (30), and mild to moderate demineralization were noted. In many cases joint spaces were preserved until late in the course of the disease. The distribution of radiographic lesions is indicated in TABLE 1. One can appreciate joint predilection for the hands and feet. Other sites in decreasing order of frequency included the ankles, elbows, shoulders, sacroiliacs and knees. Involvement of the sacroiliac joints was of interest, being abnormal in two of four patients in whom appropriate films were available. Bilateral and relatively symmetrical erosions were noted in both cases with surrounding sclerosis. Sacroiliac involvement in gouty arthritis has been reported in 7-13% (29) and 17% (1) of cases. It was noted more frequently in patients with early-onset gout (which may reflect a longer and more severe clinical course) with a left-sided predominance, and demonstrable sclerosis and cystic abnormality (1). Sacroiliac gout associated with hemoglobinopathy and hypersplenism has also been reported (24). ACKNOWLEDGMENTS: We wish to thank Dr. B. J. Guttormsson (Madera, Calif.) for supplying information and roentgenograms regarding Patient Tl, and Dr. Thomas C. Brown (Honolulu, Hawaii) for doing the same regarding Patient IV. In addition, we wish to acknowledge the assistance of Miriam Blaustein, the Research Librarian at University of California, San Francisco, and Willa Johnson at Veterans Administration Hospital, San Diego, for her technical assistance. Department of Radiology Veterans Administration Hospital 3350 La ]oJla Village Drive San Diego, Calif. 92161
REFERENCES 1. Alarcon-Segovia D, Cetina ]A, Dfaz-jouanen E: Sacroiliac joints in primary gout: clinical and roeritgenographic study of 143 patients. ,Am J RoentgenoI118:438-443, j un 1973 2. Becker MH, Wallin ]K: Congenital hyperuricosuria. Associated radiologic features. Radiol Clin North Am 6:239243, Aug 1968 3. Berk ME: Gout: report of an unusual case in a young man. Am J Med Sci 215:290-295, Mar 1948 4. Bernstein SS: Gout in early life. J Mt. Sinai Hosp 14: 747-763, Sep-Oct 1947 5. Bronsky D, Bernstein A: Acute gout secondary to multiple myeloma: a case report. Ann Intern Med 41 : 820-823, Oct 1954 6. Burch TA, O'Brien WM, Need R, et al: Hyperuricaemia and gout in the Mariana Islands. Ann Rheum Dis 25: 114-116, Mar 1966 7. Caner JE, Decker JL: Recurrerit acute (?gouty) arthritis in chronic renal failure treated with periodic hemodialysis. Am J Med 36:571-582, Apr 1964 8. Duncan H, Dixon AS: Gout, familial hyperuricaemia, and renal disease. Quart J Med 29: 127-135, Jan 1960 9. Eisen AZ, Seegmiller JE: Uric acid metabolism in psoriasis. J Clin Invest 40: 1486-1494, Aug 1961 10. Emmerson BT: The clinical differentiation of lead gout from primary gout. Arthritis Rheum 11:623-634, Oct 1968 11. Grahame R, Scott ]T: Clinical survey of 354 patients with gout. Ann Rheum Dis 29:461-468, Sep 1970 12. Gutman AB: Primary and secondary gout. Ann Intern Med 39: 1062-1076, Nov 1953 13. Hall AP, Barry PE, Dawber TR, et al: Epidemiology of gout and hyperuricemia. A long-term population study. Am J Med 52:27-37, Jan 1967 14. Hollander J, McCarty DJ Jr: Arthritis and Allied Conditions. Philadelphia, Lea & Febiger, 8th ed, 1972 15. Holling HE: Gout and glycogen storage disease. Ann Intern Med 58:654-663, Apr 1963 16. Howell RR: The interrelationship of glycogen storage disease and gout. Arthritis Rheum 8:780-785, Oct 1965 17. Hoyningen-Huene CB: Gout, and glycogen storage disease in preadolescent brothers. Arch Intern Med 118:471477, Nov 1966 18. Hughes GR, Barnes CG, Mason RM: Bony ankylosis in gout. Ann Rheum Dis 27:67-70, jan 1968 19. Jaffe H: Metabolic Degenerative and Inflammatory Diseases of Bones and Joints. Philadelphia, Lea & Febiger, 1972 20. Jakovcic S, SorensenLB: Studies of uric acid metabolism in glycogen storage disease associated with gouty arthritis. Arthritis Rheum 10: 129-134, Apr 1967 21. Kelley WN Greene ML, Rosenbloom FM, et al: Hypoxanthine-guanin~ phosphoribosyltransferase deficiency in gout. Ann Intern Med 70:115-206, Jan 1969 22. Kelley WN, Rosenbloom FM, Henderson JF, et al: A specific enzyme defect in gout associated with overproduction of uric acid. Proc Nat Acad Sci 57:1735-1739, j un 1967 23. Kersley GD, Mandel L, Jeffrey MR: Gout; an unusual case with softening and subluxation of the first cervical vertebra and splenomegaly; result of ACTH administration and eventual post-mortem findings. Ann Rheum Dis 9:282-304, Dec 19~~ 24. Lambeth JT, Burns-Cox CJ, MacLean R: Sacroiliac gout associated with hernoglobin E and hypersplenism. Radiology 95:413-415, May 1970 25. Lambie CG: A study of juvenile gout in a patient suf-
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fering from chronic erythronoc1astic anaemia of obscure origin, together with observations upon the physical state of uric acid in the blood and the effects of splenectomy. Med J Austr 1: 535558, 20 Apr 1940 26. Leeper RD, Benua RS, Brener JL, et al: Hyperuricemia in rnyxederna. J Clin Endocrin Metab 20: 1457-1466, Nov 1960 27. Lesch M, Nyhan WL: A familial disorder of uric acid metabolism and central nervous system function. Am J Med 36: 561-i?70, Apr 1964 28. Lie-Injo LE, Chin J: Abnormal haemoglobin and glucose6-phosphate dehydrogenase deficiency in Malayan aborigines. Nature 204: 291-292, 17 Oct 1964 29. Malawista SE, Seegrniller JE, Hathaway BE, et al: Sacroiliac gout. JAMA 194:954-956, 29 Nov 1965 30. Martel W: The overhanging margin of bone: roentgenologic manifestation of gout. Radiology 91: 755-756, Oct 1968 31. McCracken JP, Owen PS, Pratt JH: Gout: still a forgotten disease. JAMA 131 :367-372, 1 Jun 1946 32. Michener WM: Hyperuricemia and mental retardation with athetosis and self-mutilation. Am J Dis Child 113: 195206, Feb 1967 33. Middlerniss JH, Braband H: Juvenile gout. Clin Radiol 13: 149-152, Apr 1962 34. Nyhan WL: Clinical features of the Lesch-Nyhan syndrome. Arch Intern Med 130: 186-192, Aug 1972 35. Nyhan WL, Pesek J, Sweetman L, et al: Genetics of an X-linked disorder of uric acid metabolism and cerebral function. Pediat Res 1:5-13, Ian 1967 36. Paik C, Dunea G: Thalassemia and gouty arthritis. JAMA 213:291-298,1973 37. Prior lA, Rose BS: Uric acid, gout and public health in the South Pacific. New Zeal Med J 65:295-300, May 1966
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38. Riley JD: Gout ar-d cerebral palsy in a three-year-old boy. Arch Dis Child 35:293-295, j un 1960 39. Sass JK, Itabashi HH, Dexter RA: Juvenile gout with brain involvement. Arch NeuroI13:639-655, Dec 1965 40. Scott JT: Factors inhibiting the excretion of uric acid. Proc Roy Soc Med 59:310-312, Apr 1266 41. Smith EE, Kurlander GJ, PoweIl RC: Two rare causes of secondary gouty arthritis. Am J Roentgenol 100:550-553, Tul 1967 42. Somerville J: Gout in cyanotic congenital heart disease. Br Heart J 23:31-34, j an 1961 43. Steuermann N, Farias AH: Hyperuricemia in Filipinos. Hawaii Med J 20: 151-153, Nov-Dec 1960 44. TalbottJH: Gout. New York, Grune&Stratton, 1967 45. Talbott JH: Gout and blood dyscrasias. Medicine 38: 173-205, May 1959 46. Tinney WS, PoIley HF, Hall BE, et al: Polycythemia vera and gout: report of 8 cases. Proc Staff Meet., Mayo Clin 20:49-55,21 Feb 1945 47. TreadweIl BL: Juvenile gout. Ann Rheum Dis 30:27928'!-, May 1971 48. Tsachalos P: Gout secondary to thalassemia (minor form of Cooley's disease). Rev Rhum 27:414-416, Oct 1960 49. Turner RE, Frank MJ, Van Ausdal D, et al: Some aspects of the epidemiology of gout. Sex and race incidence. Arch Intern Med 106:400-406, Sep 1960 50. Vining CW, Thomson JG: Gout and aleukaemic leukemia in a boy aged fi. Arch Dis Child 9:277-284, Oct 1934 51. Wintrobe MM: Clinical Hematology. Philadelphia, Lea & Febiger, 6th ed, 1967 52. Yu TF: Secondary gout associated with myeloproliferative diseases. Arthritis Rheum 8: 765-771, Oct 1965
Early-Onset Gouty Arthritis
l
•
Diagnostic Radiology
Donald Resnick, M.D., Robert T. Reinke, M.D., and Richard M. Taketa, M.D. Five cases of early-onset gouty arthritis are presented, with roentgcnographic abnormalities evident in the first two decades of life. Three patients suffered from "primary" gout; classification of the other two patients was difficult because of associated mental retardation, hypothyroidism and psoriasis. Radiographic alterations included soft-tissue masses and calcification, with typical erosive abnormalities and predilection for the hands and feet. The sacroiliac joints were abnormal in two patients. INDEX TERMS:
Arthritis. Gout
Radiology 114:67-73, January 1975
•
•
ness, redness and swelling about the third proximal interphalangeal joint of the right hand and right knee which persisted for one week. Four months later he had recurrent and more exaggerated symptoms in the second and third metacarpophalangeal and fourth proximal interphalangeal joints of the right hand, and right wrist. He was hospitalized in Guam, and was treated with Benemid and Colchicine for gout. In 1969, in the United States, he began having episodic joint complaints in the right shoulder, both elbows, wrists, hands, feet, knees, ankles and metatarsophalangeal joints. He was admitted to the University Hospital in 1970 for evaluation of the joint disease. A family history revealed a mother with adult-onset gout, although three brothers and four sisters had no evidence of disease. Physical examination revealed a non tender subcutaneous nodule in the soft tissues of the right hand and swelling about several metacarpophalangeal and proximal interphalangeal joints. Additional swelling was noted in the right knee. Laboratory values included a scrum uric acid of 15.4 mg/lOO ml, blood urea nitrogen of 10 mg/lOO rnl, normal electrolytes, and an elevated sedimentation rate. A 24-hour urine for uric acid was ;:178 mg. Evaluation for the Lesch- ~ yhan syndrome was undertaken without evidence of enzymc deficiency, Right heart catheterization revealed mild mitral insufficiency. Radiographs of the right hand demonstrated soft-tissue and bony abnormalities mainly confined to the proximal interphalangeal and metacarpophalangeal joints (Fig. 1). The patient was treated with Bencmid and Colchicine with good response, Following discharge from the hospital, he has continued to have episodic joint complaints and a recent radiographic survey revealed progression of the disease. Comment: Reports have indicated a higher incidence of hyperuricemia in persons of the South Pacific (::1, ::17), particularly Filipinos (3,43). A high incidence of hemoglobin E has also been reported in the indigenous population of Southeast Asia (28). The homozygous state of E-hemoglobinopathy produces mild microcytic normochromic anemia with target cells and minimal signs of hemolysis. Splenomegaly may be present (51). Our patient was not anemic and had no evidence of splenomegaly.
OUT is predominantly a disease of the adult population, males being affected in 90-95% of cases. The peak age incidence has varied from the 30s through 50s (49), the age of onset being related in some instances to the serum urate level (13). Exceptional cases of gout in early (3, 4, 33) and advanced (44) age have been reported. In some large series (11) up to 5% of gouty individuals have had the onset of the disease prior to the age of twenty. Often, in these studies, it is not stated whether one is dealing with "chemical gout" (asymptomatic patients with elevation of serum uric acid levels), or symptomatic gout without roentgenographic abnormality, nor is a clear distinction made between primary and secondary gouty arthritis. The purpose of this paper is to record five cases of early-onset gouty arthritis in which radiographic alterations were evident prior to the age of twenty, and to define the location and type of these radiologic abnormalities.
G
MATERIAL AND METHODS The medical files of gouty patients at the U niversity of California Hospitals in San Diego and San Francisco were reviewed. Five patients with early-onset gout demonstrating radiologic abnormality were discovered (TABLE I). Clinical and roentgenographic records of these patients were studied and, when possible, follow-up examinations were performed. CASE REPORTS CASE I: The patient is a 23-year-old Guamanian man who was well until the age of 16 years when he noted heat, tender-
1 From the Departments of Radiology, University of California, San Diego (D. R., R. M. T.) and San Francisco (R. T. R.), Calif. Final revision accepted in July 1974. elk
67
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DONALD R ESNICK AND OTHERS
Januar y 1975
Fig. 1. CASE 1. A. Soft-tissue swelling about multiple proximal interphalangeal joints is associated with erosive abnormalit y, best noted in the proximal phalanx of the fifth finger. Flexion deformity at the second and third meta carpophalan geal joints is seen. B. Two years later progressive soft-ti ssue and osseous abnormality is evident. C. Soft-ti ssue swelling and underl ying erosive change (arrow) of th e olecranon are apparent.
CASE 11: T his white man presented at th e age of 14 in 1961 wit h complaints of arthritis. skin ailment, and small stature . He had been th e product of a full-term pregnancy compli cated by m aternal dysentery in th e eigh th munth , and was jaundiced following birth. As a child he had had scarlet fever a nd slow ph ysical devel opment. Hypothyroidism was diagnosed and trea ted with th yroid horm une. H e began walking a t the age of 2 1/, years. A skin ras h was noted on his legs a t the age of eight. In 1960, at the age of 1:3, pain began in the hip, elbow, feet , and hands. There was swelling without redness. Thyroid hormone and steroids gave some relief, although continued symptoms necessitated hospitalization. Family hist ory at t ha t time revealed a fath er with psoriasis and an
uncle with arthritis. On phys ical exa mina tion he was obese a nd aler t. He had generalized psoriasis a nd there was some rest riction of joint mot ion. Laboratory values included a sedimentation rate of 40 mm /hour and seru m uric acid levels varying frum 7-15 mg/ lOO m\. Electrolytes were norm al. R adioact ive iodine uptake was 9% at 24 hours. Radiographs demonstrated abnor malities of multiple joints in cluding th e elbows , ankles, feet and shoulder (Fig. 2). Biopsies of tophi on the ri ght arm and proximal interphalangeal joint of the right second toe were performed . Gouty arthritis was diagnosed and treatment with Colchicine begun. A dermatologist diagnosed psori asis and a pcdiatric cnd ocrinologist th ought the te st s for hypothyr oidism were equivocal.
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Fig. 2. CASE n. A. Destruction of the proximal interphalangeal joint of the second toe (arrow) is associated with a soft-tissue mass and periosteal proliferation. B. Cortical disruption and a large subchondral lucent lesion (arrow) in the olecranon are noted. Effusion is present.
The patient was discharged on Colchicine and has continued to have episodic joint complaints. At a recent visit to his physician, the patient had widespread psoriasis, a serum uric acid of 9.2 mg/lOO ml, and symptomatic involvement of the left wrist, both feet and elbows. CASE Ill: This patient, the brother of Patient Il, was evaluated in 1962 at the age of 13. At that time he was asymptomatic and evaluation was requested because of his brother's gouty arthritis. The boy was obese but radiographic studies were within normal limits. Serum uric acid level was 9.7 mg/lOO ml, Further evaluation in 1965 revealed a serum uric acid of 14 mg/IOO ml and a BUN of 13 mg/IOO ml. Roentgenographic surveys in 1963 and 1966 demonstrated increasing abnormalities of the left foot and ankle (Fig. 3). He was last seen in 1967 when the examiner noted increased obesity and no visible tophi. No serum uric acid level at this time was noted in the chart. The patient failed to keep his next appointment and was subsequently killed in an automobile accident. Comment: The etiology of the mental retardation in the older of the two brothers was not clear. The possibility of hypothyroidism was suggested although not firmly established. One cannot totally exclude a partial deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (see discussion). Elevated uric acid levels in the serum of rnyxedernatous patients have been noted (26,40). In a study of 28 hypothyroid individuals (26) most of the male patients and onethird of the females had hyperuricemia and decreased urinary excretion of uric acid. The youngest patient was 38 years old. No clinical or roentgenographic joint abnormality was noted. Patient Il had generalized psoriasis; the relationship between gout and psoriasis is well known, although of some debate. Hyperuricernia has been described in 25-5C% of patients with psoriasis. Arthritic manifestations in psoriatic patients are well documented and in some individuals urate crystals have been recovered from biopsy material. Psoriatic patients appear to have an increased turnover rate of nucleic acid (9).
Fig. 3. CASE Ill. A. A small erosion (arrow) of the posterior surface of the calcaneus is apparent. B. Two years later the lesion has enlarged substantially and a surrounding sclerotic rim is more evident.
CASE IV: The patient, a 27-year-old white man, had been in good health until the age of 19 when he experienced an episode of pain and swelling in his left foot and toes. Following this attack, he had several episodes of joint complaints of pain, redness and swelling. He was first found to have an elevated serum uric acid level at the age of 21 and was treated with Colchicine, Butazolidin, and Benemid with some control of the symptomatology. He had subsequent multiple hospitalizations for joint complaints and recurrent nephrolithiasis. Analysis of the stones revealed uric acid. From the ages of 24 through 28 serum uric acid levels varied from 9-16 rng/lOO ml, Medications included combinations of Allopurinol, Tndocin and Prednisone. He became overtly Cushinoid, depressed, somnolent and edematous. Family history revealed a maternal grandfather who died with
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index finger was amputated because of an infected tophus. Serum uric acid levels during this period were between 9-12 mg/100 ml. The attacks continued with widespread joint involvement, induding the hands, feet, ankles, knees, sacroiliacs, and temporomandibular joints. The metatarsophalangeal joints became involved at this stage. On one admission the patient was noted to have proteinuria, although the renal chemistries were normal. Mild and then moderate hypertension developed, although an intravenous pyelogram was normal. Gouty nephritis was diagnosed; no laboratory evidence of hyperparathyroidism was established. At further admissions in subsequent years roentgenographs demonstrated progressive joint disease and calcified tophi (Fig. 5). In 1961 a tophectomy of several fingers was accomplished; in 1962 a tophus was removed from the right heel. Medication during these years although variable, induded Colchicine, Benernid, and steroids. The patient was last seen in August 1963, failing to keep his next appointment. He died shortly thereafter at the age of 42, although details of his death are not available. DISCUSSION
Fig. 4. CASE IV. Flexion deformities and erosive abnormalities of several metatarsophalangeal joints may be seen.
"arthritis and renal stones." During hospitalization in 1967, at the age of 27, the patient had obvious tophi of the left ear, elbows and left great toe. Tenderness was noted in the right elbow, wrist, hand, left knee and ankles. Laboratory data included serum uric acid determinations of 12-13 mg/IOO ml and 24-hour urinary uric acid of I1GO mg. Electrolytes were normal. Roentgenographic evaluation of multiple joints demonstrated abnormalities of the hands, particularly on the right side. While in the hospital, the patient had a carpal tunnel release on his right hand, the pathologist noting uric acid crystals about the volar tendons. Following discharge from the hospital, the patient was seen in Hawaii and was hospitalized with acute gout, renal lithiasis and cholestasis. Serum uric acid determinations varied from 5-14 mg/lOO ml and medications induded Butazolidin and Demerol. Radiographs taken in 1971 demonstrated increasing abnormalities of the left hand and feet and sacroiliac erosions (Fig. 4). CASE V: The patient, a white man, was in good health until the age of 19 when he noticed the first onset of mild arthritic pain. In the next two years severe bouts of acute arthritis developed with pain, swelling and tenderness of both ankles. Complete remission lasted for approximately one or two years. In 1946, at the age of 24, the patient was admitted with increasing joint complaints. Family history induded a father with gout and a brother with several episodes of joint discomfort. An ear tophus was biopsied. Radiographic abnormalities of the ankles and intertarsal joints were demonstrated (Fig. 5). The patient was treated with Colchicine but the attacks became more severe. In 1952 the left
Primary symptomatic gouty arthritis is uncommon prior to the third decade of life; secondary gout related to underlying disease process may occur in younger individuals. In either case roentgenographic abnormality in the first two decades of life is distinctly unusual. Specific enzYme defects may be associated with "juvenile gout" (14). Glucose 6-phosphatase deficiency (glycogen storage disease, type I) may produce severe and deforming arthritis in the first and second decades of life (15, 16, 17, 20), although frequently hyperuricemia is present without arthritic complaints. Hypoxanthine-guaninephosphoribosyltransferase deficiency may be partial or complete and associated with the Lesch-Nyhan syndrome (27, 32, 34, 35, 3R) consisting of spasticity, choreoathetosis, mental retardation and selfmutilation. Overproduction and overexcretion of uric acid are associated with renal disease and lithiasis. Radiographic abnormalities resulting from self-mutilation include amputation of soft and osseous tissues of the hands (2). Additionally, one may see retarded skeletal maturation, coxa valga deformities, soft-tissue tophi (34, 35, 39) and gouty erosions (38). A partial deficiency of the same enzyme may be found in adult patients with overproduction of uric acid (21, 22). These individuals may present in the second or third decades of life with neurological disorders, including seizures, mental retardation, ataxia and quadriplegia, renal stones and gout (14). H yperuricernia and secondary gouty arthritis may be associated with many disorders, including blood dyscrasias (11, 36, 45, 48), multiple myeloma (5), polycythemia (46), leukemia and lymphoma (11, 12, 52), lead poisoning (10), drugs, hyperparathyroidism, and chronic renal insufficiency
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F ig . 5 . C ASE V. A. Vasc ular (cur ved ar rows ) and soft-t iss ue (st rai ght arrow ) calci ficatio n ar e pre sent ab out the ankle. B. M assi ve soft -t iss ue enlargem ent , destruc t ive changes and calc ifica t ion are present at t he distal int er ph alangeal joints (closed st ra igh t arrows ). Fusion of th e fou rth di st al interphalan geal joi nt was evi dent on additional vi ews. Prox im al interphalan geal a nd metacarpoph alangeal joint a bnor mal itie s and soft-t issue (open ar row ) a nd vascular (closed curved a rro w) calcificat ion may be not ed . The second ray had been previ ously amp utated . C . E ros ive and cystic changes (a rrows) , more prominent in t he ilium, invo lving the lower asp ects of bot h sacroiliac joints, are. see n . Si milar a bnormalit ies may be seen in hyperparathyroidism, althou gh no evi dence of the latter di sease was pre sent.
(7). In many of these disorders "gout " is reflected by elevat ion of serum uric acid alone, without evidence of joint sympto mato logy. Occasionall y, however, secondary gouty a rt h rit is may produce recognizable rad iographic ch anges in the first two decades of life (41). Gout in aleuke mic leukemi a (;jO) wa s described in a 5-year -old boy with a positive family history of gout . P ostmortem examination demon strated exten sive gouty tophi. "J uvenile" gout ha s also been associat ed with congeni tal hemoly ti c anemias (25), cyanotic con genital heart disease (42) and m yeloid metaplasia (45) . I solated case s of primar y juvenil e gout have appeared in the literature (3, 4, 8, 33); larger series of a rt hrit ic patients also contain occasional cases of early-onset gout (31). A review of the literature in 1971 revealed 66 cases of primary juvenile gout at which time two additio nal cases were reported (47). The ons et of disease in most of these
indi viduals was in th e second decade of life. The sex incidence in males and females was equal in those wit h gou t in the first decade ; in the second decade the males ou t numbered th e female s three to one. As compar ed to the paucity of the disease in adult women, th e young female doe s not appear immune. A family hi story of gout is often st riking in th ese young patients (47). The art icu lar symptoms are identical to those of th e adult, although rapid and seve re deformities ma y be noted (18, 23) and ea rly death ma y result (23) . R enal disease may be a complica ting factor (R) . It would appear that t hree of our patients (C ASE S I , IV, and V) suffered from early-on set primary gout as no associat ed etiologic factor could be appreciated . The two brothers (CASE S n and Ill) are more difficult to classify. The possibility of their having a partial enzyme deficienc y or a form e fruste of the Lesch- Nyhan
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DONALD RESNICK AND OTHERS
TABLE I:
Patient
1
2 3 4 5
PATIENT ANALYSIS
DuraHon Age of Family of Onset History Disease (Yrs.) (Yrs.)
Classification of Disease
Feet
Ankles
+ + +? +
Primary ?Primary ?Primary Primary Primary
+ + + + +
+ + +
16 14 15 19 19
8 12 8* 14 23*
January 1975
Radiographs Knees
Hips
Sacroiliacs
N.A.
+
N.A.
+ +
Spine N.A. N.A. N.A. N.A.
Hands and Wrists
+ + + +
Elbows
Shoulders
+ +
+ +
N.A. N.A.
N.A. N.A.
* Expired. N.A. = Radiographs not available.
syndrome cannot be discarded, and complicating diseases such as psoriasis and hypothyroidism may be contributing factors. The radiographic manifestations of gout in these young patients did not differ significantly from those reported in adults (44). They were severe in one patient (CASE V) who had progressive gouty arthritis for 23 years and moderate in the others. Typical soft-tissue masses, bony erosions with overhanging edges (30), and mild to moderate demineralization were noted. In many cases joint spaces were preserved until late in the course of the disease. The distribution of radiographic lesions is indicated in TABLE 1. One can appreciate joint predilection for the hands and feet. Other sites in decreasing order of frequency included the ankles, elbows, shoulders, sacroiliacs and knees. Involvement of the sacroiliac joints was of interest, being abnormal in two of four patients in whom appropriate films were available. Bilateral and relatively symmetrical erosions were noted in both cases with surrounding sclerosis. Sacroiliac involvement in gouty arthritis has been reported in 7-13% (29) and 17% (1) of cases. It was noted more frequently in patients with early-onset gout (which may reflect a longer and more severe clinical course) with a left-sided predominance, and demonstrable sclerosis and cystic abnormality (1). Sacroiliac gout associated with hemoglobinopathy and hypersplenism has also been reported (24). ACKNOWLEDGMENTS: We wish to thank Dr. B. J. Guttormsson (Madera, Calif.) for supplying information and roentgenograms regarding Patient Tl, and Dr. Thomas C. Brown (Honolulu, Hawaii) for doing the same regarding Patient IV. In addition, we wish to acknowledge the assistance of Miriam Blaustein, the Research Librarian at University of California, San Francisco, and Willa Johnson at Veterans Administration Hospital, San Diego, for her technical assistance. Department of Radiology Veterans Administration Hospital 3350 La ]oJla Village Drive San Diego, Calif. 92161
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fering from chronic erythronoc1astic anaemia of obscure origin, together with observations upon the physical state of uric acid in the blood and the effects of splenectomy. Med J Austr 1: 535558, 20 Apr 1940 26. Leeper RD, Benua RS, Brener JL, et al: Hyperuricemia in rnyxederna. J Clin Endocrin Metab 20: 1457-1466, Nov 1960 27. Lesch M, Nyhan WL: A familial disorder of uric acid metabolism and central nervous system function. Am J Med 36: 561-i?70, Apr 1964 28. Lie-Injo LE, Chin J: Abnormal haemoglobin and glucose6-phosphate dehydrogenase deficiency in Malayan aborigines. Nature 204: 291-292, 17 Oct 1964 29. Malawista SE, Seegrniller JE, Hathaway BE, et al: Sacroiliac gout. JAMA 194:954-956, 29 Nov 1965 30. Martel W: The overhanging margin of bone: roentgenologic manifestation of gout. Radiology 91: 755-756, Oct 1968 31. McCracken JP, Owen PS, Pratt JH: Gout: still a forgotten disease. JAMA 131 :367-372, 1 Jun 1946 32. Michener WM: Hyperuricemia and mental retardation with athetosis and self-mutilation. Am J Dis Child 113: 195206, Feb 1967 33. Middlerniss JH, Braband H: Juvenile gout. Clin Radiol 13: 149-152, Apr 1962 34. Nyhan WL: Clinical features of the Lesch-Nyhan syndrome. Arch Intern Med 130: 186-192, Aug 1972 35. Nyhan WL, Pesek J, Sweetman L, et al: Genetics of an X-linked disorder of uric acid metabolism and cerebral function. Pediat Res 1:5-13, Ian 1967 36. Paik C, Dunea G: Thalassemia and gouty arthritis. JAMA 213:291-298,1973 37. Prior lA, Rose BS: Uric acid, gout and public health in the South Pacific. New Zeal Med J 65:295-300, May 1966
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38. Riley JD: Gout ar-d cerebral palsy in a three-year-old boy. Arch Dis Child 35:293-295, j un 1960 39. Sass JK, Itabashi HH, Dexter RA: Juvenile gout with brain involvement. Arch NeuroI13:639-655, Dec 1965 40. Scott JT: Factors inhibiting the excretion of uric acid. Proc Roy Soc Med 59:310-312, Apr 1266 41. Smith EE, Kurlander GJ, PoweIl RC: Two rare causes of secondary gouty arthritis. Am J Roentgenol 100:550-553, Tul 1967 42. Somerville J: Gout in cyanotic congenital heart disease. Br Heart J 23:31-34, j an 1961 43. Steuermann N, Farias AH: Hyperuricemia in Filipinos. Hawaii Med J 20: 151-153, Nov-Dec 1960 44. TalbottJH: Gout. New York, Grune&Stratton, 1967 45. Talbott JH: Gout and blood dyscrasias. Medicine 38: 173-205, May 1959 46. Tinney WS, PoIley HF, Hall BE, et al: Polycythemia vera and gout: report of 8 cases. Proc Staff Meet., Mayo Clin 20:49-55,21 Feb 1945 47. TreadweIl BL: Juvenile gout. Ann Rheum Dis 30:27928'!-, May 1971 48. Tsachalos P: Gout secondary to thalassemia (minor form of Cooley's disease). Rev Rhum 27:414-416, Oct 1960 49. Turner RE, Frank MJ, Van Ausdal D, et al: Some aspects of the epidemiology of gout. Sex and race incidence. Arch Intern Med 106:400-406, Sep 1960 50. Vining CW, Thomson JG: Gout and aleukaemic leukemia in a boy aged fi. Arch Dis Child 9:277-284, Oct 1934 51. Wintrobe MM: Clinical Hematology. Philadelphia, Lea & Febiger, 6th ed, 1967 52. Yu TF: Secondary gout associated with myeloproliferative diseases. Arthritis Rheum 8: 765-771, Oct 1965
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