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Sarcoidosis associated with nephrocalcinosis in young children
Volume 121 Number 6
9. Mahasandra C, Suvatte V, Cbuansumrit A, et al. Homozygous protein S deficiency in an infant with purpura fulminans. J PEDIATR 1990;117:749-53. 10. Coller BS, Owen J, Jesty J, et al. Deficiency of plasma protein S, protein C, or antithrombin III and arterial thrombosis. Arteriosclerosis 1987;7:456-62. 11. Bertina RM, Brockmans AW, Krommenhock-Van Es C, et al. The use of a functional and immunologic assay for plasma protein C in the study of the heterogeneity of congenital protein C deficiency. Thromb Haemost 1984;51:1-5. 12. Andrew M, Paes B, Milner R, et al. Development of the hu-
Clinical and laboratory observations
937
man coagulation system in the full term infant. Blood 1987; 70:165-72. 13. Comp PC, Doray D, Patton D, et al. An abnormal plasma distribution of protein S occurs in functional protein S deficiency. Blood 1986;67:504-8. 14. Griffin JH, Evatt B, Zimmerman TS, et al. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68:1370-3. 15. Gremse DA, Peevy K J, Walterspiel JN, et al. Aortic thrombosis in a neonate with undetectable protein C. Pediatr Radiol 1990;20:198-9.
Sarcoidosis associated with nephrocalcinosis in young children J a m e s J. N o c t o n , MD, J o h n E. Stork, MD, G r e t t a J a c o b s , MD, a n d A r t h u r J. N e w m a n , MD From the Department of Pediatrics and Pathology, Case Western Reserve University School of Medicine, Rainbow Babies and Childrens Hospital, Cleveland, Ohio
Three patients with nonpulmonary sarcoidosis had chronic erythema nodosum within the first 2 years of life. Each subsequently had renal sarcoidosis and nephrocalcinosis; hypercalcemia was documented in each patient and hypercalciuria in two patients. Treatment with prednisone was not uniformly successful in normalizing creatinine clearance. Nephrocalcinosis may be more common than previously reported in patients with sarcoidosis. (J PEDIATR1992;121: 937-40) Sarcoidosis in children younger than 4 years primarily involves the skin, eyes, and joints, older children with sarcoidosis are likely to have initial lung involvement. ~ Renal involvement occurs infrequentlyin both children and adults.2, 3 Altered calcium metabolism is a common finding, but nephrocalcinosis occurs in fewer than 5% of all patients with sarcoidosis 2 and is not reported to be a significant clinical feature in young children. This report describes three patients with sarcoidosis whose disease appeared at an early age. Despite varied degrees of altered calcium metabolism, asymptomatic nephrocalcinosis developed in each patient.
atric rheumatology clinic at Rainbow Babies and Childrens Hospital. Serum calcium and urinary calcium and creatinine measurements were performed in the university medical laboratories. Serum angiotcnsin converting enzyme assays were performed by Roche Biomedical Laboratories (Dublin, Ohio), and serum 1,25-dihydroxyvitamin D assays were performed by Nichols Institute Reference Laboratory (San Juan Capistrano, Calif.). All radiologic studies were performed in the University Hospitals of Cleveland Department of Radiology and interpreted by a staff radiologist. All biopsy specimens were reviewed by a staffpathologist (G.J.) in the University Hospitals Department of Pathology.
METHODS
RESULTS
Data were collected retrospectively from the clinical records of three patients with sarcoidosis seen in the pedi-
The progression of disease in each case was similar. Erythema nodosum and fever appeared first at an early age. Arthritis, iritis, and parotitis occurred years later. As seen in the Table, calcium and creatinine clearance measurements varied widely. The data presented were selected to reflect calcium metabolism at times of changes in clinical findings or in therapy. All patients had hypercalcemia (serum calcium concentration > 11.0 m g / d l ) on one or
Submitted for publication Nov. 27, 1990; accepted July 13, 1992. Reprint requests: Arthur J. Newman, MD, Department of Pediatrics, Rainbow Babies and Childrens Hospital, 2074 Abington Rd., Cleveland, OH 44106.
9/22/40967
938
Clinical and laboratory observations
The Journal of Pediatrics December 1992
Table. Clinical and laboratory data in three children with sarcoidosis Serum calcium Patient Age No. (yr) 1
2
3
4 7
9~ 6 7 8 9~ 10
6 7~ 8 8.2
Creatinine clearance (ml/min/ 1,73 m2) mmol/kg/day mg/kg/day Urlnecalclum
1,25-(OH)2Dt Age* (IU/ml)
Therapy
mmol/L
mg/dl
Prednisone Prednisone, hydroxychloroquine Prednisone --Prednisone Prednisone Prednisone, hydrochlorothiazide -Sulindac Prednisone Prednisone
2.55 3.42
10.2 13.7
0.100 0.292
4.0 11.7
65 46
-43 (<36)
2.52 2.30 2.80 2.27 2.32 2.57
10.1 9.2 11.2 9.1 9.3 10.3
0.175 -0.255 0.052 0.097 0.067
7.0
157
--
10.2 2.1 3.9 2.7
58 108 72 46
52 (<36) --55 (8-52)
2.80 2.47 2.25 2.32
11.2 9.9 9.0 9.3
-0.032 0.042 0.030
1.3 1.7 1.2
-
-
99 203 47
-
-
55 (8-52) ---
pmol/L (pg/ml) 249 271
104 113
94
39
65 151
27 63
o
ACE, Angiotensin convertingenzyme; 1,25-(OH)eD, 1,25-dihydroxyvitaminD. *Normal values in parentheses. tNormal concentration, 60 to 108 pmol/L. ~:Timeof discoveryof nephrocalcinosis.
more measurements. Two patients also had hypercalciuria (urinary calcium excretion >4.0 m g / k g per 24 hr); these two also usually had low creatinine clearances. Angiotensin converting enzyme values were elevated in each patient; 1,25-dihydroxyvitamin D concentration was elevated in two patients and at a high normal level in another. There was a direct correlation between the levels of 1,25dihydroxyvitamin D and urinary and serum calcium levels. For example, patient 1 had the highest 1,25-dihydroxyvitamin D levels and also had the greatest degree of hypercalcemia and hypercalciuria. Conversely, patient 3 had lower 1,25-dihydroxyvitamin D levels and a generally lower serum calcium concentration with normal urinary calcium excretion. Patient 3 also had a consistently higher creatinine clearance. For any given patient, changes in serum calcium concentration did not correlate with changes in urinary calcium excretion or creatinine clearance. Likewise, treatment did not have a consistent effect on any of these variables, with the exception of patient 2, who had a marked reduction in urinary calcium excretion with the initiation of prednisone therapy. In general, dosages ranged from 2.5 to 10 r a g / d a y for each patient, with occasional brief increases to as much as 40 r a g / d a y during periods of worsening symptoms. Because of previous experience with two adolescent patients with sarcoidosis in whom nephrocalcinosis had developed, each of these three patients had a renal ultrasound
examination to identify nephrocalcinosis and a subsequent renal biopsy. Each biopsy specimen revealed noncaseating granulomas and nephrocalcinosis (Figure). DISCUSSION The degree of renal involvement in our patients was not suspected before biopsy. Granulomas have been found in the kidneys in 15% to 40% of adult patients with sarcoidosis. z The incidence in children is unknown but is believed to be less. Only 6% of 113 children reviewed by McGovern and Merritt 4 had renal involvement. In a recent review, 5 a decrease in creatinine clearance was found in more than 60% of children w~(h sarcoidosis, and nephrolithiasis was recognized as a possible complication. However, other evidence of renal dysfunction, such as abnormal urinalysis results and elevated blood urea nitrogen and serum creatinine values, was found in fewer than 40% of children; nephrocalcinosis was not mentioned as a potential complication. In reviews of adults and children with sarcoidosis, nephrocalcinosi~ has been a rare finding. Although it would seem to be a frequent complication of hypercalciuria, it occurs in fewer than 5% of adult patients. 2 To our knowledge the association of nephrocalcinosis with sarcoidosis at a young age has not been previously reported. The development of nephrocalcinosis was discovered in each patient several years after the onset of disease. Hypercalciuria had been present in two of the patients for several
Volume 121 Number 6
Clinical and laboratory observations
939
Figure. A, Biopsy specimen from patient 3: Low-power view of large aggregate of proliferating granulomas containing inconspicuous giant cells. (Hematoxylin-eosin stain; original magnification, X 100.) B, Biopsy specimen from patient 1. Focus of tubular calcinosis. (Hematoxylin-eosin stain; original magnification, x400.)
years, and in one patient, hypercalciuria decreased with corticosteroid therapy. The third patient did not have documented hypercalciuria. The lack of correlation between serum and urinary calcium measurements, renal function, and the development of nephrocalcinosis is unexplained. It is possible that unsupervised collections of urine resulted in falsely low measurements of urinary calcium. However, if this were the case, one would expect low urinary calcium excretion to correlate with low creatinine clearance. An alternative explanation is that factors other than calcium levels in urine and serum contribute to the development of nephrocalcinosis. Sarcoid granulomas may affect renal tubular handling of calcium, resulting in calcium resorption and deposition. Renal tubular abnormalities, such as concentration and acidification defects, have been reported in sarcoidosis,2 and, although not searched for in our patients, may play a role in the development of nephrocalcinosis. Chesney et al. 6 demonstrated a reduction in hypercalciuria with glucocorticoid treatment in patients with sarcoidosis. Each of our patients was treated with prednisone. In one, hypercalciuria resolved with prednisone therapy years before the discovery of nephrocalcinosis. In another patient, prednisone therapy failed to reduce elevated urinary calcium excretion, and years later nephrocalcinosis was discovered. The third patient never had documented hypercalciuria and was not treated with glucocorticoids before the discovery of nephrocalcinosis. This variability in calcium excretion and response to therapy suggests that factors
other than serum and urinary calcium levels contribute to the development of nephrocalcinosis. We treated one of our patients unsuccessfully with hydroxychloroquine in an attempt to lessen hypercalciuria, after a report 7 that its analog, chloroquine, had been useful in reducing urinary calcium excretion. A subsequent report s noted success in using hydroxychloroquine for this purpose. The significance of nephrocalcinosis in our patients is unknown. Except for abnormal creatinine clearance measurements, none of these patients has overt renal disease. However, renal failure has developed in one of our adolescent patients. We conclude that the onset of sarcoidosis in the young child produces the typical clinical findings of erythema nodosum, iritis, arthritis, and parotitis. These children are at risk for the development of nephrocalcinosis, which may be asymptomatic. Serum and urinary calcium levels probably contribute to this development, but other factors are likely to be involved. Further prospective studies of calcium metabolism in patients with sarcoidosis would be helpful in clarifying the pathophysiology of nephrocalcinosis.
REFERENCES 1. Hetherington S. Sarcoidosis in young children. Am J Dis Child 1982;136:13-5. 2. Muther RS, McCarron DA, Bennett WM. Renal manifestations of sarcoidosis. Arch Intern Med 1981;141:643-5. 3. Bautista A" Childh~176 sarc~176 inv~ j~ and kidneys" Am J Dis Child 1970;119:259-63.
940
Clinical and laboratory observations
4. McGovern JP, Merritt DH. Sarcoidosis in childhood. Adv Pediatr 1956;8:97-135. 5. Pattishall EN, Strope GL, Spinola SM, Denny FW. Childhood sarcoidosis. J PEDIATR 1986;108:169-77. 6. Chesney RW, Hamstra A J, DeLuca HF, et al. Elevated serum 1,25-dihydroxyvitamin D concentrations in the hypercalcemia of sarcoidosis: correction by glucocorticoid therapy. J PEDIATR 1981;98:919-22.
The Journal of Pediatrics December 1992
7. O'Leary T J, Jones G, Yip A, Lohnes D, Cohanim M, Yendt ER. The effect of chloroquine on serum 1,25-dihydroxyvitamin D and calcium metabolism in sarcoidosis. N Engl J Med 1986;315:727-30. 8. DeSimone DP, Brilliant HL, Basile J, Bell NH. Granulomatous infiltration of the talus and abnormal vitamin D and calcium metabolism in a patient with sarcoidosis: successful treatment with hydroxychloroquine. Am J Med 1989;87:694-6.
3-Methylglutaconic aciduria associated with Pearson syndrome and respiratory chain defects K. M. G i b s o n , PhD, M. J. B e n n e t t , PhD, C, E. M i z e , MD, PhD, C. J a k o b s , PhD, A. Rotig, PhD, A. Munnich, MD, PhD, U. Lichter-Konecki, MD, a n d F. K. Trefz, MD From the Kimberiy H. Courtwright and Joseph W. Summers Metabolic Disease Center and BayIor Research Institute, Baylor University Medical Center, Dallas, Texas, the University of Texas Southwestern Medical Center, Dallas, the Department of Pediatrics, Free University Hospital, Amsterdam, The Netherlands, the Unite de Recherches sur les Handicaps Genetiques de I'Enfant INSERMU-12, H6pital des Enfants-Malades, Paris, France, and the Ruprecht-Karls-Universitat, Universitats-Kinderklinik, Heidelberg, Germany
3-Methylglutaconic aciduria was d e t e c t e d in four patients with Pearson syndrome, a multitissue disorder with h e m a t o l o g i c abnormalities, lactic acidosis resulting from defective oxidative phosphorylation, and deletions in the mitochondrial genome. 3-Methylglutaconic a c i d m a y be an additional useful marker for Pearson syndrome and m a y be a more specific marker than other organic acids identified in this disorder. (J PEDIATR1992;124:940-2)
Pearson syndrome (McKusick 260560) is a disorder affecting the hematopoietic system, characterized by aplastic anemia, neutropenia, and thrombocytopenia.l3 A t the molecular level there is a rearrangement of the mitochondrial genome, resulting in abnormalities of mitochondrial respiratory chain function. Jakobs et al. 4 described the pattern of urinary organic acids for a patient with Pearson syndrome, in which there were elevations in lactic, 3-hydroxybutyric, 2-ketoglutaric, fumaric, and malic acids, further suggesting impairment of the respiratory chain. We extend the findings of Jakobs et al. by reporting our results of increased 3-methylglutaconic acid in urine derived from four patients with Pearson syndrome. Supported by a Research Fellowshtp ,from the Alexander von Humboldt Foundation, Federal Republic of Germany (K.M.G.). Submitted for publication May 14, 1992; accepted July 17, 1992. Reprint requests: K. M. Gibson, PhD, Baylor Research Institute, 3812 Elm St., Dallas, TX 75226. 9/22/41046
CASE REPORTS Patient 1, a boy, was born to unrelated, healthy parents after a normal pregnancy. 2 Examination at 9 months of age revealed failure to thrive and aplastic anemia, requiring multiple transfusions. From 15 to 17 months of age, the patient had many clinical problems, including fever, drowsiness , chronic diarrhea, neutropenia, and thrombocytopenia, eventually accompanied by hepatomegaly kb 3-MGC 3-MG-CoA NAD(H)
Kilobase 3-Methylglutaconic [acid] 3-Methylglutaconyl-coenzyme A Nicotinamide-adenine dinucleotide (reduced form)
and hepatocellular dysfunction. A dual mitochondrial DNA population was detected in circulating peripheral leukocytes, with one species showing a 5-kilobase deletion. The patient died at 2 years of age. Patient 2, a girl, was born to healthy parents after a term pregnancy. From 5 to 7 months of age, clinical problems included aplastic anemia, thrombocytopenia, vomiting, diarrhea, and failure
9. Mahasandra C, Suvatte V, Cbuansumrit A, et al. Homozygous protein S deficiency in an infant with purpura fulminans. J PEDIATR 1990;117:749-53. 10. Coller BS, Owen J, Jesty J, et al. Deficiency of plasma protein S, protein C, or antithrombin III and arterial thrombosis. Arteriosclerosis 1987;7:456-62. 11. Bertina RM, Brockmans AW, Krommenhock-Van Es C, et al. The use of a functional and immunologic assay for plasma protein C in the study of the heterogeneity of congenital protein C deficiency. Thromb Haemost 1984;51:1-5. 12. Andrew M, Paes B, Milner R, et al. Development of the hu-
Clinical and laboratory observations
937
man coagulation system in the full term infant. Blood 1987; 70:165-72. 13. Comp PC, Doray D, Patton D, et al. An abnormal plasma distribution of protein S occurs in functional protein S deficiency. Blood 1986;67:504-8. 14. Griffin JH, Evatt B, Zimmerman TS, et al. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68:1370-3. 15. Gremse DA, Peevy K J, Walterspiel JN, et al. Aortic thrombosis in a neonate with undetectable protein C. Pediatr Radiol 1990;20:198-9.
Sarcoidosis associated with nephrocalcinosis in young children J a m e s J. N o c t o n , MD, J o h n E. Stork, MD, G r e t t a J a c o b s , MD, a n d A r t h u r J. N e w m a n , MD From the Department of Pediatrics and Pathology, Case Western Reserve University School of Medicine, Rainbow Babies and Childrens Hospital, Cleveland, Ohio
Three patients with nonpulmonary sarcoidosis had chronic erythema nodosum within the first 2 years of life. Each subsequently had renal sarcoidosis and nephrocalcinosis; hypercalcemia was documented in each patient and hypercalciuria in two patients. Treatment with prednisone was not uniformly successful in normalizing creatinine clearance. Nephrocalcinosis may be more common than previously reported in patients with sarcoidosis. (J PEDIATR1992;121: 937-40) Sarcoidosis in children younger than 4 years primarily involves the skin, eyes, and joints, older children with sarcoidosis are likely to have initial lung involvement. ~ Renal involvement occurs infrequentlyin both children and adults.2, 3 Altered calcium metabolism is a common finding, but nephrocalcinosis occurs in fewer than 5% of all patients with sarcoidosis 2 and is not reported to be a significant clinical feature in young children. This report describes three patients with sarcoidosis whose disease appeared at an early age. Despite varied degrees of altered calcium metabolism, asymptomatic nephrocalcinosis developed in each patient.
atric rheumatology clinic at Rainbow Babies and Childrens Hospital. Serum calcium and urinary calcium and creatinine measurements were performed in the university medical laboratories. Serum angiotcnsin converting enzyme assays were performed by Roche Biomedical Laboratories (Dublin, Ohio), and serum 1,25-dihydroxyvitamin D assays were performed by Nichols Institute Reference Laboratory (San Juan Capistrano, Calif.). All radiologic studies were performed in the University Hospitals of Cleveland Department of Radiology and interpreted by a staff radiologist. All biopsy specimens were reviewed by a staffpathologist (G.J.) in the University Hospitals Department of Pathology.
METHODS
RESULTS
Data were collected retrospectively from the clinical records of three patients with sarcoidosis seen in the pedi-
The progression of disease in each case was similar. Erythema nodosum and fever appeared first at an early age. Arthritis, iritis, and parotitis occurred years later. As seen in the Table, calcium and creatinine clearance measurements varied widely. The data presented were selected to reflect calcium metabolism at times of changes in clinical findings or in therapy. All patients had hypercalcemia (serum calcium concentration > 11.0 m g / d l ) on one or
Submitted for publication Nov. 27, 1990; accepted July 13, 1992. Reprint requests: Arthur J. Newman, MD, Department of Pediatrics, Rainbow Babies and Childrens Hospital, 2074 Abington Rd., Cleveland, OH 44106.
9/22/40967
938
Clinical and laboratory observations
The Journal of Pediatrics December 1992
Table. Clinical and laboratory data in three children with sarcoidosis Serum calcium Patient Age No. (yr) 1
2
3
4 7
9~ 6 7 8 9~ 10
6 7~ 8 8.2
Creatinine clearance (ml/min/ 1,73 m2) mmol/kg/day mg/kg/day Urlnecalclum
1,25-(OH)2Dt Age* (IU/ml)
Therapy
mmol/L
mg/dl
Prednisone Prednisone, hydroxychloroquine Prednisone --Prednisone Prednisone Prednisone, hydrochlorothiazide -Sulindac Prednisone Prednisone
2.55 3.42
10.2 13.7
0.100 0.292
4.0 11.7
65 46
-43 (<36)
2.52 2.30 2.80 2.27 2.32 2.57
10.1 9.2 11.2 9.1 9.3 10.3
0.175 -0.255 0.052 0.097 0.067
7.0
157
--
10.2 2.1 3.9 2.7
58 108 72 46
52 (<36) --55 (8-52)
2.80 2.47 2.25 2.32
11.2 9.9 9.0 9.3
-0.032 0.042 0.030
1.3 1.7 1.2
-
-
99 203 47
-
-
55 (8-52) ---
pmol/L (pg/ml) 249 271
104 113
94
39
65 151
27 63
o
ACE, Angiotensin convertingenzyme; 1,25-(OH)eD, 1,25-dihydroxyvitaminD. *Normal values in parentheses. tNormal concentration, 60 to 108 pmol/L. ~:Timeof discoveryof nephrocalcinosis.
more measurements. Two patients also had hypercalciuria (urinary calcium excretion >4.0 m g / k g per 24 hr); these two also usually had low creatinine clearances. Angiotensin converting enzyme values were elevated in each patient; 1,25-dihydroxyvitamin D concentration was elevated in two patients and at a high normal level in another. There was a direct correlation between the levels of 1,25dihydroxyvitamin D and urinary and serum calcium levels. For example, patient 1 had the highest 1,25-dihydroxyvitamin D levels and also had the greatest degree of hypercalcemia and hypercalciuria. Conversely, patient 3 had lower 1,25-dihydroxyvitamin D levels and a generally lower serum calcium concentration with normal urinary calcium excretion. Patient 3 also had a consistently higher creatinine clearance. For any given patient, changes in serum calcium concentration did not correlate with changes in urinary calcium excretion or creatinine clearance. Likewise, treatment did not have a consistent effect on any of these variables, with the exception of patient 2, who had a marked reduction in urinary calcium excretion with the initiation of prednisone therapy. In general, dosages ranged from 2.5 to 10 r a g / d a y for each patient, with occasional brief increases to as much as 40 r a g / d a y during periods of worsening symptoms. Because of previous experience with two adolescent patients with sarcoidosis in whom nephrocalcinosis had developed, each of these three patients had a renal ultrasound
examination to identify nephrocalcinosis and a subsequent renal biopsy. Each biopsy specimen revealed noncaseating granulomas and nephrocalcinosis (Figure). DISCUSSION The degree of renal involvement in our patients was not suspected before biopsy. Granulomas have been found in the kidneys in 15% to 40% of adult patients with sarcoidosis. z The incidence in children is unknown but is believed to be less. Only 6% of 113 children reviewed by McGovern and Merritt 4 had renal involvement. In a recent review, 5 a decrease in creatinine clearance was found in more than 60% of children w~(h sarcoidosis, and nephrolithiasis was recognized as a possible complication. However, other evidence of renal dysfunction, such as abnormal urinalysis results and elevated blood urea nitrogen and serum creatinine values, was found in fewer than 40% of children; nephrocalcinosis was not mentioned as a potential complication. In reviews of adults and children with sarcoidosis, nephrocalcinosi~ has been a rare finding. Although it would seem to be a frequent complication of hypercalciuria, it occurs in fewer than 5% of adult patients. 2 To our knowledge the association of nephrocalcinosis with sarcoidosis at a young age has not been previously reported. The development of nephrocalcinosis was discovered in each patient several years after the onset of disease. Hypercalciuria had been present in two of the patients for several
Volume 121 Number 6
Clinical and laboratory observations
939
Figure. A, Biopsy specimen from patient 3: Low-power view of large aggregate of proliferating granulomas containing inconspicuous giant cells. (Hematoxylin-eosin stain; original magnification, X 100.) B, Biopsy specimen from patient 1. Focus of tubular calcinosis. (Hematoxylin-eosin stain; original magnification, x400.)
years, and in one patient, hypercalciuria decreased with corticosteroid therapy. The third patient did not have documented hypercalciuria. The lack of correlation between serum and urinary calcium measurements, renal function, and the development of nephrocalcinosis is unexplained. It is possible that unsupervised collections of urine resulted in falsely low measurements of urinary calcium. However, if this were the case, one would expect low urinary calcium excretion to correlate with low creatinine clearance. An alternative explanation is that factors other than calcium levels in urine and serum contribute to the development of nephrocalcinosis. Sarcoid granulomas may affect renal tubular handling of calcium, resulting in calcium resorption and deposition. Renal tubular abnormalities, such as concentration and acidification defects, have been reported in sarcoidosis,2 and, although not searched for in our patients, may play a role in the development of nephrocalcinosis. Chesney et al. 6 demonstrated a reduction in hypercalciuria with glucocorticoid treatment in patients with sarcoidosis. Each of our patients was treated with prednisone. In one, hypercalciuria resolved with prednisone therapy years before the discovery of nephrocalcinosis. In another patient, prednisone therapy failed to reduce elevated urinary calcium excretion, and years later nephrocalcinosis was discovered. The third patient never had documented hypercalciuria and was not treated with glucocorticoids before the discovery of nephrocalcinosis. This variability in calcium excretion and response to therapy suggests that factors
other than serum and urinary calcium levels contribute to the development of nephrocalcinosis. We treated one of our patients unsuccessfully with hydroxychloroquine in an attempt to lessen hypercalciuria, after a report 7 that its analog, chloroquine, had been useful in reducing urinary calcium excretion. A subsequent report s noted success in using hydroxychloroquine for this purpose. The significance of nephrocalcinosis in our patients is unknown. Except for abnormal creatinine clearance measurements, none of these patients has overt renal disease. However, renal failure has developed in one of our adolescent patients. We conclude that the onset of sarcoidosis in the young child produces the typical clinical findings of erythema nodosum, iritis, arthritis, and parotitis. These children are at risk for the development of nephrocalcinosis, which may be asymptomatic. Serum and urinary calcium levels probably contribute to this development, but other factors are likely to be involved. Further prospective studies of calcium metabolism in patients with sarcoidosis would be helpful in clarifying the pathophysiology of nephrocalcinosis.
REFERENCES 1. Hetherington S. Sarcoidosis in young children. Am J Dis Child 1982;136:13-5. 2. Muther RS, McCarron DA, Bennett WM. Renal manifestations of sarcoidosis. Arch Intern Med 1981;141:643-5. 3. Bautista A" Childh~176 sarc~176 inv~ j~ and kidneys" Am J Dis Child 1970;119:259-63.
940
Clinical and laboratory observations
4. McGovern JP, Merritt DH. Sarcoidosis in childhood. Adv Pediatr 1956;8:97-135. 5. Pattishall EN, Strope GL, Spinola SM, Denny FW. Childhood sarcoidosis. J PEDIATR 1986;108:169-77. 6. Chesney RW, Hamstra A J, DeLuca HF, et al. Elevated serum 1,25-dihydroxyvitamin D concentrations in the hypercalcemia of sarcoidosis: correction by glucocorticoid therapy. J PEDIATR 1981;98:919-22.
The Journal of Pediatrics December 1992
7. O'Leary T J, Jones G, Yip A, Lohnes D, Cohanim M, Yendt ER. The effect of chloroquine on serum 1,25-dihydroxyvitamin D and calcium metabolism in sarcoidosis. N Engl J Med 1986;315:727-30. 8. DeSimone DP, Brilliant HL, Basile J, Bell NH. Granulomatous infiltration of the talus and abnormal vitamin D and calcium metabolism in a patient with sarcoidosis: successful treatment with hydroxychloroquine. Am J Med 1989;87:694-6.
3-Methylglutaconic aciduria associated with Pearson syndrome and respiratory chain defects K. M. G i b s o n , PhD, M. J. B e n n e t t , PhD, C, E. M i z e , MD, PhD, C. J a k o b s , PhD, A. Rotig, PhD, A. Munnich, MD, PhD, U. Lichter-Konecki, MD, a n d F. K. Trefz, MD From the Kimberiy H. Courtwright and Joseph W. Summers Metabolic Disease Center and BayIor Research Institute, Baylor University Medical Center, Dallas, Texas, the University of Texas Southwestern Medical Center, Dallas, the Department of Pediatrics, Free University Hospital, Amsterdam, The Netherlands, the Unite de Recherches sur les Handicaps Genetiques de I'Enfant INSERMU-12, H6pital des Enfants-Malades, Paris, France, and the Ruprecht-Karls-Universitat, Universitats-Kinderklinik, Heidelberg, Germany
3-Methylglutaconic aciduria was d e t e c t e d in four patients with Pearson syndrome, a multitissue disorder with h e m a t o l o g i c abnormalities, lactic acidosis resulting from defective oxidative phosphorylation, and deletions in the mitochondrial genome. 3-Methylglutaconic a c i d m a y be an additional useful marker for Pearson syndrome and m a y be a more specific marker than other organic acids identified in this disorder. (J PEDIATR1992;124:940-2)
Pearson syndrome (McKusick 260560) is a disorder affecting the hematopoietic system, characterized by aplastic anemia, neutropenia, and thrombocytopenia.l3 A t the molecular level there is a rearrangement of the mitochondrial genome, resulting in abnormalities of mitochondrial respiratory chain function. Jakobs et al. 4 described the pattern of urinary organic acids for a patient with Pearson syndrome, in which there were elevations in lactic, 3-hydroxybutyric, 2-ketoglutaric, fumaric, and malic acids, further suggesting impairment of the respiratory chain. We extend the findings of Jakobs et al. by reporting our results of increased 3-methylglutaconic acid in urine derived from four patients with Pearson syndrome. Supported by a Research Fellowshtp ,from the Alexander von Humboldt Foundation, Federal Republic of Germany (K.M.G.). Submitted for publication May 14, 1992; accepted July 17, 1992. Reprint requests: K. M. Gibson, PhD, Baylor Research Institute, 3812 Elm St., Dallas, TX 75226. 9/22/41046
CASE REPORTS Patient 1, a boy, was born to unrelated, healthy parents after a normal pregnancy. 2 Examination at 9 months of age revealed failure to thrive and aplastic anemia, requiring multiple transfusions. From 15 to 17 months of age, the patient had many clinical problems, including fever, drowsiness , chronic diarrhea, neutropenia, and thrombocytopenia, eventually accompanied by hepatomegaly kb 3-MGC 3-MG-CoA NAD(H)
Kilobase 3-Methylglutaconic [acid] 3-Methylglutaconyl-coenzyme A Nicotinamide-adenine dinucleotide (reduced form)
and hepatocellular dysfunction. A dual mitochondrial DNA population was detected in circulating peripheral leukocytes, with one species showing a 5-kilobase deletion. The patient died at 2 years of age. Patient 2, a girl, was born to healthy parents after a term pregnancy. From 5 to 7 months of age, clinical problems included aplastic anemia, thrombocytopenia, vomiting, diarrhea, and failure