- Email: [email protected]
Elevated 1,25-dihydroxyvitamin D serum concentrations in infants with subcutaneous fat necrosis
Clinical and laboratory observations Elevated ,25-dihydroxyvitamin D serum concentrations in infants with subcutaneous fat necrosis Klaus Kruse, MD, Ulrich Irle, MD, a n d Rainer Uhlig, MD From the Departments of Pediatrics, University of LObeck, Bremen-Nord, and Lippstadt, Federal Republic of Germany
Two Infants with subcutaneous fat necrosis had hypercalcemla that normalized during glucocorticoid treatment. The combination of hypercalcemia, normal concentration of 25-hydroxyvitamin D, an elevated concentration of 1,25-dihydroxyvitamin D, a suppressed parathyroid hormone level, and low-normal bone turnover indicated abnormal 4,25~ D production with increased Intestinal absorption of calcium. Unregulated production of 4,25-dihydroxyvitamin D by the granulomatous cells of fat necrosis may cause hypercalcemla. (J PEDIATR1993;422:460-3)
Subcutaneous fat necrosis is a transient disorder of adipose tissue that occurs primarily in newborn infants after trauma or asphyxia at birth. Histopathologic studies demonstrate necrosis of fat and granulomatous inflammatory infiltration containing foreign body-type giant ceils with needle-shaped crystals resembling cholesterol. The condition may be associated with hypercalcemia, but the mechanism is incompletely understood) "4 Veldhuis et al. 3 reported increased prostaglandin production in one patient, but it is not clear whether this was the cause of hypercalcemia or only the result of therapy with furosemide and of vomiting, s Finne et al. 6 described hypercalcemia associated with an increased serum level of 1,25-dihydroxyvitamin D in an infant with SFN. We investigated calcium and bone metabolism in two hypercalcemic infants with SFN, and confirmed the findings of Finne et al. 6 METHODS Calcium, phosphate, creatinine, and alkaline phosphatase activity were measured with standard automatic analyzer Submitted for publication Aug. 10, 1992; accepted Oct. 9, 1992. Reprint requests: Klaus Kruse, MD, Klinik fiir Paediatrie der Medizinischen Universit~it zu Liibeck, Dw-2400 Liibeck, Federal Republic of Germany. Copyright 9 1993 by Mosby-Year Book, Inc. 0022-3476/93/$1.00 + .10 9/24/43299 460
techniques. Hydroxyproline and cyclic adenosine-3',5'monophosphate in spontaneously voided morning urine samples, as well as osteocalcin in serum, were assayed as previously described. 7 Hydroxyproline and Ca were related to Cr; cAMP was expressed relative to 100 ml glomerular filtrate by multiplying the values obtained relative to urinary Cr (in nanomoles per milligram) by the corresponding serum Cr value (in milligrams per deciliter). Serum 25-hydroxyvitamin D was measured with a competitive protein-binding assay, the normal range being I0 to 60 ng/ml (24 to 144 nmol/L). Serum 1,25-(OH)2 D was ALP cAMP Cr 25-OHD 1,25-(OH)2D PTH SFN
Alkaline phosphatase Cyclic adenosine-3',5'-monophosphate Creatinine 25-Hydrox)atitamin D 1,25-Dihydroxyvitamin D Parathyroid hormone Subcutaneous fat necrosis
assayed according to Holliss by using the test kit of Nichols Institute Diagnostics (San Juan Capistrano, Calif.). The detection limit is 3 pg/ml; the intraassay and interassay variances at a concentration of 40 pg/ml are 10% and 14%, respectively. The normal range in infants is 25 to 90 pg/ml (60 to 216 pmol/L). Intact serum parathyroid hormone was measured with a
The Journal of Pediatrics Volume 122, Number 3
Kruse, lrle, atzd Uhlig
46 1
Patient 2
Patient I Therapy gtucocorticoid 2
o[ Serum CaLcium (rra'not/L)
t, O9
3
. _- _-
.
9 9 9 99
9
O0
2 Phosphate (mmot/t) PTH 1- 86 (pg/mt) 25OHD (rig/mr)
2 1 0 100 50 0
9
9
a 0
9
"-I
9
0
-1100 U9
U
1~ f .
.
.
9149
9
. .
9
al'eJ
0"
0
-1100
9
(pg/rnt)
9 .jvs
0"
9
=-
0
9
Ca/Or
,
2
9
(mg/mg)
, 9
9
9
9 9
cAMP/GFR (nmot/dt)
0" :
.
"
"
9
9
9
"
I
I
I
&
6
8
I
I
I
10 12 /. Age in weeks
"e
9
I
i
6
8
9
B
-..] i
I~1
0 I
10 122060
Fig. 1. Effect of glucocorticoid therapy on Ca and bone metabolism in two infants with subcutaneous fat necrosis. The normal ranges for age are indicated. two-site immunochemiluminometric assay (Ciba Corning Diagnostics Corp., Medfield, Mass.). The detection limit is I p g / m l ; the intraassay and interassay variances at a concentration of 40 p g / m l are 3% and 6%, respectively. The normal range is 10 to 55 p g / m l .
CASE R E P O R T S Patient 1. A female infant, weight 4.6 kg, was born by cesarean section because of failure to progress with frank breech presentation at 38 weeks of gestation, and had Apgar scores of 6 and 8 after 1 and 5 minutes, respectively. At 14 days of age, irregularly shaped, hard lesions with overlying red skin appeared on the neck, back, and cheeks. Two weeks later the infant had fever, anorexia, and a serum Ca level of 3.5 mmol/L (14 mg/dl; normal, 2.1 to 2.7 mmol/L). Serum P level was 2.1 mmol/L (6.3 mg/dl; normal, 1.6 to 2.6 mmol/L), ALP activity, 239 U / L (normal, 200 to 600 U/L),
osteocalcin 7.4 ng/ml (normal, 7 to 15 ng/ml), intact PTH <6 pg/ ml, 25-OHD 41.6 ng/ml (99.8 rim 9 and 1,25-(OH)zD 125 pg/ml (299 pmol/L). Urinary Ca/Cr ratio was 1.23 mg/mg (3.5 mmol/mmol; normal, 0.02 to 0.6 mg/mg), urinary hydroxyproline/Cr ratio 1.26 mg/mg (1 mmol/mmol); normal, 0.32 to 1.4 mg/mg), and cAMP/GF 1.9 nmol/dl (normal, 2.0 to 6.0 nmol/dl). Treatment was started with a low-Ca diet and hydration, but Ca and 1,25-(OHhD in serum further increased to 3.7 mmol/L (14.8 mg/dl) and 135.5 pg/ml (325 pmol/L), respectively (Fig. 1). During additional therapy with flu9149 2 mg/kg per day, the serum Ca level decreased to 2.8 mmol/L (11.2 mg/dl) after 3 days, remained at this level until the patient's age reached 10 weeks, and normalized at the age of 11.4 weeks. The 1,25-(OH)zD value and the urinary Ca/Cr ratio normalized in parallel. The skin lesions decreased in size after 2 weeks of glucocorticoid treatment. The dose of flu9149 was tapered slowly, and discontinued by 9
462
Kruse, lrle, and Uhlig
r= 0,65 p<0,05
The Jo,~rnal of Pediatrics March 1993
9 Patient 1 o Patient 2
DISCUSSION
O
E E E
O O
~
u - , Cl
and subsequent follow-updisclosed normal Ca values and normal bone metabolism at the age of 12 weeks.
3
E t.,. O..I
t/')
2
t 'o 0 100 200 Serum 1,25(OH)2D (pg/mt)
Fig. 2. Relationship between Ca and 1,25-(OH)zD in serum before and during glucocorticoidtherapy. The normal serum Ca and 1,25-(Ott)2D values are indicated by the square box.
weeks of age. By this time the fat necrosis had resolvedcompletely, and all biochemical measurements were normal (Fig. I). Patient 2. A girl born at term and weighing3.4 kg was delivered by cesarean section, performed because of decelerations in fetal heart rate and maternal toxemia, tter Apgar scores at ! and 5 minutes were 2 and 6, respectively.The amniotic fluid was meconium-stained, and meconium was noted below the vocal cords. Septicemia with group B streptococcus developed and was treated with penicillinand cefotaxime. At the age of 19 days the infant was noted to have SFN on the upper arms, back, and buttocks. A skin biopsyspecimenobtained at 8 weeksof age from one of the affected areas revealed typical histopathologiclesionsof SFN. Hypercalcemia (Ca level, 2.8 mmol/L [ 11.6 mg/dl]) was noted at the age of 3 weeks. One week later the serum Ca value was 3.4 mmol/L (13.6 mg/dl), P 1.84 mmol/L (5.7 mg/dl), intact PTH <6 pg/ml, ALP activity 162 U/L, osteocalcin4.6 ng/ml, 25-OttD 36.4 ng/ml (87 nmol/L), 1,25-(OH)2D 112 pg/ml (269 pmol/L), urinary Ca/Cr ratio 1.5 mg/mg (4.2 mmol/mmol), urinary hydroxyproline/Cr ratio 0.74 mg/mg (0.64 mmol/mmol), and urinary cAMP/ glomerular filtrate 32 nmol/dl. The patient was treated with a low-Ca diet and saline solution intravenously,followed by furosemide (1 to 4 mg/kg per day) and prednisolone(2 mg/kg per day). After a further increase of serum levels of 1,25-(OH)2D to 154 pg/ml (370 pmol/L) at the age of 7 weeks and persistenceof high Ca levelsat 3.3 mmol/L (13.2 mg[ dl) until this age, there was a concomitant normalization of Ca, 1,25(OH)zD, and intact PTH levelsin serum, as wellas Ca/Cr and cAMP/glomerular filtrate in urine (Fig. l). There was a gradual resolution of SFN during the next weeks,
Both of our patients had hypercalcemia, hypercalciuria, and low osteoblastic activity (ALP activity and osteocalcin level in serum), but normal osteoclastic bone degradation (urinary hydroxyproline), low-normal serum P values, suppressed or low parathyroid secretion (intact PTH in serum) or function (urinary cAMP), and normal 25-OHD levels. but elevated 1,25-(OH)2D levels in serum. Glucoeorticoid therapy caused a parallel normalization of Ca and 1,25(OH)2D values with a significant positive relationship between both values before and during treatment (Fig. 2), indicating that the hypercalcemia was related to the increase in serum 1,25-(OH)2D concentration. The combination of elevated 1,25-(OH)2D levels in serum despite hypercalcemia and suppressed Parathyroid activity indicates abnormal unregulated 1,25-(OH)2D production. Bone turnover was not increased but was low normal; thus hypercalcemia in our patients was due not to increased bone degradation but to 1,25-(OH)2D-stimulated intestinal absorption of Ca. Our finding of elevated serum 1,25-(OH)eD levels confirms that of Finne et al.,6 but does not agree with two case reports of normal concentrations of the vitamin D hormone.3,5 However, these reports were based on a single measurement before or on two determinations during glucocorticoid treatment. In both studies the reported "normal values" of 1,25-(OH)2D might be considered relatively elevated with regard to hypercalcemia and suppressed parathyroid activity. One of our patients had almost an immediate drop of 1,25-(OH)2D after the start ofsteroid therapy. This observation may explain the results of Cook et al., 5 who found relatively high but still normal 1,25-(OH)2D levels after 36 hours of steroid treatment. Elevated serum 1,25-(OH)2D levels caused by enhanced production of activated alveolar macrophages have been found in hypercalcemic patients with sarcoidosis.9, lo The synthesis of the vitamin D hormone by macrophages of patients with sarcoidosis and other granulomatous diseases such as tuberculosis, II leprosy, t2 and disseminated candidiasis 13 is independent of the presence of PTH and 1,25(OH)2D, suggesting unregulated production of the vitamin D hormone. Our findings support the hypothesis of Finne et al. 6 that extrarenal production of 1,25-(OH)2D by the granulomatous ceils of fat necrosis may cause hypercalcemia in infants with SFN. Other possibilities include unregulated renal overproduction of 1,25-(OH)2D. In patients with sarcoidosis the therapeutic effects of glucocorticoids, I~ chloroquine,t4 and ketoconazole 15on hypercalcemia maybe explained by an inhibition of the conversion of 25-OHD to
The Journal of Pediatrics Volume 122, Number 3
Kruse, Irle, attd Uhlig
1,25-(OH)2D by macrophages. This mechanism may also be involved in hypercalcemic patients with S F N and should be further studied in these infants.
9.
REFERENCES !. Harrison G, McNee J. An investigation of sclerema neonatorum, with special reference to the chemistry of the subcutaneous tissues. Part I. Arch Dis Child 1926;1:63-84. 2. Clay P. Idiopathic hypercalcemia with subcutaneous calcium deposits following pseudosclerema. Proc R Soc Med 1956;49: 598-600. 3. Veldhuis J, Kulin H, Demers L, Lambert P. Infantile hypercalcemia with subcutaneous fat necrosis: endocrine studies. J PEmATR 1979;95:460-2. 4. Yasuda T, Sunami S, Ogussa N, Nishioka T, Nakagima It. Infantile hypercalcemia with subcutaneous fat necrosis. Acta Paediatr Scand 1986;75:1042-5. 5. Cook JS, Stone MS, Hansen JR. Hypercalcemia in association with subcutaneous fat necrosis of the newborn: studies of calcium-regulating hormones. Pediatrics 1992;90:93-6. 6. Finne P, Sanderud J, Aksnes L, Bratlid D, Aarskog D. Hypercalcemia with increased and unregulated 1,25-dihydroxyvitamin D production in a neonate with subcutaneous fat necrosis. J PEDXATR1988;i 12:792-4. 7. Kruse K, Kracht U, Wohlfart K, Kruse U. Biochemical markers of bone turnover, intact serum parathyroid hormone and renal calcium excretion in patients with pseudohypoparathyroidism and hypoparathyroidism before and during vitamin D treatment. Eur J Pediatr 1989;148:535-9.
10.
11.
12.
13.
14.
15.
463
Hollis BW. Assay of circulating 1,25-dihydrox)witamin D involving a novel single cartridge extraction and purification procedure. Clin Chem 1986;32:2060-3. Bell NH, Stern PH, Pantzer E, Sinha TK, DeLuca HF. Evidence that increased circulating la-25-dihydrox)vitamin D is a probable cause for abnormal calcium metabolism in sarcoidoris. J Clin Invest 1979;64:218-25. Reichel H, Koeffler HP, Barbers R, Norman AW. Regulation of 1,25-dihydroxyvitamin D 3 production by cultured alveolar macrophages from normal human donors and from patients with pulmonary sarcoidosis. J Clin Endocrinol Metab 1987;65: 1201-9. Gkonos PJ, London R, Hendler ED. Hypercalcemia and elevated 1,25-dihydroxyvitamin D levels in a patient with endstage renal disease and active tuberculosis. N Engl J Med 1984;311:1683-5. ttoffman VN, Korzemiowski OM. Leprosy, hypercalcemia, and elevated serum calcitriol levels. Ann Intern Med 1986;! 05: 890-1. Kantarjian HM, Saad M F, Estey EH, Sellin RV, Samaan NA. ltypercalcemia in disseminated candidiasis. Am J Med 1983; 74:721-4. O'Leavy T J, Jones G, Yip A, et al. The effects of chloroquine on serum 1,25-dihydroxyvitamin D and calcium metabolism in sareoidosis. N Engl J Med 1986;315:727-30. Adams JS, Sharma UP, Diz MM, Endres DB. Ketoconazole decreases the serum 1,25-dihydroxyvitamin D and calcium concentration in sarcoidosis-associated hypercalcemia. J Clin Endocrinol Metab 1990;70:1090-5.
FELLOWSHIPS Fellowships available in pediatric subspecialties and those for general academic pediatric training are listed once a year, in January, in TIlE JOURNAL OF PEDIATRICS. Each June, forms for listing fellowships available for the academic year beginning 18 months after publication are sent to the Chairman of the Department of Pediatrics at major hospitals in the United States and Canada. In addition, a copy of the application form appears in the July, August, and September issues of TIlE JOURNAL (please use the current form). Should you desire to list fellowships, a separate application must be made each year for each position. All applications must be returned to Mosby by October 15 preceding the listing year to ensure publication. Additional forms will he supplied on request from the Journal Editing Department, Mosby, 11830 Westline Industrial Drive, St. Louis, M O 63146-3318/800-325-4177, ext. 4317, or 314-453-4317.
Two Infants with subcutaneous fat necrosis had hypercalcemla that normalized during glucocorticoid treatment. The combination of hypercalcemia, normal concentration of 25-hydroxyvitamin D, an elevated concentration of 1,25-dihydroxyvitamin D, a suppressed parathyroid hormone level, and low-normal bone turnover indicated abnormal 4,25~ D production with increased Intestinal absorption of calcium. Unregulated production of 4,25-dihydroxyvitamin D by the granulomatous cells of fat necrosis may cause hypercalcemla. (J PEDIATR1993;422:460-3)
Subcutaneous fat necrosis is a transient disorder of adipose tissue that occurs primarily in newborn infants after trauma or asphyxia at birth. Histopathologic studies demonstrate necrosis of fat and granulomatous inflammatory infiltration containing foreign body-type giant ceils with needle-shaped crystals resembling cholesterol. The condition may be associated with hypercalcemia, but the mechanism is incompletely understood) "4 Veldhuis et al. 3 reported increased prostaglandin production in one patient, but it is not clear whether this was the cause of hypercalcemia or only the result of therapy with furosemide and of vomiting, s Finne et al. 6 described hypercalcemia associated with an increased serum level of 1,25-dihydroxyvitamin D in an infant with SFN. We investigated calcium and bone metabolism in two hypercalcemic infants with SFN, and confirmed the findings of Finne et al. 6 METHODS Calcium, phosphate, creatinine, and alkaline phosphatase activity were measured with standard automatic analyzer Submitted for publication Aug. 10, 1992; accepted Oct. 9, 1992. Reprint requests: Klaus Kruse, MD, Klinik fiir Paediatrie der Medizinischen Universit~it zu Liibeck, Dw-2400 Liibeck, Federal Republic of Germany. Copyright 9 1993 by Mosby-Year Book, Inc. 0022-3476/93/$1.00 + .10 9/24/43299 460
techniques. Hydroxyproline and cyclic adenosine-3',5'monophosphate in spontaneously voided morning urine samples, as well as osteocalcin in serum, were assayed as previously described. 7 Hydroxyproline and Ca were related to Cr; cAMP was expressed relative to 100 ml glomerular filtrate by multiplying the values obtained relative to urinary Cr (in nanomoles per milligram) by the corresponding serum Cr value (in milligrams per deciliter). Serum 25-hydroxyvitamin D was measured with a competitive protein-binding assay, the normal range being I0 to 60 ng/ml (24 to 144 nmol/L). Serum 1,25-(OH)2 D was ALP cAMP Cr 25-OHD 1,25-(OH)2D PTH SFN
Alkaline phosphatase Cyclic adenosine-3',5'-monophosphate Creatinine 25-Hydrox)atitamin D 1,25-Dihydroxyvitamin D Parathyroid hormone Subcutaneous fat necrosis
assayed according to Holliss by using the test kit of Nichols Institute Diagnostics (San Juan Capistrano, Calif.). The detection limit is 3 pg/ml; the intraassay and interassay variances at a concentration of 40 pg/ml are 10% and 14%, respectively. The normal range in infants is 25 to 90 pg/ml (60 to 216 pmol/L). Intact serum parathyroid hormone was measured with a
The Journal of Pediatrics Volume 122, Number 3
Kruse, lrle, atzd Uhlig
46 1
Patient 2
Patient I Therapy gtucocorticoid 2
o[ Serum CaLcium (rra'not/L)
t, O9
3
. _- _-
.
9 9 9 99
9
O0
2 Phosphate (mmot/t) PTH 1- 86 (pg/mt) 25OHD (rig/mr)
2 1 0 100 50 0
9
9
a 0
9
"-I
9
0
-1100 U9
U
1~ f .
.
.
9149
9
. .
9
al'eJ
0"
0
-1100
9
(pg/rnt)
9 .jvs
0"
9
=-
0
9
Ca/Or
,
2
9
(mg/mg)
, 9
9
9
9 9
cAMP/GFR (nmot/dt)
0" :
.
"
"
9
9
9
"
I
I
I
&
6
8
I
I
I
10 12 /. Age in weeks
"e
9
I
i
6
8
9
B
-..] i
I~1
0 I
10 122060
Fig. 1. Effect of glucocorticoid therapy on Ca and bone metabolism in two infants with subcutaneous fat necrosis. The normal ranges for age are indicated. two-site immunochemiluminometric assay (Ciba Corning Diagnostics Corp., Medfield, Mass.). The detection limit is I p g / m l ; the intraassay and interassay variances at a concentration of 40 p g / m l are 3% and 6%, respectively. The normal range is 10 to 55 p g / m l .
CASE R E P O R T S Patient 1. A female infant, weight 4.6 kg, was born by cesarean section because of failure to progress with frank breech presentation at 38 weeks of gestation, and had Apgar scores of 6 and 8 after 1 and 5 minutes, respectively. At 14 days of age, irregularly shaped, hard lesions with overlying red skin appeared on the neck, back, and cheeks. Two weeks later the infant had fever, anorexia, and a serum Ca level of 3.5 mmol/L (14 mg/dl; normal, 2.1 to 2.7 mmol/L). Serum P level was 2.1 mmol/L (6.3 mg/dl; normal, 1.6 to 2.6 mmol/L), ALP activity, 239 U / L (normal, 200 to 600 U/L),
osteocalcin 7.4 ng/ml (normal, 7 to 15 ng/ml), intact PTH <6 pg/ ml, 25-OHD 41.6 ng/ml (99.8 rim 9 and 1,25-(OH)zD 125 pg/ml (299 pmol/L). Urinary Ca/Cr ratio was 1.23 mg/mg (3.5 mmol/mmol; normal, 0.02 to 0.6 mg/mg), urinary hydroxyproline/Cr ratio 1.26 mg/mg (1 mmol/mmol); normal, 0.32 to 1.4 mg/mg), and cAMP/GF 1.9 nmol/dl (normal, 2.0 to 6.0 nmol/dl). Treatment was started with a low-Ca diet and hydration, but Ca and 1,25-(OHhD in serum further increased to 3.7 mmol/L (14.8 mg/dl) and 135.5 pg/ml (325 pmol/L), respectively (Fig. 1). During additional therapy with flu9149 2 mg/kg per day, the serum Ca level decreased to 2.8 mmol/L (11.2 mg/dl) after 3 days, remained at this level until the patient's age reached 10 weeks, and normalized at the age of 11.4 weeks. The 1,25-(OH)zD value and the urinary Ca/Cr ratio normalized in parallel. The skin lesions decreased in size after 2 weeks of glucocorticoid treatment. The dose of flu9149 was tapered slowly, and discontinued by 9
462
Kruse, lrle, and Uhlig
r= 0,65 p<0,05
The Jo,~rnal of Pediatrics March 1993
9 Patient 1 o Patient 2
DISCUSSION
O
E E E
O O
~
u - , Cl
and subsequent follow-updisclosed normal Ca values and normal bone metabolism at the age of 12 weeks.
3
E t.,. O..I
t/')
2
t 'o 0 100 200 Serum 1,25(OH)2D (pg/mt)
Fig. 2. Relationship between Ca and 1,25-(OH)zD in serum before and during glucocorticoidtherapy. The normal serum Ca and 1,25-(Ott)2D values are indicated by the square box.
weeks of age. By this time the fat necrosis had resolvedcompletely, and all biochemical measurements were normal (Fig. I). Patient 2. A girl born at term and weighing3.4 kg was delivered by cesarean section, performed because of decelerations in fetal heart rate and maternal toxemia, tter Apgar scores at ! and 5 minutes were 2 and 6, respectively.The amniotic fluid was meconium-stained, and meconium was noted below the vocal cords. Septicemia with group B streptococcus developed and was treated with penicillinand cefotaxime. At the age of 19 days the infant was noted to have SFN on the upper arms, back, and buttocks. A skin biopsyspecimenobtained at 8 weeksof age from one of the affected areas revealed typical histopathologiclesionsof SFN. Hypercalcemia (Ca level, 2.8 mmol/L [ 11.6 mg/dl]) was noted at the age of 3 weeks. One week later the serum Ca value was 3.4 mmol/L (13.6 mg/dl), P 1.84 mmol/L (5.7 mg/dl), intact PTH <6 pg/ml, ALP activity 162 U/L, osteocalcin4.6 ng/ml, 25-OttD 36.4 ng/ml (87 nmol/L), 1,25-(OH)2D 112 pg/ml (269 pmol/L), urinary Ca/Cr ratio 1.5 mg/mg (4.2 mmol/mmol), urinary hydroxyproline/Cr ratio 0.74 mg/mg (0.64 mmol/mmol), and urinary cAMP/ glomerular filtrate 32 nmol/dl. The patient was treated with a low-Ca diet and saline solution intravenously,followed by furosemide (1 to 4 mg/kg per day) and prednisolone(2 mg/kg per day). After a further increase of serum levels of 1,25-(OH)2D to 154 pg/ml (370 pmol/L) at the age of 7 weeks and persistenceof high Ca levelsat 3.3 mmol/L (13.2 mg[ dl) until this age, there was a concomitant normalization of Ca, 1,25(OH)zD, and intact PTH levelsin serum, as wellas Ca/Cr and cAMP/glomerular filtrate in urine (Fig. l). There was a gradual resolution of SFN during the next weeks,
Both of our patients had hypercalcemia, hypercalciuria, and low osteoblastic activity (ALP activity and osteocalcin level in serum), but normal osteoclastic bone degradation (urinary hydroxyproline), low-normal serum P values, suppressed or low parathyroid secretion (intact PTH in serum) or function (urinary cAMP), and normal 25-OHD levels. but elevated 1,25-(OH)2D levels in serum. Glucoeorticoid therapy caused a parallel normalization of Ca and 1,25(OH)2D values with a significant positive relationship between both values before and during treatment (Fig. 2), indicating that the hypercalcemia was related to the increase in serum 1,25-(OH)2D concentration. The combination of elevated 1,25-(OH)2D levels in serum despite hypercalcemia and suppressed Parathyroid activity indicates abnormal unregulated 1,25-(OH)2D production. Bone turnover was not increased but was low normal; thus hypercalcemia in our patients was due not to increased bone degradation but to 1,25-(OH)2D-stimulated intestinal absorption of Ca. Our finding of elevated serum 1,25-(OH)eD levels confirms that of Finne et al.,6 but does not agree with two case reports of normal concentrations of the vitamin D hormone.3,5 However, these reports were based on a single measurement before or on two determinations during glucocorticoid treatment. In both studies the reported "normal values" of 1,25-(OH)2D might be considered relatively elevated with regard to hypercalcemia and suppressed parathyroid activity. One of our patients had almost an immediate drop of 1,25-(OH)2D after the start ofsteroid therapy. This observation may explain the results of Cook et al., 5 who found relatively high but still normal 1,25-(OH)2D levels after 36 hours of steroid treatment. Elevated serum 1,25-(OH)2D levels caused by enhanced production of activated alveolar macrophages have been found in hypercalcemic patients with sarcoidosis.9, lo The synthesis of the vitamin D hormone by macrophages of patients with sarcoidosis and other granulomatous diseases such as tuberculosis, II leprosy, t2 and disseminated candidiasis 13 is independent of the presence of PTH and 1,25(OH)2D, suggesting unregulated production of the vitamin D hormone. Our findings support the hypothesis of Finne et al. 6 that extrarenal production of 1,25-(OH)2D by the granulomatous ceils of fat necrosis may cause hypercalcemia in infants with SFN. Other possibilities include unregulated renal overproduction of 1,25-(OH)2D. In patients with sarcoidosis the therapeutic effects of glucocorticoids, I~ chloroquine,t4 and ketoconazole 15on hypercalcemia maybe explained by an inhibition of the conversion of 25-OHD to
The Journal of Pediatrics Volume 122, Number 3
Kruse, Irle, attd Uhlig
1,25-(OH)2D by macrophages. This mechanism may also be involved in hypercalcemic patients with S F N and should be further studied in these infants.
9.
REFERENCES !. Harrison G, McNee J. An investigation of sclerema neonatorum, with special reference to the chemistry of the subcutaneous tissues. Part I. Arch Dis Child 1926;1:63-84. 2. Clay P. Idiopathic hypercalcemia with subcutaneous calcium deposits following pseudosclerema. Proc R Soc Med 1956;49: 598-600. 3. Veldhuis J, Kulin H, Demers L, Lambert P. Infantile hypercalcemia with subcutaneous fat necrosis: endocrine studies. J PEmATR 1979;95:460-2. 4. Yasuda T, Sunami S, Ogussa N, Nishioka T, Nakagima It. Infantile hypercalcemia with subcutaneous fat necrosis. Acta Paediatr Scand 1986;75:1042-5. 5. Cook JS, Stone MS, Hansen JR. Hypercalcemia in association with subcutaneous fat necrosis of the newborn: studies of calcium-regulating hormones. Pediatrics 1992;90:93-6. 6. Finne P, Sanderud J, Aksnes L, Bratlid D, Aarskog D. Hypercalcemia with increased and unregulated 1,25-dihydroxyvitamin D production in a neonate with subcutaneous fat necrosis. J PEDXATR1988;i 12:792-4. 7. Kruse K, Kracht U, Wohlfart K, Kruse U. Biochemical markers of bone turnover, intact serum parathyroid hormone and renal calcium excretion in patients with pseudohypoparathyroidism and hypoparathyroidism before and during vitamin D treatment. Eur J Pediatr 1989;148:535-9.
10.
11.
12.
13.
14.
15.
463
Hollis BW. Assay of circulating 1,25-dihydrox)witamin D involving a novel single cartridge extraction and purification procedure. Clin Chem 1986;32:2060-3. Bell NH, Stern PH, Pantzer E, Sinha TK, DeLuca HF. Evidence that increased circulating la-25-dihydrox)vitamin D is a probable cause for abnormal calcium metabolism in sarcoidoris. J Clin Invest 1979;64:218-25. Reichel H, Koeffler HP, Barbers R, Norman AW. Regulation of 1,25-dihydroxyvitamin D 3 production by cultured alveolar macrophages from normal human donors and from patients with pulmonary sarcoidosis. J Clin Endocrinol Metab 1987;65: 1201-9. Gkonos PJ, London R, Hendler ED. Hypercalcemia and elevated 1,25-dihydroxyvitamin D levels in a patient with endstage renal disease and active tuberculosis. N Engl J Med 1984;311:1683-5. ttoffman VN, Korzemiowski OM. Leprosy, hypercalcemia, and elevated serum calcitriol levels. Ann Intern Med 1986;! 05: 890-1. Kantarjian HM, Saad M F, Estey EH, Sellin RV, Samaan NA. ltypercalcemia in disseminated candidiasis. Am J Med 1983; 74:721-4. O'Leavy T J, Jones G, Yip A, et al. The effects of chloroquine on serum 1,25-dihydroxyvitamin D and calcium metabolism in sareoidosis. N Engl J Med 1986;315:727-30. Adams JS, Sharma UP, Diz MM, Endres DB. Ketoconazole decreases the serum 1,25-dihydroxyvitamin D and calcium concentration in sarcoidosis-associated hypercalcemia. J Clin Endocrinol Metab 1990;70:1090-5.
FELLOWSHIPS Fellowships available in pediatric subspecialties and those for general academic pediatric training are listed once a year, in January, in TIlE JOURNAL OF PEDIATRICS. Each June, forms for listing fellowships available for the academic year beginning 18 months after publication are sent to the Chairman of the Department of Pediatrics at major hospitals in the United States and Canada. In addition, a copy of the application form appears in the July, August, and September issues of TIlE JOURNAL (please use the current form). Should you desire to list fellowships, a separate application must be made each year for each position. All applications must be returned to Mosby by October 15 preceding the listing year to ensure publication. Additional forms will he supplied on request from the Journal Editing Department, Mosby, 11830 Westline Industrial Drive, St. Louis, M O 63146-3318/800-325-4177, ext. 4317, or 314-453-4317.