- Email: [email protected]
Hypercalcemia with increased and unregulated 1,25-dihydroxyvitamin D production in a neonate with subcutaneous fat necrosis
792
8.
9. 10. 11.
12.
13.
Clinical and laboratory observations
thrombocytopenia in the neonate. J PEDIATR 1983;103:6545. Ciccimarra F, DeCurtis M, Paludetto R, Romano G, Troncore R. Treatment of neonatal passive immune thrombocytopenia. J PEDIATR 1984;105:677-8. O'Reilly RA, Taber BZ. Immunologic thrombocytopenic purpura and pregnancy. Obstet Gynecol 1978;51:590-7. Horger EO, Keone MWD. Platelet disorders in pregnancy. Clin Obstet Gynecol 1979;22:843. Kelton JG. Management of the pregnant patient with idiopathic thrombocytopenic purpura. Ann Intern Med 1983; 99:796-800. Karpatkin M. Corticosteroid therapy in thrombocytopenic infants of women with autoimmune thrombocytopenia. J PEDIATR 1984;105:623-5. Fehr J, Hofmann V, Kappeler U. Transient reversal of
The Journal of Pediatrics May 1988
thrombocytopenia in idiopathic thrombocytopenic purpura by high dose intravenous gammaglobulin. N Engl J Med 1982;306:1254-8. 14. Salama A, Mueller-Eckhardt C, Kiefel V. Effect of intravenous immunoglobulin in immune thrombocytopenia: Competitive inhibition of reticuloendothelial system function by sequestration of autologous red blood cells? Lancet 1983; 2:,193-5. 15. Burdach StEG, Evers KG, Geursen RG. Treatment of acute idiopathic thrombocytopenic purpura of childhood with intraVenous immunoglobulin G: comparative efficacy of 7S and 5S preparations. J PEDIATR 1986;109:770-5. 16. Chirico G, Randini G, Plebani A, Chiara A, Massa M, Ugazio AG. Intravenous gammaglobulin therapy for prophylaxis of infection in high-risk neonates. J PEDIATR 1987; 110:437-42.
Hypercalcemia with increased and unregulated 1,25-dihydroxyvitamin D production in a neonate with subcutaneous fat necrosis Per H. Finne, MD, Jon Sanderud MD, Lage Aksnes, PhD, Dag Bratlid, MD, and
Dagfinn Aarskog, MD From the Center for Child Research, University of Trondheim, and the Departments of Pediatrics, National Hospital, Oslo, and Haukeland Hospitar, Bergen, Norway
S u b c u t a n e o u s fat necrosis in the newborn infant m a y be associated with hypercalcemia2 -3 Infants with subcutaneous fat necrosis often have a history of t r a u m a or asphyxia at birth. 1'3 In some cases the fat necrosis has been followed by hypercalcemia, the cause of which is obscure. Several possible endocrine pathogenic mechanisms h a v e been proposed, including increased vitamin D sensitivity, increased p a r a t h y r o i d h o r m o n e a n d prostaglandin E2 activity, a n d increased calcium release from necrotic fat tissue? W e describe the occurrence of hypercalcemia associated with a n increased s e r u m level of 1,25-dihydroxyvitamin D in a n infant with subcutaneous fat necrosis. T h e chemical a n d h o r m o n a l data were r e m a r k a b l y similar to those reported in hypercalcemia of sarcoidosis. 4 CASE REPORT This infant girl was delivered at 11 days post term by cesarean section because of delayed delivery and fetal bradycardia. Her Supported by the Norwegian Research Council for Science and the Humanities, and the Norwegian Cancer Society. Submitted for publication April 10, 1987; accepted Dec. 15, 1987. Reprint requests: P. H. Finne, MD, Department of Pediatrics, National Hospital, Oslo, Norway.
birth weight was 4510 g. The infant was asphyxiated, with Apgar scores of 0 and 1 after 1 and 5 minutes, respectively. She was resuscitated, and mechanical ventilation was started. In the neonatal period she had signs of cerebral damage, with convulsions. Routine cerebral ultrasound scanning and computed tomography demonstrated subsequent cerebral infarcts. 1,25(OH)2D PTH UcAMP
1,25-Hydroxyvitamin D Parathyroid hormone Urinary adenosine 3 ' 5 '-monophosphate
Six days after birth, typical clinical signs of subcutaneous fat necrosis were found on the back and upper arms. The overlying skin was red and seemed tender to palpation. A skin biopsy specimen obtained at 5 weeks of age from one of the affected areas revealed granulomatous inflammatory infiltration, with macrophages, scattered lymphocytes, and some multinuclear giant cells. At 4 weeks of age the infant had failure to thrive, with anorexia, a tendency to vomit, decreased weight gain, and irritabihty. Concomitant with these clinical signs hypercalcemia was found, with a serum calcium concentration of 3.8 mmol/L (15.2 mg/dL, normal 2.15 to 2.95 mmol/L), ionized calcium 1.99 mmol/L (8.0 mg/dL), phosphorus 1.7 mmol/L (5.3 mg/dL, normal 1.39 to
Volume 112 Number 5
Clinical and laboratory observations
,
0
,000800
i,//"
~<6oo.
"~
<
'=-
200.
~,
o
~ '~
9
'~ '~x ' __.
/ f
~....
o
] ,50. x :_E [
130"
"~ ~ ~
,,o90.
1
,' 11
LocasotPrednis~
t
Ketovite
t
=
-
_
, I
1
"*-._ ".........
./~...
70.
"'-e- ......
2.0-
o.
~ ..........
// ....
* .................
............
~
793
~. ~ 3s I -~= 2951 |
~ 2.0~,.
~J. ~-...j
~ ....
t"%-
9
~
~....~.~ ~,~,~,
,.~..A/ /
~". ............
.Z" Ionized-Ca
~" I ~ ~ ~ ~ I0 115
~
...............
" u i,'...........9 ...........9 ................................ .... 9 A.~..~ ....~,.,,,,,,~ ,...~,....,.,~
............
~ ~ ~ I . . . . . . . . . . . 15/6 117
(," . . . . . . . . . . . . . 1816 119
* ~ '
I 2119
Figure. Serum concentrations of calcium, ionized calcium, phosphorus, alkaline phosphatase, creatinine, and 1,25(OH)2D during clinical course. Dates listed on horizontal axis (date/month); birth date 30/4. To convert serum calcium, phosphorus and creatinine values to milligrams per deciliter, multiply by 4, 3.1, and 0.011, respectively. To convert 1,25-(OH)2D to picograms per milliliter, multiply by 0.4.
3.03 mmol/L), alkaline phosphatase 387 U / L (normal 124 to 574 U/L), and urinary calcium 7.1 mmol/L (28.4 mg/dL, normal 0.5 to 1.65 mmol/L). At the time hypercalcemia was diagnosed, radiographs showed calcification of the renal papillae and sclerotic calcification in the metaphyses of the long bones. Treatment with a low-calcium diet (Locasol, <7 mg/dL, 700 mL/d) and a multivitamin preparation without vitamin D (Ketovite tablets), together with prednisone (5 mg/d) and furosemide (7 mg/d) was started. This produced a decrease in the serum Ca values (Figure). After normalization of the serum Ca value, prednisone and furosemide treatment was stopped. The lowcalcium and vitamin D-free diet was continued for about 2 months. At this time radiographs of the kidneys and long bones were normal. The increased alkaline phosphatase level at the end of the treatment period returned to normal after introduction of a normal diet, and was probably a result of the long-term lowcalcium intake. Immunoreactive parathyroid hormone (carboxyterminal), calcitonin, vitamin D metabolites, s and urine adenosine 3',5'monophosphate were measured at the peak of hypercalcemia, just before the therapy was started, q~he results showed normal levels of immunoreactive PTH (0.35 #g/L, normal <0.6 ug/L), calcitonin (0.34 ~g/L, normal <0.5 #g/dL), 25-OHD (69.0 nmol/L [27.6 ng/ml], normal 25 to 130 nmol/L), and 24,25-(OH)2D (3.6 nmol/L [1.5 ng/mL], normal 3% to 6% of 25-OHD). However,
the level of 1,25-(OH)2D (380 pmol/L [158 pg/mL), normal 60 to 210 pmol/L) was markedly elevated, and UcAMP was low (1.0 izmol/g creatinine, normal 5 to 10 #mol/g). After therapy and normalization of the clinical signs of subcutaneous fat necrosis and hyperealcemia, the levels of immunoreacrive PTH (0.33 ug/L), calcitonin (0.20 #g/L), 1,25-(OH)2D (63 pmol/L [26.3 ng/mL]), and UcAMP (8.4 #mol/g creatinine) were all normal9 (All normal values refer to age-matched controls.) DISCUSSION Severe hypercalcemia has been described in conjunction with subcutaneous fat necrosis in newborn infants./3 The infants generally have been full term, with a history of perinatal difficulties such as asphyxia. The subcutaneous fat necrosis usually develops within 1 to 2 weeks of age; clinical and laboratory signs of hypercalcemia appear after approximately 4 weeks. O f the known endocrine factors affecting calcium homeostasis, we were able to demonstrate an increased serum level of 1,25-(OH)2D, which can explain the hypercalcemia and the increased bone mineralization and calcification of the renal papillae. Elevated 1,25-(OH)2D concentrations together with hypercalcemia
794
Clinical and laboratory observations
have been described in infants with the hypercalcemia elfin facies syndrome? Normal endogenous production of 1,25-(OH)ED occurs in significant amounts only in the kidneys, where 25-OHD undergoes 1-c~-hydroxylation by a highly specific and well-regulated enzyme. PTH and hypocalcemia are known stimulators of renal 25-OHD-l-o~-hydroxylase and increase the serum level of 1,25-(OH)2D. ImmunoreactivePTH was not elevated in this patient, and the low level of UcAMP strongly indicates reduced PTH secretion related to the feedback effect of hypercalcemia. The finding of increased bone mineralization also contradicts the possibility of increased PTH secretion, because PTH in concert with 1,25-(OH)2D increases calcium by mobilization from bone. Inasmuch as 25-OHD, an accepted measure of vitamin D nutritional status, showed a mid-normal value, vitamin D intoxication from exogenous sources can be excluded as a cause of the high 1,25-(OH)2-D level. Our finding of elevated serum 1,25-(OH)2D level associated with hypercalcemia and subcutaneous fat necrosis does not agree with a previous case report, in which a normal 1,25-(OH)2D level was observed,2 and may indicate that different mechanisms for hypercalcemia are involved. However, each report is based on a single measurement of 1,25-(OH)2D, and the different findings can be related to fluctuations in the 1,25-(OH)2D level or to the fact that the samples were taken during different phases of the hypercalcemic episode. The simultaneous appearance of hypercalcemia, normal 25-OHD, and high level of 1,25-(OH)ED in the face of reduced or normal PTH secretion and reduced UcAMP excretion suggest abnormal and unregulated extrarenal 1,25-(OH)2D production. The hypercalcemia was probably caused by increased intestinal calcium absorption resulting from the increased serum level of 1,25-(OH)2D. The~ same chemical and hormonal pattern is found in patients with sarcoidosis and hypercalcemia. 4 Extrarenal production of 1,25-(OH)2D has been shown in an anephric patient with sarcoidosis, 7 and subsequent studies have demonstrated 1,25-(OH)2D production in pulmonary macrophages obtained from bronchoalveolar lavage, in sarcoid lymph node homogenates, and in cultured pulmonary alveolar macrophages? High levels of 1,25-(OH)~D also have been reported in conjunction with hypercalcemia in other granulomatous diseases, such as tuberculosis,9 candidiasis, 1~and silicone-induced granulomas. 11
The Journal of Pediatrics May 1988
In an analogy with the present concepts regarding granulomas of sarcoidosis, we speculate that granulomatous inflammation of the fat necrosis, with infiltration of different cells, including macrophages, was the source of the unregulated 1,25-(OH)2D production in our patient. The response to prednisone therapy 4 and normalization of the 1,25-(OH)2D production after healing of the fat necrosis support this suggestion. We thank Dr. K. M. Gautvik at the Institute for Surgical Research, The National Hospital, Oslo, for performing the PTH and calcitonin measurements; and Dr. K. Elgjo, Institute of Pathology, The National Hospital, Oslo, for histologic examination of the skin biopsy tissue. REFERENCES
1. Sharlin DN, Koblenzer P. Necrosis of subcutaneous fat with hypercalcemia. Clin Pediatr 1970;9:290-4. 2. Veldhuis JD, Kulin HE, Demers LM, Lambert PW. Infantile hypercalcemia with subcutaneous fat necrosis: endocrine studies. J PEDIATR1979;95:460-2. 3. Thomsen RJ. Subcutaneous fat necrosis of the newborn and idiopathic hypercalcemia. Arch Dermatol 1980;116:1155-8. 4. Papapoulos SE, Clemens TL, Fraher LJ, Lewin IG, Sandler LM, O'Riordan JLH. 1,25-Dihydroxycholecalciferolin the patbogeneis of hypercalcemia of sarcoidosis. Lancet 1979;1:627-30. 5. Aksnes L. Quantitation of the main metabolites of vitamin D in a single serum sample. II. Determination by UV-absorption and competitive protein binding assay. Clin Chim Acta 1980;104:147-59. 6. Garabedian M, Jacoz E, Guillozo H, et al. Elevated 1,25dihydroxyvitamin D concentrations in infants with hypercalcemia and an elfin facies. N Engl J Med 1985;312:948-52. 7. Barbour GL, Coburn JW, SlatopolskyE, Norman AW, Horst RL. Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D. N Engl J Med 1981;305:441-3. 8. Adams JS, Mercedes AG. Characterization of lalphahydroxylation of vitamin D3 sterols by cultured alveolar macrophages from patients with sarcoidosis. J Exp Med 1985;161:755-65. 9. Gkonos PJ, London R, Hendler ED. Hypercalcemia and elevated 1,25-dihydreoxyvitaminD levels in a patient with end-stage renal disease and active tuberculosis. N Engl J Med 1984;311:1683-5. 10. Kantarjian HM, Saad MF, Estey EH, Sellin RV, Samaan NA. Hypercalcemia in disseminated candidiasis. Am J Med 1983;74:721-3. 11. Kozeny GA, Barbato AL, Bansai VK, Vertuno LL, Hano JE. Hypercalcemia associated with silicone-inducedgranulomas. N Engl J Med 1984;311:1103-4.
8.
9. 10. 11.
12.
13.
Clinical and laboratory observations
thrombocytopenia in the neonate. J PEDIATR 1983;103:6545. Ciccimarra F, DeCurtis M, Paludetto R, Romano G, Troncore R. Treatment of neonatal passive immune thrombocytopenia. J PEDIATR 1984;105:677-8. O'Reilly RA, Taber BZ. Immunologic thrombocytopenic purpura and pregnancy. Obstet Gynecol 1978;51:590-7. Horger EO, Keone MWD. Platelet disorders in pregnancy. Clin Obstet Gynecol 1979;22:843. Kelton JG. Management of the pregnant patient with idiopathic thrombocytopenic purpura. Ann Intern Med 1983; 99:796-800. Karpatkin M. Corticosteroid therapy in thrombocytopenic infants of women with autoimmune thrombocytopenia. J PEDIATR 1984;105:623-5. Fehr J, Hofmann V, Kappeler U. Transient reversal of
The Journal of Pediatrics May 1988
thrombocytopenia in idiopathic thrombocytopenic purpura by high dose intravenous gammaglobulin. N Engl J Med 1982;306:1254-8. 14. Salama A, Mueller-Eckhardt C, Kiefel V. Effect of intravenous immunoglobulin in immune thrombocytopenia: Competitive inhibition of reticuloendothelial system function by sequestration of autologous red blood cells? Lancet 1983; 2:,193-5. 15. Burdach StEG, Evers KG, Geursen RG. Treatment of acute idiopathic thrombocytopenic purpura of childhood with intraVenous immunoglobulin G: comparative efficacy of 7S and 5S preparations. J PEDIATR 1986;109:770-5. 16. Chirico G, Randini G, Plebani A, Chiara A, Massa M, Ugazio AG. Intravenous gammaglobulin therapy for prophylaxis of infection in high-risk neonates. J PEDIATR 1987; 110:437-42.
Hypercalcemia with increased and unregulated 1,25-dihydroxyvitamin D production in a neonate with subcutaneous fat necrosis Per H. Finne, MD, Jon Sanderud MD, Lage Aksnes, PhD, Dag Bratlid, MD, and
Dagfinn Aarskog, MD From the Center for Child Research, University of Trondheim, and the Departments of Pediatrics, National Hospital, Oslo, and Haukeland Hospitar, Bergen, Norway
S u b c u t a n e o u s fat necrosis in the newborn infant m a y be associated with hypercalcemia2 -3 Infants with subcutaneous fat necrosis often have a history of t r a u m a or asphyxia at birth. 1'3 In some cases the fat necrosis has been followed by hypercalcemia, the cause of which is obscure. Several possible endocrine pathogenic mechanisms h a v e been proposed, including increased vitamin D sensitivity, increased p a r a t h y r o i d h o r m o n e a n d prostaglandin E2 activity, a n d increased calcium release from necrotic fat tissue? W e describe the occurrence of hypercalcemia associated with a n increased s e r u m level of 1,25-dihydroxyvitamin D in a n infant with subcutaneous fat necrosis. T h e chemical a n d h o r m o n a l data were r e m a r k a b l y similar to those reported in hypercalcemia of sarcoidosis. 4 CASE REPORT This infant girl was delivered at 11 days post term by cesarean section because of delayed delivery and fetal bradycardia. Her Supported by the Norwegian Research Council for Science and the Humanities, and the Norwegian Cancer Society. Submitted for publication April 10, 1987; accepted Dec. 15, 1987. Reprint requests: P. H. Finne, MD, Department of Pediatrics, National Hospital, Oslo, Norway.
birth weight was 4510 g. The infant was asphyxiated, with Apgar scores of 0 and 1 after 1 and 5 minutes, respectively. She was resuscitated, and mechanical ventilation was started. In the neonatal period she had signs of cerebral damage, with convulsions. Routine cerebral ultrasound scanning and computed tomography demonstrated subsequent cerebral infarcts. 1,25(OH)2D PTH UcAMP
1,25-Hydroxyvitamin D Parathyroid hormone Urinary adenosine 3 ' 5 '-monophosphate
Six days after birth, typical clinical signs of subcutaneous fat necrosis were found on the back and upper arms. The overlying skin was red and seemed tender to palpation. A skin biopsy specimen obtained at 5 weeks of age from one of the affected areas revealed granulomatous inflammatory infiltration, with macrophages, scattered lymphocytes, and some multinuclear giant cells. At 4 weeks of age the infant had failure to thrive, with anorexia, a tendency to vomit, decreased weight gain, and irritabihty. Concomitant with these clinical signs hypercalcemia was found, with a serum calcium concentration of 3.8 mmol/L (15.2 mg/dL, normal 2.15 to 2.95 mmol/L), ionized calcium 1.99 mmol/L (8.0 mg/dL), phosphorus 1.7 mmol/L (5.3 mg/dL, normal 1.39 to
Volume 112 Number 5
Clinical and laboratory observations
,
0
,000800
i,//"
~<6oo.
"~
<
'=-
200.
~,
o
~ '~
9
'~ '~x ' __.
/ f
~....
o
] ,50. x :_E [
130"
"~ ~ ~
,,o90.
1
,' 11
LocasotPrednis~
t
Ketovite
t
=
-
_
, I
1
"*-._ ".........
./~...
70.
"'-e- ......
2.0-
o.
~ ..........
// ....
* .................
............
~
793
~. ~ 3s I -~= 2951 |
~ 2.0~,.
~J. ~-...j
~ ....
t"%-
9
~
~....~.~ ~,~,~,
,.~..A/ /
~". ............
.Z" Ionized-Ca
~" I ~ ~ ~ ~ I0 115
~
...............
" u i,'...........9 ...........9 ................................ .... 9 A.~..~ ....~,.,,,,,,~ ,...~,....,.,~
............
~ ~ ~ I . . . . . . . . . . . 15/6 117
(," . . . . . . . . . . . . . 1816 119
* ~ '
I 2119
Figure. Serum concentrations of calcium, ionized calcium, phosphorus, alkaline phosphatase, creatinine, and 1,25(OH)2D during clinical course. Dates listed on horizontal axis (date/month); birth date 30/4. To convert serum calcium, phosphorus and creatinine values to milligrams per deciliter, multiply by 4, 3.1, and 0.011, respectively. To convert 1,25-(OH)2D to picograms per milliliter, multiply by 0.4.
3.03 mmol/L), alkaline phosphatase 387 U / L (normal 124 to 574 U/L), and urinary calcium 7.1 mmol/L (28.4 mg/dL, normal 0.5 to 1.65 mmol/L). At the time hypercalcemia was diagnosed, radiographs showed calcification of the renal papillae and sclerotic calcification in the metaphyses of the long bones. Treatment with a low-calcium diet (Locasol, <7 mg/dL, 700 mL/d) and a multivitamin preparation without vitamin D (Ketovite tablets), together with prednisone (5 mg/d) and furosemide (7 mg/d) was started. This produced a decrease in the serum Ca values (Figure). After normalization of the serum Ca value, prednisone and furosemide treatment was stopped. The lowcalcium and vitamin D-free diet was continued for about 2 months. At this time radiographs of the kidneys and long bones were normal. The increased alkaline phosphatase level at the end of the treatment period returned to normal after introduction of a normal diet, and was probably a result of the long-term lowcalcium intake. Immunoreactive parathyroid hormone (carboxyterminal), calcitonin, vitamin D metabolites, s and urine adenosine 3',5'monophosphate were measured at the peak of hypercalcemia, just before the therapy was started, q~he results showed normal levels of immunoreactive PTH (0.35 #g/L, normal <0.6 ug/L), calcitonin (0.34 ~g/L, normal <0.5 #g/dL), 25-OHD (69.0 nmol/L [27.6 ng/ml], normal 25 to 130 nmol/L), and 24,25-(OH)2D (3.6 nmol/L [1.5 ng/mL], normal 3% to 6% of 25-OHD). However,
the level of 1,25-(OH)2D (380 pmol/L [158 pg/mL), normal 60 to 210 pmol/L) was markedly elevated, and UcAMP was low (1.0 izmol/g creatinine, normal 5 to 10 #mol/g). After therapy and normalization of the clinical signs of subcutaneous fat necrosis and hyperealcemia, the levels of immunoreacrive PTH (0.33 ug/L), calcitonin (0.20 #g/L), 1,25-(OH)2D (63 pmol/L [26.3 ng/mL]), and UcAMP (8.4 #mol/g creatinine) were all normal9 (All normal values refer to age-matched controls.) DISCUSSION Severe hypercalcemia has been described in conjunction with subcutaneous fat necrosis in newborn infants./3 The infants generally have been full term, with a history of perinatal difficulties such as asphyxia. The subcutaneous fat necrosis usually develops within 1 to 2 weeks of age; clinical and laboratory signs of hypercalcemia appear after approximately 4 weeks. O f the known endocrine factors affecting calcium homeostasis, we were able to demonstrate an increased serum level of 1,25-(OH)2D, which can explain the hypercalcemia and the increased bone mineralization and calcification of the renal papillae. Elevated 1,25-(OH)2D concentrations together with hypercalcemia
794
Clinical and laboratory observations
have been described in infants with the hypercalcemia elfin facies syndrome? Normal endogenous production of 1,25-(OH)ED occurs in significant amounts only in the kidneys, where 25-OHD undergoes 1-c~-hydroxylation by a highly specific and well-regulated enzyme. PTH and hypocalcemia are known stimulators of renal 25-OHD-l-o~-hydroxylase and increase the serum level of 1,25-(OH)2D. ImmunoreactivePTH was not elevated in this patient, and the low level of UcAMP strongly indicates reduced PTH secretion related to the feedback effect of hypercalcemia. The finding of increased bone mineralization also contradicts the possibility of increased PTH secretion, because PTH in concert with 1,25-(OH)2D increases calcium by mobilization from bone. Inasmuch as 25-OHD, an accepted measure of vitamin D nutritional status, showed a mid-normal value, vitamin D intoxication from exogenous sources can be excluded as a cause of the high 1,25-(OH)2-D level. Our finding of elevated serum 1,25-(OH)2D level associated with hypercalcemia and subcutaneous fat necrosis does not agree with a previous case report, in which a normal 1,25-(OH)2D level was observed,2 and may indicate that different mechanisms for hypercalcemia are involved. However, each report is based on a single measurement of 1,25-(OH)2D, and the different findings can be related to fluctuations in the 1,25-(OH)2D level or to the fact that the samples were taken during different phases of the hypercalcemic episode. The simultaneous appearance of hypercalcemia, normal 25-OHD, and high level of 1,25-(OH)ED in the face of reduced or normal PTH secretion and reduced UcAMP excretion suggest abnormal and unregulated extrarenal 1,25-(OH)2D production. The hypercalcemia was probably caused by increased intestinal calcium absorption resulting from the increased serum level of 1,25-(OH)2D. The~ same chemical and hormonal pattern is found in patients with sarcoidosis and hypercalcemia. 4 Extrarenal production of 1,25-(OH)2D has been shown in an anephric patient with sarcoidosis, 7 and subsequent studies have demonstrated 1,25-(OH)2D production in pulmonary macrophages obtained from bronchoalveolar lavage, in sarcoid lymph node homogenates, and in cultured pulmonary alveolar macrophages? High levels of 1,25-(OH)~D also have been reported in conjunction with hypercalcemia in other granulomatous diseases, such as tuberculosis,9 candidiasis, 1~and silicone-induced granulomas. 11
The Journal of Pediatrics May 1988
In an analogy with the present concepts regarding granulomas of sarcoidosis, we speculate that granulomatous inflammation of the fat necrosis, with infiltration of different cells, including macrophages, was the source of the unregulated 1,25-(OH)2D production in our patient. The response to prednisone therapy 4 and normalization of the 1,25-(OH)2D production after healing of the fat necrosis support this suggestion. We thank Dr. K. M. Gautvik at the Institute for Surgical Research, The National Hospital, Oslo, for performing the PTH and calcitonin measurements; and Dr. K. Elgjo, Institute of Pathology, The National Hospital, Oslo, for histologic examination of the skin biopsy tissue. REFERENCES
1. Sharlin DN, Koblenzer P. Necrosis of subcutaneous fat with hypercalcemia. Clin Pediatr 1970;9:290-4. 2. Veldhuis JD, Kulin HE, Demers LM, Lambert PW. Infantile hypercalcemia with subcutaneous fat necrosis: endocrine studies. J PEDIATR1979;95:460-2. 3. Thomsen RJ. Subcutaneous fat necrosis of the newborn and idiopathic hypercalcemia. Arch Dermatol 1980;116:1155-8. 4. Papapoulos SE, Clemens TL, Fraher LJ, Lewin IG, Sandler LM, O'Riordan JLH. 1,25-Dihydroxycholecalciferolin the patbogeneis of hypercalcemia of sarcoidosis. Lancet 1979;1:627-30. 5. Aksnes L. Quantitation of the main metabolites of vitamin D in a single serum sample. II. Determination by UV-absorption and competitive protein binding assay. Clin Chim Acta 1980;104:147-59. 6. Garabedian M, Jacoz E, Guillozo H, et al. Elevated 1,25dihydroxyvitamin D concentrations in infants with hypercalcemia and an elfin facies. N Engl J Med 1985;312:948-52. 7. Barbour GL, Coburn JW, SlatopolskyE, Norman AW, Horst RL. Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D. N Engl J Med 1981;305:441-3. 8. Adams JS, Mercedes AG. Characterization of lalphahydroxylation of vitamin D3 sterols by cultured alveolar macrophages from patients with sarcoidosis. J Exp Med 1985;161:755-65. 9. Gkonos PJ, London R, Hendler ED. Hypercalcemia and elevated 1,25-dihydreoxyvitaminD levels in a patient with end-stage renal disease and active tuberculosis. N Engl J Med 1984;311:1683-5. 10. Kantarjian HM, Saad MF, Estey EH, Sellin RV, Samaan NA. Hypercalcemia in disseminated candidiasis. Am J Med 1983;74:721-3. 11. Kozeny GA, Barbato AL, Bansai VK, Vertuno LL, Hano JE. Hypercalcemia associated with silicone-inducedgranulomas. N Engl J Med 1984;311:1103-4.