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Healing of rickets during vitamin D therapy despite defective vitamin D receptors in two siblings with vitamin D-dependent rickets type II
The Journal of Pediatrics Volume 126, Number 1
3.
4.
5.
6.
7.
8.
Human neutrophil cytochrome b light chain (p22-phox). J Clin Invest 1990;86:1729-37. Isaacs D, Wright VM, Shaw DG, Raafat F, Walker-Smith JA. Chronic granulomatous disease mimicking Crohn's disease. J Pediatr Gastroenterol Nutr 1985;4:498-501. International Chronic Granulomatous Disease Study Group. A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. N Engl J Med 1991;324:50916. Silliman CC, Lawellin DW, Lohr JA, Rodgers BM, Donowitz, LG. Paeeilomyces lilacinus infection in a child with chronic granulomatous disease. J Infect 1992;24:191-5. Williamson PR, Kwon-Chung K J, Gallin JI. Successful treatment of Paeeilomyces variotii infection in a patient with chronic granulomatous disease and a review of Paecilomyces species infections. Clin Infect Dis 1992;14:1023-6. Werlin SL, Chusid M J, Caya J, Oechler HW. Colitis in chronic granulomatous disease. Gastroenterology 1982;82: 328-31. Strober W, Ehrhardt RO. Chronic intestinal inflammation: an unexpected outcome in cytokine or T cell receptor mutant mice. Cell 1993;75:203-5.
Kruse and Feldmann
14 5
9. Brynskov J, Freund L, Rasmussen SN. A placebo-controlled double-blind randomized trial of cyclosporine therapy in active chronic Crohn's disease. N Engl J Med 1989;321:845-50. 10. Present D, Lichtiger S. Efficacy of cyclosporine in treatment of fistula in Crohn's disease. Dig Dis Sci 1994;39:374-80. 11. Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330:1841-5. 12. Feagan BG, McDonald JWD, Rochon J, Laupacis A, Fedorak RN, et al. Low-dose cyclosporine for the treatment of Crohn's disease. N Engl J Med 1994;330:1846-51. 13. Treem WR, Davis PM, Hyams JS. Cyclosporine treatment of severe ulcerative colitis in children. J PEDIATR1991; 119:994-7. 14. Benkov K J, Rosh JR, Schwersenz AH, Janowitz HD, LeLeiko NS. Cyclosporine as an alternative to surgery in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1994;19:290-4. 15. $echler JMG, Malech HL, White C J, Gallin JI. Recombinant human interferon-'r reconstitutes defective phagocyte function in patients with chronic granulomatous disease of childhood. Proc Natl Acad Sci U S A 1988;85:4874-8.
Healing of rickets during vitamin D therapy despite defective vitamin D receptors in two siblings with vitamin D-dependent rickets type II Klaus Kruse, MD, a n d Evemarie Feldmann, MD From the Departments of Pediatrics, University of Luebeck and Neunkirchen, Germany
We report the healing of severe rickets despite hypocalcemia in two siblings with absent vitamin D receptors; long periods of treatment with excessive doses of vitamin D led to relative hypoparathyroidism and a return to normal of calcium metabolism during calcitriol treatment, This finding suggests that some other regulating factor may substitute for the defective vitamin D receptor. (J PEDIATR 4995;126:445-8) Vitamin D-dependent rickets type II is a rare disorder characterized by early-onset rickets, hypocalcemia, secondary hyperparathyroidism, and increased circulating levels of 1,25-dihydroxyvitamin D. l About half of the affected
Presented in part at the Seventh Workshop on Vitamin D, Rancho Mirage, Calif., April 24-29, 1988. Submitted for publication June 10, 1994; accept Aug. 16, 1994. Reprint requests: Klaus Kruse, MD, Klinik fuer Paediatrie der Medizinischen Universitaet zu Luebeck, Kahlhorststrasse 31-35, D-23538 Luebeck, Germany. Copyright © 1995 by Mosby-Year Book, Inc. 0022-3476/95/$3.00 + 0 9/22/59942
children have total alopecia, which does not improve with otherwise satisfactory therapy. Two main classes of defects have been identified, reflecting point mutations in the gene
1,25-(OH)2D 1,25-(OH)2D3 PTH VDDR II VDR
1,25-Dihydroxyvitamin D 1,25-Dihydroxyvitamin D3 (calcitriol) Parathyroid hormone Vitamin D-dependent rickets type II Vitamin D receptor
that codes for the vitamin D receptor-hormone-binding domain mutations and DNA-binding mutations. 2
146
Kruse and Feldmann
The Journal of Pediatrics January 1995
Healing
of Rickets
Trecttment calcitriol
Patient 1 (born1977)
Patient 2 (born1979)
20
(pg/d) 0 vitamin
D3
0
serum Ca (mmol/I)
F- /
2 r-
(Mio.U/d)
3 ~
/
I O0 w
serum P
3
(mmol/I)
ii
M-PTH
2001-
(pmol/l)
100 ~-
• •
•
• • 000
O00
•
•
• -~°oo
°oo
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oo
• •
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o°°
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go
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PTH1. ~ (pmol/I)
li1 f
000
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0 LAP (U/I)
1 500 l1 000}--
•
o o
/
• o °oo
••
•
• °oo
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500 ~0~
OHP/Cr 200 (pmol/mmol) 100 0 TmP/GFR 3~ (mmol/l) 2
e%o •
• O0
t
L
• 00
0 ~ 0 ,L--
L.__°
1
cAMP/GFR (nmol/dl)
• OoO~
10r5 0
L_ O0 0
• • •
I
I
I
I
t
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I
t
°ooo°
P
I
t
l
I
0 2 1, 6 8 10 12 11, 16 0 2 L 6 Age (years) Age (years)
[ I I ] I 8 10 12 11, 16
Figure. Treatment regimens, serum calcium (Ca), phosphate (P), mid-regional PTH (M-PTH), intact PTH (PTHt-s4), alkaline phosphatase activity (AP), urinary hydroxyproline in relation to creatinine (OHP/Cr), tubular maximal rate of phosphate reabsorption in relation to the glomerular filtration rate (TmP/GFR) and adenosine 3':5'-cyclic phosphate in relation to the glomerular filtration rate (cAMP/GFR) in patient 1 (left panel) and patient 2 (right panel). The age-dependent normal ranges are indicated.
Some patients may be cured by high-dose vitamin D therapy, whereas those with receptor-negative mutations and truncated VDRs usually have no response to therapy with excessive doses of vitamin D or vitamin D metabolites. The absence of effective therapy may have severe conse-
quences; death during the first years of life, mainly caused by pulmonary complications and hypocalcemic convulsions, has been reported. 1 We report the healing of severe rickets in two siblings with absent VDRs after long periods of treatment with ex-
The Journal of Pediatrics Volume 126, Number 1
cessive doses of vitamin D in the presence of hypocalcemia, and a return to normal of calcium metabolism during calcitriol treatment. CASE REPORTS Patient 1. Patient 1, a girl, was born in 1977 after an uneventful gestation and labor. The Turkish parents were first cousins and were healthy, as were the patient's three eider siblings. Alopecia developed within the first 5 weeks of life. At the age of 19 months, she was unable to walk and was referred with clinically and radiologically severe rickets and total absence of body and scalp hair. Her initial serum calcium concentration was 2.0 mmol/L (normal, 2.1 to 2.6 mmol/L), phosphate 1.26 mmol/L (normal, 1.3 to 2.0 mmol/L), and alkaline phosphatase activity 990 U/L (normal, 200 to 600 U/L). Patient 2. The brother, born in 1979, had convulsionsbecause of hypocalcemia (1.4 mmol/L), complete alopecia, and rickets at the age of 10 months. His serum phosphate concentration, was 1.1 retool/L, alkaline phosphatase activity 810 U/L, and the serum 1,25-(OH)2D concentration >360 pg/ml (normal, 20 to 60 pg/ml). In vitro studies in fibroblasts of patient 1, kindly done by J. Barsony and S. Marx (National Institutes of Health, Bethesda, Md.3) showed no significant induction of 24-hydroxylaseat the highest tested concentrationof 1,25-(OH)2D3 (10-6 mol/L) and no detectable saturablebindingof tritium-labeled1,25-(OH)2D3in solubleextracts from whole fibroblasts ("hormone-bindingnegative"). The mutational analysis (kindly done by K. Kristjansson, Houston, Tex.4) revealed a C-~ T transition at codon 149 (CAG to TAG), which replaced the normal glutamine codon with a termination codon and resulted in a truncated receptor missing the total hormone-binding domain. RESULTS During oral treatment with 2 million units (50 mg) of vitamin D daily and calcium, 1 to 2 gm, the serum levels of 1,25-(OH)2D were extremely elevated to >13440 pmol/L (normal, 48 to 144 pmol/L) without calcemic responses in both siblings (Figure). Despite chronic hypocalcemia the mid-regional parathyroid hormone concentrations in serum were suppressed to 75 to 86 pmol/L (normal, 30 to 90 pmol/L), and intact PTH values in serum were 4.8 and 5.5 pmol/L (normal, 1.1 to 5.8 pmol/L) at the age of 9 and 7 years, in patients 1 and 2, respectively. The relative hypoparathyroidism was associated with high-normal tubular maximum for phosphate reabsorption (in relation to the glomerular filtration rate) and serum phosphate levels, and normal or slightly elevated urinary excretion of cyclic adenosine monophosphate. Both children had a decreased growth rate until the age of 7 years, when the rate returned to normal; the children had healing of rickets at the ages of 9 and 8 years, respectively. High-dose oral vitamin D preparations were no longer available in Germany in 1989, and the treatment was changed to calcitriol (1,25-[OH]2D3) at the ages of 12 and 10 years, respectively. During the overlap phase, there was
Kruse and Feldmann
14 7
a slight transient increase of the serum concentration of PTH; during daily calcitriol doses of 15 to 20 #g and 3 to 7.5 ~zg, the PTH concentration returned to normal in patients 1 and 2, respectively, in association with serum levels of 1,25-(OH)2D between 2712 and 20280 pmol/L. During this treatment regimen, the calcium metabolism became normal in association with subsidence of bone pain and acceleration of growth in both patients. There was no improvement in hair growth. Probably because of a pubertal growth spurt with a greater calcium requirement of the skeleton, patient 1 acquired slight secondary hyperparathyroidism associated with a small increment of bone turnover, making an increase of the calcitriol dosage to 7.5 ug necessary (Figure). DISCUSSION These two siblings have the most severe form of VDDR II because of a premature stop mutation and truncation of the VDR, resulting in the absence of calcitriol binding and biologic activity.4 Our two patients had total alopecia and lacked an in vitro response of 25-hydroxyvitamin D3-24hydroxylase, suggesting the highest degree of resistance to calcitriol in vivo. 1 Although both siblings at first had no calcemic response to excessive doses of vitamin D3 that induced circulating 1,25-(OH)2D levels more than 100 times the mean normal range, they showed striking improvement, clinically and radiologically, at the ages of 9 and 8 years, respectively. The healing of rickets in the presence of low serum calcium concentrations has also been observed by Hochberg et al. 5 in a 6-year-old patient with a form of VDDR II that was as severe as in our siblings. In our patients bone healing was associated with PTH suppression, which caused an increase in the extracellular calcium X phosphate product. The relative hypoparathyroidism may result from the supression of the parathyroid glands by the excessive circulating 1,25-(OH)2D levels, mediated by vitamin D receptors. 6 This possibility suggests that there may be selective differences in the resistance to calcitriol in VDDR II, or that these effects may be caused by nongenomic actions of vitamin D or its metabolites mediated by different receptors] The return to normal of calcium metabolism was probably not due to the change from vitamin D to calcitriol, but it might also have occurred during continuation of the vitamin therapy. In other words, it was the induction of very high serum levels of 1,25(OH)2D for a long time during treatment with vitamin D or calcitriol that at first led to relative hypoparathyroidism, saturation of bone minerals, and healing of rickets, and then to a return to normal of calcium and bone metabolism. With further therapy, intermediate doses of calcitriol (or vitamin D) and orally administered calcium seem to be able to support continued remission of calcium and bone disturbances in our patients.
148
Kruse and Feldmann
The Journal of Pediatrics January 1995
Bone healing between 7 and 8 years of age, accompanied by a return to normal of serum phosphate concentrations, but without a change in vitamin D treatment, has also been described in two other patients with V D D R II. 5, s Balsan et al. 9 observed spontaneous healing of rickets in a child with V D D R II at the age of 6 years, followed by a relapse despite continuous treatment with increasing doses of vitamin D derivates. This indicates that the degree of resistance to calcitriol may vary with time within a subject, and that in some patients with the severest type of V D D R II spontaneous improvement may occur; some other regulating factor may substitute for the defective VDR. W e thus recommend long-term therapy with high doses of vitamin D or its analogs even in patients with the most severe form of V D D R II. The healing process in the patients reported by us and others began in later years; we recommend high doses of intravenously or orally administered c a l c i u m ( i n addition to very large doses of vitamin D or its analogs) during the first years of life. l°
REFERENCES 1. Marx SJ, Liberman KA, Eil C, Gamblin GT, DeGrange DA, Balsan S. Hereditary resistance to 1,25-dihydroxyvitamin D. Recent Prog Horm Res 1984;40:589-620. 2. Hughes MR, Malloy P J, O'Malley BW, Pike JW. Genetic defects of the 1,25-dihydroxyvitamin D3 receptor. J Recept Res 1991;11:699-716.
3. Barsony J, McKoy W, DeGrange DA, Liberman KA, Marx S. Selective expression of a normal action of 1,25-dihydroxyvitamin D3 receptor in human skin fibroblasts with hereditary severe defects in multiple action of this receptor. J Clin Invest 1989;83:2093-101. 4. Kristjansson K, Rut AR, Hewison M, O'Riordan JLH, Hughes MR. Two mutations in the hormone binding domain of the vitamin D receptor cause tissue resistance to 1,25-dihydroxyvitamin D3. J Clin Invest 1993;92:12-6. 5. Hochberg Z, Benderli Z, Levy J, Weisman Y, Chen T, Feldman D. 1,25-Dihydroxyvitamin D resistance, rickets, and alopecia. Am J Med 1984;77:805-11. 6. Silver J, Nareh-Many T, Mayer H, Schmelzer H J, Popovtzer MM. Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest 1986;78:1296-301. 7. Norman AW, Nemere J, Zhou L-X, et al. 1,25(OH)2-Vitamin D3, a steroid hormone that produces biologic effects via both genomic and nongenomic pathways. J Steroid Biochem Mol Biol 1992;41:231-40. 8. Tsuchiya Y, Matsao N, Cho H, et al. An unusual form of vitamin D-dependent rickets in a child: alopecia and marked end-organ hyporesponsivity to biological active vitamin D. J Clin Endocrinol Metab 1980;51:685-90. 9. Balsan A, Garab~dian M, Liberman KA, et al. Rickets and alopecia with resistance to 1,25-dihydroxyvitamin D: two different clinical courses with two different cellular defects. J Clin Endocrinol Metab 1983;57:803-11. 10. Hochberg Z, Tiosano D, Even L. Calcium therapy for calcitriol-resistant rickets. J J PEDIATR 1992;121:803-8.
BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes of the 1995 issues of THE JOURNAL OF PEDIATRICS are available to subscribers (only) from the Publisher, at a cost of $77.00 for domestic, $99.51 for Canadian, and $93.00 for international subscribers, for Vol. 126 (January-June) and Vol. 127 (July-December), shipping charges included. Each bound volume contains subject and author indexes, and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram, with the Journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact M o s b y - Y e a r Book, Inc., Subscription Services, 11830 Westline Industrial Dr., St. Louis, M O 63146-3318, USA/800-453-4351, or 314-453-435 i. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular Journal subscription.
3.
4.
5.
6.
7.
8.
Human neutrophil cytochrome b light chain (p22-phox). J Clin Invest 1990;86:1729-37. Isaacs D, Wright VM, Shaw DG, Raafat F, Walker-Smith JA. Chronic granulomatous disease mimicking Crohn's disease. J Pediatr Gastroenterol Nutr 1985;4:498-501. International Chronic Granulomatous Disease Study Group. A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. N Engl J Med 1991;324:50916. Silliman CC, Lawellin DW, Lohr JA, Rodgers BM, Donowitz, LG. Paeeilomyces lilacinus infection in a child with chronic granulomatous disease. J Infect 1992;24:191-5. Williamson PR, Kwon-Chung K J, Gallin JI. Successful treatment of Paeeilomyces variotii infection in a patient with chronic granulomatous disease and a review of Paecilomyces species infections. Clin Infect Dis 1992;14:1023-6. Werlin SL, Chusid M J, Caya J, Oechler HW. Colitis in chronic granulomatous disease. Gastroenterology 1982;82: 328-31. Strober W, Ehrhardt RO. Chronic intestinal inflammation: an unexpected outcome in cytokine or T cell receptor mutant mice. Cell 1993;75:203-5.
Kruse and Feldmann
14 5
9. Brynskov J, Freund L, Rasmussen SN. A placebo-controlled double-blind randomized trial of cyclosporine therapy in active chronic Crohn's disease. N Engl J Med 1989;321:845-50. 10. Present D, Lichtiger S. Efficacy of cyclosporine in treatment of fistula in Crohn's disease. Dig Dis Sci 1994;39:374-80. 11. Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330:1841-5. 12. Feagan BG, McDonald JWD, Rochon J, Laupacis A, Fedorak RN, et al. Low-dose cyclosporine for the treatment of Crohn's disease. N Engl J Med 1994;330:1846-51. 13. Treem WR, Davis PM, Hyams JS. Cyclosporine treatment of severe ulcerative colitis in children. J PEDIATR1991; 119:994-7. 14. Benkov K J, Rosh JR, Schwersenz AH, Janowitz HD, LeLeiko NS. Cyclosporine as an alternative to surgery in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1994;19:290-4. 15. $echler JMG, Malech HL, White C J, Gallin JI. Recombinant human interferon-'r reconstitutes defective phagocyte function in patients with chronic granulomatous disease of childhood. Proc Natl Acad Sci U S A 1988;85:4874-8.
Healing of rickets during vitamin D therapy despite defective vitamin D receptors in two siblings with vitamin D-dependent rickets type II Klaus Kruse, MD, a n d Evemarie Feldmann, MD From the Departments of Pediatrics, University of Luebeck and Neunkirchen, Germany
We report the healing of severe rickets despite hypocalcemia in two siblings with absent vitamin D receptors; long periods of treatment with excessive doses of vitamin D led to relative hypoparathyroidism and a return to normal of calcium metabolism during calcitriol treatment, This finding suggests that some other regulating factor may substitute for the defective vitamin D receptor. (J PEDIATR 4995;126:445-8) Vitamin D-dependent rickets type II is a rare disorder characterized by early-onset rickets, hypocalcemia, secondary hyperparathyroidism, and increased circulating levels of 1,25-dihydroxyvitamin D. l About half of the affected
Presented in part at the Seventh Workshop on Vitamin D, Rancho Mirage, Calif., April 24-29, 1988. Submitted for publication June 10, 1994; accept Aug. 16, 1994. Reprint requests: Klaus Kruse, MD, Klinik fuer Paediatrie der Medizinischen Universitaet zu Luebeck, Kahlhorststrasse 31-35, D-23538 Luebeck, Germany. Copyright © 1995 by Mosby-Year Book, Inc. 0022-3476/95/$3.00 + 0 9/22/59942
children have total alopecia, which does not improve with otherwise satisfactory therapy. Two main classes of defects have been identified, reflecting point mutations in the gene
1,25-(OH)2D 1,25-(OH)2D3 PTH VDDR II VDR
1,25-Dihydroxyvitamin D 1,25-Dihydroxyvitamin D3 (calcitriol) Parathyroid hormone Vitamin D-dependent rickets type II Vitamin D receptor
that codes for the vitamin D receptor-hormone-binding domain mutations and DNA-binding mutations. 2
146
Kruse and Feldmann
The Journal of Pediatrics January 1995
Healing
of Rickets
Trecttment calcitriol
Patient 1 (born1977)
Patient 2 (born1979)
20
(pg/d) 0 vitamin
D3
0
serum Ca (mmol/I)
F- /
2 r-
(Mio.U/d)
3 ~
/
I O0 w
serum P
3
(mmol/I)
ii
M-PTH
2001-
(pmol/l)
100 ~-
• •
•
• • 000
O00
•
•
• -~°oo
°oo
oo
oo
• •
g
o°°
olPoo
go
oo~oo •
eo
Ot--
PTH1. ~ (pmol/I)
li1 f
000
• ,o
0 LAP (U/I)
1 500 l1 000}--
•
o o
/
• o °oo
••
•
• °oo
°oo
500 ~0~
OHP/Cr 200 (pmol/mmol) 100 0 TmP/GFR 3~ (mmol/l) 2
e%o •
• O0
t
L
• 00
0 ~ 0 ,L--
L.__°
1
cAMP/GFR (nmol/dl)
• OoO~
10r5 0
L_ O0 0
• • •
I
I
I
I
t
OOOO0
[
I
t
°ooo°
P
I
t
l
I
0 2 1, 6 8 10 12 11, 16 0 2 L 6 Age (years) Age (years)
[ I I ] I 8 10 12 11, 16
Figure. Treatment regimens, serum calcium (Ca), phosphate (P), mid-regional PTH (M-PTH), intact PTH (PTHt-s4), alkaline phosphatase activity (AP), urinary hydroxyproline in relation to creatinine (OHP/Cr), tubular maximal rate of phosphate reabsorption in relation to the glomerular filtration rate (TmP/GFR) and adenosine 3':5'-cyclic phosphate in relation to the glomerular filtration rate (cAMP/GFR) in patient 1 (left panel) and patient 2 (right panel). The age-dependent normal ranges are indicated.
Some patients may be cured by high-dose vitamin D therapy, whereas those with receptor-negative mutations and truncated VDRs usually have no response to therapy with excessive doses of vitamin D or vitamin D metabolites. The absence of effective therapy may have severe conse-
quences; death during the first years of life, mainly caused by pulmonary complications and hypocalcemic convulsions, has been reported. 1 We report the healing of severe rickets in two siblings with absent VDRs after long periods of treatment with ex-
The Journal of Pediatrics Volume 126, Number 1
cessive doses of vitamin D in the presence of hypocalcemia, and a return to normal of calcium metabolism during calcitriol treatment. CASE REPORTS Patient 1. Patient 1, a girl, was born in 1977 after an uneventful gestation and labor. The Turkish parents were first cousins and were healthy, as were the patient's three eider siblings. Alopecia developed within the first 5 weeks of life. At the age of 19 months, she was unable to walk and was referred with clinically and radiologically severe rickets and total absence of body and scalp hair. Her initial serum calcium concentration was 2.0 mmol/L (normal, 2.1 to 2.6 mmol/L), phosphate 1.26 mmol/L (normal, 1.3 to 2.0 mmol/L), and alkaline phosphatase activity 990 U/L (normal, 200 to 600 U/L). Patient 2. The brother, born in 1979, had convulsionsbecause of hypocalcemia (1.4 mmol/L), complete alopecia, and rickets at the age of 10 months. His serum phosphate concentration, was 1.1 retool/L, alkaline phosphatase activity 810 U/L, and the serum 1,25-(OH)2D concentration >360 pg/ml (normal, 20 to 60 pg/ml). In vitro studies in fibroblasts of patient 1, kindly done by J. Barsony and S. Marx (National Institutes of Health, Bethesda, Md.3) showed no significant induction of 24-hydroxylaseat the highest tested concentrationof 1,25-(OH)2D3 (10-6 mol/L) and no detectable saturablebindingof tritium-labeled1,25-(OH)2D3in solubleextracts from whole fibroblasts ("hormone-bindingnegative"). The mutational analysis (kindly done by K. Kristjansson, Houston, Tex.4) revealed a C-~ T transition at codon 149 (CAG to TAG), which replaced the normal glutamine codon with a termination codon and resulted in a truncated receptor missing the total hormone-binding domain. RESULTS During oral treatment with 2 million units (50 mg) of vitamin D daily and calcium, 1 to 2 gm, the serum levels of 1,25-(OH)2D were extremely elevated to >13440 pmol/L (normal, 48 to 144 pmol/L) without calcemic responses in both siblings (Figure). Despite chronic hypocalcemia the mid-regional parathyroid hormone concentrations in serum were suppressed to 75 to 86 pmol/L (normal, 30 to 90 pmol/L), and intact PTH values in serum were 4.8 and 5.5 pmol/L (normal, 1.1 to 5.8 pmol/L) at the age of 9 and 7 years, in patients 1 and 2, respectively. The relative hypoparathyroidism was associated with high-normal tubular maximum for phosphate reabsorption (in relation to the glomerular filtration rate) and serum phosphate levels, and normal or slightly elevated urinary excretion of cyclic adenosine monophosphate. Both children had a decreased growth rate until the age of 7 years, when the rate returned to normal; the children had healing of rickets at the ages of 9 and 8 years, respectively. High-dose oral vitamin D preparations were no longer available in Germany in 1989, and the treatment was changed to calcitriol (1,25-[OH]2D3) at the ages of 12 and 10 years, respectively. During the overlap phase, there was
Kruse and Feldmann
14 7
a slight transient increase of the serum concentration of PTH; during daily calcitriol doses of 15 to 20 #g and 3 to 7.5 ~zg, the PTH concentration returned to normal in patients 1 and 2, respectively, in association with serum levels of 1,25-(OH)2D between 2712 and 20280 pmol/L. During this treatment regimen, the calcium metabolism became normal in association with subsidence of bone pain and acceleration of growth in both patients. There was no improvement in hair growth. Probably because of a pubertal growth spurt with a greater calcium requirement of the skeleton, patient 1 acquired slight secondary hyperparathyroidism associated with a small increment of bone turnover, making an increase of the calcitriol dosage to 7.5 ug necessary (Figure). DISCUSSION These two siblings have the most severe form of VDDR II because of a premature stop mutation and truncation of the VDR, resulting in the absence of calcitriol binding and biologic activity.4 Our two patients had total alopecia and lacked an in vitro response of 25-hydroxyvitamin D3-24hydroxylase, suggesting the highest degree of resistance to calcitriol in vivo. 1 Although both siblings at first had no calcemic response to excessive doses of vitamin D3 that induced circulating 1,25-(OH)2D levels more than 100 times the mean normal range, they showed striking improvement, clinically and radiologically, at the ages of 9 and 8 years, respectively. The healing of rickets in the presence of low serum calcium concentrations has also been observed by Hochberg et al. 5 in a 6-year-old patient with a form of VDDR II that was as severe as in our siblings. In our patients bone healing was associated with PTH suppression, which caused an increase in the extracellular calcium X phosphate product. The relative hypoparathyroidism may result from the supression of the parathyroid glands by the excessive circulating 1,25-(OH)2D levels, mediated by vitamin D receptors. 6 This possibility suggests that there may be selective differences in the resistance to calcitriol in VDDR II, or that these effects may be caused by nongenomic actions of vitamin D or its metabolites mediated by different receptors] The return to normal of calcium metabolism was probably not due to the change from vitamin D to calcitriol, but it might also have occurred during continuation of the vitamin therapy. In other words, it was the induction of very high serum levels of 1,25(OH)2D for a long time during treatment with vitamin D or calcitriol that at first led to relative hypoparathyroidism, saturation of bone minerals, and healing of rickets, and then to a return to normal of calcium and bone metabolism. With further therapy, intermediate doses of calcitriol (or vitamin D) and orally administered calcium seem to be able to support continued remission of calcium and bone disturbances in our patients.
148
Kruse and Feldmann
The Journal of Pediatrics January 1995
Bone healing between 7 and 8 years of age, accompanied by a return to normal of serum phosphate concentrations, but without a change in vitamin D treatment, has also been described in two other patients with V D D R II. 5, s Balsan et al. 9 observed spontaneous healing of rickets in a child with V D D R II at the age of 6 years, followed by a relapse despite continuous treatment with increasing doses of vitamin D derivates. This indicates that the degree of resistance to calcitriol may vary with time within a subject, and that in some patients with the severest type of V D D R II spontaneous improvement may occur; some other regulating factor may substitute for the defective VDR. W e thus recommend long-term therapy with high doses of vitamin D or its analogs even in patients with the most severe form of V D D R II. The healing process in the patients reported by us and others began in later years; we recommend high doses of intravenously or orally administered c a l c i u m ( i n addition to very large doses of vitamin D or its analogs) during the first years of life. l°
REFERENCES 1. Marx SJ, Liberman KA, Eil C, Gamblin GT, DeGrange DA, Balsan S. Hereditary resistance to 1,25-dihydroxyvitamin D. Recent Prog Horm Res 1984;40:589-620. 2. Hughes MR, Malloy P J, O'Malley BW, Pike JW. Genetic defects of the 1,25-dihydroxyvitamin D3 receptor. J Recept Res 1991;11:699-716.
3. Barsony J, McKoy W, DeGrange DA, Liberman KA, Marx S. Selective expression of a normal action of 1,25-dihydroxyvitamin D3 receptor in human skin fibroblasts with hereditary severe defects in multiple action of this receptor. J Clin Invest 1989;83:2093-101. 4. Kristjansson K, Rut AR, Hewison M, O'Riordan JLH, Hughes MR. Two mutations in the hormone binding domain of the vitamin D receptor cause tissue resistance to 1,25-dihydroxyvitamin D3. J Clin Invest 1993;92:12-6. 5. Hochberg Z, Benderli Z, Levy J, Weisman Y, Chen T, Feldman D. 1,25-Dihydroxyvitamin D resistance, rickets, and alopecia. Am J Med 1984;77:805-11. 6. Silver J, Nareh-Many T, Mayer H, Schmelzer H J, Popovtzer MM. Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest 1986;78:1296-301. 7. Norman AW, Nemere J, Zhou L-X, et al. 1,25(OH)2-Vitamin D3, a steroid hormone that produces biologic effects via both genomic and nongenomic pathways. J Steroid Biochem Mol Biol 1992;41:231-40. 8. Tsuchiya Y, Matsao N, Cho H, et al. An unusual form of vitamin D-dependent rickets in a child: alopecia and marked end-organ hyporesponsivity to biological active vitamin D. J Clin Endocrinol Metab 1980;51:685-90. 9. Balsan A, Garab~dian M, Liberman KA, et al. Rickets and alopecia with resistance to 1,25-dihydroxyvitamin D: two different clinical courses with two different cellular defects. J Clin Endocrinol Metab 1983;57:803-11. 10. Hochberg Z, Tiosano D, Even L. Calcium therapy for calcitriol-resistant rickets. J J PEDIATR 1992;121:803-8.
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