Original Paper
Nephron 1992;62:176-181
Pediatric Nephrology Unit, Assaf Harofeh Medical Center, Zerifin: Unit of Metabolic Diseases, Beilinson Medical Center, Petah Tiqva, Sackler School of Medicine, Tel Aviv University, Tel Aviv; Bone Laboratory, Hadassah Faculty of Dental Medicine. Hebrew University, Jerusalem, Israel
Key Words Hypophosphatémie rickets 1,25-dihydroxyvitamin D Hypercalciuria Renal phosphate leak Phosphate therapy
A New Kindred with Hereditary Hypophosphatémie Rickets with Hypercalciuria: Implications for Correct Diagnosis and Treatment
Abstract Hereditary hypophosphatémie rickets with hypercalciuria (HHRH) is a new autosomal form of hypophosphatémie rickets, recently described. This disease is characterized, and differs from other forms of hereditary hypophosphatémie rickets an d /o r osteomalacia by increased serum levels of 1,25-dihydroxyvitamin D, hypercalciuria and complete remission of the disease on phosphate therapy alone. However, only another probable Israeli kindred, and seemingly a few sporadic cases from Europe, North America and Japan have been reported in the literature. We describe here a new kindred of Jewish Yemenite origin (unrelated to other Israeli families) with typical HHRH. Two additional members of this family suffer from a milder asymptomatic form of the disease, which presents as absorptive hypercalciuria without signs or symptoms of bone disease. It seems to us that HHRH is underdiagnosed, due to its similarity to other hypophos phatémie syndromes in clinical, radiological and most biochemical parameters. Therefore, it is recommended that urinary calcium excretion and serum 1,25-di hydroxyvitamin D concentrations be measured in every patient with hypophos phatémie rickets/and or osteomalacia before the initiation of any therapy. The correct diagnosis of HHRN is of immense therapeutic implications. Phosphate therapy alone could cause a complete remission in HHRH, while the addition of active vitamin D metabolites, as is recommended in hypophosphatémie vitamin D resistant rickets, could cause deterioration in the patient’s condition.
Introduction Several genetic forms of hypophosphatémie rickets and/or osteomalacia are associated with a primary impair ment of renal phosphate reabsorption [1, 2], They differ in the mode of inheritance, in some of the biochemical param
Presented in pan at the 8th Workshop on Vitamin D. Paris. July 1991.
Accepted: November 18,1991
eters and in the response to treatment. The most prominent form is the X-linked hypophosphatemia (XLH), but differ ent autosomal variants have been well characterized as well
IU2]. We have recently described a new autosomal form of hypophosphatémie rickets prevailing in a Bedouin tribe:
M. Ticder, M D Pediatric N ephrology Unit Assaf Harofeh M edical C enter Zerifin 70300 (Israel)
€> 1992 S. K arger AG, Basel 0028 2766/92/ 0622 0I76S2.75/0
Downloaded by: UCL 144.82.238.225 - 2/6/2018 10:06:26 AM
Martin Ttedera Raphael Arieh Itai Babc Joseph Maor' Uri A. Libermanb
Methods Subjects Patient C.R. (fig. i, 111-1), bom to healthy, nonrelated parents of Yemenite Jewish origin, was referred to us at the age of 13 years because of skeletal deformities, muscle weakness and bone pain. His past medical and nutritional history was unremarkable until the age of 10 years. From then on, deformities of the lower extremities appeared, which progressed slowly. By the age of 11.5 years, he started to complain of bone pain, mainly of the lower limbs and back, which progressively grew worse, increasingly limiting his activities. On ad mission, his height was 145 cm (10th percentile) and his weight 31.8 kg (between the 3rd and 10th percentile): He displayed severe deformities of the lower extremities, consisting of asymmetric genu varum (with a standing intermalleolar distance of 15 cm), mild kyphoscoliosis of the dorsal spine, thickening of the wrist, and costochondral rosaries. X-ray examination of the skeleton revealed features of rickets with meta physeal cupping and fraying and generalized osteopenia. Patient C. H., sister of C. R. (fig. 1,111-2), started to develop defor mities of the lower limbs at the age of 9, which progressively worsened. When examined a the age of 10.5, she showed a severe asymmetric genu varum (with a standing intermalleolar distance of 13 cm), and mild clinical signs of rickets. Her height, 135 cm, and weight, 26.7 kg, were on the 25th and 10th percentile, respectively. Radiological exam ination showed typical signs of rickets. Ultrasound of the kidneys and intravenous pyelography were normal in both patients. Physical and radiological examination of the parents and the 2 siblings of the patients (fig. 1) revealed no pathological findings. A 3rd sibling bom 3 months earlier had not yet been examined at the time of this study.
Fig-1- Genetic relationship of two siblings with HHRH.
Study Protocol The patients and their 1st degree relatives were evaluated according to an outpatient protocol. Urine was collected for 24 h and 2 h after a 12-hour overnight fast. Blood samples were drawn in the middle of the 2-hour urine collection. In each urine collection, calcium, phosphorus, sodium, potassium, creatinine, uric acid and cyclic AMP were measured. Calcium, phosphorus, electrolytes, urea, creatinine, uric acid, albumin and globulins, immunoreactive parathyroid hormone, 25-hydroxyvitamin D [25(OH)D], 24,25-dihydroxyvitamin D [24,25(OH)iD] and l,25(OH):D were measured in the serum. The following indices were calculated: urinary calcium/creatinine ratio and cyclic AMP excretion (per deciliter of glomerular filtrate) in each urine sample, creatinine clearance in the 24-hour urine collection and the ratio between maximal tubular reabsorption rate for phosphorus and glomerular filtration rate (TmP/GFR) form the 2-hour urine sample, according to the nomograms of Bijvoet and Morgan [14]. The two patients were subsequently evaluated in the metabolic unit under controlled conditions, and an oral calcium- and phosphate loading test was performed as described before [3-5]. To test the effect of prolonged fasting on urinary calcium excretion, the 12-hour over night fast was extended for 3 additional hours, and during each hour, urine samples were obtained for the determination of the calcium/cre atinine ratio. A transilial bone biopsy, 5 mm in diameter, was obtained from patient C.H. and processed as described previously [15]. In short, the specimen obtained after double tetracycline labelling (Ledermycin, Lederle. FRG) with a 14-day interlabel space, was embedded in low-viscosity resin and sectioned undecalcified. Sections, 5 pm thick, were stained with the modified Masson’s stain for general marrow histology, demonstration of bone cells and distinction between osteoid and mineralized bone. Osteoid lamellae were differentiated from mineralized bone lamellae in 5-urn sections stained with Von Kossa and toluidine blue and examined by polarized light microscopy. Unstained 10-um sections were used for fluorescent microscopy of the tetracycline label. Static histomorphometric measurements were per-
177
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hereditary hypophosphatemic rickets with hypercalciuria (HHRH) [3, 4]. However, only another probable Israeli kindred [5] and seemingly a few sporadic cases [6-9] from Europe, North America and Japan have been reported in the literature. We describe here a new kindred with typical HHRH that is unrelated ethnically to the other Israeli families. We feel that HHRH remains an underdiagnosed condi tion, some of the affected patients being included within the framework of familial hypophosphatemic vitamin D resis tant rickets [1] and/or within the group of childhood idio pathic hypercalciuria with stunted linear growth and bone lesions [10-12]. In both cases, these patients would be treated not only with phosphate supplementation, but with unnecessary and potentially harmful high dosage of active vitamin D metab olites as well [13]. Therefore, we would recommend the inclusion of bio chemical markers of HHRH, i.e., urinary calcium excretion and serum 1,25-dihydroxyvitamin D [l,25(OH)2D] concen trations in the laboratory investigation of every patient with hypophosphatemic rickets and/or osteomalacia.
Fig. 2. Pretreatment biochemical data on all subjects. Data are presented as m ean±S D for each group. • =T he two patients with HH RH ; 0 = t h e i r two immediate relatives with hypercalciuria alone; A = th e two normal members of the family. SD units = standard deviation units of normal rangefor age. T m P/G FR = ratio between the maximal tubular reabsorption rate for phosphorus and glomerular filtration rate; cAMP = 3',5'-cyclic adenosine monophosphate; G F= glom erular filtrate. To convert values for urinary calcium to milligram/kilogram body weight per 24 h, multiply by 40.08.
Biochemical Methods Calcium, phosphorus, uric acid and creatinine were measured with a Technicon Auto-Analyzer. Urinary cyclic AMP excretion was as sayed with a kit (Radiochemical Centre, Amersham, UK). Serum immunoreactive parathyroid hormone (iPTH) was measured with a PTH-MM antibody (Immunonuclear Corporation, Stillwater, Minn., USA). Serum levels of 25(OH)D, 24,25(OH)2D and l,25(OH)2D were measured as described elsewhere [3,4].
178
Results Baseline Data Figure 2 summarizes the relevant biochemical data in all immediate family members, including the patients, before treatment. Since TmP/GFR, serum phosphorus levels and alkaline phosphatase activity vary with age, these data are presented as means denoted by zero ± S D of the normal range for age [16]. As can be seen, the two patients present ed significant hypophosphatemia, decreased Tm P/G FR , elevated serum alkaline phosphatase activity of bone origin and hypercalciuria. Urinary cyclic AMP excretion, as well as serum immunoreactive parathyroid hormone levels (21.6 ±3.7 pmol/1), were slightly below the normal range in the patients (normal range: 1.5-4.3 nmol/100 ml GF, and 29-85 pmol/I for cyclic AMP and iPTH, respecti-
Tieder/A rie/Bab/M aor/Liberm an
Hereditary H ypophosphatém ie Rickets with Hypercalciuria
Downloaded by: UCL 144.82.238.225 - 2/6/2018 10:06:26 AM
formed using a computerized digitizing system. Quantitation of the tetracycline labelling was done with a Merz grid. The separation between double labels (dynamic measurements) was measured with a calibrated eyepiece micrometer.
The osteoid volume (OV/BV) was fivefold higher than normal, reflecting respective increases in bone osteoid surface (OS/BS) and osteoid thickness (O/Th). The double-labelled surface (dLS/BS) and bone formation rate (BFR/BS) showed an approximately 50% decrease and the mineralization lag time (MLT) a twofold prolon gation. These values, in particular the increased MLT and number of osteoid lamellae, indicate a mineralization defect the extent of which is similar to that found in our other patients with H H RH as well as in patients with X LH [15]. Response to Therapy The two patients were subsequently treated with neutral phosphate only, 2 g of elemental phosphorus given orally in 5 divided daily doses. This treatment has continued for 3 years. Bone pain disappeared and muscular strenght im proved markedly within several weeks. Radiological signs of rickets disappeared completely after 4-5 months of treat ment. A marked liner growth acceleration of 13.2 and 7.2 cm per year in patients C.R. and C. H., respectively, was doc umented. The biochemical data obtained before and during the administration of oral phosphate are shown in table 1. Serum phosphorus levels increased towards normal (measurements during treatment were performed in the fasting state, 2 h after the 1st dose of neutral phosphate). Serum concentrations of l,25(OH)2D and 24-hour urinary calcium excretion returned to the normal range. A small but significant drop in serum calcium levels was observed, as well as an increase in urinary cyclic AMP excretion. Serum alkaline phosphatase declined within normal limits, con currently with the disappearance of radiological signs of rickets. TmP/GFR, however, remained unchanged.
Discussion The diagnosis of HHRH in these patients is based on the following: (a) Familial occurrence of rickets and osteoma lacia; (b) The characteristic biochemical features, i.e., de creased renal tubular phosphate reabsorption, hypophos phatemia, elevated l,25(OH)2D serum levels, increased gas trointestinal calcium and phosphorus absorption and hypercalciuria; (c) Complete remission of the disease on inorganic phosphate therapy alone. As suggested before [3, 4], we believe that in HHRH, there is a primary hereditary renal tubular defect in phos phate reabsorption leading to hypophosphatemia, that, on one hand, if severe enough will cause defective mineraliza-
179
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tively). Serum concentrations of 25(OH)D and 24,25(OH)2D were normal (data not shown), but serum levels of l,25(OH)2D were significantly elevated in the patients. In 2 members of the family (fig. 1, mother, 11-6, and brother, III-3), all biochemical data were within the nor mal range, while in the other 2 (fig. 1, father, II-5, and sister, III-4), a significant hypercalciuria was documented. Hypercalciuria was defined as a urinary calcium excretion exceeding 0.1 mmol/kg body weight (4 mg/kg body weight) per 24 h, or a calcium/creatinine ratio of 0.65 mmol/mmol (0.23 mg/mg). Though all other biochemical parameters were within the normal range, it is worth noting that serum phosphorus levels and the Tm P/GFR tended to be in the low normal range while serum l,25(OH):D concentrations were in the high normal range in these two hypercalciuric subjects (fig. 2). Serum calcium levels, renal creatinine clearance and tubular functions, as well as liver function tests, protein electrophoresis, immunoelectrophoresis and a complete hematological workup were all within the normal range in the patients and their relatives. After a 12-hour overnight fast, the urinary calcium/cre atinine ratio of the patients remained elevated, at 1.04±0.34 mmol/mmol (0.37±0.12 m g/m g; m ean±SD ), normal below 0.31 m m ol/m mol (0.11 mg/mg); but it fell to the normal range after an additional 3-hour fast (0.25±0.03 m m ol/m m ol; 0.09±0.01 mg/mg). With an oral calcium load, the increments in urinary calcium/creatinine ratio in the two patients were 1.05 ±0.28 mmol/mmol (0.37 ±0.10 mg/mg, mean ± SD), as compared to 0.34±0.06 mmol/m mol (0.12± 0.02 m g/ mg) in 99 normal controls. Simultaneously, mean serum calcium levels rose abnormally by 0.18 ±0.13 mmol/1 (0.74 ±0.53 m g/dl) in the patients, as compared with 0.11 ±0.01 mmol/1 (0.43 ±0.05 m g/dl) in normal controls. The maximal increment in the mean serum phosphorus level after an oral phosphate load was 1.79 ±0.21 mmol/1 (5.55 ±0.64 m g/dl) in the patients, as compared with 0.39 ±0.06 mmol/1 (1.20 ±0.20 m g/dl) in normal controls. The bone biopsy specimen showed decreased trabecu lar density with small, rounded trabecular cross-sectional profiles. There was an apparent osteoid component, lining most of the trabecular surfaces. In several instances, the number of osteoid lamellae was increased to a maximum of 8, a figure consistent with a mineralization defect [15], Osteoblasts and osteoclasts were fewer than normal. This appearance was expressed in the histomorphometric re sults. The trabecular bone volume (B V/TV) was two thirds the normal. The other parameters showed values similar to those reported recently in children with HHRH [15].
Table 1. Bio chemical measure ments before and during phosphate treatment in 2 patients with HHRH
Before treatment
Measurement
No. of deter minations
During treatment11
No. of deter minations
p value
Fasting serum levels Calcium, mmol/l Phosphorus, mmol/l Alkaline phosphatase, IU/I 1.25 (OH) ,D. pmol/l TmP/GFR, mmol/l
2.3910.04 0.9010.04 14921554 252174 0.7910.12
4 4 4 3 4
2.29 + 0.04 1.2910.1.3 4861194 6415 0.8210.27
4 4 4 2 6
p
Nephron 1992;62:176-181
Pediatric Nephrology Unit, Assaf Harofeh Medical Center, Zerifin: Unit of Metabolic Diseases, Beilinson Medical Center, Petah Tiqva, Sackler School of Medicine, Tel Aviv University, Tel Aviv; Bone Laboratory, Hadassah Faculty of Dental Medicine. Hebrew University, Jerusalem, Israel
Key Words Hypophosphatémie rickets 1,25-dihydroxyvitamin D Hypercalciuria Renal phosphate leak Phosphate therapy
A New Kindred with Hereditary Hypophosphatémie Rickets with Hypercalciuria: Implications for Correct Diagnosis and Treatment
Abstract Hereditary hypophosphatémie rickets with hypercalciuria (HHRH) is a new autosomal form of hypophosphatémie rickets, recently described. This disease is characterized, and differs from other forms of hereditary hypophosphatémie rickets an d /o r osteomalacia by increased serum levels of 1,25-dihydroxyvitamin D, hypercalciuria and complete remission of the disease on phosphate therapy alone. However, only another probable Israeli kindred, and seemingly a few sporadic cases from Europe, North America and Japan have been reported in the literature. We describe here a new kindred of Jewish Yemenite origin (unrelated to other Israeli families) with typical HHRH. Two additional members of this family suffer from a milder asymptomatic form of the disease, which presents as absorptive hypercalciuria without signs or symptoms of bone disease. It seems to us that HHRH is underdiagnosed, due to its similarity to other hypophos phatémie syndromes in clinical, radiological and most biochemical parameters. Therefore, it is recommended that urinary calcium excretion and serum 1,25-di hydroxyvitamin D concentrations be measured in every patient with hypophos phatémie rickets/and or osteomalacia before the initiation of any therapy. The correct diagnosis of HHRN is of immense therapeutic implications. Phosphate therapy alone could cause a complete remission in HHRH, while the addition of active vitamin D metabolites, as is recommended in hypophosphatémie vitamin D resistant rickets, could cause deterioration in the patient’s condition.
Introduction Several genetic forms of hypophosphatémie rickets and/or osteomalacia are associated with a primary impair ment of renal phosphate reabsorption [1, 2], They differ in the mode of inheritance, in some of the biochemical param
Presented in pan at the 8th Workshop on Vitamin D. Paris. July 1991.
Accepted: November 18,1991
eters and in the response to treatment. The most prominent form is the X-linked hypophosphatemia (XLH), but differ ent autosomal variants have been well characterized as well
IU2]. We have recently described a new autosomal form of hypophosphatémie rickets prevailing in a Bedouin tribe:
M. Ticder, M D Pediatric N ephrology Unit Assaf Harofeh M edical C enter Zerifin 70300 (Israel)
€> 1992 S. K arger AG, Basel 0028 2766/92/ 0622 0I76S2.75/0
Downloaded by: UCL 144.82.238.225 - 2/6/2018 10:06:26 AM
Martin Ttedera Raphael Arieh Itai Babc Joseph Maor' Uri A. Libermanb
Methods Subjects Patient C.R. (fig. i, 111-1), bom to healthy, nonrelated parents of Yemenite Jewish origin, was referred to us at the age of 13 years because of skeletal deformities, muscle weakness and bone pain. His past medical and nutritional history was unremarkable until the age of 10 years. From then on, deformities of the lower extremities appeared, which progressed slowly. By the age of 11.5 years, he started to complain of bone pain, mainly of the lower limbs and back, which progressively grew worse, increasingly limiting his activities. On ad mission, his height was 145 cm (10th percentile) and his weight 31.8 kg (between the 3rd and 10th percentile): He displayed severe deformities of the lower extremities, consisting of asymmetric genu varum (with a standing intermalleolar distance of 15 cm), mild kyphoscoliosis of the dorsal spine, thickening of the wrist, and costochondral rosaries. X-ray examination of the skeleton revealed features of rickets with meta physeal cupping and fraying and generalized osteopenia. Patient C. H., sister of C. R. (fig. 1,111-2), started to develop defor mities of the lower limbs at the age of 9, which progressively worsened. When examined a the age of 10.5, she showed a severe asymmetric genu varum (with a standing intermalleolar distance of 13 cm), and mild clinical signs of rickets. Her height, 135 cm, and weight, 26.7 kg, were on the 25th and 10th percentile, respectively. Radiological exam ination showed typical signs of rickets. Ultrasound of the kidneys and intravenous pyelography were normal in both patients. Physical and radiological examination of the parents and the 2 siblings of the patients (fig. 1) revealed no pathological findings. A 3rd sibling bom 3 months earlier had not yet been examined at the time of this study.
Fig-1- Genetic relationship of two siblings with HHRH.
Study Protocol The patients and their 1st degree relatives were evaluated according to an outpatient protocol. Urine was collected for 24 h and 2 h after a 12-hour overnight fast. Blood samples were drawn in the middle of the 2-hour urine collection. In each urine collection, calcium, phosphorus, sodium, potassium, creatinine, uric acid and cyclic AMP were measured. Calcium, phosphorus, electrolytes, urea, creatinine, uric acid, albumin and globulins, immunoreactive parathyroid hormone, 25-hydroxyvitamin D [25(OH)D], 24,25-dihydroxyvitamin D [24,25(OH)iD] and l,25(OH):D were measured in the serum. The following indices were calculated: urinary calcium/creatinine ratio and cyclic AMP excretion (per deciliter of glomerular filtrate) in each urine sample, creatinine clearance in the 24-hour urine collection and the ratio between maximal tubular reabsorption rate for phosphorus and glomerular filtration rate (TmP/GFR) form the 2-hour urine sample, according to the nomograms of Bijvoet and Morgan [14]. The two patients were subsequently evaluated in the metabolic unit under controlled conditions, and an oral calcium- and phosphate loading test was performed as described before [3-5]. To test the effect of prolonged fasting on urinary calcium excretion, the 12-hour over night fast was extended for 3 additional hours, and during each hour, urine samples were obtained for the determination of the calcium/cre atinine ratio. A transilial bone biopsy, 5 mm in diameter, was obtained from patient C.H. and processed as described previously [15]. In short, the specimen obtained after double tetracycline labelling (Ledermycin, Lederle. FRG) with a 14-day interlabel space, was embedded in low-viscosity resin and sectioned undecalcified. Sections, 5 pm thick, were stained with the modified Masson’s stain for general marrow histology, demonstration of bone cells and distinction between osteoid and mineralized bone. Osteoid lamellae were differentiated from mineralized bone lamellae in 5-urn sections stained with Von Kossa and toluidine blue and examined by polarized light microscopy. Unstained 10-um sections were used for fluorescent microscopy of the tetracycline label. Static histomorphometric measurements were per-
177
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hereditary hypophosphatemic rickets with hypercalciuria (HHRH) [3, 4]. However, only another probable Israeli kindred [5] and seemingly a few sporadic cases [6-9] from Europe, North America and Japan have been reported in the literature. We describe here a new kindred with typical HHRH that is unrelated ethnically to the other Israeli families. We feel that HHRH remains an underdiagnosed condi tion, some of the affected patients being included within the framework of familial hypophosphatemic vitamin D resis tant rickets [1] and/or within the group of childhood idio pathic hypercalciuria with stunted linear growth and bone lesions [10-12]. In both cases, these patients would be treated not only with phosphate supplementation, but with unnecessary and potentially harmful high dosage of active vitamin D metab olites as well [13]. Therefore, we would recommend the inclusion of bio chemical markers of HHRH, i.e., urinary calcium excretion and serum 1,25-dihydroxyvitamin D [l,25(OH)2D] concen trations in the laboratory investigation of every patient with hypophosphatemic rickets and/or osteomalacia.
Fig. 2. Pretreatment biochemical data on all subjects. Data are presented as m ean±S D for each group. • =T he two patients with HH RH ; 0 = t h e i r two immediate relatives with hypercalciuria alone; A = th e two normal members of the family. SD units = standard deviation units of normal rangefor age. T m P/G FR = ratio between the maximal tubular reabsorption rate for phosphorus and glomerular filtration rate; cAMP = 3',5'-cyclic adenosine monophosphate; G F= glom erular filtrate. To convert values for urinary calcium to milligram/kilogram body weight per 24 h, multiply by 40.08.
Biochemical Methods Calcium, phosphorus, uric acid and creatinine were measured with a Technicon Auto-Analyzer. Urinary cyclic AMP excretion was as sayed with a kit (Radiochemical Centre, Amersham, UK). Serum immunoreactive parathyroid hormone (iPTH) was measured with a PTH-MM antibody (Immunonuclear Corporation, Stillwater, Minn., USA). Serum levels of 25(OH)D, 24,25(OH)2D and l,25(OH)2D were measured as described elsewhere [3,4].
178
Results Baseline Data Figure 2 summarizes the relevant biochemical data in all immediate family members, including the patients, before treatment. Since TmP/GFR, serum phosphorus levels and alkaline phosphatase activity vary with age, these data are presented as means denoted by zero ± S D of the normal range for age [16]. As can be seen, the two patients present ed significant hypophosphatemia, decreased Tm P/G FR , elevated serum alkaline phosphatase activity of bone origin and hypercalciuria. Urinary cyclic AMP excretion, as well as serum immunoreactive parathyroid hormone levels (21.6 ±3.7 pmol/1), were slightly below the normal range in the patients (normal range: 1.5-4.3 nmol/100 ml GF, and 29-85 pmol/I for cyclic AMP and iPTH, respecti-
Tieder/A rie/Bab/M aor/Liberm an
Hereditary H ypophosphatém ie Rickets with Hypercalciuria
Downloaded by: UCL 144.82.238.225 - 2/6/2018 10:06:26 AM
formed using a computerized digitizing system. Quantitation of the tetracycline labelling was done with a Merz grid. The separation between double labels (dynamic measurements) was measured with a calibrated eyepiece micrometer.
The osteoid volume (OV/BV) was fivefold higher than normal, reflecting respective increases in bone osteoid surface (OS/BS) and osteoid thickness (O/Th). The double-labelled surface (dLS/BS) and bone formation rate (BFR/BS) showed an approximately 50% decrease and the mineralization lag time (MLT) a twofold prolon gation. These values, in particular the increased MLT and number of osteoid lamellae, indicate a mineralization defect the extent of which is similar to that found in our other patients with H H RH as well as in patients with X LH [15]. Response to Therapy The two patients were subsequently treated with neutral phosphate only, 2 g of elemental phosphorus given orally in 5 divided daily doses. This treatment has continued for 3 years. Bone pain disappeared and muscular strenght im proved markedly within several weeks. Radiological signs of rickets disappeared completely after 4-5 months of treat ment. A marked liner growth acceleration of 13.2 and 7.2 cm per year in patients C.R. and C. H., respectively, was doc umented. The biochemical data obtained before and during the administration of oral phosphate are shown in table 1. Serum phosphorus levels increased towards normal (measurements during treatment were performed in the fasting state, 2 h after the 1st dose of neutral phosphate). Serum concentrations of l,25(OH)2D and 24-hour urinary calcium excretion returned to the normal range. A small but significant drop in serum calcium levels was observed, as well as an increase in urinary cyclic AMP excretion. Serum alkaline phosphatase declined within normal limits, con currently with the disappearance of radiological signs of rickets. TmP/GFR, however, remained unchanged.
Discussion The diagnosis of HHRH in these patients is based on the following: (a) Familial occurrence of rickets and osteoma lacia; (b) The characteristic biochemical features, i.e., de creased renal tubular phosphate reabsorption, hypophos phatemia, elevated l,25(OH)2D serum levels, increased gas trointestinal calcium and phosphorus absorption and hypercalciuria; (c) Complete remission of the disease on inorganic phosphate therapy alone. As suggested before [3, 4], we believe that in HHRH, there is a primary hereditary renal tubular defect in phos phate reabsorption leading to hypophosphatemia, that, on one hand, if severe enough will cause defective mineraliza-
179
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tively). Serum concentrations of 25(OH)D and 24,25(OH)2D were normal (data not shown), but serum levels of l,25(OH)2D were significantly elevated in the patients. In 2 members of the family (fig. 1, mother, 11-6, and brother, III-3), all biochemical data were within the nor mal range, while in the other 2 (fig. 1, father, II-5, and sister, III-4), a significant hypercalciuria was documented. Hypercalciuria was defined as a urinary calcium excretion exceeding 0.1 mmol/kg body weight (4 mg/kg body weight) per 24 h, or a calcium/creatinine ratio of 0.65 mmol/mmol (0.23 mg/mg). Though all other biochemical parameters were within the normal range, it is worth noting that serum phosphorus levels and the Tm P/GFR tended to be in the low normal range while serum l,25(OH):D concentrations were in the high normal range in these two hypercalciuric subjects (fig. 2). Serum calcium levels, renal creatinine clearance and tubular functions, as well as liver function tests, protein electrophoresis, immunoelectrophoresis and a complete hematological workup were all within the normal range in the patients and their relatives. After a 12-hour overnight fast, the urinary calcium/cre atinine ratio of the patients remained elevated, at 1.04±0.34 mmol/mmol (0.37±0.12 m g/m g; m ean±SD ), normal below 0.31 m m ol/m mol (0.11 mg/mg); but it fell to the normal range after an additional 3-hour fast (0.25±0.03 m m ol/m m ol; 0.09±0.01 mg/mg). With an oral calcium load, the increments in urinary calcium/creatinine ratio in the two patients were 1.05 ±0.28 mmol/mmol (0.37 ±0.10 mg/mg, mean ± SD), as compared to 0.34±0.06 mmol/m mol (0.12± 0.02 m g/ mg) in 99 normal controls. Simultaneously, mean serum calcium levels rose abnormally by 0.18 ±0.13 mmol/1 (0.74 ±0.53 m g/dl) in the patients, as compared with 0.11 ±0.01 mmol/1 (0.43 ±0.05 m g/dl) in normal controls. The maximal increment in the mean serum phosphorus level after an oral phosphate load was 1.79 ±0.21 mmol/1 (5.55 ±0.64 m g/dl) in the patients, as compared with 0.39 ±0.06 mmol/1 (1.20 ±0.20 m g/dl) in normal controls. The bone biopsy specimen showed decreased trabecu lar density with small, rounded trabecular cross-sectional profiles. There was an apparent osteoid component, lining most of the trabecular surfaces. In several instances, the number of osteoid lamellae was increased to a maximum of 8, a figure consistent with a mineralization defect [15], Osteoblasts and osteoclasts were fewer than normal. This appearance was expressed in the histomorphometric re sults. The trabecular bone volume (B V/TV) was two thirds the normal. The other parameters showed values similar to those reported recently in children with HHRH [15].
Table 1. Bio chemical measure ments before and during phosphate treatment in 2 patients with HHRH
Before treatment
Measurement
No. of deter minations
During treatment11
No. of deter minations
p value
Fasting serum levels Calcium, mmol/l Phosphorus, mmol/l Alkaline phosphatase, IU/I 1.25 (OH) ,D. pmol/l TmP/GFR, mmol/l
2.3910.04 0.9010.04 14921554 252174 0.7910.12
4 4 4 3 4
2.29 + 0.04 1.2910.1.3 4861194 6415 0.8210.27
4 4 4 2 6
p
