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Division of Endocrinology (O.M., S.W.K., E.S.), Diagnostic Imaging (A.Do., A.Da.), and Orthopedic Surgery (W.G.C.), The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8
Address all correspondence and requests for reprints to: Outi Mäkitie, M.D., Ph.D., Division of Endocrinology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. E-mail: outi.makitie{at}helsinki.fi.
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Abstract |
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1.0 yr). The median height z-score was higher in group 1 (n = 8) than in group 2 (n = 11) at treatment onset [-0.4 SD score (SDS) vs. -1.7 SDS; P = 0.001], at the end of the first treatment year (-0.7 SDS vs. -1.8 SDS; P = 0.009), throughout childhood (P > 0.05) and until predicted adult height (-0.2 SDS vs. -1.2 SDS; P = 0.06). The degree of hypophosphatemia was similar in both groups, but serum alkaline phosphatase remained higher in group 2 throughout childhood. Radiographic signs of rickets were more marked in group 2, but even patients with early treatment developed significant skeletal changes of rickets. These data suggest that treatment commenced in early infancy results in improved outcome in patients with XLH, but does not completely normalize skeletal development. |
Introduction |
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Conventional therapy with 1,25-(OH)2D3 or 1
-OH D3 and Pi has been shown to result in improved growth and healing of rickets in patients with XLH (4, 5, 6, 7). However, despite improved blood biochemistry, the growth response may be unsatisfactory, and some patients remain unresponsive (4, 8). In XLH significant deceleration of growth occurs during the first 2 yr of life when, before the diagnosis and onset of treatment, affected children develop skeletal signs of rickets (9, 10). Therefore, initiation of treatment during early infancy, before overt manifestation of rickets and growth retardation, would be expected to result in improved height gain compared with the effect of treatment commenced at a later time. Anecdotal case reports are indeed suggestive of this (11, 12, 13), but no long-term studies to final height have previously been published.
To examine this hypothesis we have therefore retrospectively analyzed growth data, biochemistry, and radiological findings in eight patients with XLH who, because of a positive family history, were diagnosed during early infancy and commenced on Pi-1,25-(OH)2D3 treatment before 1 yr of age. Compared with the data for patients with later onset of treatment, early treatment resulted in improved height outcome at all stages of growth, with somewhat milder x-ray changes in disease activity and improved biochemistry, and without an increased rate of treatment-related complications.
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Subjects and Methods |
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Patients were studied every 3 months at a specialized metabolic bone clinic, mostly by the same staff physician (S.W.K.; >90% of all clinic visits), for compliance, growth, deformities, biochemical status, and possible complications of the treatment. Compliance was assessed by family interview by the clinic nurse and physician at each visit. Serum levels of calcium, Pi, ALP, and PTH were obtained every 3 or 6 months. Treatment consisted of oral Pi (divided into four or five daily doses) and 1,25-(OH)2D3 (divided into one or two daily doses). The doses were adjusted individually; the goals of treatment were to normalize growth and radiographic changes, to prevent deformities and nephrocalcinosis, and to maintain blood biochemistry as close to normal as possible. As the dose adjustments were made by one clinician, the treatment protocol was uniform for all patients.
Of the 24 patients identified with XLH, 19 were included in the study, and five were excluded because of noncompliance (3), inadequate follow-up data (1), or inadequate length of treatment (1). Patients were divided into two groups based on age at treatment onset. Group 1 comprised patients who were diagnosed before development of clinically manifest rickets on the basis of positive family history and biochemistry; their treatment onset was always before age 1.0 yr. Group 2 consisted of patients who presented after development of clinical signs of rickets, and their treatment onset was at 1.0 yr of age or later.
All available growth data were collected from the hospital records. Individual growth curves were drawn using these data. Heights at every half and full year were interpolated (only if the interval between two measurements was <18 months); this interpolated data were used only to evaluate prepubertal growth after the first treatment year. Final height was determined as height after age 16.0 yr (girls) or 18.0 yr (boys) when height velocity was less than 1.0 cm/yr. All measurements were transformed into z-scores [SD scores (SDS)] by comparing them with age- and sex-specific norms for healthy children (15). The height z-scores for boys and girls were combined to allow for comparison between groups 1 and 2. One patient in group 2 (no. 19, Table 1
) had been treated with recombinant human GH for 1 yr (from age 9.9–10.9 yr). During this time she remained prepubertal; her height velocity was 5.7 cm/yr before the treatment, 8.2 cm/yr during the treatment, and 5.6 cm/yr during the following year. Only pre- or post-GH treatment measurements were used for the present analysis.
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The activity of rickets was estimated on the basis of radiographic appearance of the distal metaphysis at radius and ulna, metacarpals and phalanges, and/or distal femur and proximal tibia at diagnosis, at the end of first treatment year, and at the latest prepubertal time point available for analysis. The x-ray films were reviewed independently by two pediatric radiologists (A.Do. and A.Da.) who were blinded for the patient’s age at treatment onset. The degree of rickets was graded (in ascending order of severity) as normal, normal/mild, mild, mild/moderate, moderate, moderate/severe, or severe rickets. For statistical analysis, these seven grades of severity were given a numeric value ranging from 0 (normal) to 6 (severe). The criteria for mild rickets were 1) shallow cupping/fraying of only one of the long bones, or 2) shallow cupping/fraying of both long bone (radius + ulna/femur + tibia) without other positive findings, or 3) widening of growth plates, or 4) mild tunneling of metacarpals, or 5) cupping of long bones plus improved ossification of the metaphysis of the long bones. Moderate rickets was characterized by 1) severe tunneling of metacarpals, 2) slight deformity of long bones, and/or 3) deeper cupping/fraying of both long bones with other positive findings (e.g. widening of growth plates). The criteria for severe rickets were 1) acrosteolysis, 2) periosteal resorption, 3) severe deformity of long bones, and/or 4) pathological fracture. Wrist/hand and knee x-rays were reviewed at each time point (41 occasions); only wrist x-rays were available on 3 and only knee x-rays on 2 occasions. When the degree of severity of rickets at wrists/hands and that at knees differed, the more severe grading was used for analyses.
Bone age films were read independently by a pediatric radiologist (A.Do.) and a pediatric endocrinologist (E.S.) according to the Greulich-Pyle method (17). Only bone age radiographs obtained after age 9.0 yr (9.1 - 15.7 yr; mean, 12.8 yr) were used to calculate predicted adult heights (PAH) according to the Bayley-Pinneau method (18). For discordant readings the mean of PAHs based on the two readings was used.
Simple regression analysis and t test (StatView 4.51 for Macintosh, Abacus Concepts, Inc., Berkley, CA) were used for statistical analyses. P < 0.05 was considered statistically significant.
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Results |
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). Growth
At treatment onset, patients in group 2 had significantly lower height z-scores than patients in group 1, and the difference between the two groups persisted throughout the prepubertal growth period. At treatment onset, the median height z-score was -0.4 SDS (range, -0.9 to +0.7 SDS) for group 1 and -1.7 SDS (-3.4 to -0.2 SDS) for group 2 (P = 0.001; Table 1 and Fig. 1). At the end of the first year of treatment, the height z-score remained essentially unchanged (defined as a change from treatment onset, -0.3 to +0.3 SDS) in three and seven patients. It decreased by more than 0.3 SDS in four and three patients in groups 1 and 2, respectively. Only one patient in each group showed catch-up growth (change from treatment onset, >0.3 SDS). The mean change in height SDS during the first treatment year for group 1 was -0.5 SDS, and that for group 2 was -0.2 SDS (P = 0.4). At the end of the first treatment year, the height z-score was still significantly higher in group 1 (median, -0.7 SDS) than in group 2 (median, -1.8 SDS; P = 0.009), and this difference, although no longer statistically significant, persisted throughout the prepubertal years (median, 9.0 yr -1.3 SDS and -2.0 SDS; P = 0.054; Table 1 and Fig. 1). The mean change in height z-score after the first treatment year until age 9.0 yr was -0.3 SDS in group 1 and -0.5 SDS in group 2.
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), we used PAHs in all patients to compare adult height outcome between the groups. The median PAH for group 1 was -0.2 SDS (-1.4 to +0.4 SDS), and that for group 2 was -1.2 SDS (-3.7 to -0.3 SDS; P = 0.06; Table 2 and Fig. 1).
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). The height z-score after the first year of treatment correlated significantly with the height z-scores at 9.0 yr (r = 0.89; P < 0.0001) and at adulthood (PAH; r = 0.66; P = 0.017; Fig. 3).
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All patients were hypophosphatemic at diagnosis, and the degree of its severity was similar in both groups; the median S-Pi z-score for group 1 was -3.3 SDS, and that for group 2 was -3.5 SDS. By the end of the first treatment year the improvement in the S-Pi z-score was greater in group 1 (mean change, +2.2 SDS) than in group 2 (mean change, +0.8 SDS; P = 0.005), and S-Pi had normalized in six of eight patients in group 1 (median, -1.5 SDS), but in only 1 of 11 patients in group 2 (median, -3.0 SDS; P > 0.05). This change in S-Pi z-score was independent of the dose of oral Pi in both groups (r = 0.4; P > 0.05). Prepubertally (at a median age of 10.8 yr) most patients were hypophosphatemic (median S-Pi z-score, -2.6 SDS and -2.5 SDS in groups 1 and 2, respectively; Table 3).
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). The age at diagnosis significantly correlated with S-ALP (but not with S-Pi) z-score at diagnosis (r = 0.63; P = 0.005): the later the diagnosis, the higher the S-ALP z-score. Further, the earlier the treatment onset, the more significant the improvement in S-ALP z-score during the first treatment year (r = -0.63; P = 0.004). The change in height z-score during the first treatment year did not correlate with S-Pi and S-ALP z-scores or with their changes, but negatively correlated with the oral Pi dose (r = -0.47; P = 0.04); patients with a high Pi dose (>100 mg/kg·d; n = 6) tended to grow less (mean change, -0.5 SDS) than patients treated with lower doses (mean change, -0.2 SDS; P > 0.05) during the first year of treatment.
Radiographic findings
At treatment onset the patients in group 1 had milder rickets compared with those in group 2; the median score for the severity of rickets was 2.0 ± 0.3 (±SE) for group 1 (mild) and 4.5 ± 0.3 for group 2 (between moderate and moderate/severe; P = 0.0002; Table 4). At the end of the first treatment year the median score for group 1 was unchanged, and it improved to 4.0 ± 0.4 in group 2 (P = 0.052). At prepuberty (median age, 10.4 yr; range, 8.6–12.0 yr), the median scores were 4.0 ± 0.5 and 5.0 ± 0.7 for groups 1 and 2, respectively (P = 0.27; Table 4).
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The z-score for S-ALP correlated with the severity of rickets at the end of the first treatment year (r = 0.57; P = 0.015) and at prepuberty (r = 0.61; P = 0.019), but not at treatment onset (r = 0.47; P = 0.076). No correlations were found between the degrees of hypophosphatemia and rickets.
Complications
There were no significant differences in the rate of complications between the two groups; secondary hyperparathyroidism was observed in seven and 11 patients and nephrocalcinosis in six and five patients in groups 1 and 2, respectively. In one patient in each group the secondary hyperparathyroidism later developed into tertiary hyperparathyroidism (at age 15 and 16 yr, after final height had been achieved). In group 1, one patient had been operated on for varus deformity and one for craniosynostosis. In group 2, one patient was operated on for both varus deformity and craniosynostosis.
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Discussion |
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-hydroxyvitamin D3 and inorganic oral Pi salts increases the S-Pi concentration, normalizes other biochemical parameters, and results in healing of rickets and correction of deformities (5, 6, 19, 20). The impact of the treatment on growth and final adult height remains controversial; some studies have shown improved final heights, but in others no such beneficial effect has been observed (5, 7, 10, 21). Children with XLH have normal length at birth and show increasing growth retardation during the first years of life (9, 10, 22, 23). As the pubertal growth spurt in patients with XLH appears to be normal (10, 24), it is probable that most of the height deficit in treated patients results from the height loss before diagnosis and treatment onset. Anecdotal case reports suggest that initiation of therapy in infancy, before the development of severe growth deficit and manifest rickets, may lead to more satisfactory results than treatment commenced later (11, 12, 13). Lapatsanis et al. (12) reported two children who were treated from age 6 wk; their heights at the ages of 26 and 60 months were just below the 50th percentile, and the rachitic lesions in x-rays remained absent or were mild. In another study, of the eight infants who commenced treatment at or before age 3 months, two showed a decline in height below the third percentile, whereas the other six remained within normal range (13). These patients showed only mild radiographic signs of rickets, and none presented with severe leg deformities. The median duration of follow-up, however, in this study was only 27 months (13). Although these results suggest beneficial effects of early treatment, no long-term follow-up data have previously been available.
In the present study we have retrospectively evaluated the impact of early treatment, commenced during the first year of life (median, 0.35 yr), on growth, disease activity, and complications in 8 XLH patients and compared their data with those of 11 patients with later onset of treatment (median age, 2.1 yr). These treatment groups differed in gender ratio; males were overrepresented in the early treatment group and females in the group with later treatment onset. Although earlier reports suggested that males would be more severely affected than females (25), more detailed studies have failed to show such a gene dose effect in XLH (26). The overall gender ratio (12 females/7 males) in the present study was close to that expected in an X-linked dominant condition (2:1); the gender difference between the two groups was thus merely coincidental and did not influence the interpretation of the results.
Overall, the later the diagnosis of XLH, the more severe the growth deficit and radiographic appearance of rickets, and the higher the S-ALP at diagnosis. Patients who were diagnosed during the first year of life had only subtle clinical and radiological evidence of rickets, and the height was in each case normal (greater than -1.0 SDS; median height z-score, -0.4 SDS). In contrast, many of the patients with late diagnosis presented with some degree of growth deficit (median height z-score, -1.7 SDS), and all had moderate to severe radiographic evidence of rickets. Based on previous reports of normal length at birth and progressive growth retardation during the first years of life in untreated children with XLH (9, 10, 22, 23), it is likely that the difference in median height between our two groups at treatment onset was due to the prolonged period of pretreatment growth disturbance in late treated subjects rather than to any inherent difference in the two groups.
The growth response during the first treatment year was unsatisfactory in most cases. Only two patients, one in each group, demonstrated significant catch-up growth, defined here as a change or more than 0.3 SDS in height z-score. The height z-score decreased by more than 0.3 SDS in half of the patients in the early treatment group, whereas patients in the late treatment group tended to retain their height z-scores. This suggests that even very early commencement of treatment does not completely prevent height loss during the rapid growth period of the first year of life.
Overall there was a very significant correlation (r = 0.89; P < 0.0001) between the height z-scores after the first treatment year and at age 9.0 yr, suggesting that no further catch-up or deterioration of growth occurs after the first treatment year. After the first treatment year and throughout the prepubertal period, shorter stature in the late treated group appears to be explained by the cumulative growth deficit before treatment onset compounded by poor catch-up growth. Patients with early commencement of treatment also tended to have better PAHs than patients with later onset of treatment. The PAH z-score was -2.0 SDS or less in none of the patients in the early treatment group, but in two of six patients in the late treatment group; the median PAH z-scores for the two groups were -0.2 and -1.2 SDS, respectively. In patients who had reached their final heights, the PAHs were accurate and within 2–3 cm of the final heights. Based on this, it is probable that the more favorable height outcome in the early treatment group, compared with the late treatment group, will persist until final height.
The degree of hypophosphatemia at diagnosis was similar in both treatment groups. Patients who commenced treatment early had a tendency to normalize low S-Pi and high S-ALP, whereas in the other group these biochemical parameters remained practically unchanged during the first treatment year. It is therefore not surprising that the radiographic healing of rickets in group 2 was unsatisfactory, and most patients had moderate signs of rickets even after 1 yr of treatment. In group 1 the radiographic findings remained usually unchanged and were therefore milder than in group 2 even at the end of the first treatment year.
At the onset of puberty the degree of hypophosphatemia was similar in the two groups, but only the patients in the late treatment group tended to have increased S-ALP levels. It is possible that the development of severe rickets initially leads to permanent disturbance in growth plate development, and therefore S-ALP does not normalize even with proper treatment. Surprisingly, the radiographic signs of rickets were moderate to severe in almost all patients at prepuberty regardless of the age at treatment commencement. As compliance in both groups was considered satisfactory, this finding suggests that the presently used Pi-1,25-(OH)2D3 treatment does not completely normalize bone metabolism in XLH, and better, more targeted treatment is needed to achieve full clinical, biochemical, and radiological recovery.
In conclusion, the present study shows that in patients with XLH commencement of oral Pi-1,25-(OH)2D3 therapy in early infancy before the development of significant growth retardation and rickets results in improved height outcome and decreased disease activity compared with commencement of treatment later. To introduce the treatment early enough, the offspring of affected parents should be followed carefully during the first 3 months of life. The diagnosis of XLH in infancy can be based, in addition to positive family history, on hypophosphatemia and increased S-ALP, which are usually evident before age 3 months (Refs. 13 and 14 and this study); decreased tubular reabsorption of phosphate and x-ray changes should not be required for early diagnosis (14). Mutational analysis provides the most accurate and rapid diagnostic test, especially in families with already identified PHEX mutation. Increased awareness of XLH and more active biochemical screening for hypophosphatemia in children with impaired growth are needed for earlier recognition of patients with no known family history for XLH.
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Footnotes |
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Abbreviations: ALP, Alkaline phosphatase; 1,25-(OH)2D3, 1,25-dihydroxyvitamin D3; PAH, predicted adult height; Pi, phosphate; S-, serum level; SDS, SD score; XLH, X-linked hypophosphatemic rickets.
Received January 8, 2003.
Accepted May 9, 2003.
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References |
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-hydroxylase activity in the X-linked hypophosphatemic mouse. J Clin Invest 71:400–403
-hydroxyvitamin D3. J Pediatr 99:16–25[CrossRef][Medline]
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) and group 2 (
) at treatment onset, at the end of first treatment year, at age 9.0 yr, and at final height (adult height or PAH). The bottom of each box indicates the first, the cross line indicates the second (median), and the top indicates the third quartile; the bottom and top lines indicate the minimum and maximum values. P values refer to the difference between groups 1 and 2. Rx, Treatment.
, group 2).