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Effects of Growth Hormone Treatment on Body Proportions and Final Height
Among Small Children With X-Linked Hypophosphatemic Rickets
Dieter Haffner, Richard Nissel, Elke Wühl and Otto Mehls
Pediatrics 2004;113;e593
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2004 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org by guest on September 9, 2014
Effects of Growth Hormone Treatment on Body Proportions and Final
Height Among Small Children With X-Linked Hypophosphatemic Rickets
Dieter Haffner, MD*; Richard Nissel, MD*; Elke Wu¨hl, MD‡; and Otto Mehls, MD‡
ABSTRACT. Background. X-linked hypophosphatemic
rickets (XLH) is characterized by rickets, disproportionate short stature, and impaired renal phosphate reabsorption and vitamin D metabolism. Despite oral phosphate
and vitamin D treatment, most children with XLH demonstrate reduced adult height.
Objective. To determine the beneficial effects of recombinant human growth hormone (rhGH) therapy on
body proportions and adult height among patients with
XLH.
Methods. Three initially prepubertal short children
(age, 9.4 –12.9 years) with XLH were treated with rhGH
for 3.1 to 6.3 years until adult height was attained.
Results. rhGH treatment led to sustained increases in
standardized height for all children. The median adult
height was 0.9 SD (range: 0.5–1.3 SD) greater than that at
the initiation of rhGH treatment and exceeded the predicted adult height by 6.2 cm (range: 5.3–9.8 cm). However, longitudinal growth of the trunk was stimulated
more than leg growth. During rhGH treatment, the standardized sitting height increased by 1.6 SD (range: 1.1–
2.7 SD), compared with baseline values. In contrast, the
median subischial leg length did not change consistently
(median change: 0.3 SD; range: ⴚ0.1 to 0.6 SD).
Conclusion. The increase in final height after rhGH
treatment is of potential benefit for children with XLH.
However, the exaggeration of disproportionate truncal
growth observed for our prepubertal patients is a potential negative effect of treatment and should be confirmed
with additional studies. Pediatrics 2004;113:e593–e596.
URL: http://www.pediatrics.org/cgi/content/full/113/
6/e593; growth hormone treatment, hypophosphatemic
rickets, growth failure, disproportionate growth, final
height.
ABBREVIATIONS. XLH, X-linked hypophosphatemic rickets;
GH, growth hormone; rhGH, recombinant human growth
hormone.
X
-linked hypophosphatemic rickets (XLH) is an
inherited disorder of phosphate homeostasis
characterized by disproportionate short stature, rickets and osteomalacia, hypophosphatemia,
aberrant phosphate reabsorption, and disturbance of
vitamin D metabolism.1 XLH is caused by mutations
From the *Department of Pediatric Nephrology, University Hospital
Charite´, Berlin, Germany; and ‡Division of Pediatric Nephrology, University Children’s Hospital, Heidelberg, Germany.
Received for publication Jun 4, 2003; accepted Dec 29, 2003.
Address correspondence to Otto Mehls, MD, Division of Pediatric Nephrology, University Children’s Hospital Heidelberg, Im Neuenheimer Feld 150,
69120 Heidelberg, Germany. E-mail: [email protected]
PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Academy of Pediatrics.
in the PHEX gene, encoding a membrane-bound endopeptidase. PHEX is expressed in bones and teeth
but not in kidney, and efforts are underway to elucidate how PHEX function relates to the mutant phenotype.2
Pharmacologic treatment consists of oral phosphate supplementation and calcitriol administration.
Although this therapy usually leads to an improvement of rickets, the effects on longitudinal growth
are often disappointing.3 Despite adequate phosphate and calcitriol treatment, most previous studies
reported reduced adult height among children with
XLH.4–7 In addition, children with XLH present with
disproportionate growth, ie, relatively preserved
trunk growth but severely diminished leg growth.8
Previous studies demonstrated that treatment with
recombinant human growth hormone (rhGH) was
able to improve short- and long-term longitudinal
growth among small children with XLH.9–15 However, we and others11,12 noted that short-term rhGH
treatment could aggravate disproportionate growth
among these children. Here we report the effects of
long-term rhGH treatment on longitudinal growth
and body proportions among 3 initially prepubertal,
short children with XLH who were prospectively
monitored after the initiation of rhGH treatment,
until their final heights were achieved.
PATIENTS AND METHODS
Three short prepubertal children with XLH, with ages of 12.9
years (patient 1), 9.4 years (patient 2), and 11.1 years (patient 3),
began to receive rhGH treatment. Patient 1 was female, and patients 2 and 3 were male siblings. At the time of diagnosis, all
patients fulfilled the clinical, biochemical, and radiologic criteria
for diagnosis of the disease.1 In each case, X-linked dominant
inheritance was confirmed by analysis of the pedigrees. The children had been treated with calcitriol and phosphate supplements
for at least 5 years. They had prescriptions of fixed individual
doses of calcitriol (1–1.5 ␮g/day) and oral phosphate supplementation (0.8 –2.1 g/day) during the year before rhGH treatment. The
individual prescriptions were not changed during the study period. Growth hormone (GH) deficiency was excluded with GH
stimulation tests with l-arginine (peak serum GH concentration of
⬎10 ␮g/L) and normal night serum GH concentration profiles (⬎2
peaks of ⬎10 ␮g/L). rhGH (0.33 mg/kg per week) was administered daily, in the evening, as subcutaneous injections.
Anthropometric measurements were performed at 3-month intervals, with standard techniques.16 For calculations of age- and
gender-related SD scores, the first Zurich longitudinal study was
used as a reference.17 SD values for sitting height and subischial
leg length were used to evaluate disproportionate growth. Bone
age was assessed at yearly intervals with the method described by
Greulich and Pyle.18 Pubertal stage was assessed according to the
method described by Tanner.19 Predicted adult height was calculated from the patient’s height and bone age by the method
described by Bayley and Pinneau.20 Final (adult) height was de-
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PEDIATRICS Vol. 113 No. 6 June 2004
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e593
fined as epiphysial closure on hand radiographs and/or a height
increase of ⬍1 cm/year in the preceding year. The laboratory
methods used were described elsewhere.11 Ultrasonographic imaging of the kidneys was performed at yearly intervals. The study
protocol was approved by the ethics committee of the University
of Heidelberg, and written informed consent was obtained from
the parents, with assent by the patients.
RESULTS
For each of the 3 patients, rhGH treatment led to a
sustained increase in standardized height (Fig. 1).
The median adult height was 0.9 SD (range: 0.5–1.3
SD) greater than that at the initiation of rhGH treatment, exceeded the predicted adult height by 6.2 cm
(range: 5.3–9.8 cm), and was close to the genetic
target height for 2 of the 3 patients (median difference: ⫺3.8 cm; range: ⫺13.4 to 0.1 cm) (Table 1). At
baseline, trunk growth was more preserved than leg
growth. During rhGH treatment, the standardized
sitting height continuously increased for all patients
(Fig. 1). At the final height, the median sitting height
was increased by 1.6 SD (range: 1.1–2.7 SD), compared with baseline values. In contrast, the median
subischial leg length did not change consistently
(median change: 0.3 SD; range: ⫺0.1 to 0.6 SD). During rhGH treatment, there was no obvious change in
the degree of bowing of the legs. The median distance between the medial condylars of the tibia was
5.8 cm (range: 4.3–7.6 cm) at baseline and was 6.3 cm
(range: 5.2– 8.7 cm) at the final height.
During the first 6 months of rhGH treatment, a
transient increase in the renal tubular maximal reabsorption of phosphate, relative to the glomerular filtration rate, from 0.53 mmol/L (range: 0.43– 0.58
mmol/L) to 0.67 mmol/L (range: 0.52– 0.69 mmol/L)
and a concomitant increase in serum phosphate levels from 0.7 mmol/L (range: 0.5– 0.8 mmol/L) to 0.9
mmol/L (range: 0.7–1.1 mmol/L) were noted. In addition, serum intact parathyroid hormone concentrations transiently increased above the upper normal
limit of 6 pmol/L. During rhGH treatment, there
were no changes in creatinine clearance, urinary calcium and phosphate excretion, serum glucose levels,
or the degree of nephrocalcinosis on renal ultrasonograms, which was noted for 2 of 3 patients at baseline
(data not shown).
DISCUSSION
Our study provides evidence that rhGH treatment
improves longitudinal growth and final height
among small prepubertal children with XLH. Before
the initiation of rhGH treatment, the children pre-
TABLE 1.
Anthropometric Characteristics of rhGH-Treated
Children with XLH
Gender
Age at baseline* (y)
Bone age at baseline* (y)
Height at baseline* (SD)
Subischial leg length at
baseline* (SD)
Sitting height at baseline* (SD)
Genetic target height (cm)
Genetic target height (SD)
Predicted adult height at
baseline* (cm)
Predicted adult height at
baseline* (SD)
Duration of rhGH treatment (y)
Age at adult height (y)
Adult height (cm)
Adult height (SD)
Subischial leg length at adult
height (SD)
Sitting height at adult
height (SD)
Patient
1
Patient
2
Patient
3
Female
12.9
11.4
⫺2.1
⫺2.3
Male
9.4
8.0
⫺2.0
⫺2.2
Male
11.1
9.0
⫺2.0
⫺2.3
⫺1.5
170.5
1.0
147.3
⫺1.6
166.8
⫺1.6
156.8
⫺1.4
166.8
⫺1.6
161.6
⫺2.9
⫺3.1
⫺2.4
3.1
16.0
157.1
⫺1.2
⫺1.7
5.6
15.0
163.0
⫺0.7
⫺2.3
6.3
17.4
166.9
⫺1.5
⫺2.0
0.1
1.1
⫺0.3
* Time of initiation of rhGH treatment.
sented with body disproportion, ie, short legs and
relatively preserved trunk growth. For all children,
rhGH therapy predominantly stimulated trunk
growth, whereas leg growth was stimulated less,
thereby increasing the preexisting body disproportion.
Despite early positive reports of short-term studies, previous long-term studies of children with XLH
could not demonstrate sustained catch-up growth
during calcitriol and phosphate treatment.3,5 In the
present study, vitamin D and phosphate administration was not changed during the observation period.
In addition, metabolic control with respect to serum
levels of phosphate, parathyroid hormone, and alkaline phosphatase did not change with time. However, the final height was 5 to 10 cm greater than the
predicted adult height for our patients. It has been
demonstrated that height prediction for children
with XLH is quite accurate and might actually overestimate adult height for these children.5 Therefore,
we assume that rhGH treatment increased the adult
height for our patients. However, crucial methodologic factors in this study were the small number of
patients and the lack of a control group.
Several clinical trials (mostly uncontrolled) on the
effect of rhGH treatment on longitudinal growth
Fig. 1. Effects of rhGH treatment on standardized height, sitting height, and subischial leg length for three children with XLH.
e594
GH TREATMENT IN XLH
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among short children with XLH have been reported.9–15 The patients were treated for periods of 0.5 to
9 years, with rhGH doses of 0.15 to 0.56 mg/kg per
week. The median increase in standardized height
amounted to 1.2 SD (range: 0.7–1.4). Baroncelli et al15
recently reported final height data for 6 children with
XLH who were treated with rhGH for up to 9 years.
Whereas the mean standardized height increased by
1.0 SD at the final height for the rhGH-treated children, the standardized height did not change significantly in the control group.
It is unclear whether rhGH therapy affects the
onset or duration of the pubertal growth spurt
among children with XLH. Among children with
XLH without rhGH treatment, a pubertal growth
spurt of normal magnitude has been observed.5 In a
previous study of rhGH treatment of children with
XLH, longitudinal growth was stimulated mainly
during the prepubertal growth period, whereas the
standardized height during the pubertal growth period even decreased.15 In accordance with this finding, 2 of our patients demonstrated a slight decrease
in standardized height after 3 years of rhGH treatment during the pubertal growth period. These observations suggest that the expected increase in final
height during the prepubertal growth period might
be counterbalanced partly by decreased pubertal
growth.
Why patients with XLH demonstrate disproportionate growth is not fully understood. Various skeletal abnormalities have been demonstrated in an animal model of XLH, ie, Hyp mice.21,22 In addition to
rickets and osteomalacia, Hyp mice exhibit craniosynostosis because of premature fusion of the coronal suture and abnormal skull morphology, with
deficient linear growth of the nasal bone. It has been
assumed that the abnormal bone formation in Hyp
mice is determined not only by hypophosphatemia
but also by an intrinsic osteoblast defect in the mutant strain.23 In view of an underlying osteoblast
defect among patients with XLH, the predominant
involvement of the lower limbs, compared with
lesser involvement of the spine, might be attributable
partly to the greater mechanical stress of the legs,
compared with the spine, and/or to a differential
pattern of organ-specific activation of PHEX within
the skeleton.24
Phosphate and vitamin D treatment fails to normalize body proportions among children with XLH.8
In vitro studies showed that bone formation in bone
cells from Hyp mice was only partly normalized
with high-dose 1,25-dihydroxy-vitamin D3 treatment.23 In the present study, rhGH treatment preferentially stimulated trunk growth rather than leg
growth, thereby aggravating the preexisting body
disproportion. This was not explained by increased
bowing of the legs.11 Body proportions have been
measured in only 3 previous studies of children with
XLH treated with rhGH.11,12,15 In accordance with
our study, Reusz et al12 reported an increase in body
disproportion among children treated with rhGH for
1 year. In contrast, Baroncelli et al15 did not observe
changes in body proportions for 6 children treated
with rhGH until final height. It is important to note
that the patients reported in those studies differed
significantly with respect to the degree of stunting at
the initiation of rhGH therapy. The median standardized height at baseline was ⫺2.0 SD in the present
study and was ⫺3.4 SD in the Italian study, which
used the old reference values of Tanner,19 thereby
underestimating the degree of stunting by at least 0.5
SD, compared with more recent standards.17 Therefore, the conflicting results might be influenced
partly by differences in stunting, ie, severity of the
disease.
Recent studies indicate that in various forms of
short stature, eg, uremic growth failure, longitudinal
growth of the lower limbs is generally more affected
than trunk growth, leading to body disproportion.25
It has been speculated that this is attributable to the
vital need of the body to maintain the function of the
internal organs within the trunk. rhGH therapy
among short children with chronic renal failure has
been shown to improve body disproportion.25 The
finding that this is not the case for patients with XLH
suggests that, in this particular disease, the underlying osteoblast defect might be more evident in the
long bones of the legs than in the vertebrae.
When these findings are taken together, it is tempting to speculate that the growth-stimulating properties of rhGH only partly overcome the underlying
osteoblast defect in XLH, thereby preferentially stimulating the less diseased part of the skeleton. Unfortunately, data on the effect of rhGH on bone formation in Hyp mice are lacking.
It has been speculated that the growth-stimulating
effect of rhGH in XLH might be attributable to increased renal phosphate reabsorption, promoting
bone formation. In accordance with this hypothesis,
Baroncelli et al15 reported a sustained increase in the
renal phosphate threshold concentration during
rhGH treatment. However, we and others7,12 did not
observe consistent effects of rhGH treatment on renal
phosphate reabsorption. In addition, the finding of
Roy et al26 that rhGH treatment failed to stimulate
renal phosphate reabsorption in Hyp mice argues
against a major effect of rhGH treatment on the
phosphorous threshold in XLH.
CONCLUSIONS
Treatment with rhGH might have potential positive effects on final height and thus psychosocial
rehabilitation among short patients with XLH. However, the aggravation of disproportion observed for
our patients must be viewed critically. Randomized,
clinical trials are needed to clarify the effects of rhGH
on segmental growth among patients with XLH.
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GH TREATMENT IN XLH
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Effects of Growth Hormone Treatment on Body Proportions and Final Height
Among Small Children With X-Linked Hypophosphatemic Rickets
Dieter Haffner, Richard Nissel, Elke Wühl and Otto Mehls
Pediatrics 2004;113;e593
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2004 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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