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American Journal of Kidney Diseases Volume 33 • Number 4 • April 1999 Copyright © 1999 W. B. Saunders Company CASE REPORTSRecombinant Human Growth Hormone and Gitelman's Syndrome
Received June 16, 1998; accepted in revised form September 25, 1998. Presented at the Annual Meeting of the American Society of
Nephrology, San Antonio, TX, December 1997. Supported by the Kyungpook National University Research
Foundation. Address reprint requests to Cheol W. Ko, MD, PhD, Associate
Professor, Department of Pediatrics, Kyungpook National University Hospital, 50,
Samduk-2 Ga, Joong-Gu, Taegu 700-721, South Korea. E-mail: cwko@bh.kyungpook.ac.kr © 1999 by the National Kidney Foundation, Inc. 0272-6386/99/3304-0022$3.00/0
Gitelman's syndrome is a primary renal tubular disorder with hypokalemic
metabolic alkalosis, hypocalciuria, and magnesium deficiency. Short stature is
one of clinical manifestations in children. The pathogenesis of short stature in
Gitelman's syndrome is not known. To evaluate whether growth hormone (GH) is
deficient and whether recombinant human GH (rhGH) improves growth rate, rhGH
therapy was tried in a child with Gitelman's syndrome. Both height and body
weight were less than the third percentile. Laboratory and radiologic findings
suggested GH deficiency. During the first 6 months, rhGH therapy with potassium
supplement markedly elevated growth rate from 3.8 cm/yr to 12.0 cm/yr. After
cessation of rhGH, height increment markedly decreased to the pretreatment level
of 3.6 cm/yr during the second 6 months. Additionally, hypomagnesemia was
corrected after rhGH therapy. Accordingly, GH deficiency may contribute to short
stature in children with Gitelman's syndrome, and rhGH therapy would be an
excellent adjunctive treatment for short children with Gitelman's syndrome whose
condition is resistant to conventional therapies in terms of growth.
INDEX WORDS:
BARTTER'S SYNDROME is a primary renal tubular disorder with a characteristic set of metabolic abnormalities, including hypokalemia, metabolic alkalosis, and normal blood pressure despite hyperreninemia and hyperaldosteronism.[1] [2] Gitelman's syndrome is a more benign condition. Hypomagnesemia and hypocalciuria are usually present.[3] Growth retardation is noted in many children with Bartter's syndrome or Gitelman's syndrome.[4] [5] [6] Recently, growth hormone (GH) deficiency has been reported in a few patients with Bartter-like diseases.[7] [8] However, a clear pathogenesis of growth retardation has not been illucidated. Moreover, some authors have reported that natural growth is not improved by conventional treatments such as potassium or magnesium supplements. [4] However, others reported that treatment with spironolactone led to impressive catch-up growth[9] and under indomethacin treatment, long-term skeletal growth of children with the neonatal form of Bartter's syndrome is similar to that of other preterm children. [10] We evaluated the status of GH secretion in a short child with Gitelman's syndrome. Various treatment regimens with or without recombinant human growth hormone (rhGH) were tried to evaluate the effect of rhGH on growth velocity. CASE REPORTA boy aged 9 years 10 months was referred to our department for evaluation of
hypokalemia. He had experienced two episodes of tetanic attack in the past 2
years. No family history of Bartter's syndrome or related disorders was found.
Moderate dehydration and growth retardation were found. Body weight was 21 kg,
and height 118 cm. The diagnosis of Gitelman's syndrome was made on the basis of
the following findings: hypokalemia, metabolic alkalosis, normal blood pressure
despite high plasma renin activity and hyperaldosteronism, hypomagnesemia, and
magnesium wasting and marked decrease in urinary calcium excretion (
Table 1 ). There was no glycosuria, hyperaminoaciduria, proteinuria, or
hematuria. Percutaneous renal biopsy showed mild hyperplasia of the
juxtaglomerular apparatus.
Therapeutic regimens consisted of rhGH (0.1 IU/kg/d) along with potassium supplement during the first 6 months and potassium chloride supplement (3 mEq/kg/d) alone during the second 6 months. A magnesium supplement was needed during the second 6 months when only the potassium supplement was given to maintain normal range of serum magnesium. METHODSStanding height was measured using the Harpenden stadiometer. Height and weight standard deviation score (SDS) were calculated according to The Growth Chart of Korean Children.[11] Pubertal development was evaluated according to Tanner and Whitehouse.[12] Both testicular volumes were measured using an orchidiometer provided by Pharmacia-Upjohn. Bone age was determined according to Greulich and Pyle.[13] Plasma renin activity and aldosterone were measured by radioimmunoassay. Twenty-four-hour urine collection was done to determine creatinine clearance and urinary prostaglandin E2 excretion. Plasma peak GH levels were measured by radioimmunoassay after provocations with insulin-induced hypoglycemia, clonidine, and levodopa.[14]
RESULTSEvaluations of Growth RetardationBody weight was 21 kg (-3.31 SDS) and height 118 cm (-2.35 SDS). The status
of sexual maturation was prepubertal. Bone age was 3 years younger than the
chronological age. GH provocative tests with insulin-induced hypoglycemia,
clonidine, and levodopa showed peak GH levels of 2.1, 3.2, and 1.8 ng/mL,
respectively ( Table 2 ). All of these findings were
compatible with GH deficiency.
Efficacy of rhGH TherapyDuring the first 6 months, potassium was given as potassium chloride, 3 mEq/kg/d. And therapy with rhGH, 0.1 IU/kg/d, was combined with the above. Thereafter, therapy with rhGH was stopped, and only potassium was given during the next 6 months. Before therapy, the patient's growth rate was subnormal (3.8 cm/yr). However,
it increased significantly during the first 6 months of
rhGH therapy with potassium supplement (12 cm/yr). Discontinuation of rhGH
abruptly lowered growth rate toward the pretreatment subnormal level (3.6 cm/yr)
during the second 6 months ( Table 3 ). Our patient exhibited an excellent effect on short-term linear growth with
rhGH therapy together with potassium supplement. Yearly height increment
increased threefold during rhGH therapy compared with that of pretreatment. This
increment is almost twofold that of normal children at his age. In a review of
literature, it was noted that other forms of treatments kept growth velocity
within normal range or slightly higher than normal range.[4]
[9] [10]
[15] [16]
Therefore, the effect of rhGH therapy on growth velocity in this child exceeded
that of other treatments. Serum magnesium level normalized after rhGH therapy (1.3 to 2.4 mg/dL) and
decreased to 1.7 mg/dL after withdrawal of rhGH. Urinary magnesium excretion
rates (urinary magnesium-to-creatinine ratio) were not changed by rhGH therapy (
Table 1 ). Serum phosphorus level rose sharply after rhGH therapy when compared with the
level before rhGH therapy (2.5 to 4.3 mg/dL). After withdrawal of rhGH, it
decreased to 3.0 mg/dL. Changes of serum calcium levels by rhGH therapy were not
marked. Urinary calcium excretion rates (urinary calcium-to-creatinine ratio)
also were not changed markedly by rhGH therapy ( Table 1
). Immunoactive parathyroid hormone (PTH) levels before, after, and during
withdrawal of rhGH were 25, 13, and 38 pg/mL, respectively. However, they were
all within normal ranges ( Table 1 ). In many children with Bartter's syndrome and its variants, body growth was
reported to be retarded,[4]
[5] [6]
but only a few studies analyzed growth retardation in this disease. In 1979,
Simopoulos[4]
concluded that conventional treatments such as potassium or magnesium
supplementation do not positively influence linear growth, bone age, or weight
gain in children with Bartter's syndrome. Other reports suggest that some
beneficial effect on short-term growth may be obtained by potassium
supplementation, especially in mild forms of the disease. [17]
Good growth velocity has been reported with spironolactone.[4]
[9] More
recently, the cyclooxygenase inhibitor, indomethacin, has appeared to improve
the growth of older children with Bartter's syndrome.[15] Indomethacin therapy seems to yield quite good results in terms of growth.
Seidel et al[16]
hypothesized that indomethacin supports skeletal growth by suppression of
osteolysis and by reduction of calciuria. However, other reports suggest that
bone resorption leading to hypercalciuria is indomethacin resistant.[18]
Proesmans et al[10]
reported a patient with Bartter's syndrome in whom growth normalized with
indomethacin therapy, although the hypercalciuria was not corrected, and
nephrocalcinosis was observed by ultrasonography at the age of 19 years.[10]
Therefore, growth retardation is not directly related to bone resorption, but it
seems to be caused by a pathogenesis not known as yet. Compared with
indomethacin, rhGH therapy seems to be a better treatment in terms of growth.
rhGH therapy has been known to be safe and to have a very excellent effect on
long-term growth in children with short stature with various causes since the
1980s. Recently, it has been known that GH plays a role in the metabolism of
magnesium. Pointillart et al[19]
reported that porcine GH treatment did not change plasma magnesium value, but it
markedly increased magnesium absorption and retention in growing pigs.[19]
The Pointillart's opinion has not been proved in humans as yet. However, our
patient showed definite hypomagnesemia at the time of diagnosis and needed
magnesium supplement. During 6 months of rhGH therapy, magnesium was not
required to maintain normal serum magnesium level. In addition, hypomagnesemia The pathogenesis of growth retardation in Bartter's syndrome and Gitelman's
syndrome has not been clearly defined. Simopoulous concluded that potassium per
se is not related to growth retardation in Bartter's syndrome.[4]
The disturbance of calcium metabolism related to osteopenia may be another cause
of growth retardation.[18]
Some degree of malnutrition may contribute to growth retardation in many
patients with Bartter's syndrome.[16]
Recently, GH deficiency has been reported in patients with Bartter-like
diseases. [7] [8]
We now report that growth hormone was deficient in a short child with Gitelman's
syndrome. Therefore, we recommend that GH provocative tests should be done in
short children with Bartter's syndrome or Gitelman's syndrome showing delayed
bone age to evaluate their GH status. We suggest that it is also necessary for
future study to gather a cohort of these patients and to measure GH levels. In summary, we evaluated the status of GH secretion in a short child with
Gitelman's syndrome and found that GH was deficient and rhGH therapy markedly
improved this patient's growth rate and also restored the serum magnesium level
to normal. We believe that rhGH therapy should be considered in short children
with Gitelman's syndrome or Bartter's syndrome that are resistant to
conventional therapies in terms of growth or that reveal limited effect on
growth velocity with conventional therapies such as potassium supplement,
spironolactone, or indomethacin. We thank Dr GA Quamme, University of British Columbia, Vancouver, Canada, for
his valuable advice.
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