Growth Hormone and Gitelman’s Syndrome

Recombinant Human Growth Hormone and Gitelman’s Syndrome

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.

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 REPORT

A 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.

TABLE 1Table 1. Changes of Various Laboratory Findings

After and During Withdrawal of Recombinant Human Growth Hormone

Therapy

Before Treatment rhGH + K+ K+ Only
Serum Na+ (140-148 mEq/L) 126 139 140
Serum K+ (3.5-5.2 mEq/L) 1.7 3.4 3.1
Serum Cl- (100-108 mEq/L) 93 95 94
Serum Mg++ (1.8-2.4 mg/dL) 1.3 2.4 1.7
Serum Ca++ (8.8-10.8 mg/dL) 9.8 9.7 10.0
Serum PO4 -2 (2.9-5.4 mg/dL) 2.5 4.3 3.0
Arterial blood gas analysis
pH (7.38-7.46) 7.53 7.46 7.51
PCO2 (32-46 mm Hg) 43 38 40
PO2 (74-108 mm Hg) 95 94 98
HCO3 – (21-29 mmol/L) 32 23 27
Spot urine Ca/Cr ratio (0.03-0.20 mg/mg) 0.03 0.03 0.01
24-Hour urine Ca excretion (1.0-4.0 mg/kg/d) 0.33
Spot urine Mg/Cr ratio (0.2-2.0 mg/mg) 0.45 0.55 0.49
iPTH (1-43 pg/mL) 25 13 38
Plasma aldosterone (<5.9 ng/mL/h) 18.52
Plasma renin activity (3-35 pg/mL) 68.3
24-Hour urine PGE2 excretion (>27 ng/h/1.73 m2 ) 37
NOTE. During the first 6 months of therapy, combined recombinant human growth hormone and potassium supplement (rhGH + K+ ) were given. During the next 6 months of therapy, only a potassium supplement (K+ ) was given. Parentheses indicate normal values.

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.

METHODS

Standing 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]

RESULTS

Evaluations of Growth Retardation

Body 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.

TABLE 2Table 2. Changes of Clinical and Laboratory Findings

Pertinent to Growth Retardation by Recombinant Human Growth

Hormone Therapy

Before Treatment rhGH + K+ K+ Only
Height 118 cm (-2.35 SDS) 124 cm (-2.15) 125.8 cm (-2.39)
Weight 21 kg (-3.31 SDS) 25 kg (-0.17) 26 kg (-1.55)
Chronological age 9 yr 10 mo 10 yr 4 mo 10 yr 10 mo
Bone age 7 ? 1 yr 7 ? 1 yr 8 ? 1 yr
Sexual maturity rate (Tanner)
Pubic hair Stage 1 Stage 1 Stage 1
Penis Stage 1 Stage 1 Stage 1
Testicular volume 2 cc (Rt, Lt) 2 cc (Rt, Lt) 2 cc (Rt, Lt)
Peak serum GH level provoked with
Insulin-induced hypoglycemia 2.1 ng/mL
Clonidine 3.2 ng/mL
Levodopa 1.8 ng/mL
Serum IGF-I 55 ng/mL 129 ng/mL 68 ng/mL
NOTE. During the first 6 months of therapy, combined recombinant human growth hormone and potassium supplement (rhGH + K+ ) were given. During the next 6 months of therapy, only a potassium supplement (K+ ) was given.
Abbreviations: GH, growth hormone; IGF-I, insulin-like growth factor-I.

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