(Acta Paediatr Jpn 1991; 33: 357

- 362)

Growth-Promoting Effect of Human Growth Hormone on Patients with Achondroplasia Takashi Okabe, M.D., Ken Nishikawa, M.D., Chiaki Miyamori, M.D. and Tamotsu Sato, M.D. Department of Pediatrics, School of Medicine, Kanaza wa University, Kanaza wa

To evaluate the effect of human growth hormone (hGH) on the growth of children with achondroplasia, three patients with achondroplasia and one patient with hypochondroplasia were treated with 0.5 IU/kg/ W of pituitary-extracted hGH for 6-12 months. Mean height velocity was significantly increased from 4.0 0.4 to 7.5 k 0.7 cm/year (P< 0.05) by hGH. The tibia1 index, defined as the length/width ratio of left tibia, did not change during the treatment, indicating that hGH promotes growth without exaggeration of tubular bone deformity. Case 2, who had atlantoaxial dislocation, developed sleep apnea and neurological deficits during the second hGH treatment, but these were cured by operation. Thus, hGH therapy is effective in promoting growth in patients with achondroplasia, but the complication of atlantoaxial dislocation should be explored and corrected before the treatment. Key Words Achondroplasia, Hypochondroplasia, Growth hormone, Height velocity, Dwarfism

Introduction Achondroplasia is the most common form of short-limbed dwarfism. This growth disturbance is caused by decreases in the rate of cartilage growth and endochondral ossification of the tubular bones [l]. A variety of agents, such as human growth hormone (hGH) or tolbutamide, have been used in efforts to increase height, but to date no specific medical treatment exists for improving stature in achondroplasia [2, 31. Surgical lengthening of

lower limb has recently been performed to increase overall height and improve body proportion [4], but surgical procedures require long-term hospitalization and have serious complication, such as postoperative infection, fractures and deviations of the bone axis [5]. Growth hormone stimulates, by direct action or through the mediation of insulin-like growth factor (IGF), the growth of cartilage in the epiphyseal growth plate [6]. We therefore administered pituitary-extracted human growth hormone (p-hGH) for 1 year to patients with achondroplasia and evaluated its growthpromoting effect.

Received September 19, 1990 Accepted December 14, 1990

Methods

Correspondence address: Takashi Okabe, M.D., Department of Pediatrics, School of Medicine, Kanazawa University, 13-1 Takaramachi, Kanazawa-shi, Kanazawa 920, Japan

Three patients with achondroplasia and one with hypochondroplasia were examined; their

358 (80) Okabe el at. Table I . Physical and laboratory data Case KO.

Sex

Age

Family history

GH peak GH dose Duration (ngiml) (Iuikgiw) ( M )

BW (kg)

Height (cm)

~

I

M

4y 7m

(-)

2-I

F

I!

5m

(-)

2yllm

(-)

'-2 3

M

12) I l m

(-)

4**

M

4y 8m

(+I

88.0 15.3 (-4.0 SD*) (-0.8 SD) 65.0 8.9 ( - 5 . 2 SD) ( - 1 . 1 SD) 73.7 10.5 ( -4.9 SD) ( - 1.8 SD) 112.0 32.4 ( - 5 . 3 SD) ( - 1.4 SD) 92.3 14.7 ( - 3.0 SD) ( - 1.2 S D )

20.3

0.4

12

38.2

0.5

6

0.5

6

20.6

0.5

7

ND

0.5

10

B W : body weight. GH peak: peak GH, response to insulin or arginine provocative stimuli, ND: not done; * SD from the mean height or weight of normal Japanese children: ** Case 4 is the patient with hypochondroplasia.

a

physical data before treatment are listed in Table I . Informed consent was obtained from all parents of the patients. Case 2 was treated twice for a period of 6 months. There was no familial occurrence of the disease except in the father of Case 4, who had short-limbed dwarfism. Growth hormone response to insulin or arginine provocation was normal in each case. The patients received 0 . 4 4 . 5 I U kg week ot p-hGH (CorpormonK), in three divided doses per week, by intramuscular injection. Change in height velocity was evaluated by the standard growth curve for achondroplasia proposed by Holton et al [7]. Bone age was estimated according to the standards of Greulich and Pyle [8]. Plasma somatomedin-C (SM-C) concentration was measured by radioimmunoassay using commercially available kit (Nichols Institute, USA). Thyroid hormones (T, and T4), Ca, P and alkali-phosphatase (ALP) were measured by the standard autoanalyzer techniques. To evaluate the effects of p-hGH on bone growth, we measured the metacarpal index (MCI) and tibial index. As shown in Fig. la, MCI was defined as the ratio of the cortical thickness (d, + d J to the total diameter (D) at the midpoint of the second metacarpus of the left hand ( d , + d ? / D ) as determined by roentgenogram-microdensitometry (Mitsubishi Yuka Co., Ltd.) [9].Correlative data between age and MCI were obtained from 83 healthy

b MCI: d,

Tibial index:

+ d, D

L D, +

D2

Fig. I : (a) Definition of metacarpal index (MCI). MCI is the ratio of cortical thickness (d, d,) to total diameter at the midpoint of the second metacarpus of the left hand. a< determined by roentgenogram-microdesitometry; (b) Definition of tibial index. Tibial index is the ratio of length (L) to total of widths (upper (D,) and lower (D,)/ of left tibia on X-ray films.

+

Japanese boys [lo]. These showed a mean increase of MCI of 0.00554 per year. Tibial index was determined by measuring left tibial length (L) and upper and lower widths (D, and D,) on x-ray films and calculating the ratio of length to total of widths (L/D, -I-DJ (Fig. Ib). Statistical analysis was carried out by the paired t tests.

Acta Paediatr Jpn

Treatment of Achondroplasia with hGH (81) 359

a.

b . case 2

case 1

ACHONDROPLASIA ACHONDROPLASIA

NORMAL

- - - 97% - - MEAN

+2SD MEAN -2SD

L

- - - 3%

m

25

4

+2SD MEAN

NORM A1 .

_ _ _ 97%... ._ _ _ MEAN

E

0

B

I

Z

AGE

3

4

5

I

6

- Years

2

3

1

AGE - Years

c . case 3

d . case 4 ACHONDROPLASIA ACHONDROPLASIA

k

a

5

NORMAL

+2SD MEAN -250

_ _ _ 97% - - MEAN _ _ _ 3%

MEAN

25-

NORMAL

_ _ _ 97% - _ MEAN _ _-3%

>

\

61

20-

GH

t

k 0

s

I

15-

W

>

+

//-\,

lo-,

i

'.

I _ I 2 3 4 5 6

B

AGE - Years

AGE

- Years

Fig. 2: (a)4d) Changes of height velocity curve before and after p-hGH treatment in each case. Shaded areas indicate standard height velocity range (mean k 2SD) of achondroplasia.

Vol. 33 No. 3 June 1991

360 (82) Okahe et a]. respectively). There were no significant changes in serum T,, T,, Ca, P and ALP levels before and after treatment. Changes of MCI and tibial index before and after treatment are shown in Table 3. MCI was increased by 5% of the pretreatment value and A M C I was 3 to 6 times that of normal boys during the treatment period in each case. The mean of tibial index did not change before and after treatment (1.75 f0.27 and 1.77 0.27, respectively). Case 2 was delayed in motor development: she could not sit until 15 months nor stand until 34 months. She was treated with hGH at l y 5m for 6m, and the second treatment was started at 2y I Im. At 3 years, apneic episodes

Results Changes in height velocity before, during and after treatment in each case are shown in Figs. 2a-d. Except in the second treatment of Case 2, all patients showed a Fignificant increase in height velocity from 4.0 f0.4 cm/ year to 7.5_+0.7cm/year (P

Growth-promoting effect of human growth hormone on patients with achondroplasia.

To evaluate the effect of human growth hormone (hGH) on the growth of children with achondroplasia, three patients with achondroplasia and one patient...
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