Acta Prediatr Scand 79: 796-803, 1990

Growth and Growth Hormone Therapy in Hypochondroplasia S. APPAN, S. LAURENT, M. CHAPMAN,’ P. C. HINDMARSH and C. G. D. BROOK From the Endocrine Unit and ‘Department of Radiology, The Middlesex Hospital, London W1. UK

ABSTRACT. Appan, S., Laurent, S., Chapman, M., Hindmarsh, P. C. and Brook, C. G. D. (Endocrine Unit and ‘Department of Radiology, The Middlesex Hospital, London, UK). Growth and growth hormone therapy in hypochondroplasia. Acta Paediatr Scand 79: 796,1990. The growth of 84 patients with hypochondroplasia (56 male, 28 female) was studied. A wide spectrum of severity was found from quite severe short limbed dwarfism to short apparently normal prepubertal children who manifested disproportion only at puberty when growth failed. The onset of puberty was at the normal time but the pubertal growth spurt appeared not to materialize and it is this lack which resulted in severely compromised adult heights of 145-165 cm in boys and 133-151 cm in girls. Twenty (12 M, 8 F) hypochondroplastic children aged between 4.3 and 12.8 years were recruited to a study of the effects of biosynthetic growth hormone. All had normal growth hormone responses (> 15 mU/I) to a pharmacological test of growth hormone secretion. Biosynthetic growth hormone in doses between 12-32 u/m2/week produced a significant acceleration in height velocity standard deviation score (SDS) for chronological age (CA) from a pretreatment mean of - 1.66 (SD 1.36) to 1.62 (SD 1.52) (p < 0.001). Significant increases were also observed in the height SDS for bone age (BA), sitting height (SH) SDS and subischial leg length (SILL) SDS. A longer period will be required to assess the effect of treatment on adult height prognosis. Key words: skeletal dysplasia, growth, growth hormone.

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Hypochondroplasia is a skeletal dysplasia inherited as an autosomal dominant trait. Spontaneous mutations are frequently seen. The term “hypochondroplasia” was first used by Leri & Linossier (1) in 1924 and this entity has been reviewed since then (2-7) but reports have been few and far between. Final height attainment has been reported to range between 120 and 152 cm but little is known of the pattern of growth in this condition (8). This appears to be due to a lack of recognition of the condition as it appears to be a common skeletal dysplasia in our experience and that of others (8). The object of this study was to analyse more fully the growth pattern and to ascertain the effect of biosynthetic human growth hormone (hGH). CASE REPORT In 1983, a boy aged 10.8 years was referred to our department for an opinion about short stature. Clinical examination revealed a short normal boy (Fig. 1). Investigations showed normal endocrine function and a delayed bone age of 7.5 years. In view of the demonstration of a normal growth velocity over the succeeding two years, a diagnosis of constitutional delay of growth was made and he was discharged from the clinic. In June 1988, he was referred having, at the age of 16 years, attained a height of only 152.6 cm after completed puberty. Clinical examination revealed obvious disproportion and a skeletal survey confirmed the diagnosis of hypochondroplasia (Fig. 2). This missed diagnosis prompted us to review our experience of the patients we had diagnosed with hypochondroplasia over the last 15 years.

MATERIALS AND METHODS Growth study. Eighty-four patients (56 male, 28 female) were seen between 1974 and 1988 with a diagnosis of hypochondroplasia. The diagnosis was made on clinical and radiological

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Fig. 1. Growth chart of index case with clinical appearance at presentation (inset). criteria as described by Smith (9). Patients had short stature with near-normal craniofacies and the invariable radiographic finding of a failure of increase in the interpedicular distance in the lumbar spine from L, to L, (Fig. 2) in the absence of any other gross measurable radiological abnormality. Sixty-six patients were seen on two or more occasions and 18 were seen once only, because they were referred at final height often with histories such as the one described above.

Table 1. Height velocity in untreated patients with hypochondroplasia Boys

Girls Height velocity (cm/yr)

Height velocity (cmlyr) Age (Yr)

No. of subjects

2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 11.5 12.5 13.5 14.5 15.5 16.5 17.5

2 3 4 5 5 3 4 4 8 6 7 8 6 3 4

Mean

SD

4.75 5.43 5.17 5.40 4.60 5.06 4.17 5.50 4.10 5.20 5.00 5 .OO 4.40 4.15 0.90

1.06 0.1 1 0.56 1.11 0.82 1.40 0.56 2.38 1.34 1.71 2.56 1.82 2.72 1.79 0.57

No. of subjects

Mean

SD

2 3 3

5.6 5.5 4.83 4.72 4.60 4.1 1 4.36 4.22 5.15 5.0 4.9

0.84 0.50 0.73 1.13 0.64 1.15 0.76 1.58 0.63 0.00 0.60

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Fig. 2. Antero posterior radiograph of lumbar spine of index case aged 16 years. Note constant interpedicular distances.

Standard auxological assessment was performed at every visit and height, sitting height (SH) and subischial leg length (SILL) plotted on standard charts. Puberty was staged according to the method of Tanner (10). The onset of puberty in boys was defined as the attainment of a testicular volume of 4 ml and in girls breast stage 2 development (10). Growth curves for the hypochondroplastic boys and girls were constructed by the method described by Tanner & Gupta (1 I ) with the adaptations for growth analysis by Brook et al. (12). Briefly, the growth curves for boys and girls were centred on the age at which most height data were available. By reading off heights attained at annual intervals (age 3.0, 4.0 etc.) from the lines connecting the actual points of individual children, it was possible to estimate individual whole year height velocities. Table 1 shows the number of subjects and the mean height velocities described at each age (age 2.5 indicates the year between ages 2.0 and 3.0) for boys and girls. Values for heights attained were available for 12 boys at 14 years and the mean height was 137.8 cm; from this value, yearly mean height velocities were added or subtracted and the mean height curve of hypochondroplastic boys derived. In the case of girls, data were available on 8 at 7 years and the mean height attained was 101.7. The mean height curve of hypochondroplastic girls was centred on this value. Growth hormone treatment. The aim of treating children with hypochondroplasia with biosynthetic hGH was to determine whether such therapy could accelerate growth. Entry to the study was based on auxology (growth velocity) and endocrine criteria. All children had pretreatment height velocities calculated over a period of 1 year before commencing treat-

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ment. No chronological or bone age criteria were set as our preliminary analysis of the cross sectional growth study had demonstrated the absence of a pubertal spurt; hence this complicating factor in other short stature studies was effectively excluded. Prior to commencement of therapy the children underwent a pharmacological test of growth hormone secretion to exclude G H insufficiency. An insulin-induced hypoglycaemia test (ITT) (0.15 units insulin/kg body weight) combined with administration of exogenous gonadotrophin releasing hormone (100 pg) and thyrotrophin releasing hormone (200 pg) was performed. A normal serum G H response was defined as a peak value of more than 15 mU/I following the stimulus and only patients with normal responses are reported in this study. Biosynthetic h G H (Genotropin, Kabi, Stockholm; Norditropin, Nordisk, Gentofte) was administered to 20 patients (12 M, 8 F). The treatment was given on a nightly basis by subcutaneous injection in doses between 12 t o 32 units/m2/week. Standard auxological measurements were made in the pretreatment year and during the first year of GH therapy. Bone age was assessed at the beginning and end of the first year of G H therapy using the TannerWhitehouse method ( 1 3). Statistics. The method used for the calculation of the mean height values has already been summarised. For evaluation of the effects of B-hGH on growth all data were expressed as standard deviation scores (SDS) using the standards for the British population (14) and the formula:

X-8 SDS = SD

x

x

where is the observed value, is the value for the population mean and SD the standard deviation of that mean. The Wilcoxon ranked sign sum test was used to compare the treatment data which were not normally distributed (15). The 2 test was used t o compare the age at pubertal onset of hypochondroplastic children and the normal data of Marshall & Tanner ( 1 6, 17). Stepwise multiple regression analysis was used to investigate predictive factors of the growth response to B-hGH. The following factors were investigated: pretreatment height velocity SDS, chronological (CA) and bone age (BA), height SDS for CA and BA and dose of B-hGH received. The phenomenon of regression to the mean when regressing pretreatment height velocity SDS against change was excluded using the method of Oldham (1 8).

RESULTS

Spontaneous growth in childhood. Figs. 3 a and 4 a show composite graphs of all the longitudinal data of boys and girls respectively. A mean height curve was derived for the boys from age 3 years through to 18 years (Fig. 3 b).The most striking feature of the growth chart was the loss of the height spurt at puberty. Final adult height in boys ranged from 145.0 to 165.0 cm. The mean height curve for the girls is shown in Fig. 4 b . This graph depicts the curve from age 2 to 13 years. Less data were available for the pubertal growth spurt but Fig. 4 a suggests that the pubertal growth spurt is not evident in the girls. Final adult height in the girls ranged between 133.4-1 50.6 cm. SH and SILL curves were derived by the same method using for boys the mean SH at 14 yr of 73.6 cm and the mean SILL of 63.9 cm at the same age (Fig. 5 a ) . Fig. 5 b shows the SH and SILL curves of girls derived by using mean SH of 60.3 and SILL of 40.4 cm at 7 yr of age. Puberty. Onset of puberty in hypochondroplastic children was the same as for normal children. Median onset of puberty in 12 boys (testicular volume 4 ml) was 12.2 years and in 6 girls (B2) was 1 1 . 1 years (normal values: boys 1 1.8 yr; girls 1 1.2 yr; /’ =NS). Growth hormone therapy. Twenty children aged between 4.3 and 12.8 years

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Fig. 5 a . Mean SH and SILL curves of hypochondroplastic boys. Fig. 5 b. Mean SH and SILL curves of hypochondroplastic girls.

received B-hGH treatment for one year. Of the 20 children, 15 were prepubertal at the start of the treatment and remained so till the end of the year. Two boys and three girls were in early puberty at the start of treatment. The median GH response to insulin tolerance test was 30.0 mU/1 (range 15.2 to 80.8). Table 2 shows the growth variables at the start of B-hGH treatment and one year later. None of the factors tested in the stepwise multiple regression analysis were predictive of the response to B-hGH treatment. No significant dose-response relationship could be demonstrated. DISCUSSION

In spite of the paucity of publications, we have found hypochondroplasia to be a quite common cause of short stature. There is a wide spectrum of severity and mild cases can easily be misdiagnosed and labelled as "constitutional", as our case report Table 2. Changes in growth variables over one year of hGH treatment

Ht SDS for CA Ht SDS for BA Ht velocity SDS for CA Sitting Ht SDS Subischial leg length SDS 51 -908307

At start (mean (SD))

At one year (mean (SD))

-2.77 (0.92) -2.36 (1.15) -1.66(1.36) -2.17 (0.97) -2.91 (1.17)

-2.48 (0.94) -1.99 (1.26) +1.62(1.52) -1.82 (0.97) -2.66 (1.25)

Significance of difference (p value) 0.006 0.018