Eur J Pediatr (1992) 151 : 283-287

EuropeanJournal of

Pediatrics

9 Springer-Verlag1992

Spontaneous growth in Turner syndrome: evidence for a minor pubertal growth spurt G. H a e u s l e r 1, M. S c h e m p e r 2, H . Frisch I , P. Bliimel 3, K. Schmitt 4, and E. Pl6chl 5

Departments of 1Paediatrics, 2Surgery I, University Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria 3Department of Paediatrics, Preyer Spital, Vienna, Austria 4Department of Paediatrics, Linz Hospital, Linz, Austria 5Department of Paediatrics, Salzburg Hospital, Salzburg, Austria

Abstract. Spontaneous growth of 141 untreated girls with Turner syndrome was analysed. Of the patients 25% were born prematurely; their weight and height were normal when compared to prematurely born healthy infants. However, birth weight and height was significantly retarded in Turner patients born at term. A curve for height and growth velocity for the age range 0 16 years was constructed with a sensitive statistical method. By use of a mathematical model equations were created for calculating z-scores and the related percentiles for the height of individual patients at given age. Median height of 18 untreated patients at 18 years was 143.8 cm. Analysis of growth velocity revealed a minor but significant growth spurt at the age of 12.5 years. This growth spurt was also detectable in patients without signs of spontaneous puberty and occurred later in patients with 45,X0 karyotype. Bone age progression was linear up to the age of 7.5 years and decelerated thereafter.

height and growth velocity in 141 untreated patients with TS. This growth curve was the basis for mathematical description of growth dynamics and revealed a minor pubertal growth spurt. Furthermore, this statistical method allowed the calculation of quantiles for various ages and thus provides a sufficient tool for clinical studies and evaluation of therapeutic effects.

Patients

We retrospectively analysed 580 individual height measurements from 141 Austrian girls with TS born between 1961 and 1981. Table 1. Chromosomal constitution of 141 patients with TS

n patients 45,XO

K e y words: Turner syndrome - Growth - Growth velocity - Growth chart

Introduction

Spontaneous growth in Turner syndrome (TS) has been studied in various populations and disease specific growth charts have been created [1, 5, 6, 8]. The data indicate that reduced adult height in patients with TS is the result of intra-uterine growth retardation, impaired prepubertal growth and complete lack of a pubertal growth spurt. However, the methods applied have been rather insensitive to evaluate minor dynamic changes in growth velocity. In this investigation we have applied a more sensitive statistical method [3] for description of percentiles for

10 13 2 2

Complex mosaics

13

Pyle; BARUS = bone age-Tanner Whitehouse; CA = chronological age; TS = Turner syndrome

67.3

4 2

2.8 1.4

40

28.5

141

100.0

'~

Total

Table 2. Pubertal development in patients with TS (defined as spontaneous development of breast stage 2)

n

Breast stage 2 (Tanner) Yes

Total group 45 X0 Other karyotypes

No

n

(%)

n

(%)

137

26

18.9

111

81.1

92 45

11 15

11.9 33.3

81 30

88.1 66.7

Offprint requests to: H. Frisch Abbreviations: BA = bone age; BAGP = bone age-Greulich

95

46,X,i(Xq) 46,X,del(Xp) 45,X0/46,XX 45,X0/46,X,i(Xq) 45,X0/47,XXX 45,X0/46,XX/47,XXX

% of total group

284 Table 3. Birth data of 86 patients with TS.

Gestational age compared to healthy controls [41

Gestational age

Turner patients 35 weeks (n = 20)

Height (cm) x _+SD

Austrian reference 38-42 weeks (n = 62) ns

I

45.2 +

2.8

47.6+

2.9

I [

Weight (g) x + SD

Height data were only taken prior to growth promoting or hormonal therapy. Chromosome constitution of the patients is shown in Table 1. Occurrence of spontaneous puberty was registered and defined by development of breast stage 2 (Tanner). It was seen in 26 patients (18.4%) and was more frequent in patients with mosaicism (Table 2).

Methods

Birth data (length, weight, gestational age) were taken from records of four Austrian centres and compared with Austrian reference data [4]. Height data were collected in a cross sectional-longitudinal way, including only measurements which were more than 3 months apart. Growth velocity was calculated in individual patients longitudinally, including measurements collected at an interval between 0.5 and 1.5 years. The number of height measurements from 0 to 16 years amounted to 15-55 individual data per year. In the age range 9-14 years more than 40 measurements were recorded each year. To demonstrate that the height data during this age period were not impaired by the addition of newly diagnosed and selected patients who were different from those presented at earlier ages, height at diagnosis was analysed in yearly sections. Height SDS at diagnosis were identical during this period (between 0.0 SDS at age 10 and - 0 . 4 SDS at age 13, respectively) when compared with a previously published sample [8]. X-ray films of the hand and wrist were available from 54 patients resulting in a total number of 160 examinations. Bone age was determined by the methods of Greulich and Pyle [2] and Tanner (TW2, RUS) [9] by the same investigator.

Statistics

For statistical analysis of the growth data the method of Healy and Rasbash [3] was applied: data pairs (age/height or age/velocity) were sorted by increasing age. A "window" covering 50 pairs was moved over the data set proceeding from minimal to maximal age. For each subgroup defined by such a "window" the mean age and corresponding percentiles (0.05, 0.25, 0.5, 0.75, 0.95) of height (or velocity) were obtained using the residuals of a subgroup-specific linear regression. These percentiles of all subgroups were then smoothed by multiple regression techniques allowing for a polynomial height (or velocity) trend over age as well as a changing spread of age-related percentiles. The adequacy of this smoothing was checked by means of scatter plots and overlayed percentile curves. Of various mathematical functions tested, the most parsimonious model which showed adequate fit was selected in each application. Based on the regression equation expected height or velocity can be determined for all age-specific percentiles 0.01 to 0.99. All computations were based on Statistical Analysis System (1985) programme [10] specifically developed to utilize the methods of Healy and Rasbash [3]. The increase in growth velocity in a given age span was analysed by means of the Spearman coefficient of association.

2370

35 weeks (n = 65)

+ 380

I 44.9+

38-42 weeks (n = 554) 3.5

P < 0.001

ns 2790 _+490 2364 [ - P < 0.001

49.9+

1.8

I

+ 479

3353 l

_+444

Bone age development with increasing chronological age was described by means of linear regression analysis. The age of beginning bone age deceleration was explored by examining various breakpoints for the two linear regression lines. Results

Birth data T h e s e w e r e a v a i l a b l e f r o m 81 p a t i e n t s a n d a r e s h o w n in T a b l e 3. T h e f r e q u e n c y o f p r e m a t u r e l y b o r n infants was distinctly i n c r e a s e d in T u r n e r p a t i e n t s w h e n c o m p a r e d to h e a l t h y c o n t r o l s [4]. M e a n b i r t h w e i g h t a n d l e n g t h o f T u r n e r p a t i e n t s b o r n b e f o r e t h e 38th w e e k o f g e s t a t i o n ( m e a n 35th w e e k ) was n o t d i f f e r e n t f r o m age m a t c h e d h e a l t h y controls. M e a n w e i g h t a n d l e n g t h o f T u r n e r p a tients b o r n b e t w e e n t h e 38th a n d 42nd w e e k o f g e s t a t i o n was, h o w e v e r , significantly r e d u c e d w h e n c o m p a r e d to age m a t c h e d c o n t r o l s ( T a b l e 3).

Height T h e c o n s t r u c t e d g r o w t h c h a r t is s h o w n in Fig. 1. F o r a d e s c r i p t i o n o f t h e g r o w t h curve a 4th d e g r e e p o l y n o m i a l g a v e a s a t i s f a c t o r y fit: H e i g h t ( 0 - 1 5 y e a r s ) = 49,32829 + 3,30368.z + 18,76042. age + 0,19566. z. age 2,63482. a g e 2 - 0,02178. z. age 2 + 0,19965. age 3 + 0 , 0 0 1 3 9 3 . z . a g e 3 0,005393. age 4. D u e to t h e s p a r s e n e s s o f d a t a a f t e r t h e age o f 15 y e a r s , t h e c u r v e e n d s with 15 y e a r s a n d t h e e q u a t i o n s h o u l d n o t b e a p p l i e d a f t e r this age. B e t w e e n 16 a n d 19 y e a r s , 35 o b s e r v a t i o n s w e r e a v a i l a b l e . M e d i a n h e i g h t at 16 y e a r s was 1 4 1 . 0 c m , at 18 y e a r s 1 4 3 . 8 c m (Fig. 1):

Growth velocity (Fig. 2) T h e c o n s t r u c t e d c u r v e for g r o w t h v e l o c i t y was f i t t e d b y the equation: G r o w t h vel. ( 4 - 1 6 y e a r s ) = - 3 5 . 5 9 2 + 5.0209. z + 20.4154. age 0.6468.z.age - 3 . 6 6 2 1 . age 2 + 0.0307.z.age 2 + 0.2758. age 3 - 0 . 0 0 7 4 3 . age 4

285 Turner syndrome growth velocity

6

\

/'-\

\

21--~ 3

0

Fig. 1. Height of untreated patients with TS, 0-18 years compared to the Swiss longitudinal data (7)

For the clinical application the deviation of the actual height or growth velocity of an individual at a given age can be calculated by use of the following equations1:

~

2

:3 4 5

6

7

50

8

9 10 11 12 13 14 15 16 17 Age (years) Austria 1990

Fig. 2, Growth velocity of untreated patients with TS, 4-16 years compared to the Swiss longitudinal data (10)

z-score for height: Length- 49.32829- 18.76042.age+ 2.63482.age2- 0.19965.age3+ 0,005393.age4 3.30368 + 0.19566.age - 0.02178.age2+ 0.001393.age3

IIIII

z-score for growth velocity:

8\

Turner syndrome

Growthvelocity+35.592-20.4154.age+3.6621.age2 -0.2758.age3 +0.00743.age4 5.0209- 0.6468.age + 0.0307.age2

7

growth velocity

In contrast to already published data, the method applied here revealed a small growth spurt, beginning at the age of 9.5 years with a p e a k at 12.5 years (Fig. 2). This was a true increase of the median growth velocity curve (Spearman coefficient of association ( r = 0 . 2 2 ; e = 0.037).

6

When patients were analysed according to their chromosomal constitution, the growth spurt of patients with 45,X0 constitution occurred 1.5 years later and was slightly smaller than in patients with other karyotypes (Fig. 3). Spontaneous puberty, as defined by development of breast stage 2 (Tanner) occurred in 26 patients (18.4%) of the total group, in 11.5% of patients with 45,X0 karyotype and 32% of patients with other karyotypes, respecThe complete table of z-scores and percentiles can be obtained on request from the authors

~"" "-~ ~

5

5 .,._

= L__.

\

E O

t

3

k

) 45 XO Other karyotypes I,

3 4 5 6

I

i

i

I

I

I

\

\

50 %

7 8 9101112131415 Age (years)

Fig. 3. Growth velocity of patients with TS dependent on karyotype

286 0.9079, P < 0.001). As indicated by the equations, progression of bone age after the age of 7.5 years was identical with both methods (0.8 "years" per year), with a difference of 0.5 "years" between the methods (Fig. 5).

IIIIIII Turner syndrome growth velocity

7

\

/

'\

Comments

k

E

\

2

1_1... Totalgroup l No spontaneous puberty 01 3 4 5 6 7 8 9 10 11 12 13 14 Age(years) i

i

L

k

\ 50 %

J

15

Fig. 4. Growth velocity of patients with TS without spontaneous breast developmentcompared to the total group

16

Turner syndrome bone

~

age

x

14

--

y

. RUS

12

P

~ 10 8

/

~'// ff~"

2

0

~ -'//

;Y

2

4

6

8

10

17

1'4

t'6

1'8

CA (years)

Fig. 5. Bone age developmentin patients with TS

tively (Table 2). The growth spurt was also detectable in patients without spontaneous breast development, occurring at the same time (12.5 years)-(Fig. 4) as in the total group. Bone age (Fig. 5)

Both methods applied revealed linear progression of bone age from birth until age of 7.5 years (y (BARUS) = - 0 . 3 + • (CA), r = 0.9311, P