Constitutional Delay of Growth and Adolescent ... - GGH Journal

Constitutional Delay of Growth and
Adolescent Development
JOrgen R. Bierich, M.D. (particularly those lesions re- the chronological age. In re-
Associate Editor suiting from CNS irradiation) as sponse to stimulation with luteiniz-
Growth, Genetics, patients with GHNSD, one would ing-hormone-releasing hormone
and Hormones not be justified at this time to use (LHRH), the follicle-stimulating
this term to describe patients who hormone (FSH) levels usually rise
In 1957, Lawson Wilkins first gave may have CDGAD. higher than do the luteinizing hora
comprehensive description of a
mone (LH) levels. The reverse ocsyndrome
called "constitutional Incidence and Growth Patterns curs as pubertal development endelay
of growth and adolescent CDGAD is more common than any sues. It has been found that this
development (CDGAD)." His defi- other type of short stature. Esti- test cannot differentiate patients
nition included retarded linear mates indicate that 60% to 90% of with CDGAD from those with pargrowth
beginning early in child- the parents of children with tial GH deficiency (GHD) that may
hood, retarded skeletal maturation CDGAD themselves also experi- be accompanied by a similar de-
(often with a two- to four-year de- enced delayed growth and ado- lay in skeletal maturation.
lay), retarded sexual develop- lescent development. As a rule, GH release following proment,
and a familial incidence. Wil- this condition is inherited from one vocative stimuli (pharmacologic
kins stated, "A certain level of parent. Mendelian recessive in- agents) is usually normal.4-s In a
general maturity must be reached heritance, therefore, can be ex- minority of children, the GH rebefore
the pituitary gonadotropic cluded. Simple dominant trans- sponses are within the hypomechanism
can be activated." In mission is possible, but it certainly pituitary range, but retesting these
this way, the concept emerged does not account for all cases. same children during puberty ofthat
the delayed sexual maturity is The auxological features of ten yields peaks of GH concentraa
secondary phenomenon-a se- CDGAD include normal birth tions that are within the normal
que! to the retarded growth. length and weight. Growth velocity range. For example, in 1979,
Numerous alternative names frequently slows during the first Gourmelen et al7 reported the rehave
been used to denote five years of life. When they begin suits of ornithine stimulation of GH
CDGAD. These include con- primary school, these children are secretion in 105 children with restitutional
delay of development, typically among the smallest. The tarded growth, the majority of
idiopathic short stature, simple de- growth curve then parallels the whom had significant delay of
lay of growth, and essential growth third percentile, and the velocity bone age. Significant concentraretardation.
CDGAD must be dif- may sometimes be less than 3 cm/ tions of GH were present after orniferentiated
from "genetic short year. thine and/or insulin stimulation in
stature," which has been called The pubertal growth spurt 74, but not in 31. Of these, seven
"constitutional short stature" by commences two to four years after had confirmed GHD with peak levsome.
Genetic short stature and the usual age (mean age) for ado- continued on page 10
CDGAD may occur coincidentally. lescent development, though this
Tanner et al coined the term "small/ is the appropriate time based on
delay" for these patients. These skeletal maturation, and the peak
patients have two common but dis- height velocity is lower than aver- Table I. Correlation Between
tinct entities and not either simply age for children who mature at the Bone Age (BA) and Parameters of
CDGAD or simply genetic short usual time. Skeletal maturation is Development (Coefficient of
stature. Furthermore, some of the often delayed by several years. Correlation r) in Patients With
children with "normal variant short
stature" described by Rudman 1
The high correlation coefficients
between bone maturation and
CDGAD
have CDGAD; some children with other parameters of development Height age/gA 0.92
what is today called "growth hor- are presented in Table 1.3 .
mone neurosecretory dysfunction
Testicular
(GHNSD)" probably have CDGAD Endocrine Findings development/SA 0.86
as well. Spiliotis et al2 in 1984 The endocrinologic findings are
wrote, "Children with GHNSD rep- related to alterations in gonado- Pubic hair/SA 0.83
resent a substantial number of tropin, growth hormone (GH), and
short children previously diag- somatomedin-C (Sm-C) or insulin- 17 oxosteroids/BA 0.71
nosed as having CDGAD." AI- like growth factor-I (IGF-I) secrethough
one is justified in classi- tion. The gonadotropin con centra- Testosterone
fying children with short stature tions correlate with bone age and (urine)/BA 0.86
due to acquired cerebral lesions delayed maturation but not with

Constitutional Decay Of Growth II. These data indicate that pa- Growth, Genetics, and Hormones,
And Adolescent Development tients with CDGAD secrete less Vol. 1, No.4).
continued from page 9 GH at all stages of pubertal devel- At least three groups of investi-
opment than do control children. gators have reported increased
els.o! less th~n 3 ng/ml. The re-
Differences between the patients
and controls were statistically sig-
IGF-I levels in tall children (com-
pared with children of normal statmalnlng
24 children were betwe~n nificant in all groups, except for ure); others have reported de-
11 and 15 years of age and In those in stage 2 of sexual devel- creased IGF-I values in short
pubertal stages 1 and 2. Their opment. The interpretation of children (compared with children
peak GH levels were 3 to 8 ng/ml. these data prompts the hypothesis of normal size).19-21 Children with
Ten of. these 24 were retested after that there is permanently dimin- CDGAD have IGF-I values in acreaching
stage 3 of sexual devel- ished GH secretion. cord with their skeletal maturation
opment, a~d they had peak GH A second form of growth delay, rather than with their chronological
concentrations of between 8 and which is designated as "short stat- age. Link et al22 demonstrated that
45 ng/ml, with a mean of 21 ng/ml.
The authors interpreted these observations
as indicative of
t" htran~~;-~~-P hartial GbHD." dOthedr au- Table II. Sleep-Induced GH Secretion in 124 Patients With CDGAD and 28
ors ..av.e 0 serv~ an. re- Controls
ported similar Instances In patients
who appear to have GHD pre-
Puberty stages
pubertally but who have normal P1 P2 P3
respo~ses to provocative tests (Number of cases) (86) (18)t (31) (3.)f (7) (7)t
following the onset of puberty. Sleep-induced
It is probably incorrect, how- GH secretion 2469** 4349 3347 5905 3580** 9794
ever, to compare normal values 5V2 hrs :t 1068 :t 1134 :t 1619 -:t 1633 :t 1711
obtained after the onset of puberty (ng/ml x 330 min)
with the normal values found in
prepubertal children. The mean Peak GH level 22.5*' 38.8 27.2 49.8 21.2' 66.2
stimulated values in normal ado- :t 8.1 :t 27.0
Ie scents are approximately twice
those of prepubertal children. With 'Statistically significant difference v controls P > 001
stimulation, patients with CDGAD "Statistically significant difference v controls P > 0.001
reportedly do not have GH peaks tControl children
of the same magnitude as do normal
children during puberty.
Because of the variability of
results obtained after pharma- ure due to an immunologically re- the administration of testosterone
cologic stimuli, several au- active but biologically inactive to these patients increased both
thors5.11-13 have examined the GH," is sometimes clinically indis- GH production and IGF-llevels. It
spontaneous secretion of GH tinguishable from CDGAD. In this is on this basis, as well as upon the
throughout the day or night or entity, growth retardation is pre- observation that IGF-I levels inaround
the clock. In only a few sumed to result from the produc- crease early in puberty, that one
instances were abormally low tion of a GH molecule that is bio- may hypothesize that testosterone
peaks found during sleep, eg, in logically inactive, since the GH increases the circulating concentwo
of 14 patients reported by levels are normal or high and IGF-I trations of GH and the generation
Wise and colleagues.13 In 1979, is low as in GH-deficient children. of IGF-I in early adolescence.
and again in 1985, Bierich and However, patients with this entity,
co-workers14.15 investigated sleepinduced
GH secretion. The
which was described by Hayek
and co-workers 16 and Kowarski et
The Need for Therapy
The need for therapy and the
results in children with CDGAD al,17 are usually more severely re- treatment chosen should be conwere
compared with those in tarded in growth than are patients sidered for each individual ch,ild.
healthy controls with equivalent with CDGAD. Subsequent patients The adult stature eventually
sexual maturation. These investi- also have been described by reached by children with CDGAD
gators determined the area under Bierich et al,4 Rudman and co- varies considerably and is related
the GH-v-time curve to obtain the workers,1 and Valenta et al. 18 The to the heights of the parents. The
integrated total secretion over 5.5 only attempt to determine the majority of patients attain a height
hours at night. The highest peak structure of GH was made by within the normal range, unless.
levels were also determined. The Valenta et al,18 who proposed a they are in the small/delay catresults
obtained from 124 patients circulating GH molecule of ab- egory. Nevertheless, Preece and
and 28 controls are shown in Table normal structure. (See abstract in colleagues23 first demonstrated

that the adult height of those with The use of testosterone is lim- GH of patients with CDGAD should
CDGAD is below the mean for the ited to boys, usually 14 years of be reserved for the most severely
general population. This was con- age and over, who have signifi- dwarfed children. Additional studfirmed
by Ranke et al.24 Whether cant concern about their delayed ies under controlled conditions are
therapy will increase ultimate sexual development. Martin and urgently required before GH
height or whether it will affect only co-workers26 showed that doses treatment-outside of centers
the rate of growth during treatment of 50 mg of a long-acting testos- where the efficacy of GH treatment
is a question of great importance. terone ester (testosterone en- in patients who are not GH-
If testosterone or androgens are anthate) once a month will en- deficient is being studied-can be
used, one must consider whether hance sexual development recommended for patients with
adult height may be reduced. without affecting adult height. CDGAD.
Treatment certainly is indicated in Doses of 100 mg or greater very The use of other agents, such
many patients and, in particular, in possibly reduce the ultimate as growth-hormone-releasing
adolescent boys who are psycho- stature. Treatment is often con- hormone (GHRH) and clonidine,
logically less able to cope with tinued for six to 12 months, an alpha2 adrenergic drug that
their shortness, their delayed sex- at which time the testosterone stimulates the release of GH, reual
maturation, and their high- is discontinued to determine quires further study. Results evalpitched
voices. At no other time in whether spontaneous puberty uating GHRH in the treatment of
childhood is the height gap with has occurred. Occasionally, a CDGAD have not been reported.
relation to age mates as great as it repeat course of therapy begin- In 1985, Pintor et al29 administered
is during early adolescence, par- ning six months after the end of clonidine to four patients with
ticularly since the growth rate of the first course is appropriate. CDGAD over a period of two
children with CDGAD reaches its months, and they described innadir
at the same time that the Treatment with GH creased values of circulating GH
adolescent growth spurt occurs in Studies evaluating GH for the and IGF-I and accelerated growth.
normal children of the same age. treatment of CDGAD are few in However, this is an exceedingly
Treatment should be seriously number. The first report of the suc- small series of patients treated for
considered for patients who are in cessful administration of GH to a short period of time. Currently,
danger of developing a severe in- such patients was from Grunt et al several investigators are involved
feriority complex. One of two forms in 1972,27 who stimulated growth in studying the effect of clonidine
of therapy can be chosen: the use in four of ten children with CDGAD. in CDGAD further.
of testosterone with or without an- In a subsequent report by Kastrup
abolic steroids, or the use of GH. et al,8 growth velocity rose from 3.7 Summary
to 8.4 cm/year during therapy. CDGAD is the most common form
Therapy With Testosterone Bierich and co-workers4 in 1983 of short stature. Preliminary studand/or
Anabolic Steroids reported an increased growth rate ies suggest that children with
Testosterone and/or anabolic (from 4.1 cm/year to 8.3 cm/year) CDGAD have inadequate GH prosteroids
have been employed for with therapy. Gertner and co- duction, whereas children of the
many years to treat CDGAD. The workers28 have reported similar same age who do not have
anabolic steroids are derived findings. Individual differences are CDGAD, have adequate GH profrom
testosterone. With the pos- considerable, but the greater the duction. Some would call this a
sible exception of oxandrolone delay in bone age, the better the physiological state (partial GHD).
(Anavar), all anabolic steroids acceleration of growth velocity. In this sense, CDGAD is similar to
display similar androgenic or The growth rate in children with the previously described GHNSD.
virilizing effects-including in- CDGAD had been maximal during Testosterone, and probably estrocreased
skeletal maturation- the first year of treatment and de- gen as well, stimulates increased
in comparison with testoster- creased thereafter, a pattern that production and secretion of GH.
one. However, oxandrolone has occurs with GH-deficient patients This, in turn, stimulates increased
a significant growth-promoting receiving GH. IGF-I concentrations in normal
effect in relation to its minimal, Although adequate data are early puberty.
modest virilizing action. At a presently unavailable to evaluate The use of GH as a therapeutic
dosage of 0.1 mg/kg/day, oxan- the long-term effect of GH treat- agent in CDGAD is under clinical
drolone has been used suc- ment on children with CDGAD, this investigation. Currently, oxancessfully
in patients between the author has the clinical impression drolone (0.1 mg/kg/day) is the
ages of 11 and 16 who are more that the growth prognosis of most treatment of choice in patients unconcerned
about their height of these children improves. Since der 14 years of age who require a
than their delayed sexual devel- none of the patients in our series growth-promoting agent for priopment.
In Europe, Stanhope has reached final height, no defin- marily psychological reasons. Deand
Brook25 reported favorable itive statements can be made re- potestosterone (long-acting enresults
with oxandrolone in 24 garding an increase in ultimate anthate or cypronate) is the
boys with CDGAD. height. At present, treatment with continued on page 12